KAIMRC Compilation Issue by Nature Research Custom Media

2018 - SPECIAL ISSUE

ISSN 7901-2398 innovations.kaimrc.med.sa

TRANSFORMING HEALTHCARE THROUGH RESEARCH

National Center for Stem Cell Technology With research partnerships spanning the globe, KACST is at the heart of the drive to reach innovative therapies for different diseases prevalent in Saudi Arabia, such as diabetes, through stem cells research. By establishing the National Center for Stem Cell Technology in April 2014, KACST is driving advances applied research in regenerative medicine and promoting technology transfer and localization. www.kacst.edu.sa

Transforming healthcare through research

s the kingdom of Saudi Arabia makes significant strides in scientific research in line with Saudi Vision 2030, KAIMRC has been at the forefront of advancing medicine. With some of the most advanced medical facilities and experienced researchers, since its inception in 2006 the centre has already contributed significantly to transforming healthcare. Through a unique understanding of health issues that are important to the kingdom, and a deeper understanding of the Saudi population, KAIMRC transforms lab results into products that improve quality of life, while training skillful researchers in the healthcare sector. The past year was a busy one for KAIMRC, ending with the 9th Annual Forum for Medical Research held in November to bring together talented and experienced researchers, experts and specialists to share experiences. This special issue of KAIMRC Innovations offers an opportunity to look back at the centreâ&#x20AC;&#x2122;s most significant research over the past two

years, and how KAIMRC has contributed to healthcare and clinical research in Saudi Arabia, the region, and the world. The issue showcases several research projects in the field of cancer treatment, including chemotherapy options to treat breast cancer, a study of oral cancer in the Arab world, and a new approach to treating childhood leukemia. We also share many of our researchersâ&#x20AC;&#x2122; work involving baby and children health. In the rapidly evolving field of therapeutics, we also reflect on work KAIMRC has done in improving drug delivery, including a project that uses smart nanoparticles for cancer drug delivery to avoid some of the harmful side effects of chemotherapy. Since the emergency of the MERS coronavirus, KAIMRC researchers have been working tirelessly to fight the disease and come up with a vaccine, and several studies here show some of their important breakthroughs. We hope this glimpse at our research inspires you, as much as it continues to inspire us.

Dr Ahmed Alaskar KAIMRC Executive Director

Special Issue

P. 9 NANOCARRIERS TO LIGHT UP AND TREAT DISEASE

P.10 RECIPES FOR BETTER DRUG DELIVERY

P. 12 TARGETING BURKITTâ&#x20AC;&#x2122;S LYMPHOMA

Diseases could be diagnosed, treated and monitored by multi-tasking biodegradable nanoparticles.

Fine-tuned nanocarriers loaded with natural products may improve targeted drug delivery and enhance anti-cancer activity.

Antibody-driven death if lymphoma cells may lead to anticancer treatments.

P. 14 SMART NANOPARTICLES FOR CANCER DRUG DELIVERY

P. 16 MANIPULATING METALS FOR MEDICINE

P. 18 IMPROVING STEM CELL DONATION

Nanoparticles successfully deliver anti-cancer drug to breast cancer cells.

A robust synthetic method could help magnetic metal oxide nanoparticles reach their potential as a powerful clinical tool.

Stem cells could be collected from donors more safely by using a less invasive catheter.

P. 19 LIGHT-RESPONSIVE SHAPECHANGING MOLECULES

P. 20 CONCERNS RAISED ABOUT DIGOXIN SAFETY

P. 22 HOW TO TELL BONE MARROW CELLS APART

Ligh-sensitive nanowires could act as artificial tails to steer drugs around the body.

A drug commonly used to treat heart failure could be associated with an increased risk of death in certain patient groups.

Stem cells may express different molecular markers depending on whether they form bone or other tissue types.

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COVE R P HOTO BY P HI L DE G G I NG E R / A L A M Y S TOCK P HOTO

TABLE OF CONTENTS

P. 23 PREDICTING STEM CELL THERAPY OUTCOMES

P. 24 INJURY PREVENTION COULD STEM OPIOID ABUSE

DNA ringlets carried by immune cells could provide routine insight into the progress of stem-cell-based immunotherapy.

People are 1.4 times more likely to become persistent users of opioid painkillers after suffering a traumatic injury.

P. 26 ORAL CANCER IN THE ARAB WORLD

P. 28 A BIOMARKER FOR COLORECTAL CANCER

P. 30 NEW ANTICANCER MOLECULE PROMISES IMPROVED THERAPY

Qat and tobacco chewing have been linked to a higher incidence of oral cancer in Yemen, Sudan and Saudi Arabia.

A mutated tumour suppressor gene could provide a useful marker for the diagnosis and prognosis of bowel cancer.

Chemotherapy without side effects, or the risk of relapse, could soon be possible.

P. 31 GENE DEFECTS REDUCE LEUKAEMIA SURVIVAL

P. 32 BATTLING A TRANSPLANTED RISK

P. 34 NEW CHEMOTHERAPY PROMISING FOR BREAST CANCER

Genetic variations can explain poorer survival rates in Pakistani children from a prevalent type of leukaemia.

Current strategies are not reducing the incidence of infection-related malignancies after organ transplantations.

A trial for a new chemotherapy treatment has shown promising results for locally advanced breast cancer. Special Issue

TABLE OF CONTENTS

P. 35 HOW LONG DO WE TREAT THE CRITICALLY ILL?

P. 36 TIMING TREATMENT PERFECTLY

Researchers are developing objective measures to decide whether critically ill cancer patients can benefit from intensive care.

Understanding how leukaemia affects the body’s circadian clock may unlock ways to treat the disease.

P. 37 THE SAUDI APPROACH TO CURING LEUKAEMIA

P. 38 MOLECULAR TOOL DETECTS EARLY-STAGE BREAST CANCER

The survival rate for paediatric acute myeloid leukaemia in Saudi Arabia has rose to equal developed nations.

A cheap, simple test shows potential for reducing uncertainty in the diagnosis of early-stage breast cancer.

P. 40 AUTISTIC CHILDREN COULD RECEIVE TAILORED TREATMENT

P. 41 DONATING BLOOD MIGHT IMPROVE DIABETES

P. 42 ELIMINATING RISK FACTORS OF HEART ATTAC

A new method of identifying autism means the hope of earlier treatment for children.

Recent research suggests giving blood may temporarily improve insulin production and glucose tolerance.

A person’s sex has no effect on increasing the risk of a major heart attack for patients with extensive coronary artery disease.

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TABLE OF CONTENTS

P. 44 THE RIGHT TO KNOW

P.45 EXPLORING DIABETES IMPACT ON TEENAGERS

P. 46 COMBATING MERS IN CAMELS WITH A SINGLE-DOSE VACCINE

A survey in Saudi Arabia finds broad support for returning significant results to biobank donors.

A multidisciplinary approach is needed to support diabetics and their families.

Vaccines for camels could be optimized by varying their viral and DNA content and adjusting their administration.

P. 48 MORE MAY NOT BE BETTER FOR THE CRITICALLY ILL

P. 49 KEEPING A CLOSE EYE ON DIABETES COMPLICATIONS

P. 50 EARLY FITNESS IMPROVES HEART ATTACK SURVIVAL

A diet containing lower calories may offer better chances to critically ill adults.

Survey highlights link between molecular markers and potential complications of type II diabetes.

Keeping fit early on can increase chances of survival from a heart attack later in life.

P. 52 MYRRH DETOXIFIES WHEN LIVER CANNOT

P. 54 NEW MUTATION LINKED TO LEIGH SYNDROME

P. 56 WEIGHING TREATMENT OPTIONS IN HEART DISEASE

The resin of a native shrub from the Arabian Peninsula and Africa relieves the symptoms of ammonia excess.

A new mutation causing Leigh syndrome has been detected in two newborns in Saudi Arabia.

Stents and bypass surgery are better than drugs, but only for patients with more severe forms of heart disease. Special Issue

TABLE OF CONTENTS

P. 57 DISTURBED SLEEP PATTERNS NEGATE FASTING BENEFITS

P.58 LEARNING TO PREDICT DIABETES

P. 60 AN ATTRACTIVE AND ABUNDANT STEM CELL ALTERNATIVE

Disturbed sleep offsets the health benefits from fasting in the holy month.

Machine learning could be used to identify high-risk patients and improve healthcare services.

Stem cells derived from the human placenta may find unique therapeutic applications.

P. 62 THE MYSTERIES OF INTELLECTUAL DISORDERS

P. 63 A NEW PLAYER IN GENE REGULATION

P. 64 TREATING CANCER PATIENTS WITH RARE GENETIC CONDITIONS

DNA sequencing offers help for patients with unexplained intellectual disorders.

A familiar molecule may affect the molecular mechanism controlling gene expression.

A case study of a boy with Bloom syndrome highlights the need to screen patients for rare disorders before treatment for cancer.

P. 65 TWENTY NEW MUTATIONS LINKED TO RARE GENETIC DISEASE

P. 66 FANCONI ANAEMIA MAY BE UNDER-DIAGNOSED

P. 68 THE RARE MUTATION THAT CAUSED MISDIAGNOSIS

Study finds mutations in a rare inherited disease called pyroglutamic aciduria.

Genetic analysis of Saudi patients with Fanconi anaemia reveals distinct patterns of mutation that may affect diagnosis.

A mutation found in two Saudi brothers is believed to have led to misdiagnosing cerebellar ataxia as multiple sclerosis.

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TABLE OF CONTENTS

Protecting confidentiality is a major priority in medical settings, crucial to the effectiveness of Saudi Arabia’s newly established biobank.

P.70 SCREENING FOR AN ENZYME DEFECT IN NEWBORNS

P. 71 STRATEGY URGED TO TACKLE GENETIC DISEASE

Study boosts argument for cord blood screening to detect an enzyme defect in infants.

A high rate of inherited metabolic disorders in Saudi Arabia is prompting calls for action.

P. 72 UNDERSTANDING THE GENETICS OF CONGENITAL HEART DEFECTS

P. 73 SINGLE GENE DEFECT FOUND FOR UNEXPLAINED DWARFISM

P. 74 HIV RESISTANCE GENE UNCOMMON AMONG SAUDIS

New evidence traces congenital heart defects to healthy parents.

Mutations in a DNA replication gene cause a rare developmental disorder seen in Saudi children.

A mutation that could provide resistance to HIV/AIDS is too rare among Saudis to screen for.

P. 69 STRICTLY CONFIDENTIAL

P. 75 UNDERSTANDING RISKS OF CONSANGUINEOUS REPRODUCTION

P. 76 CAUSE FOUND FOR RARE AMINO ACID DISEASE

Saudi Arabia needs a strong education program on genetic risks to children born in inter-family marriages.

A young girl’s metabolic disorder may be due to a newly-discovered gene mutation. Special Issue

P. 78 HEPATITIS C: TRANSFORMING TREATMENT FOR TRICKY GENOTYPES

P.80 POTENTIAL FOR A MERS ANTIBODY THERAPY

P. 82 STRIKING AT THE HEARTLAND OF MERS

A hepatitis C genotype prevalent in the Middle East can be treated by combining existing drugs with a new antiviral.

MERS patients may produce sufficient antibodies to help more recent victims.

Dozens of new cases of MERS have been reported, but Saudi Arabia is fighting back.

KAIMRC Innovations is published for the King Abdullah International Medical Research Center (KAIMRC) by Nature Research Custom Media.

P. 84 WHEN LIVER DISEASE PATIENTS FALL OFF THE MEDICAL RADAR

P. 86 ANTIBIOTIC MISUSE A LOOMING CRISIS FOR SAUDI ARABIA

People with viral hepatitis often do not return for follow-up treatment, highlighting the need for more robust support strategies.

Warning over high levels of illegitimate antibiotic dispensing and public misconceptions about their use.

King Abdullah International Medical Research Center (KAIMRC) Ar Rimayah, Riyadh 14611, Saudi Arabia Email: kaimrc@ngha.med.sa Web: kaimrc.med.sa Springer Nature The Campus – 4 Crinan Street – London, N1 9XY, UK Email: nature@nature.com Web: www.nature.com

KAIMRC innovations Phone: +966 11 429 4516 Email: innovations@ngha.med.sa Web: innovations.kaimrc.med.sa

P. 87 GENE TWEAK INDUCES STRONGER IMMUNITY

P. 88 PEPTIDE PROMISE FOR DIAGNOSTICS

Changing the switch that turns on vaccine protein production elicits a stronger immune response in mice.

Rapid diagnosis of HIV may soon be possible thanks to a novel peptide-based diagnostic tool.

2018

The Researcher Newsletter Phone: +966 11 429 4516 Email: theresearcher@ngha.med.sa Web: innovations.kaimrc. med.sa/en/newsletter

“We hope our work will eventually help to treat cancer with minimal side effects on healthy cells.”

Nanocarriers to light up and treat disease

Cancer and other diseases could be diagnosed, treated and monitored by multi-tasking biodegradable nanoparticles. Most serious diseases present three key challenges: diagnosis, targeted treatment, and monitoring of disease progression and response to therapy. KAIMRC researchers, led by nanoscientist Khalid Abu-Salah, with colleagues in Sweden and the US have developed nanoparticles that might perform these roles simultaneously1. Their system is based on therapeutic and diagnostic nanocarriers built of tiny spherical structures called micelles, composed of poly-ethyleneglycol (PEG) and poly-caprolactone (PCL) polymers. The micelles have been used as vehicles

to carry the anti-cancer drug busulphan along with iron oxide particles that make them visible in MRI scans. They can also be labelled with fluorescent dyes to become readily detectable under suitable illumination. They are compatible with biological tissues, promoting no adverse reactions such as inflammation, and have biodegradable properties that assist their excretion after they have fulfilled their mission. The researchers hope to be able to target specific sites of disease by coating the micelles with molecules, such as antibodies, that

Abu-Salah is keen to target breast cancer, which is affecting more women in Saudi Arabia every year2. “We will investigate the potential on animals with breast cancer and leukaemia, then hopefully move onto tests with cancer patients,” he says. “The multi-functional ability is the key advantage of our system.” The ability to follow the distribution of the micelles by MRI and fluorescence imaging techniques will be used to find the most efficient method to get the micelles to selectively target diseased tissues. Such targeting could also prove useful to indicate if a cancer, for example, is shrinking after treatment and to reveal the extent to which a disease has spread to other regions of the body. Once any targeting procedure has been validated it could be used in the early stages of clinical investigation to diagnose where a specific cancer is located and how far it has advanced. “We hope our work will eventually help to treat cancer with minimal side effects on healthy cells,” says Abu-Salah. 1 .Asem, H., Zhao, Y., Ye, F., Barrefelt, Å., Manuchehr, A-V. et al. Biodistribution of biodegradable polymeric nano-carriers loaded with busulphan and designed for multimodal imaging.

Journal of Nanobiotechnology 14, 82 (2016). 2. Saggu, S., Rehman, H., Abbas, Z. K. & Ansari, A. A. Recent incidence and descriptive epidemiological survey of breast cancer in Saudi Arabia.

Saudi Medical Journal 36, 1176-80 (2015).

Special Issue

L E VE NT KONU K / I S TOCK / G E T T Y I M AG E S P LU S

selectively bind to receptors on the surface of diseased cells. The combined drug delivery and imaging system has been tested in mice. These animal trials were complemented by tests with cultured cells that demonstrated efficient release of the drug over timescales that could prove clinically useful.

Recipes for better drug delivery Fine-tuned nanocarriers loaded with natural products may improve targeted drug delivery and enhance anti-cancer activity.

evelopment of anti-cancer treatments is often thwarted by drug resistance and drug side effects. Researchers are increasingly turning to naturally occurring products to help overcome these challenges. Beta-glucans, sugars found in the cell walls of fungi, yeasts, bacteria and cereals, are of particular interest to cancer researchers, as they are known to activate innate immune responses. A joint study between researchers in Saudi Arabia and Canada has shown that beta-glucans encapsulated into tailor-made “liposomes” — tiny spheres composed of lipids and cholesterol — can be used as an adjunct approach to fight cancer. “Natural products have been gaining attention due to their ability to act as modulators and enhancers for several anti-cancer drugs,” says KAIMRC biomolecular scientist Majed Halwani. “Our liposomal beta-glucan formulations were designed to help reduce the adverse effects of doxorubicin — a key drug effective

2018

against many types of cancer — and enhance its activity.” By preparing a series of liposomal “recipes” with different lipid-to-cholesterol ratios, the team achieved higher encapsulation efficiency of mushroom-derived beta-glucan as well as higher stability under varying biological conditions. The researchers observed that their formulations with a relatively high amount of cholesterol remained stable in plasma at both four and 37 degrees Celsius. Three of the liposomal formulations containing the highest

Beta glucans can be found in the cell walls of the field mushroom.

amount of beta-glucans were shown to be particularly effective in suppressing human lung cancer epithelial cells. “Combining different phospholipids to form the liposomal vesicles that are able to carry beta-glucan and/or doxorubicin individually or together at the same time is not straightforward,” says Halwani. “We're now collecting new data about this.” “As a first stage, we were interested in presenting formulations that have lower nanometre particle sizes to ensure that they are suitable for pharmaceutical applications and transportable

within the bloodstream.” The next step for the research team will be to examine the effects of the formulations on animal models and conduct other laboratory studies, with the long-term goal of performing human clinical trials. Halwani, M., Hossain, Z., Khiyami, M. A., & Omri, A. Liposomal β-glucan: Preparation, characterization and anticancer activities. Journal of Nanomedicine & Nanotechnology http://dx.doi.org/10.4172/2157-7439.1000319 (2015).

Special Issue

2018

Targeting Burkitt’s lymphoma

Insight into the antibody-driven death of lymphoma cells may lead to anti-cancer treatments with enhanced efficacy and selectivity.

AIMRC researchers have unveiled tivates the transmembrane receptor exand proliferation in addition to inhibithow the so-called transmembrane pressed in these malignant cells. ing apoptosis, decreased. This antibody receptor CD-95 governs the proThe antibody treatment caused the treatment also reduced the cell viability grammed death, or apoptosis, of cancer cells to undergo apoptosis. Furand phosphorylation of protein kinase B, lymphoma cells. This breakthrough thermore, the expression of the Pim-1 an enzyme involved in cell survival pathis expected to give rise to novel therapies protein, which stimulates cell survival ways, by 50% in 72 hours. However, the against aggressive forms of cancer, team found that the cell death rate “Elucidating molecular such as Burkitt’s lymphoma (BL). remained below 46%. More prevalent in Africa than in the According to Matou-Nasri, her mechanisms was necessary to United States and Western Europe, team has demonstrated that the anBL is a rare type of lymphoma that afidentify novel therapeutic targets ti-CD95 monoclonal antibody treatfects adults and children. It starts in ment partly destroyed BL because and enhance the efficacy and immune system cells called B-cells of the partial inhibition of survival before growing and spreading rapidpathways. “Our results have proven specificity of immunotherapy.” ly in the body. Existing anti-cancer that targeting Pim-1 is insufficient to therapies, including chemotherapy fully eradicate BL, which suggests a and radiation, have proven unsuitaneed for combinatory treatments ble against BL because of its aggresagainst other main survival cytoplassiveness. Specifically, when applied mic proteins,” she adds, noting the to BL, these conventional approachcurrent tremendous efforts deployed es are linked to high risk of tumour to develop pharmacological inhibilysis syndrome, a potentially fatal tors that block Pim-1 anti-apoptotic complication that disrupts electroactivities. These treatments would lyte and metabolite levels in blood associate the anti-CD95 monocloresulting from the release of cancer nal antibody with target-specific cell content into the bloodstream. chemotherapeutic agents. Sabine Matou-Nasri and co-work“In future work, we are planning ers investigated the molecular mechato undertake a gene–immune theranismsunderlyingCD95-mediatedappy approach against BL by knocking optosis to eliminate these side-effects down the gene expressing Pim-1, and improve the clinical outcomes then targeting its induced cell surface of anti-BL treatments. “Elucidating proteins that are likely to be involved these mechanisms was necessary to in cell survival,” says Matou-Nasri. identify novel therapeutic targets and enhance the efficacy and specificity of Matou-Nasri, S., Rabhan, Z., Al-Baijan, H., immunotherapy,” she adds. Al-Eidi, H., Bin Yahya, W. et al. CD95-mediated The researchers evaluated the apoptosis in Burkitt’s lymphoma B-cells is assoresponse of lymphoma B-cells to ciated with Pim-1 down-regulation, Biochimica anti-CD95 monoclonal antibody, et Biophysica Acta (BBA) - Molecular Basis of DisBurkitt’s lymphoma is a rare form of cancer that is more which specifically binds to and acease S0925-4439, 30230-7 (2016). common in Africa than in the US and Western Europe. Special Issue

Smart nanoparticles for cancer drug delivery Magneto-fluorescent nanoparticles successfully deliver anti-cancer drug to breast cancer cells.

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Drug-loaded nanoparticles target and kill breast cancer cells.

two types of cancerous breast cells and on healthy cells the results surpassed expectations. Not only were the drug-loaded particles more effective at killing the cancerous cells than the free doxorubicin, but, more importantly, their effect was greater on the cancerous cells than on the non-cancerous cells. Thanks to the particles’ magnetic and fluorescent properties, the authors were able to electronically image the drug-loaded nanoparticles and demonstrate cell uptake, even in tumour tissue derived from patients with breast cancer. Unlike free doxorubicin, which is internalised by passive diffusion through the cell membrane, the drug-loaded nanoparticles trigger endocytosis, a process whereby the cell actively engulfs them. The ability of these particles to selectively deliver the chemotherapy drug to cancerous cells is somewhat sur-

"Even with a passivetargeted, well-designed delivery system, enhanced toxic responses [in cancerous cells] can be attained” prising given that they have not been designed against a molecular target on these cells. In El-Boubbou’s own words “these results suggest that even with a passive-targeted, well-designed delivery system, enhanced toxic responses [in cancerous cells] can be attained,” offering huge potential as selective anti-cancer drug carriers. El-Boubbou, K., Ali, R., Bahhari, H. M., AlSaad, K.O., Nehdi, A., et al. Magnetic fluorescent nanoformulation for intracellular drug delivery to human breast cancer, primary tumors, and tumor biopsies: Beyond targeting expectations. Bioconjugate Chemistry 27, 1471-1483 (2016).

Special Issue

hemotherapeutics have markedly increased cancer survival rates. However, they cause serious side-effects due to their inability to differentiate between cancerous and healthy cells. Research aiming to reduce these adverse effects is important to ensure treatment compliance and improve patients’ quality of life. Kheireddine El-Boubbou has been designing nanoparticles that combine diagnostic and therapeutic capabilities, also known as theranostics, for more than ten years. In a recent study published in Bioconjugate Chemistry, El-Boubbou and his team at King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center and Saudi Arabia’s Ministry of National Guard—Health Affairs describe how novel magnetic and fluorescent nanoparticles are able to deliver an anti-cancerous drug to breast cancer cells with high selectivity. Magnetic metal oxide nanoparticles have demonstrated considerable promise for disease diagnosis, as magnetic resonance contrast agents, and as drug delivery agents, but mass production of such particles for clinical applications has been particularly challenging. Researchers led by El-Boubbou have developed a unique approach for producing magnetic metal oxide nanoparticles easily, cheaply and safely. Their ‘Ko-precipitation Hydrolytic Basic (KHB)’ methodology allows the synthesis of particles two to six nanometres in size from affordable, non-toxic and readily available starting materials at far lower temperatures (80 °C) than existing thermal techniques (200–300 °C). With the appropriate coating, the generated particles can be used for widespread biomedical applications, such as disease diagnosis and to aid targeted drug delivery, explains El-Boubbou. When the researchers loaded their nanoparticles with the chemotherapy drug doxorubicin and evaluated the effects on

Manipulating metals for medicine

A simple and robust synthetic method could help magnetic metal oxide nanoparticles reach their potential as a powerful clinical tool.

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agnetic metal oxide nanoparticles have demonstrated considerable promise for a wide variety of biomedical applications, but researchers have struggled to identify an optimal strategy for producing them. Researchers, led by nanobiochemist Kheireddine El-Boubbou of King Abdullah International Medical Research Center, have now developed an approach for producing these particles easily, cheaply and safely. â&#x20AC;&#x153;Tailored nanoprobes of controlled sizes and compositions based on iron oxides can be used for applications such as detection, imaging and drug delivery, both in vitro [in the body] and in vivo [in the lab],â&#x20AC;? says El-Boubbou. Unfortunately, most existing

ÂŠ K A I MR C

El-Boubbou and his team are developing iron oxide nanoprobes that can be used in imaging and drug delivery.

homogeneous populations of iron-oxide nanoparticles. El-Boubbou and colleagues subsequently demonstrated that by modulating the ratio of fatty acid to iron salt solution, they could accurately control the size of the resulting clusters, consistently generating spherical nanoparticles with diameters ranging from two to ten nanometres.

"We will utilize these functional nanoparticles for cancer imaging and as carriers to deliver drugs." This approach proved to extend to metals other than iron—including copper, nickel and zinc—widening the potential range of applications. The researchers were also able to modulate the chemical properties of the final product. The first batch of nanoparticles produced was not

soluble in water, but by modifying their protocol slightly, they were able to generate iron oxide nanoparticles that are. These could prove more useful for applications that require the particles to function within the interior of living cells. El-Boubbou has spent much of the past decade developing magnetic nanoprobes for biomedical applications. He has already begun to test the performance of these KHB-derived nanoparticles as a clinical research tool. “We will utilize these functional nanoparticles for cancer imaging and as carriers to deliver drugs to tumours in an attempt to develop chemotherapeutic approaches,” he says. El-Boubbou, K., Al-Kaysi, R.O., Al-Muhanna, M.K., Bahhari, H.M., Al-Romaeh, A.I. et al. Ultra-small fatty acid-stabilized magnetite nanocolloids synthesized by in situ hydrolytic precipitation. Journal of Nanomaterials http://dx.doi.org/ 10.1155/2015/620672

(2015).

methods yield aggregation-prone nanoparticles that vary in size and shape, or require the use of costly and toxic chemicals. “The lack of simple, fast, large-scale and cost-effective preparation remains a major hurdle toward real-world biomedical applications,” he says. El-Boubbou and his colleagues devised a strategy they call Ko-precipitation hydrolytic basic (KHB). It involves combining metal-based salts dissolved in water with different fatty acids in the presence of chemicals known as alkylamines. This forms highly stable acid-coated metal oxide nanocrystals. All of the materials involved are inexpensive and readily available, and the process can be performed at much lower temperatures (80 °C) than existing techniques, which require temperatures in the range of 200 to 300 °C. Electron microscopy confirmed that the KHB method can readily produce highly

Special Issue

Improving stem cell donation

OL A F DOE R I NG / A L A M Y S TOCK P HOTO

Stem cells could be collected from donors more safely by using a less invasive catheter.

Collecting stem cell donations using a peripheral venous catheter is safer and just as effective as using a central venous catheter.

safe, effective method for collecting stem cells from the blood of volunteer donors has been successfully trialled by scientists at KAIMRC and clinicians at King Abdulaziz Medical City in Riyadh (KAMC-R). Donated stem cells provide a supply for patients with cancer, damaged bone marrow, or impaired immunity and help them generate new blood. Until recently, this process of ‘hematopoietic stem cell transplantation’ involved the use of a central line, or central venous catheter (CVC), placed into a major vein, often in the donor’s chest or thigh. A CVC was thought to be preferable because the blood needs to flow at high pressure through a filtering machine, which separates stem cells and then returns the blood to the donor’s body. Now, it is believed that the less invasive peripheral venous catheter (PVC), which taps into peripheral veins in the upper arm,

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is safer and may be just as effective. “The use of CVC is still common in some hospitals in the Middle East, regardless of the donor’s ability to provide enough blood from their peripheral veins,” says Samer Ghazi at KAMC-R, who led the project. “However, inserting a CVC carries a high risk of bleeding, infection, clotting, and even death. We wanted to prove that PVCs could potentially do the job just as well in most cases.” Ghazi’s team believes that the donation process should be guided by collaborations between different medical professionals; for example, anaesthetists, intravenous therapy specialists and haematologists. The researchers aimed to reduce CVC use at KAMC hospital to less than 20% by encouraging nurses and clinicians to work together and try to use PVCs on every adult donor. The study, conducted over 16 months and including 42 adult donors, reduced CVC use from 72% to 0%. On the first

cycle of the trial, one in four cases had to revert to CVC; this reduced to one in eight by the second cycle, and all 30 donors in the third cycle successfully provided enough blood and stem cells using PVCs without any complications. “The advantages of switching to PVC are multiple, not least because of safety and quality of care,” says Ghazi. “PVC is readily accessible and there is no need to admit donors to the hospital, saving US$3000-4000 per case. It also frees up inpatient services and the radiology department, which were previously used for CVC insertion. Hopefully, our study will encourage the wider use of PVCs for stem cell donation.” Ghazi, S., Alaskar, A., Alzahrani, M., Damlaj, M., Abeulgasim, K.A. et al. Reducing central venous catheter use in peripheral blood stem cell donation: Quality improvement report. BMJ Quality Improve-

ment 6, u211975.w4817 (2017).

Light-responsive shape-changing molecules

Nanowires that undergo reversible shape changes in response to light could act as artificial tails to steer drugs around the body. © JA M ES K I N G - H OLM ES /OC M S /S C I EN C E P H OTO L I BR A RY / G E T T Y I M AG E S

dvances in nanotechnology are often inspired by designs found in nature. Tiny molecules that can change their shape in response to stimuli and swim through the body, mimicking bacteria, might one day help scientists develop novel, targeted drug delivery systems. Based on this principle, KAIMRC researchers have developed nanowires that bend in response to visible wavelengths of light and revert back in the presence of UV light. “We were inspired by the way bacteria propel themselves through liquid using their flagella, or tails, utilizing chemical energy as fuel,” explains Rabih Al-Kaysi, the KAIMRC materials chemist who led the project in collaboration with scientists at the University of California Riverside in the US. “We aimed to mimic nature by fabricating flagella-like nanowires that could move using light as fuel instead.” Scientists have already developed molecular crystals that respond to light of different wavelengths and undergo conformational changes. These ‘photomechanical’ properties are highly desirable, particularly if the shape-changes are reversible, so that a motion can be repeated or the molecule can be re-used. There are two types of reversibility: T-type (in which a molecule induced to change by light slowly reverts to its original shape after a time) or P-type (where shape-change is controlled in both directions by exposure to light of different wavelengths). “Until now, researchers were unable to create a nanoscale light-activated P-type actuator – a component that converts energy into mechanical motion,” says Al-Kaysi. “By synthesizing the appropriate organic molecule, we have generated the first P-type photomechanical actuators with nanometer thickness.”

Under X-ray diffraction, the scientists found the molecules switched between two shapes, allowing them to move through a liquid.

The researchers synthesized their novel molecule, called 9DVAM, by reacting a derivative of the hydrocarbon anthracene with an organic compound called malononitrile and fabricating molecular crystal nanowires that bent and straightened repeatedly under light stimulation. Further analysis of 9DVAM’s structural changes using X-ray diffraction revealed that the molecule was switching between two isomer shapes (different orientations of the atoms within the molecule) in response to light. “These conformational changes offer the largest possible displacement in the molecule, meaning maximum energy is generated,” explains Al-Kaysi. “This

lays the foundations for building molecular switches, or making artificial robotic flagella that could be attached to drug-loaded carriers, allowing them to be steered towards target tumour sites.” “We’re at the early stages of developing systems that can be used inside the body, where it is dark. By utilising clever synthesis, we could develop molecules activated using near-infrared radiation, which can penetrate the body.” Zhu, L., Tong, F., Zaghloul, N., Baz, O., Bardeen, C.J. et al. Characterization of a P-type photomechanical molecular crystal based on the E – Z photoisomerization of 9-divinylanthracene malonitrile. Journal of Materials Chemistry C 4, 8245-8252 (2016).

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2018

Concerns raised about digoxin safety

Researchers at KAIMRC have shown that the commonly used drug digoxin, used to treat heart failure and irregular heartbeat, is linked with increased risk of mortality in certain patient groups.

AIMRC researchers have shown that a drug, commonly used to treat various types of heart failure, appears to increase mortality risk in certain groups of patients when it is used in place of current guideline-recommended treatments. Digoxin is used extensively in combination with other medications in the treatment of heart failure, and is often prescribed to patients with atrial fibrillation — a kind of irregular heartbeat — to help slow and stabilize their heart rate. However, concerns have recently been raised about potentially harmful effects of digoxin, with research pointing to an association between digoxin and increased chances of death under certain circumstances. “Many patients are still regularly using this medication for heart failure or irregular heartbeat,” says KAIMRC’s Mouaz Al-Mallah, who led the study with colleagues from the King Abdulaziz Cardiac Center. “However, digoxin has a narrow therapeutic window and as a result it can easily reach toxic levels in the body. We were keen

to establish the long-term effects of taking digoxin, and to determine which patient groups might be at risk of any potential ill-effects.”

77%

Researchers found that digoxin use was associated with a 77% higher risk of mortality Al-Mallah’s team conducted a retrospective study of 2,298 patients seen at the heart failure clinic at the Ministry of National Guard–Health Affairs in Riyadh between 2000 and 2015. All the patients received appropriate treatment as outlined by current guidelines. The team matched 325 digoxin users with 750 non-digoxin users, making sure that considerations such as clinical variables and demographics were matched as closely as possible between individuals in each group. This helped to

limit other factors influencing the patients’ health, and allowed the team to achieve a meaningful analysis of the effects of digoxin. The researchers followed up patients two to six years after they commenced digoxin treatment. They found that digoxin use was associated with a 77% higher risk of mortality, mostly in digoxin users who did not suffer from atrial fibrillation. “We’ll investigate whether digoxin can still be helpful in certain subgroups of patients, but we believe digoxin users should be closely monitored for side-effects and switched to other safer drugs as soon as clinically possible,” says Al-Mallah. “We also hope to verify if the digoxin-associated increase in mortality can be prevented if the levels are closely monitored and are kept within a therapeutic range.” Al-Khateeb. Qureshi, M. W., Odeh, R., Ahmed, A. M., Sakr, S. et al. The impact of digoxin on mortality in patients with chronic systolic heart failure: A propensity-matched cohort study. The International Journal of

Cardiology 228, 214-218 (2017).

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S EB AS T I A N K AULI T ZK I / A L A M Y S TOC K P H OTO

A drug commonly used to treat heart failure could be associated with an increased risk of death in certain patient groups.

Stem cells found in the bone marrow are not all the same. These cells comprise different subpopulations, each with their own distinct morphological and functional characteristics. A Saudi-led investigation has discovered a molecular marker that can differentiate between bone-forming and other types of precursor stem cells in the marrow. In the future, the findings could be put to clinical use to enhance bone regeneration following injury, for example. This application would be relatively straightforward, according to Amer Mahmood, a stem cell biologist from King Saud University (KSU) in Riyadh. “A clinician could sort the bone marrow cells and only inject those involved in making bone to get better results and faster healing in patients,” he says. The team of researchers isolated two groups of bone marrow cells on the basis of their morphology under the microscope. One subpopulation of cells, which he and his colleagues call CL1, had a cuboid-like geometry, whereas the other, dubbed CL2, was composed of spindle-shaped cells. Both cell populations expressed some of the same surface markers that denote bone marrow stem cells (BMSCs). 22

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A protein called ALP delineates a population of bone-marrow stem cells, known as CL1, which can form bone tissue.

However, a complete gene expression analysis revealed some major differences. CL1 cells, the researchers found, were enriched for more than 80 different genes related to bone mineralization and skeletal muscle development. In contrast, CL2 cells exhibited higher expression levels of

some 75 genes involved in regulating the immune system. The researchers tested the differentiation potential of each cell type. CL1 cells could more readily be coaxed into forming bone or fat precursors. However, blocking the expression of a gene called alkaline phosphatase (ALP) impaired this potential and reduced the expression of 62 genes involved in bone formation. This revealed the central role of ALP in guiding CL1 cells toward bone formation. What’s more, the team showed that simply testing for the expression of ALP alone could discriminate between CL1 and CL2 cells in a mixture of BMSCs. “ALP is a unique marker of osteoblast differentiating cells,” Mahmood says. Heterogeneous concoctions of BMSCs are currently used to treat everything from orthopaedic disorders, such as osteoarthritis, to autoimmune diseases, like lupus. The findings suggest that pre-sorting the stem cells and using only the subpopulation involved in the disease process being treated could improve health outcomes. Elsafadi, M., Manikandan, M., Atteya, M., Hashmi, J. A., Iqbal, Z. et al. Characterization of cellular and molecular heterogeneity of bone marrow stromal cells. Stem Cells International 2016, 9378081 (2016).

A M ER M A H M OOD @ 20 1 6

Stem cells in the bone marrow express different molecular markers depending on whether they form bone or other tissue types.

JUA N G A E R T NE R / S P L / G E T T Y I M AG E S

How to tell bone marrow cells apart

M OP I C / A L A M Y S TOCK P HOTO

DNA circles help predict stem cell therapy outcomes DNA ringlets carried by immune cells could provide routine insight into the progress of stem-cellbased immunotherapy.

Tiny DNA remnants from the birth of immune T cells carry valuable information about the progress of immune system reconstitution following haematopoietic stem cell transplantation (HSCT), a research review involving KAIMRC scientists has found. These blood-borne biomarkers could be used to track the progress of HSCT therapy and help improve clinical outcomes for a wide range of blood and autoimmune diseases. The transplantation of blood-forming ‘haematopoietic’ stem cells is one of medicine’s fastest expanding therapies for diseases like leukaemia and various haematological and immunological disorders. The therapy works by replacing the dysfunctional immune system of the patient with a ‘reconstituted’ immune system derived from the transplanted healthy HSCs. Yet there are many ways in which this reconstitution can go wrong. In the first months, HSCT patients have profound immunodeficiency and are at high risk of infection. As reconstitution progresses, they then become increasingly susceptible to potentially lethal immunological responses, such as graft-versus-host disease (GVHD), in which the newly

DNA excision circles could be used as biomarkers to track the progress of haematopoietic stem cell transplantation therapy.

reconstituted immune system starts attacking the patient’s own cells. Complications like these are very difficult to treat, as the immunosuppressive drugs used to treat GVHD impair the immune system’s ability to combat infections. Tracking the progress of reconstitution and pre-empting the need for intervention thus remains a major obstacle to improving HSCT therapy. Based on a rapidly improving understanding of these interactions, the director of KAIMRC’s stem cells and regenerative medicine department, Muhamed Abumaree, and collaborating researchers from Karolinska Institutet in Sweden have been reviewing research into possible biomarkers that could be used to monitor the progress of immune system reconstitution. Their review focused on ‘T cell receptor excision circles’ (TRECs): tiny ringlets of DNA left over from the creation of immune T cells, which can be found in sufficient concentrations in blood to be detected using conventional DNA analysis methods.

From an extensive data and literature review, the team identified a certain type of DNA excision circle, called single-joint T cell receptor excision circles (sjTRECs), that could be used to distinguish between the activity of the early-developing innate immune system and the more powerful but slower-developing adaptive antigen-specific immune system. Abumaree and his co-workers suggest that such a biomarker could be used to identify problems or delays in immune system development and provide useful information regarding the status of the reconstitution of functional T cell immunity, with significant potential as a standard clinical approach to predict the risk of severe infection and hence improve HSCT survival rates. Gaballa, A., Sundin, M., Stikvoort, A., Abumaree, M., Uzunel, M., Sairafi, D., Uhlin, M. T cell receptor excision circle (TREC) monitoring after allogeneic stem cell transplantation; a predictive marker for complications and clinical outcome. International

Journal of Molecular Sciences 17, 1705 (2017).

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Injury prevention could stem opioid abuse People are 1.4 times more likely to become persistent users of opioid painkillers after suffering a traumatic injury.

roken bones, sprains and other physical injuries are often a pathway to opioid abuse, a new study has found. Public health efforts promoting injury prevention might not only help reduce death and disability, but could also reduce addiction to prescription painkillers and illicit opiate drugs, a problem responsible for an estimated 70,000 deaths worldwide each year. “Primary injury prevention could facilitate reduction of persistent opioid use and thus improve population health and reduce health expenditures,” says Suliman Alghnam, a KAIMRC epidemiologist and public health researcher who also led the study. The United States has the

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most cases of opioid abuse and approximately 80% of the world’s opioid supply is consumed there. Doctors often prescribe opioids, such as hydrocodone and oxycodone, to treat pain stemming from car accidents, falls and other kinds of injuries. But the contribution of these debilitating accidents to the growing opioid epidemic in the country was not known. Alghnam, who now focuses on tracking the burden of traumatic injuries in Saudi Arabia, decided to investigate the link between injuries and persistent opioid abuse in the United States during a postdoctoral fellowship at Johns Hopkins University in Baltimore, Maryland. He and his advisor, Renan Castillo, pored over data from a large government survey that

tracks how Americans interact with the medical care system. They identified a population of trauma victims who took opioids at least once immediately after sustaining an injury. Among them, around one in six became repeat users over the course of the two years they were followed. Overall, injuries accounted for about 11% of Americans on long-term opioid treatment. Alghnam and Castillo then compared the rate of persistent opioid use among those who experienced an injury and those who didn’t. After accounting for socioeconomic variables and other known predictors of drug abuse, the researchers found that injured individuals were about 1.4 times more likely to become

chronic opioid users. Notably, that estimate includes people with fairly mild knocks and bruises. “We certainly feel the magnitude would be higher had we limited the sample to severe cases,” Alghnam says. So, what’s driving so many Americans to start popping opiate pills after an injury? “Clearly chronic pain is a factor — but so might be overprescribing by physicians,” says Alghnam. “I think it’s several reasons that would need further research to dismantle,” he says. Alghnam, S. & Castillo, R. Traumatic injuries and persistent opioid use in the USA: Findings from a nationally representative survey.

Injury Prevention 23, 87–92 (2017).

P EO P LEI M AGES / E+ /G ET T Y I M AG ES

Chronic pain is driving many Americans to take painkillers after injury.

Leading Reliable Healthcare An outstanding, timely and much awaited contribution to the healthcare sector in the Kingdom of Saudi Arabia and globally.

Edited by Bandar Al Knawy, MD, FRCPC CEO, Ministry of National Guard Health Affairs Foreword by Dr. Paul Rothman CEO, Johns Hopkins Medicine Published by CRC Press, 2017

FEATURES

Contains contributions from recognized healthcare leaders from the UK, USA, Canada and South Korea/Singapore.

Describes how leadership can ensure reliable standards of care for patients and how excellence can be achieved.

Focuses on a different aspect of building a reliable healthcare system.

Relevant to global healthcare systems with key themes such as effective clinical practice and crisis management being universal.

Yemenis commonly chew qat leaves, a practice that is thought to be leading to higher incidences of oral cancer in the country.

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Oral cancer in the Arab World Qat and tobacco chewing have been linked to a higher incidence of oral cancer in Yemen, Sudan and southern Saudi Arabia than in other Arab countries.

n analytical review of 19 research studies has revealed high rates of oral cancer in some Arab countries, possibly due to widespread tobacco chewing. But, a lack of national cancer registries and population-based studies means the true prevalence of this disease in the region is unknown. The review, conducted by epidemiologist Ashraf El-Metwally and colleagues from King Saud bin Abdulaziz University for Health Sciences in Riyadh, found the incidences of oral cancer in Yemen and southern Saudi Arabia were possibly among the highest in the Arab world. Oral cancer is diagnosed in people younger than 40 in these two regions and could be related to widespread chewing of qat leaves and tobacco. The exact prevalence of oral cancer in

the Arab world appears to range from 0.5 per 100,000 people in Syria to 10 per 100,000 in southern Saudi Arabia and Yemen, according to studies. Very high rates of oral cancer are also seen in Sudan, where a snuff known as Toombac dipping is widely used and a habit for 34% of oral cancer patients. In Jordan, narghile, or water-pipe smoking, is popular. Both practices are significantly associated with oral cancer diagnoses in individuals averaging 45 years. Elsewhere

"One of the most significant issues is that oral cancers are not caught early enough when they are more treatable." in the world, oral cancer is usually diagnosed in people over 50. Oral cancer is the eighth most commonly diagnosed cancer worldwide, with an incidence of more than 300,000 new cases annually. In Sudan, however, it is the fifth most common type of cancer. “While men account for a higher percentage of oral cancer cases in the Arab world, we are seeing an increase in this

disease in women in the southwest areas of Saudi Arabia,” says El-Metwally. The research review found that squamous cell carcinoma was the most frequently detected kind of oral cancer in the Arab world and that it is frequently diagnosed in its late stages. “One of the most significant issues is that oral cancers are not caught early enough when they are more treatable. This occurs in areas in which patients do not have regular access to dental care,” says El-Metwally. In Saudi Arabia, oral cancer recurs in 56% of patients during the five-year period following initial diagnosis and treatment. El-Metwally says there is a pressing need to educate people about risk factors for oral cancer, such as smoking, qat and tobacco chewing, spicy food, and alcohol. It is also important that people have regular dental check-ups, which can help in the early detection of the disease, potentially increasing the five-year-survival rate to 60% for patients with early-stage tumours, compared to 20% in advanced disease. Al-jaber, A., Al-nasser, L., El-metwally, A. Epidemiology of oral cancer in Arab countries. Saudi medical journal doi: 10.15537/smj.2016.3.11388 (2016).

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A biomarker for colorectal cancer

A mutated tumour suppressor gene could provide a useful marker for the diagnosis and prognosis of bowel cancer.

n individual’s genetic makeup, including their ethnicity, determines how likely they are to develop certain diseases. A team of researchers from Saudi Arabia and India has pinpointed a mutation in a gene that may prove useful as a biomarker, indicating the presence and severity of bowel cancer. The healthy gene, called tumour suppressor gene, is responsible for protecting cells from one of the steps on the path to cancer. Genes can take a variety of different forms known as alleles. Humans have a copy of each gene (two alleles) — one from each parent — at each locus on the chromosome. The gene pairs can be identical, with two copies of the same allele, or they can be different. Such genetic diversity produces differences in inherited characteristics and can give rise to genetic propensity toward disease. Sometimes, one of the two alleles at a particular locus can be missing entirely, a phenomenon called ‘loss of heterozygosity’ (LOH). “Since LOH is a gross chromosomal mutation, it leads to a higher degree of genetic instability. For example, LOH at genes on chromosome 10 have been implicated in multiple cancers,” explains biochemist Aga Syed Sameer of King Saud bin Abdulaziz University for Health Sciences in Saudi Arabia. “We had previously analyzed the role of tumour suppressor genes in colorectal cancer, including one called PTEN found on chromosome 10. We decided to examine whether LOH at PTEN impacted on

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cancer progression.” Sameer’s team focused on bowel cancer in North Indian patients. They collected 223 tissue samples from patients visiting a New Delhi hospital between 2008 and 2012. They extracted DNA from each sample and searched for LOH at PTEN. They compared the results with a control group of healthy tissue samples. They found LOH at PTEN in 102 out of 223 cases. More significantly, they found PTEN LOH was significantly associated with cancer-related clinical factors such as the level of lymph node invasion and tumour growth. LOH is associated with a decrease in PTEN expression and consequently increases the chances of tumours developing. “We conducted further analysis on early and advanced stage colorectal cancer tissues and found that patients with advanced metastases were more likely to display PTEN LOH. The mutation could therefore be an invaluable biomarker for disease diagnosis and prognosis,” says Sameer. The team hopes that this research will help improve the diagnosis of bowel cancer, and Sameer himself may investigate similar cancer-related mutations within the Saudi Arabian population in the future. Ali, A., Mehdi, S.J., Hajela, K., Saluja, S.S., Mishra, P.K., et al. Allelic loss at PTEN locus leads to progression of colorectal carcinoma among North Indian patients. Biomarkers http://dx.doi.org/10.3109/13 54750X.2016.1172115 (2016).

ÂŠ BR A I N L I G HT / A L A M Y

Missing alleles in the tumour suppressor gene PTEN may indicate a propensity towards colorectal cancer in North Indian patients.

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Ayman Saleh is developing a new compound that has the potential to specifically target cancer cells while sparing healthy ones.

New anti-cancer molecule promises improved therapy Chemotherapy without side effects, or the risk of relapse, could soon be possible.

cientists have developed an anti-cancer agent that, in lower doses, can kill cancer cells and spare healthy ones — presenting a favourable therapeutic scenario in which relapse is unlikely. Cancer accelerates cell division and disrupts their ability to become more specialized; a process called differentiation. An ideal chemotherapeutic drug will stop proliferation of cancer cells and promote cell differentiation. Chemotherapy is a widely used option, but drug resistance is common and the treatment can be toxic to normal tissues. Pharmaceutical chemists are trying to find potent, resistance-free and safe drugs to treat cancer. This is what G-11, a new compound proposed by Ayman Saleh, lead author of two new papers on the subject is promising. The G11 molecule targets cells that develop a mutation in the FLT3 receptor, which is important for cell propagation

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and proliferation. The mutant is most common in acute myeloid leukaemia1, which represents approximately 90% of all acute leukaemias in adults. Chemotherapy is initially effective, but relapse is common and long-term survival rates are below 20%. “If the cancer is smart, once [a chemotherapeutic] drug targets a pathway, the cancer will find a new way to propagate. A few resistant cells will be left behind, they will flourish and become more vicious,” says molecular biologist Saleh from King Saud bin Abdulaziz University for Health Sciences. “Our drug, however, can target both existing and potential pathways, preventing relapse.” “What we’re doing here is developing a superior weapon; an air fighter that would minimize collateral damage by diving inside an enemy cell and killing its organelles,” he says. Organelles are the complex cell structures enclosed within lipid membranes inside a cell. These membranes carry the

1. Saleh, A. M., Taha, O. M., Aziz, M. A., Al-Qudah, M. A., AbuTayeh, R. F. et al. Novel anticancer compound [trifluoromethyl-substituted pyrazole N-nucleoside] inhibits FLT3 activity to induce differentiation in acute myeloid leukemia cells. Cancer Letters. http:// dx.doi. org/10.1016/j.canlet.2016.02.028 (2016) 2. Saleh, A. M., Aziz, M. A., Abdou, I. M., Taha, O. M., AlQudah, M. A. et al. Cytotoxic activity of the novel heterocyclic compound G-11 is primarily mediated through intrinsic apoptotic pathway. Apoptosis http://dx.doi. org/10.1007/s10495-016-1248-z (2016) .

genetic material and nucleolus. Their fuel comes from the mitochondria, another organelle that functions as the cell’s powerhouse, providing energy for all cellular activities, including growth and division. G-11 precisely targets the mutated receptor FLT3 in a cancer cell, shutting down its power supply. By disrupting mitochondrial functions, Saleh’s anti-cancer molecule destroys a cell from the inside while keeping the outer shell of the cell intact. How the cell dies makes all the difference. In necrosis, a form of premature cell death, the cell bursts, contaminating healthy cells with its contents and triggering an aggressive immune response, ultimately leading to organ damage. Many available cancer drugs can cause cell necrosis. By keeping the outer membrane of the cell unscathed in death, G-11 causes apoptosis2, which is “the dignified way to die” from a cellular perspective, says Saleh. Apoptosis doesn’t have side effects. G-11 not only inhibits FLT3 expression, but also promotes cell differentiation of blood cancer cells into mature cells1 – cells that are no longer able to divide. The compound was checked against a broad spectrum of cancers and proved effective1. It was more toxic to cancer cells than normal cells. Killing normal cells would require triple the G-11 dose that kills cancer cells. Saleh tested the compound on acute myeloid leukaemia blood samples. The promising results are “encouraging us to start the next step, which is investigating the compound in a leukaemia animal model to potentially qualify the compound to be tested on humans,” he says.

Gene defects reduce leukaemia survival Genetic variations can explain poorer survival rates in Pakistani children from a prevalent type of leukaemia.

akistani children affected by B cell acute lymphoblastic leukaemia (B-ALL), a common type, show poor survival compared to children in other parts of the world. A study conducted by KAIMRC in collaboration with hospitals and universities in Pakistan found that some genetic abnormalities normally associated with more aggressive types of cancer are common in B-ALL patients from the India-Pakistan region. B-ALL is the most prevalent type of cancer in children. It develops in blood-forming cells and is characterised by the overproduction of immature white

blood cells. One of its causes is the presence of fusion oncogenes (FOs), which are genes that form when two previously separate genes unite. Scientists analysed 188 blood samples from 2- to 15-year-old Pakistani children with B-ALL who were being treated at oncology centres in Lahore, Faisalabad, Islamabad and Peshawar. They found that 87.2% of the patients had FOs. In particular, the study investigated how four types of FOs were correlated to disease biology and treatment outcome. Similar to previous studies conducted in Pakistan and India, the fusion oncogene BCR-ABL was found to be the most common, detected in almost half of the patients. This mutation seems to be rare (2-5%) in B-ALL paediatric patients in Europe, the US, Saudi Arabia, Korea and Japan, but overrepresented in the India-Pakistan region. It is associated with older children (7 to 15 years old), lower remission (meaning temporary recovery) rates and poor survival. BCR-ABL codes for a mutant protein called tyrosine kinase, which causes unregulated cell division. Similarly, the FO MLL-AF4 was found to be relatively higher in the Pakistani patients (18%) compared to B-ALL patients in other parts of the world (1 to 17% depending on location) and it is correlated with short

survival (52 weeks on average). “Pakistani children with B-ALL have uniquely high frequencies of the FOs BCR-ABL and MLL-AF4. This, together with delays in diagnosis as well as shortage of specialised health professionals and treatment facilities may be some of the most important reasons for the overall poor outcome of paediatric B-ALL patients in Pakistan. We recommend the mandatory use of molecular testing for diagnosis and prognosis, the provision of tyrosine kinase inhibitors for treatment and the construction of more hematopoietic stem cell transplantation facilities at cancer centres,” says KAIMRC geneticist Zafar Iqbal, the leading author of this study. The reason some FOs are more abundant among Pakistanis is not clear. “Further studies with comprehensive genetic analyses are necessary to deepen our understanding of the genetic basis of the patients’ poor prognosis,” he says. Iqbal, Z., Akhtar, T., Awan, T., Aleem, A., Sabir N., et al. High frequency and poor prognosis of late childhood BCR-ABL-positive and MLL-AF4-positive ALL define the need for advanced molecular diagnostics and improved therapeutic strategies in pediatric B-ALL in Pakistan. Mol Diagn Ther. 19, 277287 (2015).

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B cell from a patient with leukaemia

Battling a transplanted risk Current strategies are not reducing the incidence of infection-related malignancies after organ transplantations.

Patients who receive solid organ transplants have a substantially increased risk of developing cancer due to exposure to tumour-producing viral infections while their immune system is suppressed. But, studies have both supported and refuted the effectiveness of antiviral prophylaxis in transplant recipients. Mona Aldabbagh, at King Abdulaziz Medical City in Jeddah, and colleagues in Canada carried out an extensive review of the published literature to determine whether systematic antiviral administration reduces the incidence of Epstein Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD). They found no significant reduction in the incidence of EBV-associated PTLD among transplant recipients that received prophylaxis compared with those who didnâ&#x20AC;&#x2122;t, regardless of age, type of antiviral used, length of treatment and type of organ transplanted. Aldabbagh was not surprised by the findings. â&#x20AC;&#x153;Data in the literature were very controversial. Conducting a systematic review was needed to resolve the confusion,â&#x20AC;? she says. 32

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“Conducting a systematic review was needed to resolve the confusion.” The authors say PTLD could be prevented more effectively by monitoring EBV viral load in transplant recipients. This will help determine the need to initiate anticancer therapy and reduce immunosuppression if viral activation is detected. They also point out that reducing the systematic use of prophylactic antivirals will contribute to reducing drug-related toxicities (as well as healthcare costs). An EBV vaccine is eagerly awaited as Cancer Research UK estimates it could prevent 200,000 new cancers worldwide annually. Several EBV vaccines have entered clinical trials in transplant recipients, but none has been sufficiently studied to establish safety and efficacy. Aldabbagh, M. A., Gitman, M. R., Kumar, D., Humar, A., Rotstein, C. et al. The role of antiviral prophylaxis for the prevention of Epstein-Barr virus-associated posttransplant lymphoproliferative disease in solid organ transplant recipients: A systematic review. Am

J Transplant. 17, 770-781 (2017).

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K AT E RY NA KON/ S P L / G E T T Y I M AG E S

EBV is a very common virus, affecting about nine in every ten adults. Although it causes no long-term problems for the vast majority of people with a healthy immune system, it is associated with 1.2% of PTLD cases in adults and up to 8.4% in children. This is mainly due to the transmission of EBV from the organ of a previously exposed donor to a recipient that has never been infected with the virus. In these cases, the patients are considered to be at high-risk for EBV infection and developing PTLD, and should be closely monitored post-transplantation. EBV-associated PTLD can progress to non-Hodgkin’s lymphoma and may be fatal. The findings, published in the American Journal of Transplantation, suggest that the routine use of antiviral prophylaxis is ineffective, highlighting the need for further research into better preventive and treatment strategies.

Coloured sagittal magnetic resonance imaging (MRI) scans of a breast of a 39- year-old woman with breast cancer.

New chemotherapy promising for breast cancer A trial for a new chemotherapy treatment has shown promising results for locally advanced breast cancer.

reast cancer is the most common type in women worldwide. When confined within the breast and the lymph nodes of the armpit it is referred to as “locally advanced breast cancer” (LABC). These patients receive a combination of anti-cancer drugs before surgery to reduce the volume of the tumour and to improve chances of survival. When successful, breast conservation, rather than mastectomy, is possible. Researchers in Saudi Arabia, Kuwait, Egypt and the United Arab Emirates conducted a clinical trial of a new pre-surgery chemotherapy treatment on 80 LABC patients to test its effectiveness and safety. The trial showed promising results, even in aggressive types of LABC. In chemotherapy, a cocktail of drugs is used to attack cancer cells. However, it is hard to know which combination leads to the best results, with the lowest toxicity. In this trial, LABC patients received a 24week treatment of the chemotherapeutic agents FEC100, cisplatin and docetaxel. Patients whose cancer cells had a high

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number of human epidermal growth factor 2 (HER2) receptor proteins were also given trastuzumab, which targets these receptors. HER2-positive breast cancers tend to grow faster and are more likely to spread and recur compared to HER2-negative ones. A quarter of the patients could not complete the course because of unacceptable toxicity. But, the invasive tumour cells were completely eliminated from the breast alone of 4% of the remaining women, the armpit alone in 32%, and from both breast and armpit in another 32%. “It is an encouraging result, considering that almost half the patients in our hospital have LABC and begin chemotherapy when the tumour is relatively large,” says oncologist Omalkhair Abulkhair from Saudi Arabia’s Ministry of National Guard – Health Affairs. Around 15% of breast cancers are classified as “triple negative” because they do not have oestrogen or progesterone receptors on their cell membranes and do not overexpress HER2. Triple negative

tumours are difficult to treat since most chemotherapies target these receptors specifically. Moreover, triple negative cancers tend to occur more often in younger women and grow more quickly than other types of breast cancer. The trial achieved good results with these more aggressive types of cancers: 36% of the triple-negative breast cancers were eradicated, as well as 62% of the HER2-positive, hormone receptor–negative group. However, “further studies are needed to improve the response of HER2-negative, hormone receptor-positive patients and to evaluate the efficacy of a shorter therapy,” says Abulkhair. AL-Tweigeri, T., AlSayed, A., Alawadi, S., Ibrahim, M., Ashour, W. A multicenter prospective phase II trial of neoadjuvant epirubicin, cyclophosphamide, and 5-fluorouracil (FEC100) followed by cisplatin-docetaxel with or without trastuzumab in locally advanced breast cancer. Cancer Chemotherapy and Pharmacology http://dx.doi.org/10.1007/ s00280-015-2906-5 (2016).

Doctors often admit critically ill patients to intensive care for a limited time to test how well they might respond to treatment.

How long do we treat the critically ill? Researchers are developing objective measures to determine whether critically ill cancer patients can benefit from intensive care.

hysicians often struggle when deciding about the appropriateness of exposing critically ill patients to intensive care; particularly in the case of cancer patients given poor prognoses who they feel might not gain substantive benefits by doing so. Doctors sometimes admit patients to the intensive care unit (ICU) for a limited time period to test whether they will benefit from the treatment. Until now, however, the optimal amount of time for an ICU trial has not been objectively determined. Researchers at Harvard University in Boston, Massachusetts and King Abdullah International Medical Research Center in Riyadh set out to determine whether time-limited trials of aggres-

sive ICU treatment for cancer patients could provide comparable patient survival to unlimited care, and if so, what the optimal length would be. The team constructed a computer-based model using data from 920 critically ill patients admitted to a hospital in Boston, Massachusetts. The model simulates the clinical problem, gives scores to patients based on how well their organs are functioning, and calculates the probability of dying, improving, deteriorating or of discharge from ICU. The results were compared by using the model on data from three other sets of patients, 624 in total, in Boston and Riyadh. The team found that critically ill cancer patients whose acute condition was less

severe benefited most from longer trials of intensive care. Trials as short as one to four days were sufficient for patients with poor-prognosis solid tumors such as mesothelioma, glioblastoma, pancreatic cancer, and small-cell lung cancer. “In cancer patients with poor prognoses, ICU physicians have to balance aggressive treatment with comfort measures,” says the study’s primary investigator, Mark Shrime, from Harvard Medical School in Boston. “Based mostly on expert opinion, physicians have often chosen to treat for 48 to 72 hours to help determine a patient’s responsiveness to ICU care, but there has been little research to determine whether that is enough time,” he says. “Studies at the end of life to provide evidence-based recommendations can be performed, as we have demonstrated, instead of relying on expert opinion alone,” says Shrime. Shrime, M., Ferket, B., Scott, D., Joon, L., & Lai, P., et al. Time-limited trials of intensive care for critically ill patients with cancer: How long is long enough? Jama oncol. http://dx. doi:10.1001/jamaoncol.2015.3336 (2016).

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healthy controls. They found that the majority of clock genes were suppressed in patients with acute myeloid leukaemia with the exception of Cry2, whose levels increased toward the end of treatment and during relapse. A similar story unfolded with chronic forms of the illness, with all analysed

Changes in the expression of circadian clock genes have been found in people with leukaemia.

Timing treatment perfectly Understanding how leukaemia affects the body’s circadian clock may unlock ways to treat the disease.

he circadian clock is the internal rhythm of the body that responds to night and day, typically following a 24-hour cycle. KAIMRC researchers have shown that many circadian clock genes are suppressed in leukaemia patients, aiding the disease’s progression. The team also suggests a role for one key protein in restoring the circadian clock in chronic myeloid leukaemia. The circadian clock controls many key processes, including metabolism, sleep-wake patterns and the regulation of genes. Circadian rhythms and clock genes are disrupted in various diseases,

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including cancer and diabetes. Leukaemia is a malignant blood cancer that manifests in both acute and chronic forms. Changes to circadian genes have been reported in leukaemia patients. Mohamed Boudjelal, at KAIMRC’s drug discovery unit, and co-workers used gene expression profiling to examine circadian clock genes in acute and chronic forms of leukaemia before, during and after treatment. The researchers analysed the expression of seven clock genes, including Cry2 and BMAL1, in blood samples collected from 75 patients at different stages of treatment for leukaemia and from 30

clock genes suppressed, except for Cry2, which was unaffected in the initial stages of the disease. The team also investigated the role of Sirt1, a protein known to regulate genes associated with the circadian clock. They found that inhibiting Sirt1 resulted in partial recovery of circadian rhythm in patients with chronic myeloid leukaemia by normalising the switching on and off of the BMAL1 clock gene. Therapies targeting Sirt1 could improve dysfunctional circadian rhythm and enhance the effectiveness of existing chemotherapeutic drugs. “A comprehensive understanding of how circadian genes behave in leukaemia will provide insights into how the molecular clock is impacted in this disease,” write the researchers in their paper published in the Journal of Circadian Rhythms. “Such an understanding could also be used to develop treatment strategies whereby drugs are administered to patients… in synchrony with their molecular clocks to facilitate greater effectiveness.” Rahman, S., Al-hallaj, A., Nedhi, A., Gmati, G., Abuelgasim, K.A., et al. Differential expression of circadian genes in leukemia and a possible role for Sirt1 in restoring the circadian clock in chronic myeloid leukemia. Journal of Circadian Rhythms 15 (1), 3 (2017).

IM AGE B R O K E R / A L A M Y S TO C K PH O TO

A comprehensive understanding of how circadian genes behave in leukaemia will provide insights into how the molecular clock is impacted in this disease.

AML represents approximately 14% of all registered paediatric leukaemia cases in Saudi Arabia.

The Saudi approach to curing childhood leukaemia

The survival rate for paediatric acute myeloid leukaemia in Saudi Arabia is now equal to that of developed nations thanks to a risk–response strategy.

cute myeloid leukaemia (AML) — a type of cancer characterized by the rapid growth of abnormal white blood cells in the bone marrow — accounts for roughly 15– 20% of all leukaemia cases in children. With recent advances in treatment and supportive care, the survival rates of AML for children in developed nations, such as Ireland, the United Kingdom and the United States, have greatly improved to 60–70%. However, the status of AML for children in developing nations, particularly those in the Middle East, is unclear. Wasil Jastaniah at the Princess Noorah Oncology Center, part of Saudi Arabia’s Ministry of National Guard—Health Affairs, and co-authors have now performed a retrospective study on the status of AML for children in the kingdom.

They found that a risk–response strategy has boosted the survival outcomes in the kingdom to world-class standards. Relapse — the recurrence of AML in patients — is currently the biggest obstacle to leukaemia treatment and recovery. The researchers followed the status of 175 AML patients aged 14 years or younger treated across nine medical institutions in Saudi Arabia over five years. They noted that of the 175 AML patients, treatment of 21 (12%) failed in the first phase, 67 (38.3%) experienced relapse and 66 (37.7%) died within the study period. The cumulative incidences of relapse and non-relapse mortality were determined to be 43.1% and 9.8% respectively. Most significantly, the overall survival was estimated to be 58.8 ± 4%, which was comparable to that of North

America (65.4 ± 4%) and those of United Kingdom, Ireland, Netherlands and New Zealand (61%). They attributed the unexpectedly high survival rate in Saudi Arabia to two things: hematopoietic stem cell transplantation and tailored treatment. The latter, in particular, utilises a risk- and response-based stratification system that optimises the selection of AML therapies for different patients. Saudi Arabia is a high-income, resource-rich country that has been providing free cancer treatment to its nationals. The number of cancer centres in Saudi Arabia has increased over the past 20 years, resulting in improved access to treatment and supportive care. The findings from this study suggest that tailored treatment for AML patients using a risk–response strategy has significant benefits and that, with the right implementation, developing countries can achieve comparable survival outcomes as those of developed countries. “Future improvements in outcomes of childhood AML in Saudi Arabia would require further refinement of risk stratification and tailoring therapy based on risk and response,” says Jastaniah. Jastaniah, W., Al Ghemlas, I., Al Daama, S., Ballourah, W. Bayoumy, M. et al. Clinical characteristics and outcome of childhood de novo acute myeloid leukemia in Saudi Arabia: A multicenter SAPHOS leukemia group study. Leukemia Research 49, 6672 (2016).

Special Issue

Molecular tool detects early-stage breast cancer A cheap, simple test shows potential for reducing uncertainty in the diagnosis of earlystage breast cancer.

new molecular test that distinguishes between gene fragments may serve as a reliable marker of early-stage breast cancer. Developed by a team of researchers from Saudi Arabia and the US, the test focuses on the Lamin A/C gene, which is associated with several kinds of cancer, as well as other diseases. When the gene is expressed, it is processed into one of five variants, similar to how a LEGO® set can be assembled into either a car or a plane. “The methods available now can’t distinguish between the variants, so they can’t reveal each variant’s biological effect or expression in different types of tissues,” explains biochemist Ahmad Aljada from KAIMRC. The new method is based on a standard molecular biology technique, called polymerase chain reaction (PCR), which makes multiple copies of DNA fragments. Aljada’s team carefully designed four pairs of “primers” – short DNA fragments that are complementary to the DNA being copied – together with helper molecules that increase their specificity. These tools helped detect and distinguish the four 38

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Scientists at KAIMRC may have found a new method to diagnose early-stage breast cancer.

variants found in breast tissue. Aljada’s team used the new technique to uncover differences in the concentration of the four variants in 47 different normal tissues and organs, though the biological significance of these differences remains a mystery. “We see that these variants have different functions and effects, but it’s going to take some time to really understand their impact on different cells and different pathways,” says Aljada. The team also measured the four variants’ concentration in 128 samples from breast cancer patients. They found that breast tumours had higher levels of one variant, Lamin C, and lower levels of another, Lamin A. The change in ratio between the two variants serves as a reliable breast cancer marker, even in early-stage tumours that are difficult to diagnose with certainty using traditional approaches.

“It’s a simple, affordable test that can be conducted in any molecular diagnostics lab,” says Aljada. “Hopefully we’ll finish larger scale studies to evaluate it clinically within two years.” The change in ratio might also be useful for diagnosing other cancers, though too few samples were tested to be certain. The team is currently screening for drugs that reverse the change in ratio, as well as exploring some of the questions raised by their findings. “Is there a correlation with prognosis? Can we use it to measure the response to chemotherapy? We don’t know at this stage,” says Aljada. Aljada, A., Doria, J., Saleh, A.M., Al-Matar, S.H., AlGabbani, S., et al. Altered Lamin A/C splice variant expression as a possible diagnostic marker in breast cancer. Cellular Oncology http://dx.doi.org/10.1007/ s13402-015-0265-1 (2016).

Translational Research Unit Is the Hub for clinical Trials with additional unique feature, phase 1 clinical Trials.

EMAIL: TRU@NGHA.MED.SA PHONE NUMBER: +966-11-429-4516

The Unit consists of: •• •• •• •• •• •• ••

Reception Ward with 16 Beds Phlebotomy Room Volunteers Screening Room Volunteer Recreation Room Centrifuge and Freezer Room Chemistry Lab

A simple screening tool can help doctors tailor the treatment of autistic children according to their individual needs.

Autistic children could receive tailored treatment A new method of identifying autism means hope of earlier treatment for children.

simple tool used by doctors to screen parents could lead to earlier identification and intervention for children with autism. Researchers from King Abdullah International Medical Research Center have found that the autism treatment evaluation checklist (ATEC) not only identifies which children have the condition, but also helps health professionals glean how they are most affected. Their research could help give parents and carers the resources they need to help tailor treatment to the child’s needs, says KAIMRC clinical psychologist Sarah Al Shirian. Autism is a complex neurodevelop40

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mental disorder in which a child’s ability to communicate and interact with others is impaired. Children with autism often display restrictive or repetitive behaviours and interests. The condition ranges hugely in severity from mild to acute. The ATEC is a simple, one-page test covering four key areas – known as “domains”: speech and language; sociability; sensory awareness and cognitive ability; and health and physical behaviour. Each domain has a number of questions that help build a qualitative picture of the child’s experience. For example, can the child say three meaningful words in a sentence, or can they hold a meaningful conversation with peers or family?

Al Shirian S, Al Dera, H. Descriptive characteristics of children with autism at Autism Treatment Center, KSA. Physiology & Behavior http://dx.doi.org/10.1016/j. physbeh.2015.09.001 (2015).

In contrast, commonly used diagnostic tools, such as the Diagnostic and Statistical Manual of Mental Disorders, do not include a focus on physical or systemic issues and are more limited in the areas that are assessed. The team used ATEC to assess 60 children between two and eight years of age who had been diagnosed with autism by specialists at the Prince Nasser Bin Abdulaziz Autism Center in Saudi Arabia. The screening tool clearly identified a range of symptoms among the children, with more than half demonstrating hyperactivity and more than 90% unable to have a meaningful conversation. It also found a range of other symptoms, with more than 60% getting “hooked” on words, or displaying what are known as “stemming” behaviours, such as head banging. Almost 60% were wetting the bed. “The key finding in our study was that health, physical and communication dysfunctions were very common among the children that were studied,” Al Shirian says. “This will have a huge impact on the quality of life of each autistic child, because both clinicians and other carers will know where to start with their medical management, education and improving social skills,” she says. “We also believe that using the ATEC will help autism centers categorize students into groups, allowing them to focus on the domains that are affected in each group.” For example, some children might need extra help understanding social cues, while others may need help with movement and speech. “When we know which domain is most affected in an autistic child, we can use this to assess the management, care and prognosis of each child individually,” says Shirian. Al Shirian says this is particularly important in Saudi Arabia, where autism is becoming more common, but is not always treated optimally.

Donating blood might improve diabetes

Recent research suggests giving blood may temporarily improve insulin production and glucose tolerance.

eart attack, stroke and type II diabetes have all been shown to be less common in individuals that regularly donate blood. But, according to a new study led by researchers at King Abdullah International Medical Research Center (KAIMRC), just a single blood donation can temporarily improve a person’s insulin production and glucose tolerance. KAIMRC pathologist Anwar Borai led an international team that tested the levels of several key diabetes-related biomarkers in the blood of 42 healthy male donors. Biomarkers, including those related to glycaemic status (the level of glucose in the donor’s blood), insulin production and iron levels, were tested before donation and then one day, one week, three weeks and three months after giving blood. The results show that regular, repeated blood donation is not required to see a beneficial effect on the donor’s glucose tolerance. “The glycaemic status of the donor can be improved even after a single blood donation,” Borai says. The improvement was particularly evident three weeks after donation. By three months, most of the tested biomarkers returned to their pre-donation levels. Borai says improvements could con-

Donating blood lowers the body’s iron stores, with potential health benefits.

tinue if donors made healthy lifestyle changes after donation. The team suspects that the improvement in glucose tolerance is linked to the levels of iron and other metals in the bloodstream. “It is well known that low iron stores may contribute to enhanced insulin sensitivity,” Borai says. Iron-containing compounds in the blood can produce damaging molecules, known as reactive oxygen species, which have been shown to interfere with insulin signalling, lowering a person’s tolerance of glucose. As Borai’s results confirm, giving blood removes some iron from the body, perhaps helping restore insulin signalling. The team next plans to repeat the study with people who have impaired glucose tolerance and full-blown type II diabetes. “Blood donation could be an alternative

way to improve glycaemic status, particularly in people with impaired glucose tolerance who are on a diet and have not started their treatment yet,” says Borai. The technique may also be used to assess how blood donation affects other areas of health, including levels of white blood cells called lymphocytes, which form part of the immune system. “I am preparing the second part of the study which is about changes in lymphocyte subsets and general immunity after whole blood donation,” Borai says. Borai, A., Livingstone, C., Farzal, A., Baljoon, D., Al Sofyani, A., et al. Changes in metabolic indices in response to whole blood donation in male subjects with normal glucose tolerance. Clinical Biochemistry dx. doi.org/10.1016/j.clinbiochem.2015.08.023 (2015)

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2018

Eliminating risk factors of heart attack

If a person has extensive obstructive coronary artery disease, either male or female, they are at increased risk of suffering a major cardiovascular event.

he likelihood of suffering a significant cardiovascular event, such as a heart attack, is significantly increased if a patient suffers from obstructive coronary artery disease (CAD). Now, a study by an international team of researchers, including KAIMRC’s Mouaz Al-Mallah, has verified that a patient’s sex has no influence on their risk of a major cardiovascular event if they are suffering from obstructive CAD. CAD occurs when the arteries that supply blood to the heart become hardened and partially blocked by fat deposits known as plaques. The condition gradually worsens, and eventually the heart muscle no longer receives the blood needed to function effectively. This can lead to severe chest pain, blood clots, heart attacks and sometimes sudden death. “Women tend to have more symptoms suggestive of CAD, including chest pain, chest heaviness or shortness of breath, but they appear to have a lower prevalence of obstructive CAD than men,” says Al-Mallah. “We did not know if sex plays a role in the relation between coronary artery blockages and clinical outcomes, and so when the international CONFIRM [Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter] registry was set up we sought to clarify this issue.” In the first long-term study into sex-specific associations in CAD, the research team followed the progress of 5,632 male and female patients with CAD from the CONFIRM registry over a period of five years. The patients were regularly screened

to determine CAD extent using coronary computed tomography angiography: CT scanning of the main vessels supplying the heart. Those patients displaying 50% or more narrowing of a coronary vessel were classed as having obstructive CAD. “We found that men were more likely to have obstructive CAD than women,” says Al-Mallah. “However, there was no evidence that a person’s sex played a role in increasing the chances of a major cardiovascular event if they suffered from obstructive CAD. For both men and women, the greater the extent of obstructive CAD, the higher the risk of suffering a severe heart episode.”

"Women tend to have more symptoms suggestive of CAD, but they appear to have a lower prevalence of obstructive CAD than men.” The researchers note that current methods for measuring the extent of CAD in the body must be improved. Further investigations are also needed to determine whether there are differences in plaque characteristics between the sexes that impact clinical outcomes. Schulman-Marcus, J., o Hartaigh, B., Gransar, H., Lin, F., Valenti, V. et al. Sex-specific associations between coronary artery plaque extent and risk of major adverse cardiovascular events: The CONFIRM long-term registry. JACC: Cardiovascular Imaging 9, 364-372 (2016).

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A person’s sex has no effect on increasing the risk of a major heart attack for patients with extensive coronary artery disease.

Having clear laws and data-handling guidelines would benefit both biobanks and donors in Saudi Arabia.

The right to know Biobanks are research facilities that collect biological specimens and health data from human donors. A scientist may find results that are clinically relevant to one or several donors â&#x20AC;&#x201D; such as biomarkers that could predict oneâ&#x20AC;&#x2122;s likelihood of inheriting certain genetic diseases. There has been much debate around the world as to whether biobanks should pass these results to donors, and whether donors should have the right to refuse knowledge of these results. Ghiath Alahmad at King Abdullah International Medical Research Center (KAIMRC) in Riyadh, Saudi Arabia and Kris Dierickx at KU Leuven in 44

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Belgium conducted a survey laypeople working, receiving in Saudi Arabia to gauge the treatment or visiting inpatients opinions of various stakeholdat King Fahd Hospital in Riyadh. ers on the return of results to Around 45% of them agreed donors. They that donors found that had the right 80% of people most people to be informed surveyed felt agreed that bioof important biobanks should results. However, banks should pass imporpass important only 9% agreed tant results to that donors d o n o r s , a n d results to donors, had this right that donors if results were but only 30% should have the felt unimportant insignificant. right to refuse Also, around knowledge of results should be 80% of those these results. surveyed agreed passed on. The researchthat biobanks ers surveyed 180 people, should pass significant results including KAIMRC researchto donors. However, if the ers, as well as physicians and results were unimportant,

only 30% thought the results should be passed on. Lastly, around 47% of those surveyed agreed that donors should have the right to refuse knowledge of important results. The numbers closely match those reported in Western countries. The results show that despite cultural differences, people living in Saudi Arabia might opt for transparency and access to research results that are of clinical significance. Alahmad, G. & Dierickx, K. Return of research results in the Saudi biobank: An exploratory survey. Genetic

Testing and Molecular Biomarkers 21, 166â&#x20AC;&#x201C;170 (2017).

SC IE N C E / GE N O M E R E UT E R S / P HI L N OB LE

A survey in Saudi Arabia finds broad support for returning significant results to biobank donors.

Exploring diabetes impact on teenagers and their families © B EN EDWA R DS / T HE I M AG E BA NK / G E T T Y I M AG E S

A multidisciplinary approach to treating teenage diabetics is needed to improve quality of life for patients and their families.

iabetes is a rapidly growing problem, with 382 million people affected worldwide. The disease affects 24% of Saudi Arabia’s predominantly youthful population; meaning many of the country’s diabetics are teenagers. KAIMRC researchers have conducted investigations into the impact of diabetes on adolescents and their families, from physical discomfort to the psychological and social impacts of living with a chronic condition. “In Saudi Arabia we have been focusing a great deal on the medical management and control of type I diabetes among our youth,” says paediatrician Fadia AlBuhairan from King Saud bin Abdulaziz University for Health Sciences. “However, we have failed to address the psychosocial impact on patients and their families.” AlBuhairan and her colleagues investigated the full impact of type I diabetes on teenagers and their caregivers. They gathered data from health-related quality-of-life questionnaires given to 315 patients aged 12 to 18 at three hospitals. The patients’ caregivers completed the same questionnaire, plus a second one related to family impacts of the disease. “We had an excellent response rate,” says AlBuhairan. “This reflects our participants’ sincere interest in addressing the complexities of this lifelong condition.” The team found that all scores were lower for Saudi Arabian families than equivalent studies in other countries. Caregivers tended to give lower scores on the quality-of-life questionnaire than the teenage patients. The lowest scores

Teenage diabetics and their families are in need of a multidisciplinary approach to improve their quality of life.

for both caregivers and teens were in the ‘worry’ category, with parents’ emotional well being affected by concern for their child’s future. Female patients in later teenage years (ages 15 to 18) were also more likely to report a lower health-related quality of life. This may partly be due to the complexities of treating diabetes in young women, as hormonal fluctuations mean their bodies require more insulin than males. Sometimes there are also issues related to unhealthy weight control practices. “Research generates the evidence

needed to impact practice,” says AlBuhairan. “Implementing a multidisciplinary care approach to diabetes and other chronic diseases is essential. We hope to study other adolescent patient populations to find out if key findings in this study, such as low ‘worry’ scores, also cut across other disease categories.” AlBuhairan, F., Nasim, M., Al Otaibi, A., Shaheen, N. A., Al Jaser, S., & Al Alwan, I. Health related quality of life and family impact of type 1 diabetes among adolescents in Saudi Arabia. Diabetes Research and Clinical Practice 114, 173-179 (2016).

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Researchers target the spike-like proteins that form a crown around the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). 46

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Combating MERS in camels with a single-dose vaccine

esearchers designed and compared four vaccines against the potentially deadly Middle East respiratory syndrome (MERS) and found one that activates a strong immune response in mice after a single dose. In June 2012, a Saudi patient died from a severe respiratory condition caused by a previously unrecognized coronavirus. Since then, the MERS-CoV virus has been reported in 27 countries and has infected more than 1,900 people, mostly in Saudi Arabia. It is mainly transmitted to humans via dromedary camels and brings a range of clinical outcomes from asymptomatic to severe. Its 40% mortality rate is higher than that caused by severe acute respiratory syndrome (SARS), but no vaccines or therapies have been clinically approved for human or veterinary use. One approach to tackle MERS is to use vaccines made from unarmed viruses that are efficient in triggering the development of a strong immune response against other dangerous viruses. ‘Viral vector vaccines’ against Ebola, HIV, malaria, tuberculosis, and influenza are already under study. To date, the only anti-MERS vaccine to be tested in camels is derived from a

highly attenuated strain of vaccinia virus, called modified vaccinia Ankara (MVA). It requires two doses to provide partial protection. An ideal vaccine would yield complete, rapid and long-lasting immunity after a single dose. Researchers from KAIMRC, the UK, and Germany compared MVA with a different viral vector, known as chimpanzee adenovirus Oxford University #1 (ChAdOx1). Previous studies have shown that one dose of ChAdOx1-based vaccine is effective against Rift Valley fever in multiple species, including camels, making it a promising vaccine tool. The scientists tested two MVA and two ChAdOx1 MERS vaccines. All of them carried the DNA sequence encoding MERS-CoV’s characteristic spikeshaped surface proteins, which are produced once the viral vector enters host cells. These are then recognized by the host’s immune cells, triggering more defence mechanisms. The production of the spike proteins is dependent on a promoter sequence. The MVA MERS vaccines were designed with one of two promoters, either mH5 or F11, to test which allows the largest production of spike proteins, enhancing the strongest immunity. The two ChAdOx1 MERS vaccines differed for the presence or

One approach to tackle MERS is to use vaccines made from unarmed viruses that are efficient in triggering the devel opment of a strong immune response against other dangerous viruses. absence of tissue plasminogen activator (tPA), another strategy to optimize the vaccine’s performance. They found that all these vaccine candidates stimulated the mouse immune system and the type of promoter did not have a significant impact on the results. Strikingly, a single dose of ChAdOx1 MERS with tPA was as immunogenic as two doses of MVA MERS (also containing tPA). The team suggests testing it as a single dose vaccine in dromedary camels, followed by a booster dose of MVA MERS vaccine if needed. Alharbi, N. K., Padron-Regalado, E., Thompson, C. P., Kupke, A., Wells, D., Sloan, M. A. et al. ChAdOx1 and MVA based vaccine candidates against MERS-CoV elicit neutralising antibodies and cellular immune responses in mice. Vaccine (2017).

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N AT I O N A L I N ST I T UT E OF A LLER GY A N D I N F EC T I OUS DI S EAS ES (N I A I D)

Anti-MERS vaccines for camels could be optimized by varying their viral and DNA content, and adjusting their administration.

More may not be better for the critically ill Critically ill adults may do as well or better on fewer calories.

large international study has found that critically ill patients may benefit from receiving fewer than their standard caloric requirements. The study involved 894 patients in seven hospitals in Saudi Arabia and Canada. Critically ill, often unconscious patients hospitalized in intensive care units are commonly fed via a nasogastric tube. Nutrition is a crucial part of their care, but doctors do not universally agree about how much they need. Some studies show that patients do better on standard caloric and protein requirements, while other research indicates that critically ill patients may benefit from a reduced regimen of calories. 48

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Researchers randomly allocated patients to a doctor-prescribed-underfed group (called permissive underfeeding) or a standard-feeding group, which determined whether they received 40 to 60% or 70 to 100% of their estimated standard caloric requirements. The underfed group received additional protein so that both groups had similar protein intake. After 90 days, the team found that the mortality rates for the groups were similar: 27.2% in the underfed group and 28.9% in the standard-feeding group. “One important difference was that patients in the permissive-underfeeding group had lower glucose levels and

required less insulin, which is consistent with other studies,” says Yaseen Arabi, chairman of the intensive care department at King Saud bin Abdulaziz University for Health Sciences in Riyadh, Saudi Arabia. Another finding was that dialysis, needed often in critically ill patients, was needed less frequently in the permissive-underfeeding group, he says. This supports the idea that higher caloric intake and higher blood sugar levels found in critically ill patients may be connected to kidney injury, Arabi and colleagues noted. “Our study opens the door to examine ways to optimize nutritional support during critical illness and provides evidence that, for these patients, more is not better when it comes to calories,” Arabi says. For his next study, Arabi will study the optimal caloric needs for patients in the first few days of critical care. Arabi, Y., Aldawood A., Haddad S., Al-Dorzi H., Tamim H., et al. Permissive underfeeding or standard enteral feeding in critically ill adults. The New England Journal of Medicine. dx.doi.org/10.1056/nejmoa1502826 (2016).

Doctors do not universally agree on the optimal caloric needs of critically ill patients in intensive care.

G A R O/ P HA NI E / A L A M Y S TOCK P HOTO

A team of researchers across the kingdom wanted to know if there was a relationship between the type of treatment used in 153 type II diabetes patients at two hospitals in Saudi Arabia, how well their glucose levels were controlled, their risk factors for heart disease, and their serum CRP and GGT levels.

Diabetes was responsible for more than 20,000 deaths in 2015 alone.

Keeping a close eye on diabetes complications Survey highlights link between molecular markers and potential complications of type II diabetes. Monitoring additional molecular markers may help avoid complications in people with diabetes, according to research from Saudi Arabia. The kingdom has one of the world’s highest rates of diabetes, with nearly 3.5 million people living with the disease and more than 20,000 deaths caused by it in 2015 alone. Current guidelines in Saudi Arabia recommend treating inadequately controlled diabetes with insulin, alone or together with oral glucose-lowering drugs. Research shows an increasing dependence by physicians on insulin therapy to decrease

vascular complications in these patients. Despite its benefits, insulin therapy is associated with weight gain and more frequent episodes of low blood glucose levels. Weight gain due to insulin therapy can directly and indirectly lead to cardiovascular complications. An increased risk of cardiovascular disease is also associated with increased blood levels of C-reactive protein (CRP), considered a non-specific marker of disease. Also, increased levels of γ glutamyl transferase (GGT) are associated with an increased risk of diabetes, hypertension and cardiovascular complications.

They found generally higher glucose levels in patients receiving insulin therapy alone compared to those also taking oral glucose-reducing drugs. The researchers caution, however, that this finding could be caused by lack of patient compliance with their insulin treatment program. They also found that the type of treatment received did not affect CRP and GGT levels. High GGT levels were associated, however, with poor control of blood glucose levels, irregular levels of blood lipids, hypertension and obesity in the abdominal region. High CRP levels were also associated with an increased waist circumference. The researchers recommend routinely measuring CRP and GGT in diabetes patients to assess factors that might increase the risk of complications such as cardiovascular disease. Others, however, say the recommendation is premature. “The data show associations in a very small population of patients, and there’s no evidence of a causal connection. The findings would need to be replicated in multiple other cohorts before these signals could be recommended for routine monitoring,” says Rhonda Cooper-DeHoff, a professor of pharmacotherapy and cardiovascular medicine at the University of Florida, who was not involved in the study. Bahijri, S. M., Ahmed, M., Al-Shali, K., Bokhari, S., Alhozali, A. et al. The relationship of management modality in Saudi patients with type 2 diabetes to components of metabolic syndrome, γ glutamyl transferase and highly sensitive C-reactive protein. Thera-

peutic Advances in Chronic Disease 7, 246-254 (2016).

Special Issue

Early fitness

The researchers searched for links between exercise capacity and heart attacks later in life. 50

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Keeping fit early on can increase chances of survival from a heart attack later in life.

“The outcome for people who have a heart attack is better if they had a high level of fitness years beforehand”

large multi-ethnic study demonstrates that a history of strong exercise capacity can be beneficial even for those who eventually suffer heart health problems. It has long been known that keeping fit can reduce the risk of heart disease, but the effect of a history of fitness on what happens if you have a heart attack years later has not been well-studied. The Henry Ford Exercise Testing Project (FIT) addressed this knowledge gap by recording the fitness regime of a large sample of people, then monitoring them as they aged. Mouaz Al-Mallah, the project’s principal investigator, undertook this research with colleagues at several medical institutions in the US, where the study was based. “The outcome for people who have a heart attack is better if they had a high level of fitness years beforehand,” says cardiologist Al-Mallah of King Abdullah International Medical Research Center. Nearly 70,000 people were recruited

into the project between 1991 and 2009. They were monitored while exercising on a treadmill to determine their “exercise capacity” (EC). This measures the maximum amount of physical exercise a person can sustain. More than 2,000 participants, who at the time of the treadmill test had no history of heart problems, eventually suffered myocardial infarction: a sudden deficiency in blood supply to the heart muscle causing a heart attack. The researchers then looked back at the FIT project data in search of links between the EC levels measured earlier and the fate of patients after their heart attacks. The data clearly revealed that patients who had very high EC levels before their heart attack were 52% less likely to die in the first year after a heart attack than those who had lower EC levels. The protective effect was identified up to one year after the heart attack. “Everyone, but especially patients who are at risk for myocardial infarction, should maintain high fitness levels since it improves survival,” says Al-Mallah. He and his co-workers are now planning further studies in other similar populations. This work will also investigate if exercise training in people with existing low fitness levels can improve their chances of survival after subsequent heart attacks. shaya, g. e., al-mallah, m. h., hung, r. k., nasir, k., blumenthal, r. s. et al. High exercise capacity attenuates the risk of early mortality after a first myocardial infarction: The Henry Ford Exercise Testing (Fit) Project Mayo Clinic Proceedings http://dx.doi.org/10.1016/j. mayocp.2015.11.012 (2016).

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improves heart attack survival

Myrrh detoxifies when liver cannot Myrrh, the resin from a shrub native to the Arabian Peninsula and Africa, relieves the symptoms of ammonia excess from liver disease.

Myrrh could help treat symptoms of a faulty liver.

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Excessive ammonia is particularly dangerous because it provokes the over-production of nitrogen and oxygen free radicals. Free radicals ‘steal’ electrons from the lipids in cell membranes, leading to cell damage. The scientists found that myrrh induced the production of several antioxidant and detoxifying proteins in the liver, kidneys and cerebrum. In particular, the team suggests that the anti-inflammatory protein Nrf2 plays a key role in this defensive process. In healthy and treated hyperammonaemic rats, Nrf2 is activated by high concentrations of oxygen free radicals and triggers the production of antioxidants, which protect the cells against free radicals. Nrf2 and antioxidant levels were significantly lower in untreated hyperammonaemic rats. Beyond the rise in Nrf2, C. molmol resin treatment also reduced protein tumour necrosis factor-alpha (TNF-α), which is known to be high in the serum of cirrhotic patients, a condition in which the liver is hardened by fibrous tissue. Although the precise mechanism of the treatment is still unclear, it might help attenuate the effects of liver disease. Mahmoud, A. M., Alqahtani, S., Othman, S. I., Germoush, M. O., Hussein, O. E., et al. Commiphora molmol modulates glutamate-nitric oxide-cGMP and Nrf2/ARE/HO-1 pathways and attenuates oxidative stress and hematological alterations in hyperammonemic rats. Oxidative Medicine and Cellular Longevity 2017, 7369671 (2017).

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A N DR EW M C C ON N ELL / A L A M Y S TOC K P H OTO

nown for its multiple beneficial properties, the dried sap of Commiphora molmol, a native shrub in the Arabian Peninsula and Africa, has been used in traditional medicine for centuries. Recently, KAIMRC’s Sultan Alqahtani, in collaboration with Beni-Suef University in Egypt, found that this resin, known as myrrh, counteracts the damaging effects of ammonia excess, a common consequence of cirrhosis and other liver diseases. When the liver cannot remove harmful substances sufficiently, they build up in the bloodstream. For example, ammonia, a by-product of protein digestion, needs to be converted into urea in the liver and eliminated via the kidneys. Accumulation of ammonia in the blood, called hyperammonaemia, is toxic to nerves and can lead to a decline of brain functions known as hepatic encephalopathy. Since current therapies to reduce ammonia levels in the blood have had limited effects, the team looked for a remedy in myrrh, whose antibacterial, anti-inflammatory, antioxidant, sugar-reducing and liver-protective properties have been used traditionally for the treatment of several diseases. The researchers induced hyperammonaemia in rats and administered an oral dose of concentrated C. molmol resin powder for eight weeks. Body weight, blood ammonia levels and other major liver and blood physiological parameters worsened in hyperammonaemic rats not treated with myrrh, but were normal in the treated rats.

New mutation linked to Leigh syndrome A new mutation causing Leigh syndrome has been detected in two newborns in Saudi Arabia.

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“A disruption in just one step of a common pathway of metabolism can lead to big changes in our bodies.”

Advances in genetic screening are critical for diagnosing extremely rare cases of Leigh syndrome

eigh syndrome is a severe genetic disorder that leads to potentially fatal respiratory failure, brain abnormalities and loss of muscle strength. In most cases, enzyme defects are thought to cause the disease by interfering with the body’s ability

P rev i o u s s t u d i e s h a d revealed different Leigh syndrome-causing mutations in the ECHS1 gene, carried by either the father or the mother. However, for the first time, researchers at KAIMRC, in collaboration with King Faisal Specialist Hospital and Research Centre in Riyadh, identified a novel homozygous variant (carried by both parents) that causes a lethal phenotype of this condition. “Given the consanguineous nature of the parents and apparent recurrence of the same condition, we assumed it is caused by a shared homozygous ancestral mutation,” says Fuad Al Mutairi, a clinical geneticist at KAIMRC. At first, despite extensive analyses using “all commercially available next-generation sequencing genetic

tests”, Al Mutairi says that the mutation remained undetected. By repeatedly ‘zooming in’ on the shared genomic region between the two children using exome sequencing, a technique that targets protein-coding portions of the genome, the researchers were able to pinpoint a single homozygous variant of the ECHS1 gene. A disruption in “just one step of a common pathway of metabolism can lead to big changes in our bodies,” says Al Mutairi. “In this rare case, there was severe damage to protein synthesis, which affected the whole gene function and stopped enzyme activity.” The study highlights the limitations of conventional genetic screening techniques, and the need for advances in bioinformatics and wider availability of population-based genomic data. To this end, the Saudi Human Genome Project, a growing resource for population-based genomic data, will play a central role in enhancing the discovery of gene–disease associations. “Knowing the cause and understanding the pathophysiology of the disease gives hope in other cases where therapeutic options may be available,” says Al Mutairi. “Identifying the genetic defect as a first step can be enormously helpful for families in order to prevent recurrence of the disease.” Al Mutairi, F., Shamseldin, H.E., Alfadhel, M., Rodenburg, R.J. & Alkuraya, F.S. A lethal neonatal phenotype of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency.

Clinical Genetics 91, 629–633 (2016).

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to produce energy in the mitochondria. Around one in 36,000 people are born with the condition. Now, a case study of two siblings, both who died within two days of birth, has led to the first report of a rare mutation that shuts down a key enzyme called short-chain enoyl-CoA hydratase (SCEH). Encoded by the ECHS1 gene, SCEH plays an essential role in converting fat into energy for healthy development, and has only recently been investigated in the context of Leigh syndrome.

at preventing heart attacks and boosting patient survival rates. Since the revascularization procedures can be riskier and more expensive than drug treatments, many cardiologists were left uncertain. The CONFIRM study should help inform

The benefit of revascularization procedures depends on the type of heart disease.

Weighing treatment options in heart disease

Stents and bypass surgery are better than drugs, but only for patients with more severe forms of heart disease. Medical procedures to improve blood flow to the heart can help reduce the risk of death for people with severely clogged arteries. But, a large study has found that those with milder signs of heart disease can probably get by with medication, improved diet and regular exercise. An international study called CONFIRM followed more than 5,500 patients after they received a heart CT scan to diagnose suspected coronary artery disease. Patients then had medical procedures to restore blood circulation. They were either treated with a stent implant or bypass surgery, collectively referred to as coronary revascularization, or they received blood-thinning 56

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drugs, cholesterol-lowering pills and other medications. The investigators, including KAIMRC cardiologist Mouaz Al-Mallah who leads the advanced imaging division at the King Abdulaziz Cardiac Center in Riyadh, then tracked their health outcomes for at least five years. “The benefit of coronary revascularization on survival in stable patients with obstructive coronary artery disease is still controversial,” Al-Mallah explains. Many studies had previously shown that stents and bypass grafts often improve symptoms of chest pain or discomfort, but the data were mixed on whether these interventions were better than drug therapies

that decision-making. In the study, Al-Mallah and his colleagues found that the benefit of revascularization depended on the degree of heart disease. For those with high-risk heart disease—defined as having significant narrowing of critical blood vessels supplying the heart — revascularization helped lower the mortality risk compared to drug treatment both one and five years after the procedure. In contrast, revascularization offered no such benefit among those with low-severity disease over the same period. Intermediate-risk patients who received a stent or bypass had a reduced mortality rate at one year, but the benefit dissipated by the five-year mark. In light of the results, Al-Mallah advises: “If a patient has high-risk anatomy, then it is better to treat them with revascularization. Intermediate-risk anatomy is still an area of research, and low-risk anatomy can be treated medically.” Al-Mallah does offer one caveat, though. The CONFIRM study was entirely observational in nature, so “we need to confirm these findings in randomized controlled studies prior to wide adoption.” Schulman-Marcus, J., Lin, F. Y., Gransar, H., Berman, D., Callister, T. et al. Coronary revascularization vs. medical therapy following coronary-computed tomographic angiography in patients with low-, intermediate- and high-risk coronary artery disease: results from the CONFIRM long-term registry. European Heart Journal

Cardiovascular Imaging 18, 841-848 (2017).

C H AN AW IT S IT TH I SO M B AT / A L AM Y S TO C K P H O TO

“The benefit of coronary revascularization on survival in stable patients with obstructive coronary artery disease is still controversial.”

T I M E WHI T E / A L A M Y S TOCK P HOTO

Disturbed sleep patterns negate Ramadan fasting benefits Disturbed sleep offsets the health benefits from fasting in the holy month. Modern Ramadan practices in Saudi Arabia, where fasting is combined with a radical shift in sleeping schedules, are probably detrimental to health, according to a recent study. Saudis fasting during Ramadan stay up at night and sleep through much of the day, mimicking the patterns of shift workers. “I had read so much about the benefits of intermittent fasting, but I’d also read about the adverse effects of disturbed sleep patterns from shift work. I wanted to study the two together, which nobody has done,” explains Suhad Bahijri of the Saudi Diabetes Research Group at King Abdulaziz University in Jeddah. Bahijri and colleagues studied 23 Saudis before the start of Ramadan and again two weeks into the holy month. They measured the levels of several cardiovascular risk factors and the expression of three genes related to our biological clock. While some risk factors improved

during Ramadan, others worsened. “Even though we found some benefits from fasting, they are masked by the disturbance in sleep patterns which introduce adverse effects,” says Bahijri. “Also, very few people restrict caloric intake in Ramadan. In fact they eat more, increasing their health risk.” According to Bahijri, sleep patterns during Ramadan changed in the 1980s, as malls and restaurants became more common in the country and young, fasting Saudis began looking for all-night entertainment. “Our changing lifestyle is increasing the risk of chronic diseases because our genes are not evolving fast enough to cope with it,” she says, linking the rise in chronic diseases such as type II diabetes and metabolic syndrome to eating and sleeping habits during Ramadan, as well as more general lifestyle changes. Bahijri recommends a return to a more traditional way of practicing Ramadan.

“During Ramadan, have a light breakfast, a snack before going to bed at around midnight, and wake up before dawn to have a light meal, pray, and get some more sleep,” she advises. Bahijri planned a follow-up study to disentangle the consequences of sleep disturbance and Ramadan fasting, which is different from intermittent fasting, but found it difficult to find participants who fast “the right way.” Instead, her next project will focus on the metabolic effects of shift work in Saudi nurses. “Hopefully, we’ll come up with recommendations to help plan shift work so it doesn’t affect their metabolism adversely.” Ajabnoor, G. M. A., Bahijri, S., Shaik, N. A., Borai, A., Alamoudi, A. A., et al. Ramadan fasting in Saudi Arabia is associated with altered expression of CLOCK, DUSP and IL-1alpha genes, as well as changes in cardiometabolic risk factors. PLoS ONE 12:e0174342 (2017).

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Learning to predict diabetes Machine learning could be used to identify high-risk patients and improve healthcare services.

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Machine learning approaches can effectively identify patients who are likely to develop diseases such as diabetes, according to new research from KAIMRC. A team led by Sherif Sakr evaluated how well several machine learning methods predicted diabetes incidence in patients who had taken part in the Henry Ford Exercise Testing (FIT) project, which collected metabolic, medical

and demographic data from thousands of patients undergoing exercise treadmill stress testing. Sherif’s team used data from more than 32,000 of the patients who had had a five-year follow-up and no previous heart conditions or coronary artery disease. About 5,000 of the patients had developed diabetes by the time of the follow-up. Sakr’s goal was to determine which

machine learning algorithm could reliably predict a patient’s likelihood of developing diabetes with high accuracy. “If you can identify people who are at risk before they get sick, that would save a lot of money and resources and improve healthcare service. Treating people before they get sick is much more effective and efficient,” Sakr says. He believes machine learning can achieve that goal.

The team identified 13 relevant clinical variables in the FIT data and tested several classification algorithms to determine how well they predicted a patient’s odds of developing diabetes. They aimed to use as few variables as possible to increase the model’s practicality. Initially, the algorithms had a performance of about 70%, with none emerging as a clear winner. However, the FIT data suffers from an imbalance common to most healthcare datasets, with many more representatives of one class than another — far more healthy patients than diseased patients, for example. Such an imbalance hampers the algorithms and posed a major challenge in this project. To rectify this, Sakr’s team evaluated two approaches. Removing data points from the larger class (healthy patients) to reduce the difference had little impact on the outcome. However, increasing the size of the smaller class (diseased patients) by generating random new data with similar characteristics significantly improved performance, raising it to nearly 92%, significantly better than traditional statistical techniques. The study has clearly shown that machine learning can identify high-risk patients, improving efforts at disease prevention and guiding the management of hospital resources. “There’s a huge amount of data in the healthcare domain, but there hasn’t yet been effective use of it,” says Sakr, who plans to cross-validate these models with another cohort, and is developing models that can accurately predict the likelihood of several other significant diseases. Alghamdi, M., Al-Mallah, M., Keteyian, S., Brawner, C., Ehrman, J. et al. Predicting diabetes mellitus using SMOTE and ensemble machine learning approach: The Henry Ford ExercIse Testing project. PLOS ONE 12, e0179805 (2017).

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Blocking FSH with an antibody produces a dramatic effect on body fat in mice.

Stem cells extracted from the placenta could have properties that surpass those derived from other parts of the body.

An attractive and abundant stem cell alternative

Stem cells derived from the maternal side of the human placenta may find unique therapeutic applications given their special properties.

esenchymal stem cells (MSCs) are ‘multipotent’, having the potential to differentiate into many adult cell types including bone, cartilage and fat cells. The majority of MSCs used in therapeutic applications are derived from bone marrow. However, they are difficult to extract and their potential to differentiate typically decreases as the age of the donor increases. Harvesting them is also notoriously time-consuming and invasive for the donor, prompting scientists to search for alternative MSC sources. Cell biologist Mohamed Abumaree, from King Abdullah International Medical Research Center, with local and in-

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ternational colleagues, has extracted and characterized MSCs from the ‘decidua basalis’, a part of the human placenta that is highly exposed to inflammation and oxidative stress during early pregnancy. The team found that decidua basalis and bone marrow MSCs can similarly differentiate into bone cells, cartilage cells and fat cells. More importantly, decidua basalis MSCs secrete a cocktail of cytokines, growth factors and immunomodulatory molecules that are normally used to safeguard the foetus. The researchers believe that the decidua basalis may prove to be an equally good source of MSCs, if not better, for use in therapeutic applications, particularly those related to neurodegenerative and autoimmune diseases.

A great variety of MSC types — including those derived from the liver, dental pulp, adipose tissues, endometrium, muscle tissues, amniotic fluid, umbilical cord blood and the placenta — has been studied in the past. However, not much study has been focussed on the genetic makeup and growth properties of decidua basalis MSCs. The researchers isolated decidua basalis MSCs and characterized their genetic and protein expression profiles. They found that these cells express adhesion molecules that help other cells bind together. They also migrate to sites of inflammation or injury upon stimulation. These properties have implications not only for regenerative medicine but also for tissue engineering where stem cells must securely bind to a scaffold called the extracellular matrix. Decidua basalis MSCs are highly abundant and can be easily collected after the delivery of babies. The researchers would like to further investigate how they can be used to treat diseases such as atherosclerosis, Alzheimer’s disease and Parkinson’s disease. Abomaray, F. M., Al Jumah, M. A., Alsaad, K. O., Jawdat, D., Al Khaldi, A. et al. Phenotypic and Functional Characterization of Mesenchymal Stem/Multipotent Stromal Cells from Decidua Basalis of Human Term Placenta. Stem Cells International 2016, 5184601 (2016).

KAIMRC Experimental Medicine

Three state of the art vivarium facilities are located in Riyadh, Jeddah and Al Hasa. The vivariums are planned and designed according to international standards. They aim to assist biomedical research by providing animals and veterinary expertise. Moreover, they offer training and education in animal use for research. The facilities also work on the development and implementation of institutional policy, animal care and use policy including animal husbandry and veterinary care.

Unravelling the mysteries of intellectual disorders

DNA sequencing offers diagnoses and treatments for patients with unexplained intellectual disorders.

KAIMRC’s Majid Alfadhel specializes in finding genetic causes of unexplained paediatric disorders.

equencing the entire protein-coding portion of the genome in people with unexplained intellectual development disorders can offer diagnoses and new treatment options for a large number of people. A Canadian-led team, which included KAIMRC paediatric geneticist Majid Alfadhel, conducted extensive clinical evaluations and DNA sequencing on 37 children and four adults with unexplained intellectual development disorder, a condition that affects an estimated 3% of the population worldwide. This approach yielded a genetic diagnosis for 28 of the patients, including a four-year-old Saudi girl with recurrent breathing problems, skin pigmentation abnormalities and fat deposits in her liver. Sequencing the 1% of this child’s genome that codes for proteins revealed that mutations in a gene called H6PD, which encodes an enzyme involved in cellular stress responses, were responsible for her condition. No therapeutic intervention could be

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found for the young girl, but the clinicians were able to change treatment protocols for 18 of the affected individuals in the study. In one patient with a newly-described condition that affects mitochondria (the power factories of the cell), the researchers found that treatment with a drug called carglumic acid could correct a dangerous imbalance of metabolites. In another, with sleep problems and seizures, amino acid and vitamin supplements brought the seizures under control and improved other symptoms caused by mutations in a gene called GOT2 that encodes a different mitochondrial enzyme. Sixty-eight percent of the people genetically analysed in this study received diagnoses—a diagnostic rate much higher than the 16% documented in previous reports using the same sequencing approach to explain unexplained intellectual disorders. Alfadhel credits the comprehensive patient evaluations for much of the high diagnostic yield. This allowed the team to isolate the sequencing of DNA

only for individuals who were likely to benefit from the approach. However, Alfadhel also points to the close collaboration between the clinical physicians and the computational scientists performing the data analyses. “Data sharing and open communication between scientists and researchers across the globe are the keys to maximizing the diagnostic potential of next-generation sequencing and its clinical benefit for patients and their families,” says Alfadhel, who trained at the British Columbia Children's Hospital in Vancouver, Canada, where most of the patients in the study were treated. This international experience, he adds, will enable “more collaboration and communication between international experts and my team, which will definitely benefit our patients in Saudi Arabia.” Tarailo-Graovac, M., Shyr, C., Ross, C.J., Horvath, G.A., Salvarinova, R. et al. Exome sequencing and the management of neurometabolic disorders. N Engl J Med 374, 2246-2255 (2016).

A new player in gene regulation

ctin, a protein generally considered a structural component of cells, is also involved in controlling the translation of DNA into RNA, a new study has found. The additional complexity revealed in regulating this transcription process, which is the first step in gene expression, may eventually shed light on diseases and disorders that are not understood. “Usually when people talk about actin, they’re thinking about its role in support, transport, or movement rather than in transcription,” says KAIMRC’s Bader Almuzzaini, the study’s lead author. Following earlier work that suggested actinmightbeinvolvedinreprogramming gene expression, Almuzzaini used a technique to isolate fragments of DNA attached to actin and then sequence them, enabling them to identify regions of the mouse genome where actin was bound. They found that actin binds throughout the genome and is enriched in specific regions, such as between genes and around promoters that control gene

expression, supporting its hypothesized role in regulating transcription. Next, the team used cells in which actin had been disabled to directly investigate its function, focusing on the regulation of the transcription of the ribosomal RNA (rRNA) gene, which plays a central role in protein synthesis. They found a significant decrease in rRNA synthesis in the absence of actin. Further investigation revealed that several molecules involved in controlling transcription were not attached to the rRNA gene when actin was missing. When the researchers reintroduced actin into the cells, the molecules bound properly to the rRNA gene, and its transcription level went back to normal. “That was an exciting moment,” says Almuzzaini. “Our results all came together and we knew we had a clear story to tell.” These results led the researchers to suggest that actin tethers various factors involved in transcription, bringing them alongside regulatory regions of the genome. Once in place, these factors add and remove tags, known as epigenetic mark-

ers, which influence DNA transcription, partly by altering how tightly it is wound. While this particular model might be specific to rRNA and similar genes, the team has shown that actin is involved in regulating other types of genes as well. For Almuzzaini, this study is just the first step towards understanding diseases and disorders. “To me, actin itself isn’t the essential story. The essential story is the overall mechanism, which includes actin and various other factors and epigenetic modifications that control transcription,” he says. Almuzzaini hopes that understanding these varied factors will shed light on why certain leukaemia patients suffer relapses and don’t respond to chemotherapy, despite being classified as low-risk. Almuzzaini, B., Sarshad, A. A., Rahmanto, A. S., Hansson, M. L., Euler, A. V. et al. In β-actin knockouts, epigenetic reprogramming and rDNA transcription inactivation lead to growth and proliferation defects. The FASEB Journal 30, 2860-73 (2016).

Research suggests that actin tethers together various factors involved in DNA transcription, bringing them alongside regulatory regions of the genome. Special Issue

The molecular mechanism controlling gene expression is found to involve a familiar molecule.

“When a child presenting with cancer also has physical characteristics associated with conditions like Bloom syndrome it is absolutely crucial to rule out genetic factors that might impede cancer treatment.”

Genetic disorders may influence the choice of the best cancer treatment for a patient.

Treating cancer patients with rare genetic conditions

A case study of a boy with Bloom syndrome highlights the need to screen patients for rare disorders before treatment for cancer. Some genetic disorders leave patients more susceptible to developing cancer, and less responsive to standard chemotherapy. A recent case study by an MNG–HA researcher has illustrated the importance of ruling out rare genetic disorders prior to cancer therapy. Bloom syndrome is a rare genetic disorder caused by a mutation that disrupts DNA repair. This results in chromosomal instability, which manifests with a variety of symptoms including growth retardation, immunodeficiency and cancer susceptibility. “I work as a consultant in paediatric oncology, and recently an 11-year-old boy arrived in a critical condition with 64

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mature B cell lymphoma,” says Wasil Jastaniah of Princess Noorah Oncology Center. “We started him urgently on standard chemotherapy, but he suffered severe side-effects and we had to find an alternative treatment.” Jastaniah treated the boy with rituximab, an existing therapy designed for children sensitive to conventional chemotherapy. Rituximab had previously been shown to be safe and effective against mature B cell lymphoma. “At this point, we had not diagnosed the patient with Bloom syndrome,” says Jastaniah. “He responded well to rituximab-based chemotherapy and went on to make a full recovery from the lymphoma.

The patient was later diagnosed with Bloom syndrome, and Jastaniah realised that successful cancer treatment with rituximab might be a viable option for such patients in the future. To date, there have been no previous studies into the treatment of cancer in patients with Bloom syndrome, and the case reveals promise for future therapies for those with the condition. Jastaniah is keen to highlight the importance of early diagnosis of inherited cancer-predisposing syndromes to optimize surveillance and treatment. “When a child presenting with cancer also has physical characteristics associated with conditions like Bloom syndrome, such as growth retardation, it is absolutely crucial to rule out genetic factors that might impede cancer treatment,” says Jastaniah. “This case study should also trigger further investigations into cancer treatments in patients with Bloom syndrome and similar disorders because data are so limited at present.” The rarity of these genetic conditions means that individual countries are unlikely to come across many cases. Jastaniah hopes to see the development of an international registry that would help researchers access data regarding cancer management in patients with chromosomal instability. Jastaniah, W. Successful treatment of mature B-cell lymphoma with rituximab-based chemotherapy in a patient with Bloom syndrome. Pedi-

atric Blood and Cancer 7: e26385 (2016).

T HE KOP M Y L I FE / I S TOCK / G E T T Y I M AG E S

The fact that standard chemotherapy was so toxic for him, however, suggested an underlying inherited cancer predisposition syndrome.”

Twenty new mutations implicated in rare genetic disease

Study finds mutations in a rare inherited disease called pyroglutamic aciduria.

dozen patients, this study focuses on the latter, which is also known as 5-oxoprolinase deficiency, and is rarer.

“More research is needed to draw the line between asymptomatic and symptomatic disease.” By analyzing the DNA of children affected by 5-oxoprolinase deficiency and their family members, the researchers discovered 20 new and unique mutations in the OPLAH gene. They found that the disease manifests when patients inherit two copies of the abnormal gene, one from each parent. Parents can carry a single copy of the faulty gene without showing the symptoms, and have a 25% risk of having an affected child with each pregnancy. Consanguinity is common in Saudi Arabia, increasing the chance of the altered gene being passed on. Unexpectedly, none of the patients

were affected by premature breakdown of red blood cells, known as haemolytic anaemia, which is a key clinical feature of patients with GSS mutations. But other symptoms varied widely: some patients had none at all, while others had psychomotor symptoms, developmental disabilities, and inappropriate weight loss. The researchers were unable to clarify the causal relationship between the symptoms and the OPLAH mutations. “More research is needed to draw the line between asymptomatic and symptomatic disease. Also, we cannot rule out that new symptoms could appear later in the life of these children, or that current symptoms might be caused by other genetic defects,” says King Saud bin Abdulaziz University for Health Sciences professor Majed Alfadhel. Sass, J. O., Gemperle-Britschgi, C., Tarailo-Graovac, M., Patel, N., Walter, M., et al. Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families. Molecular Genetics and

Metabolism, 119, 44-49 (2016).

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S HU N Y UFA N / I S TOC K / G ET T Y I M AG ES P LUS

Only seven patients with a very rare form of a hereditary disease called 5-oxoprolinuria have been reported in scientific literature. Its genetic and clinical features are still poorly understood. An international study, involving Saudi Arabia’s Ministry of National Guard Health Affairs, shed light on this disease by analyzing the DNA of 14 affected families from various ethnic groups. The condition thwarts the production of glutathione, a molecule needed by the body to neutralize other harmful molecules generated during energy production. It is also needed to build cellular components like DNA and proteins, and to metabolize foreign chemicals such as drugs and environmental pollutants. The specific symptoms of the disease vary in severity from mild, affecting only red blood cells, to severe, affecting many cell types in the body. An indicator of 5-oxoprolinuria is a large concentration of the compound 5-oxoproline in the urine. This disease can be caused by several factors, including the mutation of the glutathione synthetase (GSS) gene or the 5-Oxo-L-Prolinase (OPLAH) gene. While the former has been reported in several

Glutathione is is an important antioxidant that can help protect against damage caused by certain molecules produced within the body.

Fanconi anaemia may be

Fanconi anaemia is the most common form of inherited bone marrow failure that requires bone marrow transplantation therapy in Saudi Arabia. 66

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under-diagnosed in Saudi Arabia

anconi anaemia is an inherited genetic condition of bone marrow that causes a predisposition to cancer. Researchers at King Abdullah International Medical Research Center (KAIMRC) have gained insights into the genetic basis of this condition in Saudi patients. Their work reveals distinct genetic characteristics and may improve diagnosis and treatment in the future. Fanconi anaemia is a rare disease involving mutations in at least 18 genes. These genes encode proteins that perform essential running repairs to DNA that keep most humans healthy, despite the inevitable damage to DNA through wear and tear. With the DNA repair pathways unable to function normally, most of these patients develop cancer. They also display physical ab-

normalities, including short stature, and have a life expectancy of around 40 years. Although rare, Fanconi anaemia is the most common form of inherited bone marrow failure that requires bone marrow transplantation therapy in Saudi Arabia. Paediatrician Abdulrahman Alsultan and colleagues at the King Abdullah Specialist Children’s Hospital in Riyadh, together with co-workers at other centers in Saudi Arabia, studied the genetic causes of ten unrelated cases of Fanconi anaemia. The patients were infants and children who were diagnosed with the condition between 2011 and 2015. The researchers used state-of-the-art gene sequencing technology to identify the mutations associated with the disease in these patients. They also looked for links between specific mutations and the varying clinical consequences of Fanconi anaemia among the cohort. The results indicated that the pattern of mutations in these Saudi patients differed significantly from that found in comparable patients in Europe and North America. The researchers suggest that one consequence of these differences could be that a standard test used to diagnose some forms of Fanconi anaemia may fail to diagnose some Saudi patients. The genetic analysis also identified some new mutations to add to the list of those that can cause the disease. One aspect of particular interest is that two patients with one specific mutation belonged to the same tribe. This may indicate what the researchers call a “founder effect or hotspot” that might be used to trace the origin of this mutation. Other mutations are presumed to be “ancient”, due to being found in members of different tribes and ethnic groups. This was a small-scale preliminary study, based on patients at a single institution. Given the potential significance of these early results for diagnosing and understanding Fanconi anaemia, the researchers now plan a much larger multi-institutional follow-up study, again focused on Saudi Arabia. Ghazwani, Y., AlBalwi, M., Al-Abdulkareem, I., Al-Dress, M., Alharbi, T. et al. Clinical characteristics and genetic subtypes of Fanconi anemia in Saudi patients. Cancer Genetics http://dx.doi.org/10.1016/j.cancergen.2016.02.003 (2016).

Special Issue

Genetic analysis of Saudi patients with Fanconi anaemia reveals new mutations and distinct patterns of mutation that may affect diagnosis.

Copycat mutation masquerades as multiple sclerosis Researchers in Saudi Arabia have identified a previously unknown mutation causing a condition that had been mistaken for multiple sclerosis (MS). The discovery emphasizes the risk of genetic diseases being misdiagnosed as MS. “Our work demonstrates that neurologists must be made aware of the red flags that might suggest a diagnosis of MS is less likely,” says KAIMRC’s Hussein Algahtani, who led the research. Algahtani examined two brothers with a long-standing diagnosis of MS and found atypical clinical and radiological abnormalities, ‘red flags’ that suggested possible misdiagnosis. Spinal abnormalities found in MRI scans known as ‘patchy white matter’ had, ten years earlier, contributed to an MS diagnosis, but the KAIMRC researchers and colleagues elsewhere in Saudi Arabia suspected a different cause. The team had previously identified several genetic conditions mimicking many of the symptoms of MS. “That these two new patients were from the same family led us to investigate the possibility of a genetic disorder, rather than MS,” says Algahtani. DNA analysis of blood from the patients and their parents revealed that the patients carried a mutation in a gene known to be involved in maintaining normal nerve transmission. This ‘recessive’ mutation must be inherited from both parents to do its damage by causing a form of cerebellar ataxia: a locomotion disorder originating in the brain’s cerebellum. Algahtani cautions that the possibility of a chance association between the mutation and the brothers’ condition cannot yet be completely ruled out, but the indications are very strong. “We are planning to conduct further genetic studies in other patients,” he says. 68

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A mutation found in two Saudi brothers is believed to have led to misdiagnosing cerebellar ataxia as multiple sclerosis.

Spinal patchy white matter, visible in an MRI scan, led to a misdiagnosis of MS several years earlier.

He points out that the high incidence in the kingdom of marriages between relatives, including first cousins, makes Saudi Arabia an ideal place to search for such genetic conditions. Genetic diseases account for a large proportion of conditions seen in Algahtani’s neurology clinic. For the two brothers, the research means an end to years of treatment for the wrong disease, and the opportunity for

more appropriate care. This study should help contribute to wider awareness of the possibility of misdiagnosing MS. Algahtani, H., Marzouk, Y., Algahtani, R., Salman, S., & Shirah, B. Autosomal recessive cerebellar ataxia type 1 mimicking multiple sclerosis: A report of two siblings with a novel mutation in

SYNE1 gene in a Saudi family. Journal of the Neurological Sciences 372, 97–100 (2017).

Strictly confidential Protecting confidentiality is a major priority in medical settings, crucial to the effectiveness of Saudi Arabia's newly established biobank.

he storage of information in biobanks — collections of human samples for medical research — is viewed as essential to improve understanding of human health and disease. Launched in 2014, the Saudi Biobank is emerging as a valuable resource for the region. Its growth will depend on wider discussion of issues such as confidentiality and informed consent. “Biobanks offer a golden opportunity to study multifactorial diseases and relationships between genetics, environments and lifestyles,” says Ghiath Alahmad, a bioethicist at King Abdullah International Medical Research Center (KAIMRC). “Research based on large numbers of samples are needed to investigate diseases that are increasing rapidly among Saudis, such as hypertension and diabetes.” Due to the relative lack of surveys in the Middle East about confidentiality issues, Alahmad says it was “necessary and timely” to conduct a series of questionnaires among five different groups: researchers, physicians, medical students, donors and the general public. The responses from a total of 200 people at King Abdulaziz Medical City, the largest medical complex in Saudi Arabia, revealed that all five groups rate confidentiality as one of the most important aspects of medical care. The groups showed notable differences in the level of willingness to share genetic information with third parties. For ex-

Confidentiality is a fundamental tenet of medical ethics.

ample, researchers and physicians were the most reluctant to share information with family members, while donors and laypersons were more prepared to do so. When asked to suggest examples where confidentiality might justifiably be breached, the two main scenarios raised by respondents were those involving infectious diseases or genetic

"Confidentiality is essential in gaining donors' trust and encouraging them to participate in any biobank. It's important to explore all of the ethical repercussions." diseases. The study found that donors and laypersons were more supportive of providing confidential information in those two cases. “Confidentiality is essential in gaining donors’ trust and encouraging them to participate in any biobank,” says Alahmad. “As Saudi society is characterised

by extended families, strong interfamily relationships and a high percentage of consanguineous marriages, any breach of confidentiality may lead to serious problems such as stigma and discrimination. That's why it's important to explore all of the ethical repercussions.” The Saudi Biobank is a member of the Public Population Project in Genomics and Society (P3G), an international consortium facilitating dialogue between biobank resources internationally. Alahmad notes that, overall, his team's findings are consistent with comparable surveys conducted in other countries. The team aims to conduct further surveys with a larger sampling size. Alahmad adds, “I have also started to explore the issue of [sample] ownership, a highly complex issue in the medical field. Based on fruitful discussions with ethics experts at the Center for Bioethics at Harvard University, we hope to publish our results in the coming months.” Alahmad, G., Hifnawy, T., Abbasi, B., & Dierickx, K. Attitudes toward medical and genetic confidentiality in the Saudi research biobank: An exploratory survey. International Journal of Medical Informatics dx.doi. org/10.1016/j.ijmedinf.2015.12.015 (2016).

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Screening for an enzyme defect in newborns

Study boosts argument for cord blood screening to detect an enzyme defect in infants.

nown as the most common enzyme defect in humans, glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited condition that affects more than 300 million people worldwide. Early detection of the disorder is vital, as newborns are vulnerable to its symptoms, including jaundice and anaemia, which can be life threatening. In Saudi Arabia, screening is typically done by taking blood samples fromthe arms or legs. But blood taken from the umbilical cord immediately after birth is increasingly viewed as a preferable option, as it is easier to collect and does not cause the child or mother unnecessary pain. However, since infants undergo many physiological changes that might affect G6PD activity soon after birth, it was

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unclear how effective cord blood could be in detecting the disorder. A large-scale retrospective study of children born in Saudi Arabia from January to December 2008 sought to reveal an accurate picture of the validity of cord blood screening for G6PD deficiency. Two per cent of the 8,139 newborns from whom cord blood was taken had G6PD deficiency. Boys were significantly more affected than girls, at a ratio of almost 4:1. Just over one thousand of the newborns had samples taken both from the umbilical cord and from the arms or legs. Results from the samples were compared and suggest that cord blood is just as effective as peripheral blood in detecting G6PD deficiency. Cord blood sampling notably led to fewer false negative results, reducing the

risk of missing a G6PD deficiency diagnosis. The team of researchers, including KAIMRC senior research scientist, Mohammed Al Balwi, concludes that the study reinforces the practice of using cord blood for newborn screening. The fact that 79% of those affected in the study were males concurs with the consensus that they are more at risk of the condition. The defective gene is carried on the X chromosome. Since males have just one X chromosome, a single altered gene may cause G6PD deficiency. Females, who have two X chromosomes, usually become carriers without showing signs of the defect. The World Health Organization recommends neonatal screening in areas with a prevalence of over 3% in males. Although figures vary widely by region, the Middle East has one of the highest prevalence estimates of G6PD deficiency in the world at six per cent. For males alone this figure is 7.2%. As yet, there are no treatments for G6PD deficiency. It is a lifelong condition requiring avoidance of certain foods and medicines, such as fava beans and antimalarial drugs. The present study may serve as a basis for further surveys tracking G6PD enzyme levels in older children and adults. AlSaif, S., Ponferrada, M.B., AlKhairy, K., AlTawil, K., Sallam, A. et al. Screening for glucose-6-phosphate dehydrogenase deficiency in neonates: a comparison between cord and peripheral blood samples. BMC Pediatrics 17, 159 (2017).

P H A N I E / A L A M Y S TOC K P H OTO

Cord blood sampling offers a convenient, stress-free way of screening for hereditary disorders in newborns.

Strategy urged to tackle genetic disease

audi Arabia has one of the highest rates of inherited metabolic disorders in the world, according to a 13-year review of children diagnosed at one of the largest hospitals in the country. This grave finding, the study authors say, points to the need for urgent and coordinated action to reduce the number of people suffering from so-called inborn errors of metabolism (IEMs). “The incredibly high rate of IEMs in Saudi Arabia compels the healthcare administration in the country to develop a long-term strategic plan for the prevention of such disorders,” says KAIMRC paediatric geneticist, Majid Alfadhel, who led the research. IEMs are rare genetic disorders caused by mutations that impair the ability of different enzymes to break down parts of food into energy. Collectively, the incidence of all IEMs is generally less than 1 in 2,500 throughout much of the Western world. But in countries where marriages between cousins are common, such as Saudi Arabia, the incidence is often much higher. One 25-year study from a hospital in Dahran, in the Eastern Province of the Kingdom, documented an incidence of

A recent study shows the incidence of inborn errors of metabolism in Saudi Arabia to be 1 in 635 children, well above international rates.

about 1 in 667 . Apart from that study, however, publications in the Saudi literature have been limited to case reports and case series. This piecemeal reporting led Alfadhel to wonder whether the numbers from Dahran were representative of the country as a whole.

“The incredibly high rate of IEMs in Saudi Arabia compels the healthcare administration in the country to develop a long-term strategic plan for the prevention of such disorders.” He and colleagues from King Abdulaziz Medical City in Riyadh looked at their records. Between 2001 and 2014, a total of 110,601 children were born at the hospital complex, 187 of whom were diagnosed with an IEM. That translated to an incidence rate of 1 in 591; on par with what researchers had found previously in

Dahran. Combining the results of the two studies yielded an incidence rate of 1 in 635, one of the highest ever documented in the world. Alfadhel’s team classified the 187 patients by their type of disorder. This should help doctors know what to look for, so they can intervene with medicines when appropriate. The authors also chronicled 43 mutations never seen before by scientists, observations that could aid in future diagnoses. Based on his findings, Alfadhel has a number of recommendations for healthcare administrators in Saudi Arabia. These include a national registry to determine the most common disorders and mutations, public health educational campaigns, and genetic screening among high school students so that, when they marry and have children, they can make informed decisions about family planning. Alfadhel, M., Benmeakel, M., Hossain, M. A., Al Mutairi, F., Al Othaim, A. et al. Thirteen year retrospective review of the spectrum of inborn errors of metabolism presenting in a tertiary center in Saudi Arabia.

Orphanet Journal of Rare Diseases 11, 126 (2016).

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BRAND X

A high rate of inherited metabolic disorders in Saudi Arabia is prompting calls for action.

One in every 100 babies are born with congenital heart disease.

Congenital heart defects are one of the leading causes of infant death worldwide.

Understanding the genetics of congenital heart defects New evidence traces congenital heart defects to healthy parents. One of the largest international genetic studies of congenital heart disease (CHD) highlights the significance, in particular forms of the disease, of spontaneous gene mutations not inherited from parents. Congenital heart defects develop in the womb and are the most common cause of birth defect-related infant death worldwide, affecting approximately one in every 100 newborns. Several CHD-associated genes have been identified, but other factors, such as maternal diabetes or taking anticoagulant or antiepileptic 72

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medications during pregnancy, have been shown to slightly increase the risk of CHD. To shed more light on the genetic basis of CHD inheritance, Matthew Hurles at the Wellcome Trust Sanger Institute in Cambridge, UK and colleagues sequenced the protein-coding part of the genome of 1,891 children with CHD and their parents. Patients were recruited from medical centres in the UK, US, Canada, Germany, Belgium and Saudi Arabia. Their findings, published in Nature Genetics, provide the first clear evidence

But, children with isolated defects of the heart, known as non-syndromic CHD, did not have such spontaneous mutations and often inherited damaging gene variants from their healthy parents. The authors also describe three new rare syndromic CHD disorders caused by new mutations in genes not previously associated with CHD. Establishing the function of these genes will shed further light on important biological mechanisms involved in normal embryonic development. These findings could be useful in the design of future genetic studies. To determine the most dominant CHD-associated genes, studies of non-syndromic CHD patients, which make up 90 percent of CHD patients worldwide, will benefit from sequencing the genomes of parents and unaffected siblings. Understanding the potential causes of CHD not only accelerates research into disease mechanisms and possible therapies, it also helps physicians give more accurate advice to parents about their chances of having a second child with the disease. “These findings have an immediate and direct impact on how patients are counselled, on family planning and on prenatal diagnosis,” explains molecular pathologist Saeed Al Turki of King Abdulaziz Medical City in Riyadh. Sifrim, A., Hitz, M-P., Wilsdon, A., Breckpot, J., Al Turki, S.H., et al. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.

Nature Genetics 48, 1060–1065 (2016).

I LYA NAY M U S HI N/ R E U T E R S / A L A M Y S TOCK P HOTO

of genetic differences between two forms of the disease. In syndromic CHD, where the disease is one among several developmental problems, such as abnormalities in other organs or an intellectual disability, the defects were found to be more likely due to new mutations that aren’t inherited from the parents.

Single gene defect found for unexplained dwarfism Mutations in a DNA replication gene cause a rare developmental disorder seen in Saudi children.

Brain scans from children with normal (left) and mutated (right) versions of the DONSON gene.

microcephalic dwarfism. In total, they mutations fell in a non-coding region found 29 affected individuals from 21 that altered how the genetic code got families who all had a small head and processed, leading to an aberrant and reduced height, and who all carried less abundant protein product. mutations in both Either way, the loss copies of the DONof a functional DON“We’re pleased that these SON gene. Eight of SON gene impaired families were finally the families were the body’s ability from Saudi Arabia, to copy DNA fast able to have molecular wh e re m a r r i a g e enough to keep pace between cousins is with the needs of the diagnosis enabled by common and leads early growing brain this discovery, so they to a high rate of and body, explaining birth disorders. how a single mutacan avoid recurrence.” Collaborators in tion could have such the United Kinga devastating effect. dom then characterized the consequence of these mutations on a cellular Reynolds, J. J., Bicknell, L. S., Carroll, P., Higgs, level. For some patients, the mutations M.R., Shaheen, R. et al. Mutations in DONSON altered the coding sequence of the prodisrupt replication fork stability and cause tein produced by DONSON. But for all microcephalic dwarfism. Nature Genetics 49, of the patients from Saudi Arabia, the 537–549 (2017). Special Issue

F O W Z A N A LKUR AYA @ 20 1 7

study co-led by researchers in Saudi Arabia and the United Kingdom has identified the faulty gene behind a developmental disorder that often causes shrunken heads and short stature in Saudis. Before this discovery, the study participants, from across Europe, North America, Africa and the Middle East, had no idea what was causing their family’s disease and clinicians had no way of preventing more children being born with this debilitating illness, known as microcephalic dwarfism. Now they can point to defects in a gene called DONSON, which is needed for DNA to be faithfully copied when cells divide and grow. “We’re pleased that these families were finally able to have molecular diagnosis enabled by this discovery, so they can avoid recurrence,” says Fowzan Alkuraya, a clinical geneticist at the King Faisal Specialist Hospital and Research Center (KFSHRC) in Riyadh and a lead investigator of the study. One of the participating families was evaluated at Riyadh’s King Abdulaziz Medical City (KAMC) by a team that included Mohammed Al Balwi, a molecular geneticist at KAIMRC and a co-author of the study. Both KAMC and KFSHRC, in addition to several other Saudi hospitals, now have prenatal screening programmes designed to target DONSON mutations in prospective parents so they can avoid passing the gene on to offspring. Alkuraya and his colleagues pinpointed the gene by sequencing the protein-coding DNA of children with unexplained

KAIMRC’s newly established cord blood bank and stem cell donor registry will not routinely test for a certain mutation linked to HIV/AIDS resistance because it’s so rare in Saudi Arabia.

HIV resistance gene uncommon among Saudis

Routine screening in stem cell registries for a mutation that could help treat HIV/AIDS is not warranted in Saudi Arabia because of its rarity in this population. A gene mutation known to confer resistance to HIV/AIDS is rarely seen among Saudi nationals, two KAIMRC-led studies have found. E l s ewhere , where t he mutation is more common, cord blood banks and stem cell registries are beginning to routinely test donated samples for variants in this gene, known as CCR5. It is thought that stem cell transplantations carrying the resistance mutation could help

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treat HIV-infected patients. But with CCR5 mutations observed at such a low frequency in Saudi Arabia, this strategy likely makes little sense in the country, the study authors conclude. In the first study1, a team led by KAIMRC molecular geneticist Mohammed Al Balwi sequenced all the protein-coding DNA of 321 healthy Saudis. Their longterm goal was to build a large database of normal genetic

variation in Saudi Arabia to serve as a reference for future disease-related research. As a first analysis, they chronicled all the variants found in CCR5, a gene that encodes a protein found on the surface of some immune cells. This protein acts as a co-receptor for HIV entry into the immune cells. Al Balwi and his colleagues identified 475 variants of the gene. Seven gene variations that had been previously

1. Al Balwi, M.A., Hadadi, A.I., Alharbi, W., Ballow, M., AlAsiri, A. et al. Analysis of CCR5 gene polymorphisms in 321 healthy Saudis using Next Generation Sequencing. Human

Immunology 78, 384–386 (2017). 2. Alarifi, M., Al-Amro, F., Alalwan, A., Al-Turki, A., Fakhoury, H. et al. The prevalence of CCR5-Δ32 mutation in a cohort of Saudi stem cell donors. HLA 90, 292–294 (2017).

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reported were detected at very low frequency, including the ‘delta32’ mutation that, when harboured in duplicate, renders people immune to most HIV strains. In the other study2, Al Balwi teamed up with Dunia Jawdat, lab director of KAIMRC’s cord blood bank, to test for delta32 mutations in samples collected from 2,625 healthy stem cell donors and 400 cord blood units. Although the blood bank samples contained the mutation at a slightly higher frequency than in the first Saudi cohort, the delta32 variant still only occurred in about 1% of the samples — which is at least ten times lower than the frequency seen in Europe and Western Asia. Al Balwi surmises that the environmental factors that could have led to people carrying CCR5 mutations in other parts of the world must be lacking in the Middle East. That’s why these mutations are rarely seen today in Saudi Arabia, which means there’s an incredibly low probability of finding CCR5 mutation carriers who could serve as stem cell donors for HIV-positive patients. Accordingly, these mutations will not be routinely screened for at KAIMRC’s newly established cord blood bank and stem cell donor registry, he says.

Saudis with a higher educational background were more likely to be aware of the genetic risks of consanguineous marriages.

Understanding risks of consanguineous reproduction Saudi Arabia needs a widespread education program highlighting the genetic risks to children born as a result of marriage within families.

hildren born to genetically related people from the same family — socalled consanguineous marriages — face serious health risks. A recent study conducted in Saudi Arabia, where the practice is still common, shows that women there have a higher awareness of these risks compared to men. Consanguineous marriage can result in children with cognitive difficulties, heart defects, and impaired hearing, as well as other genetically inherited diseases. It can also lead to increased chances of a child inheriting two copies of a defective

gene from a shared common ancestor, perpetuating otherwise recessive genetic disorders. Anwar Ahmed from King Abdullah International Medical Research Center and a team of researchers from across Saudi Arabia conducted a cross-sectional study of 386 Saudis over the age of 18 to determine their level of knowledge regarding these health risks. Each participant completed two questionnaires. The first aimed to gather social details, including the level of education in their families, and included questions on

“Males are more likely to reject medical information if it is in conflict with the traditional culture” “This may be explained by the fact that females in our society tend to accept medical information in an objective manner in contrast to males, who are more likely to reject medical information if it is in conflict with the traditional culture,” the team suggest in their paper. Further, the study revealed that those from a higher educational background, together with those who had received medical information from friends, were more likely to understand the genetic risks and therefore be against consanguineous relationships. Those from backgrounds where families had less education had limited knowledge and were more likely to come from a long-held tradition of consanguineous marriages. The team urge caution in their results, because a larger, more comprehensive study of adult awareness is required. However, they believe that “Saudi Arabia must conduct widespread health awareness on the risks associated with consanguineous marriages.” Ahmed, A.E., Alharbi, O.A., Al-Hamam, A.A., AlShaia, W.A., Al-Marzoug, H.M., et al. Awareness of health consequences of consanguineous marriages among Saudi adults. The Journal of Public Health in Developing Countries. 2016; 2(1): 121-129.

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marriage and known inherited diseases. The second questionnaire focused more closely on knowledge of the genetic consequences of consanguineous marriage. Overall, knowledge of the genetic instability caused by consanguineous marriage was lower among Saudi adults than in other countries. Around 6% of respondents lacked any knowledge, and a third of those questioned had never received any information related to genetic diseases. Interestingly, there was a strong disparity between the sexes, with women demonstrating significantly greater understanding of medical consequences than men.

An MRI image of the brain of the Saudi girl, showing hyper-intensity in the white matter, caused by the accumulation of glycine.

Cause found for rare amino acid disease

A young Saudi girl’s metabolic disorder can be explained by a newly discovered gene mutation.

he rare genetic disorder known as glycine encephalopathy is usually caused by defects in the enzyme system that breaks down the amino acid glycine, resulting in an accumulation of the protein building block in the body’s tissues and fluids. Now, a team, led by geneticists from KAIMRC and King Saud bin Abdulaziz University for Health Sciences, has discovered that mutations in a protein that controls the shuttling of glycine within the brain can also trigger the disease. In a case report, Majid Alfadhel and his colleagues describe an infant girl, born to Saudi first cousins, who had all the clinical symptoms of glycine encephalopathy; which is also known as non-ketotic hyperglycinemia and affects an estimated one in 60,000 newborns worldwide.

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Her symptoms included breathing problems, seizures, low muscle tone and elevated glycine levels in various bodily fluids. Yet, the patient harboured no disease-causing mutations in any of the three glycine degradation genes previously implicated in the disorder. In search of a genetic culprit, Alfadhel’s team sequenced all the protein-coding portions of the infant’s genome. They honed in on a defect in the SLC6A9 gene that encodes the glycine transporter 1 (GlyT1) protein. The patient had two copies of this defective mutation, while her parents and older sister all had just one copy, indicating that the aberrant DNA acts in a recessive fashion. Structural analysis showed that the mutation alters the shape and chemical properties of the GlyT1 protein to disrupt its normal

function. Previous research revealed that the mutation causes a disease in rodents that’s similar to the one in human patients. When Alfadhel told the parents of the affected child that he had discovered the molecular offender responsible for their daughter’s disorder, “they were very happy,” he says, “because they had struggled for a long time, going from clinic to clinic without a diagnosis.” Now, that family — and others around the world — can undergo pre-implantation genetic testing to avoid passing on the disease to future offspring. Although the clinical consequences of this newly discovered mutation are the same as other known genetic defects responsible for glycine encephalopathy, the mechanism is quite different. GlyT1 mutations only lead to glycine build-up in the brain, whereas defects in glycine degradation cause a backlog of the amino acid throughout the body. The importance of this distinction is unclear, however, and further cases are needed to “confirm the full spectrum of SLC6A9-related phenotypes and genotypes,” says Alfadhel. Alfadhel, M., Nashabat, M., Qahtani, H. A., Alfares, A., Mutairi, F. A. et al. Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans. Human Genetics 135, 1263-1268 (2016).

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An international study involving KAIMRC has trialled a combination therapy that shows promise in curing early-stage hepatitis C virus (genotype 4).

2018

Hepatitis C: Transforming treatment for tricky genotypes

n international team of scientists, including KAIMRC’s Faisal Sanai, have had encouraging results using a new combination of antivirals on patients with a hepatitis C virus genotype common in the Middle East. Their results suggest that the combination therapy is highly effective, especially if the infection is caught in the early stages. The development of new antiviral drugs to treat the hepatitis C virus (HCV) has transformed our ability to tackle the disease, but there is scope for improvement. One challenge is to create fast-acting treatments, reducing discomfort for patients and limiting costs. HCV is a leading cause of liver disease and, if left untreated, can lead to liver cancer and cirrhosis. The virus is categorised into seven genotypes, each responding to treatment with varying degrees of success. Genotype 4 is most prevalent in the Middle East, where it accounts for 80 per cent of cases. However, it is notoriously difficult to treat, requiring a 48-week treatment regimen using peg-interferon α and ribavirin (known together as PR), with only a moderate success rate. The development of drugs called ‘direct-acting antivirals’, or DAAs, used in combination with PR, has enabled scientists to target the virus more efficiently than ever before. However, the cost of DAAs limits availability to patients, particularly in resource-poor places. The research team trialled a combination treatment of a DAA, called simeprevir, and PR on 67 patients with HCV genotype 41 who had never received treatment. All patients had mild to moderate fibrosis: thickening and scarring of liver tissues. Those who

responded well to the treatment within the first two weeks, and who showed undetectable levels of HCV RNA by week eight, were eligible for cessation of treatment at week 12. All others continued treatment until week 24. Of the 67 patients treated, 34 received the 12-week treatment, and all of these patients had undetectable HCV RNA at the end of the course. Further, 97 per cent of the group continued to be clear of the virus three months later.

“[Such] regimens may broaden the range of patients able to access effective treatment.” “[Such] regimens may broaden the range of patients able to access effective treatment … [and] decreasing treatment duration is very appealing to patients and physicians,” state the authors in their paper published in PLOS One, which reports only on the results of the 12-week regimen. “The cost-effectiveness of early treatment is well-established, particularly [considering] the risks of transmission and [disease] complications.” Asselah, T., Moreno, C., Sarrazin, C., Gschwantler, M., Foster, G.R. et al. Efficacy of a 12-week simeprevir plus peginterferon/ ribavirin (PR) regimen in treatment-naïve patients with hepatitis C virus (HCV) genotype 4 (GT4) infection and mild-to -moderate fibrosis displaying early on-treatment virologic response.

PLOS One 12 (1): e0168713 (2017).

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S TOC K T R EK I M AG ES , I N C . / A L A M Y S TOC K P H OTO

A hepatitis C genotype prevalent in the Middle East can be treated by combining existing drugs with a new antiviral.

Electron microscopy image of the MERScausing virus.

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Patients with Middle East respiratory syndrome may produce sufficient antibodies to help fight the viral infection in more recent victims.

he blood plasma of people recovering from Middle East respiratory syndrome (MERS) could be a source of antibodies to treat patients in the grip of the disease. Researchers at KAIMRC reached this conclusion from a feasibility study conducted at Saudi Arabia’s Ministry of National Guard—Health Affairs (MNGHA) with co-workers elsewhere in Saudi Arabia and in the US, Canada and Europe. Their research did not involve trials of the proposed antibody therapy, but it did establish that collecting sufficient antibodies from patients may be a realistic proposition. MERS is caused by a virus that was first identified in 2012 in a patient in Saudi Arabia. More than 36% of identified cases have proved fatal; and although the disease has been detected in many countries, 80% of cases have been in Saudi Arabia. “No therapy options have been proven to be effective, so developing a treatment using donated plasma would be of great value,” says MNGHA’s Yaseen Arabi, who led the feasibility study. Administering donated blood plasma containing anti-viral antibodies is known to be an effective treatment for other serious viral diseases. The researchers explored three possible sources of therapeutically useful plasma. These were 196 patients with acute respiratory illness and confirmed or suspected MERS virus infection, 230 healthcare workers who had been in contact with MERS patients, and 17 household contacts of patients. Blood samples from these three groups of potential donors were screened for the presence of antibodies able to bind to the MERS virus. Significant amounts of antibody were

detected in only a small number of the sample participants, with recently recovered MERS patients seeming to be the most suitable source. Although potentially useful amounts of antibody were detected in fewer than 3% of the study participants, Arabi remains positive, saying, “Our results do indicate it could be possible to obtain plasma, although with the small pool of potential donors, collecting large quantities to use in therapeutic studies may be challenging.” Moving on to clinical trials of donated plasma is the obvious next step, but there are several challenges ahead before reaching that stage. “We do need to explore other ways to obtain sufficient plasma with thera-

"No therapy options have been proven to be effective, so developing a treatment using donated plasma would be of great value.” peutically useful amounts of antibody,” says Arabi. Possible options may be to use samples from patients who have just recovered from more severe disease. Also, strict criteria must be met to include potential plasma donors in clinical trials. With the feasibility of the approach demonstrated in principle, such issues can now be addressed. Arabi, Y. M., Hajeer, A. H., Luke, T., Raviprakash, K., Balkhy, H. et al. Feasibility of using convalescent plasma immunotherapy for MERS-CoV infection, Saudi Arabia. Emerging Infectious Diseases 22, 15541561 (2016).

Special Issue

Potential for a MERS antibody therapy

Striking at the heartland of the MERS infection At least a dozen additional cases of Middle East respiratory syndrome (MERS) were reported in Saudi Arabia in September 2016, bringing the number of cases in the kingdom to more than 1,450, of which 610 have been fatal.

Identifying the source

MERS is a respiratory illness caused by the MERS-Coronavirus (MERS-CoV), which was initially thought to spread from bats to humans via consumption of food contaminated with bat droppings. In 2014, however, researchers from King Faisal University, working with 82

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ERS emerged in Saudi Arabia in September 2012, but laboratory-confirmed cases of infection have since been reported in 27 countries. Though more than 1,800 MERS cases have been reported worldwide, Saudi Arabia has been the site of the lion’s share. Every year, several million people take the Hajj pilgrimage to Mecca, increasing fears of a rapid global spread of MERS and other infectious diseases. As the epicentre of the syndrome, Saudi Arabia has become intrinsic to international efforts to combat its spread. Research carried out in the kingdom has contributed to understanding the virus’s biology and to the development of vaccines. “Saudi researchers have made significant contributions to identifying the clinical presentation of the disease, so that physicians are better able to identify infections,” says KAIMRC’s Hanan Balkhy, also executive director of the Infection Prevention and Control Department at the Ministry of National Guard– Health Affairs. “They have also made important progress in identifying risk factors for the disease, and in evaluating the effectiveness of treatments.”

MERS-CoV particles on camel epithelial cells.

collaborators in Egypt and Hong Kong, reported that they had isolated the MERS Coronavirus from a herd of dromedary camels1 on a farm in the oasis region of Al-Hasa, in eastern Saudi Arabia. This confirmed that camels harbour MERS-CoV as intermediate hosts for the virus, which replicates in large quantities in their cells. Camels are likely responsible for spreading the infection to people who come into close contact with them. Later that year, researchers at the King Fahd Center for Medical Research provided evidence of direct transmission of MERS-CoV from camels to humans2. More recently, Saudi researchers published the first MERS case control study —

a method used to compare patients with a particular disease to those without it and establish how frequently they have been exposed to risk factors. This helps determine the relationship between risk factors and the disease. Researchers from the King Faisal Specialist Hospital and Research Centre in Jeddah, together with collaborators from the U.S. Centers for Disease Control and Prevention, identified all 535 known cases of MERS infection reported in Saudi Arabia between March and November 2014, and compared them to 116 uninfected individuals by assessing their underlying medical conditions and direct environmental exposure to known

risk factors. This showed once again that those people who came into direct or indirect contact with dromedary camels were far more likely to be infected with MERS. The study findings3 reiterated that activities such as milking, feeding and slaughtering camels increased risk of infection, whereas drinking unpasteurised camel milk did not. Shortly after these findings were published, the Saudi Arabian Ministry of Agriculture issued a statement advising people who come into regular contact with camels to “exercise caution and follow preventative measures” to minimise the spread of infection by wearing face masks and gloves, and washing their hands before and after any contact. Health officials have also warned people to avoid contact with camels altogether, unless necessary.

Developing prevention strategies

Since then, the Saudi government has been working closely with the World Health Organization to put effective measures in place for the Hajj pilgrimage. Efforts include raising awareness about MERS infection and heightened surveillance to prevent outbreaks. Visitors to Mecca are also advised to cover their mouths and noses when coughing or sneezing and to wash their hands regularly to minimise spread. Healthcare workers are at a particularly high risk of infection, and there have been a number of MERS outbreaks in Saudi hospitals in the past three years. Immediately after each of these events, the Saudi Arabian Ministry of Health dispatched rapid response teams to the hospitals to identify others who may have been infected and enforce measures of infection control. Balkhy says that the research has led to major changes in healthcare policies surrounding infection risk. “Identifying the method of transmission of the virus and the risk to healthcare providers has created a major transformation in the quality and standards in hospitals,” she says. “The research also led to the creation of a specific unit in the Ministry of Health

Researchers have identified dromedary camels as a possible reservoir for the coronavirus causing MERS.

that audits infection control practices, in order to ensure that hospitals are properly prepared.” Even so, much remains unknown. The exact mechanism of animal-to-human transmission is still unclear, for example, and researchers in Saudi Arabia and elsewhere are scrambling to develop an effective vaccine. Last year, the King Abdulaziz City

“Identifying the method of transmission of the virus and the risk to healthcare providers has created a major transformation in the quality and standards in hospitals.”

searchers, funding agencies and non-governmental organizations, to discuss how to accelerate the fight against MERS. According to the workshop report, all interested parties recognize the need to cooperate, and have resolved to formalize collaborations to maximize investment in MERS research, produce reliable data, and influence public health policy. Balkhy says that she and her colleagues at KAIMRC are already collaborating on many other projects, most notably with researchers at the University of Oxford, to realise these goals. 1. Hemida, M. G., Chu, D. K. W., Poon, L. L. M., Perera, R. A. P. M., Alhammadi, M. A., et al. MERS coronavirus in dromedary camel herd, Saudi Arabia. Emerging Infectious Diseases 20, 1231-1234 (2014). 2. Azhar, E. I., El-Kafrawy, S. A., Farraj, S. A., Hassan, A. M., Al-Saeed, M. S. et al. Evidence for camel-to-human transmission of MERS coronavirus. The

for Science and Technology (KACST) launched a comprehensive MERS-CoV research program in co-operation with the Ministries of Health and Agriculture. Working with the International Vaccine Institute, the Saudi Ministry of Health also co-organized a workshop in Riyadh for re-

New England Journal of Medicine N. Engl. J. Med. 370, 2499-2505 (2014). 3. Alraddadi, B. M., Watson, J. T., Almarashi, A., Abedi, G. R., Turkistani, A. et al. Risk factors for primary Middle East respiratory syndrome coronavirus illness in humans, Saudi Arabia, 2014. Emerging Infectious Diseases 22, 49-55 (2014).

Special Issue

The hepatitis B virus can be fatal if left untreated.

When liver disease patients fall off the medical radar

People with viral hepatitis often do not return for follow-up treatment, highlighting the need for more robust support strategies.

2018

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S C I E NCE P I CT U R E CO / A L A M Y S TOCK P HOTO

ust under a third of hepatitis patients 30%) were deemed lost to follow-up. Of surveyed at King Abdulaziz Medithose 98, the top reason given (by 69% of cal City in Riyadh did not attend a respondents) for not returning for treatfollow-up appointment with the ment was that they were unaware that a hospital. More than two-thirds of those follow-up appointment was scheduled. weren’t aware an appointment had been Other reasons given were that they were scheduled. Researchers urge better infornever informed about the need for folmation, education and communication to low-up (15%) or they had a personal belief help reduce the incidence of liver disease that follow-up was not necessary (9%). complications. The number of patients lost to folMinimising the number of patients low-up was found to be higher among who become unreachable — known in those diagnosed with HBV (71.4%) the medical field as compared with ‘lost to follow-up’ HCV (28.6%). If left undiagnosed or — during treatAs yet, the full ment programmes extent of the untreated, the burden of is critical. For peoproblem nationliver disease on hospitals ple with hepatitis, wide is unknown. insufficient care Since the study and families will continue can lead to serious wa s c onduc te d to increase and lead to a complications such at just one large greater number of people as liver scarring NGHA-affili(cirrhosis), failure ated hospital, the requiring transplants. and cancer. researchers point Close to 400 out that “the million people are affected by the hepreported 30% may underestimate the atitis B virus (HBV) and another 170 magnitude of the problem at primary million are living with hepatitis C virus care centres and at the community level, (HCV) around the world. In Saudi Arawhere many people have never been bia, despite a large-scale HBV vaccidiagnosed or referred.” nation initiative launched in 1989, the If left undiagnosed or untreated, the incidence of both types of the disease burden of liver disease on hospitals and remains higher than expected. families will continue to increase and To gain a better idea of the number of lead to a greater number of people requirhepatitis patients who drop out of treating transplants. ment, and to reveal the reasons behind The study calls for a greater focus on the lack of follow-up, a multi-institueducation, as well as more efficient and tional team surveyed people diagnosed flexible referral and scheduling systems. with HBV and HCV between 2009 and A dedicated health centre for hepatitis 2010 at King Abdulaziz Medical City patients may help achieve this goal. The (KAMC) in Riyadh. team suggests that sending reminders to The team was led by Hanan Balkhy, patients via text messaging and email will chairman of KAIMRC’s infectious disalso be important. ease section and executive director of the Infection Prevention and Control ProBalkhy, H. H., El-Saed, A., Sanai, F. M., Alqahtani, gram at the Ministry of National Guard– M., Alonaizi, M. et al. Magnitude and causes of loss Health Affairs (NGHA). to follow-up among patients with viral hepatitis at Of a total of 328 patients who coma tertiary care hospital in Saudi Arabia. Journal of pleted the telephone survey, 98 (around Infection and Public Health 10, 379—387 (2017).

FS TOP I M AG E S G M BH / A L A M Y S TOCK P HOTO

Researchers warn of major public health concerns, should policies and attitudes towards antibiotic use remain unchanged.

Antibiotic misuse a looming crisis for Saudi Arabia Warning over high levels of illegitimate antibiotic dispensing and public misconceptions about their use. A recently published study from Saudi Arabia describes widespread illegal prescription of antibiotics by pharmacists under pressure from an ill-informed public of the potentially dire consequences of their overuse, and even the circumstances in which antibiotics are effective. Respondents to surveys admitted to hazardous attitudes and behaviours toward antibiotic use. The researchers suggest this is a wake-up call for policymakers to tighten restrictions on antibiotic dispensing and educate the public on the dangers. The increasing problem of antimicrobial resistance has frequently been reported as one of the greatest impending public health disasters in human history. Bacteria undergo random mutations, making them tolerant to previously effective treatments. Bacteria share their genetic traits via a 86

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process called horizontal gene transfer. By doing so, a harmless bacterium could transfer antimicrobial resistance to a pathogenic one. Antibiotic overuse increases the likelihood of this process occurring as more bacteria carry the genome for resistance to a given treatment. In their study, published in the Journal of Infection and Public Health, a team of researchers from King Fahd Medical City and King Saud bin Abdulaziz University for Health Sciences in Riyadh, Saudi Arabia surveyed 475 individuals, with the questions revolving around two key themes: public perception towards antibiotics and their use, and the accessibility of antibiotics to the population. The results were disconcerting: almost half of the participants used antibiotics without a physicianâ&#x20AC;&#x2122;s consultation or prescription. Compounding this, over a

third of those surveyed reported a belief that antibiotics could be used to treat viral diseasesâ&#x20AC;&#x201D;conditions in which they have no efficacy whatsoever. Other findings included a high propensity towards sharing antibiotics and stopping a treatment course before its completion. The study authors urge stricter control of antibiotics, such as registering them as controlled medications and requiring their provision logged and monitored via a national registry. Additionally, a large-scale education campaign is recommended, targeted at prescribers and the public, to warn against self-diagnosis and medication. Bin Nafisah, S., Bin Nafisa, S., Alamery, A.H., Alhumaid M.A., et al. Over-the-counter antibiotics in Saudi Arabia, an urgent call for policy makers. J

Infect Public Health (2017).

Gene tweak induces stronger immunity

Changing the switch that turns on vaccine protein production elicits a stronger immune response against malaria and influenza in mice.

Changing the gene promoter could help make more robust flu vaccines.

improved the expression of foreign genetic material in host cells compared to conventional promoters used in existing vaccines. This elicited a strong immune response. F11 and B8 were more active in the early stages of the MVA lifecycle, leading to higher production yields overall. The researchers tested the F11 promoter as an enhancing element to drive stronger expression of vaccine proteins from two microbes: malaria and influenza. Two weeks after vaccinating mice with the F11-containing viruses, they observed elevated levels of infection-fighting T cells directed against these pathogens compared to mice immunized with standard vectors already tested in human clinical trials. “The results show that the F11 promoter induced significantly higher immune responses in mice,” says Alharbi. “[Soon], those improved malaria and influenza vaccine candidates [with

the F11 promoter] will be tested in humans by the Jenner Institute scientists [in the UK].” Alharbi and his collaborator at the Jenner Institute, Sarah Gilbert, have also recently developed a series of vaccines — one of which is based on MVA and includes the F11 promoter — against the coronavirus responsible for Middle East respiratory syndrome, a sometimes-fatal viral illness spread by camels that first appeared in Saudi Arabia in 2012. “Those vaccines have been tested in mice,” Alhabri says, “and will be tested on camels and humans.” Alharbi, N. K., Spencer, A. J., Salman, A. M., Tully, C. M., Chinnakannan, S. K., Lambe, T., Yamaguchi, Y., Morris, S. J., Orubu, T., Draper, S. J., Hill, A. V. & Gilbert, S. C. Enhancing cellular immunogenicity of MVA-vectored vaccines by utilizing the F11L endogenous promoter. Vaccine 34, 49–55 (2016). dx.doi. org/10.1016/j.vaccine.2015.11.028

Special Issue

xperimental vaccines for protection against malaria, influenza and other infectious diseases could be made more potent if their developers made a small genetic tweak. By using a different ‘promoter’ — a DNA sequence that drives the multiplication and expression of genetic material — researchers, led by Naif Alharbi from King Abdullah International Medical Research Center, have found they can induce stronger immunity in mouse models. Modified vaccinia virus Ankara (MVA) is a weakened type of poxvirus known to be safe in humans. Scientists have engineered it to carry the genetic material of various infectious agents — including HIV, tuberculosis, and most recently Ebola — into host cells in an effort to prime the immune response against these pathogens. MVA works well enough as a vaccine carrier, but Alharbi and his colleagues at the University of Oxford’s Jenner Institute wanted to make it even better. They incorporated different naturally found promoters into MVA to see if they prompted a more robust immune response. In mice, the researchers found that two promoters, known as F11 and B8,

A new peptide-based tool for diagnosing HIV-1 and HIV-2 works by seeking out and binding to the N-terminal on the HIV p24 protein.

Peptide promise for diagnostics The human immunodeficiency virus (HIV), and its associated acquired immune deficiency syndrome (AIDS), continues to have a devastating effect on populations worldwide. Now, researchers in South Africa and Saudi Arabia have made a breakthrough in HIV diagnostics, developing a prototype tool, based on antimicrobial peptides, that offers hope of providing rapid, accurate point-ofcare diagnosis. The most common diagnostic tool for the two predominant HIV viruses, HIV-1 and HIV-2, is the p24 antigen assay. It detects HIV by searching for the presence of a protein called p24, which it recognises via the p24’s C-terminal. However, false negatives are common using this tool, due to obstruction of the C-terminal by p24 antibodies, which are generated during the body’s immune response to HIV infection. It also takes several days to receive results from the p24 assay, and so a more effective diagnostic tool is urgently needed. “South Africa has the world’s largest 88

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HIV infected population and the government is spending millions on HIV kits from overseas. Yet, as far as we know, no company in the country has produced an HIV diagnostics kit,” says Ashley Pretorius from the University of the Western Cape, who worked on the project with colleagues in South Africa, Musa Gabere from King Abdullah International Medical Research Center, and an industrial partner, Medical Diagnostech. “Producing an inexpensive kit locally will allow us to tackle HIV and AIDS more effectively while benefitting the country’s economy.” The team needed to develop a tool that did not rely on the p24 C-terminal. They decided to explore the potential of a naturally occurring subset of immune system proteins called antimicrobial peptides (AMPs), some of which have been shown to bind to the N-terminal of HIV p24. Pretorius’ team modelled combinations of AMPs and modified AMPs to find the best ‘fit’ for p24, to ensure accurate

and efficient HIV detection in samples from patients. “The point of contact between two molecules is important because it determines how tightly the molecules bind to each other,” says Pretorius. “When we have identified a molecule – in this case an AMP – that we know fits well with a target protein, we can substitute amino acids in the right places to make the binding between the two molecules even stronger.” Their resulting AMP-based prototype diagnostic tool, which is now patented, performed very well in initial tests. The tool achieves accurate diagnosis of both HIV-1 and HIV-2 in only 15 minutes; meaning that, for the first time, effective point-ofcare HIV diagnosis could be feasible. Williams, M.E., Tincho, M., Gabere, M., Uys, A., Meyer, M., & Pretorius, A. Molecular validation of putative antimicrobial peptides for improved human immunodeficiency virus diagnostics via HIV protein p24. Journal of AIDS and Clinical Research http://dx.doi. org/10.4172/2155-6113.1000571 (2016).

Rapid diagnosis of HIV may soon be possible thanks to a novel peptide-based diagnostic tool.

Medical

BIOTECHNOLOGY Park The Medical Biotechnology Park, a new company at KAIMRC/MNG-HA is a strategic project of MNG-HA to contribute to the Saudi Vision 2030 through:

The development and commercialization of biomedical R&D products, technologies and services

The contribution to economic and health improvement through science and innovations in medical and health sectors

EMAIL: KAIMRC-KMBP@NGHA.MED.SA PHONE NUMBER: +966-11-429-4516 TWITTER: @MEDICALBIOTECH

SAUDI GENOME PROJECT

The Saudi Human Genome Project (SHGP) is a national program that aims for the identification of disease-associated variants for rare and common disease in the Saudi population. The ultimate objective of this endeavor is to create a national database for genetic variants at King AbdulAziz City for Science and Technology (KACST) and to make this information available for the national and international scientific community. This program is considered one of the largest life sciences research programs in Saudi Arabia. EMAIL: KAIMRC_BGD@NGHA.MED.SA