Bioevolution vol 1 (02) may 2014

BioEvolution ISBN 978-81-925781-3-2 Vol 1 (02) May 2014

Online Research Magazine on Microbiology, Biotechnology & related issues

Managing Editor Dr Arti Goel

Published by GIAP Journals, India www.giapjournals.org/bioevolution.html

Editorial Board- BioEvolution Chief Editor Kanika Sharma, PhD Professor Department of Botany, University College of Science, M.L.S. University, Udaipur, Rajasthan, India Managing Editor Arti Goel, PhD Assistant Professor, Amity Institute of Microbial Biotechnology, Amity University, Sector- 125, Noida (U.P.) Editors / Reviewers Nidhee Chaudhary, PhD Professor Amity Institute of Biotechnology, Amity University Uttar Pradesh Sector-125, Noida Arpita Bhattacharya, PhD Associate Professor, Amity Institute of Nanotechnology, Amity University, Sector- 125, Noida (U.P.) Era Upadhyay, PhD Assistant Professor, Ansal Institute of Technology & management, Sector C, Pocket 9, Sushant Golf City, Lucknow (U.P.) Prachi Bhargava, PhD Assistant Professor Department of Biotechnology, Sri RamSwaroop Memorial University, Deva Road, Lucknow (U.P.) Rajshree Saxena, PhD Lecturer Amity Institute of Microbial Biotechnology, Amity University, Sector- 125, Noida (U.P.) Dr U K Tomar Scientist F Arid Forest Research Institure Jodhpur, Rajasthan Dr Ritu Mawar Senior Scientist (Plant Pathology) PCFC Unit, AICRP (FC), IGFRI, Jhansi

Vol 1 (1), May 2014 ISBN 978-81-925781-3-2 Contents

1. MESOTHELIOMA : CURRENT PROSPECTIVES Hema Madhav and Navkiran Kaur 2. COMMUNITY ACQUIRED MRSA Namita Bedi 3. DESIGNER T CELL THERAPY: A NOVEL APPROACH IN CANCER MANAGEMENT Tuhin Rashmi and Tapan K S Chauhan 4. ROLE OF CANCER STEM CELLS IN BREAST CANCER Sahil Nagpal and Navkiran Kaur 5. IMPACT OF NANOTECHNOLOGY ON ENVIRONMENT Arti Goel 6. NANOMATERIAL BASED SENSORS Monika Joshi 7. CITRIC FROM BIOWASTE: CHALLENGES AND PROSPECTS Seema Raj and Nidhee Chaudhary 8. AN INTRODUCTION TO AIR QUALITY INDEX AND HEALTH CONCERNS Era Upadhyay

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BioEvolution ISBN 978-81-925781-3-2, May 2014, pg 24-27

MESOTHELIOMA : CURRENT PROSPECTIVES Hema Madhav1 and Navkiran Kaur* Student, B.Sc (Hons) Medical Biotechnology *Assistant Professor, Amity Institute of Biotechnology, Amity University, Noida navkirank@amity.edu 1

INTRODUCTION Mesothelioma are rare type of cancer in which malignant cells are found in the lining of the chest or abdomen, Majority of the patients diagnosed with mesothelioma are those who traced to job-related exposure to asbestos. The disease can take anywhere from 20 to 50 years after exposure to asbestos before it shows obvious symptoms and an oncologist can make a definitive diagnosis. Mesothelioma has been described as an insidious neoplasm because of its long latency period. It arises in the mesothelial surfaces of tissues in the pleura but can also occur in the peritoneum and the tunica vaginalis. While no cure for the disease exists and the prognosis is typically poor, researchers made significant progress in recent years in understanding mesothelioma and developing new treatment options and alternative therapies. As estimated by WHO millions are dying of Asbestos related diseases each year. In India, Bihar chief Minister has demanded to ban Asbestos completely. Indian Association of Occupational Health is also in favor of complete ban on Asbestos.

TYPES OF MESOTHELIOMA There are three types of mesothelioma (i) pleural mesothelioma (ii) peritoneal mesothelioma (iii) pericardial mesothelioma. The chest abdomen and heart are surrounded by a membrane called mesothelium. This membrane is important for the movements (contraction or expansion) of heart lungs and stomach. The cancers which arise in mesothelial membrane are called malignant mesothelioma. The inhaled asbestos will cause inflammation to the surrounding lung tissue where they get lodged and cause irritation. Further, it leads to the production and secretion of various chemical substance called cytokines. These cytokines induce various inter cellular changes to lungs mesothelia cells. Hence, the interaction of asbestos fiber with combination of cytokines causes the cell to precede malignant pathway. This inturn switch on the pro-growth genes and may lead to uncontrolled cell division and develop mutations, which finally develop into malignant mesothelioma.

MOLECULAR PATHOGENESIS There is an established association between asbestos and respiratory diseases for decades. The risk of developing mesothelioma was described as 10% over the lifetime of an asbestos worker, with up to 70% of all mesothelioma cases involving documented asbestos exposure. Concomitant smoking enhances the risk of malignancy in an asbestos worker, with a 60-fold increased risk of developing non–small cell lung cancer. The chance of dying of a malignancy (mesothelioma or lung cancer) versus a nonmalignant cause is 50% in an individual exposed to asbestos compared to 18% in an individual not exposed. The majority of asbestos fibers are either amphibole (sharp, rod-like) or serpentine. The serpentine fibers contribute more towards the carcinogenicity than the amphibole type. Inhaled asbestos fibers are trapped in the lower third of the lung, where they initiate an inflammatory response. The fibers are phagocytosed into mesothelial cells and initiate an oncogenic cascade of events that includes activation of c-Myc and c-Jun oncogenes, binding with epidermal growth factor receptors (EGFRs), and promotion of anti apoptotic genes such as Bcl-xl.5. The Simian Virus SV-40 is a polyomavirus that is thought to inactivate tumor suppressor genes of the retinoblastoma family. SV-40 nucleic acids have been identified in mesothelioma cases without exposure to asbestos. Abnormalities in chromosomes 1, 3, 6 and 9 can also be observed in patients with this disorder. Occasionally, loss of one copy of ch.22 may be observed. Now it is discovered that there is a germ line mutations in the gene encoding BRCA1 associated protein-1 (BAP1)[6] .

PATHOLOGY Pathologically, there is considerable difficulty in diagnosing mesothelioma due to the tissue obtained after biopsy is often minimal and may not be adequate to perform the necessary array of tests to distinguish mesothelioma from other pleural-based malignancies. Histological variability made the diagnosis very challenging. Histological variable types of mesothelioma have been identified and can be correlated well with the diagnosis and prognosis of the disease. These types include epithelioid which is associated with the good prognosis and sarcomatoid variants with characteristic spindle morphology are associated with a worse prognosis. Often, mixed epithelioid and sarcomatoid histology can be seen. Tissue obtained by cytological analysis of pleural fluid or blind pleural biopsy is limited and it is very difficult to classify the mesothelioma on the basis of the correct histology. Hence, www.giapjournals.org/bioevolution.html

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Thoracoscopic biopsies with direct visualization of pleural nodules provide the best way. Immunohistochemical staining is important to distinguish mesothelioma from adenocarcinomas of lung origin or metastatic from other sites. Calretinin is commonly positive in mesothelioma, with a reported highly significant sensitivity and specificity. Thrombomodulin has the maximum specificity but is comparatively less sensitive. Other useful antibodies directed against mesothelial-associated antigens include mesothelin, cytokeratin 5, Wilms' tumor-1 gene product, and HBME-1 and the nonmesothelial antigens Lewis-Y blood group (antibody BG8), MOC-31, BerEp4, CD15, and the carcinoembryonic antigen family [7].

CLINICAL PRESENTATION Mesothelioma is often associated with relatively common and non specific symptoms and can be visualized in almost many intrathoracic disease processes, benign or malignant. Mostly patients suffered from persitent cough, usually nonproductive and dyspnea. Chest wall pain may be a relatively unique symptom, usually described as a focal ache. There may be palpable soft tissue fullness or mass and decreased respiratory sounds with dullness to percussion due to an underlying pleural effusion. Pleural effusions are common and and found on right side in 60% cases. Five percent may be present with bilateral effusions. Pleural plaques are common, and 1 out of 5 patients develop bibasilar fibrosis, characteristic of chronic asbestosis. Several paraneoplastic syndromes have been found to be associated with mesothelioma. These include hypercalcemia, hypoglycemia, autoimmune hemolytic anemia, hypercoagulable states, and disseminated intravascular coagulation. These syndromes are nonspecific and can be seen with a number of malignancies.

DIAGNOSIS The diagnosis of mesothelioma actually depends on adequate tissue. The conventional diagnostic procedures have included the cytology of pleural fluid obtained through the needle biopsy of pleural tissue under CT guidance technique called thoracentesis, thoracoscopy surgery with direct visualization and biopsy of pleural nodules, and open thoracotomy[8]. Indications of blood in Pleural fluid, exudative with elevated protein, lactase dehydrogenase, and cell counts may be significant but reduce the specificity during cytology, CT-guided fine needle aspiration (FNA) is limited due to small sample size, which decreases the sensitivity and is associated with increased risk of pneumothorax, Video-assisted thoracoscopy has a diagnostic accuracy of 98% in experienced hands and allows for the possibility of simultaneous pleurodesis. Other diagnostic procedures include esophageal ultrasound (EUS), mediastinoscopy, and laparoscopy, which are used more for staging purposes [9].

STAGING There are five systems for the staging of pleural mesothelioma. The most commonly used system is the Butchart system based on a simple description of the aggressiveness of the disease regardless of histologic subtype: pleural contained (Stage I), chest wall or mediastinal invasion (Stage II), peritoneal or diaphragmatic penetration (Stage III), or distant metastases (Stage IV). There is another system which is used to stage mesothioloma is the Brigham system based on the surgical resectability and lymph node involvement. Stage I disease is resectable without nodal spread; Stage II is resectable with lymph node involvement; Stage III involves the chest wall, heart, diaphragm, or abdominal cavity, with or without lymph node involvement. Stage III tumors are considered unresectable. Stage IV disease is distant metastases. This system is no longer in use to stage the disease. The most practical and most commonly used system is tumor-node-metastasis (TNM) descriptors, so the International Mesothelioma Interest Group (IMIG) developed the detailed IMIG staging system in 1995. This system is the most widely used staging system for mesothelioma[10].

CLINICAL MANAGEMENT Surgery is recommended for patients with clinical stage-I disease who are considered medically fit and can tolerate the surgery. Patients who are not operable because of compromised cardiopulmonary function are treated with chemotherapy only. Patients with stage II-III disease should be offered trimodality therapy with surgery, chemotherapy, and radiotherapy, while chemotherapy alone is recommended for patients who are not clinically fit for surgery. Pleural effusions are considered at stage IV disease managed with either talc pleurodesis (thoracoscopic drainage of the fluid followed by instillation of a sterile talc slurry) or by placement of a pleural catheter for continuous drainage along with trimodality therapy.

MESOTHELIOMA PNEUMONECTOMY A pneumonectomy is a process of surgical removal of all or part of a lung, usually performed as a cancer treatment.

Because this mesothelioma surgery will significantly reduce the patient's breathing capacity, before committing to a www.giapjournals.org/bioevolution.html

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pneumonectomy, the extensive testing is done in order to insure that the remaining lung will have enough capacity to take over the respiration process.

RADIOTHERAPY Radiotherapy is potentially helpful for reducing chest wall masses or alleviating pain, but these responses are transient; Intensity-modulated radiotherapy (IMRT) is a sophisticated modality that uses small radiation beams at various angles in a 3-dimensional conformal pattern, allowing for more intense radiation at the target with greater precision. Recommended radiotherapy, usually IMRT, after an EPP has been standard since 2003 and has been suggesting radiotherapy within 2 weeks of any pleural biopsy or tube drainage procedure to prevent possible seeding [11] . Whether such treatment is truly effective or has any impact on survival is not clear fully. There are two types by which radiotherapy can be given 1) Use of external beam radiation, a radiation source to target a specific local and eliminate or slow the growth of malignant cells in this area. 2) Internal radiation (Brachytherapy) - The process of delivering radiation via Brachytherapy involves the implantation of tiny radioactive seeds or rods in or near the tumor [12]. This method allows highly-concentrated doses to reach the area of most concern, and because delivery is so precise, fewer healthy cells are affected during the treatment process.

CHEMOTHERAPY For many years, chemotherapy treatment of mesothelioma was disappointing, partly because of the relative chemoresistance of mesothelioma and the lack of active agents with acceptable toxicity. Currently, the most widely used chemotherapeutic drug is Alimita used in tandem with a platinum agent like Cisplatin and has been shown to sustain the life of the patient up to several months in critical cases. The most common side effects of mesothelioma-related chemotherapy include Chemo Brain, mouth sores, nausea and vomiting, susceptibility to infection, bruising or bleeding and fatigue NEW APPROACHES—TARGETED THERAPIES The identification of various growth factors, glycoprotein, genetic mutations, and enzymatic catalases has led to the development of new agents to specifically target these oncogenic abnormalities. VEGFR1 and VEGFR2 receptors have been detected in the majority of mesothelioma cases and Bevacizumab is a humanized monoclonal antibody directed at the vascular endothelial growth factor receptor (VEGFR) [13]. Thus, it seems to be promising to utilize the anti-VEGF agent bevacizumab in the treatment of malignant pleural mesothelioma in humans. A randomized phase II trial of untreated mesothelioma patients compared cisplatin-gemcitabine alone or with bevacizumab[14]. The addition of bevacizumab did not improve the response rate, progression-free survival or overall survival compared to chemotherapy alone. Despite limited success with these early phase II trials, ongoing study with antiangiogenictargeted therapies continues with bevacizumab, vatalabin, cediranib, pazopanib, and others. Histone deacetylase (HDAC) inhibitors block the enzyme HDAC, which regulates the wrapping and unwrapping of DNA around protein spools called histones can be potential therapeutic molecules [15]. These inhibitors can alter the access of transcription factors and thereby either increase or decrease the expression of various genes. One of the example is Vorinostat, an oral HDAC inhibitor, has shown activity against mesothelioma in phase I trials. Researchers reproduced the harvested cells, allowing multiple infusions, and the engineered cells were then returned to the patient’s body [16]. They found that the engineered cells displayed antitumor activity and even generated a natural response by the patient’s immune system, much like a vaccine.

CONCLUSIONS Mesothelioma is relatively uncommon but potentially very lethal disease with high mortality rate. Recognition of the disease's association with asbestos has improved risk exposure in the workplace and other environmental areas.

Diagnosis, especially in the early stages, is difficult, and percent line of treatments are not very satisfactory to screen modalities for high-risk populations. Avoidance of tobacco is extremely important to decrease the risk of lung cancer with asbestos exposure. Treatment—especially with trimodality approaches combining IMRT, cisplatinpemetrexed chemotherapy, and surgery—has improved and sustained the life of patients. Unfortunately, relapses and progression are common, and second-line therapies are far from satisfactory. The exact type of surgery that is most effective remains controversial, with more interest in volume-sparing approaches. Targeted therapies offer the potential advantages of disease-specific treatment with reduced toxicity but have yet to prove sufficient activity.

Continued research for novel agents and ongoing clinical trials are critical to combat the disease.

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Bowker, M. Fatal Deception: The Untold Story of Asbestos. New York, NY: Simon & Schuster. 2003.

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Ismail Khan R , Robinson LA,Williams CC Jr ,Garnett CR, Bepler G, SimonGR Malignant Pleural Mesothelioma ; a comprehensive review. Cancer Control, 2006 Oct; 13(4): 255-263 Anna K Nowak. Chemotherapy for malignant Pleural mesothelioma: a review of current management and look to the future. Annals of cardio thoracic surgery, 2012, Nov, 1 (4):508-515 Yoshitaka Sekido . Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya. 2013, Feb, 4 ;464-8681, Yaziji H, Battifora H, Barry TS, Hwang HC, Bacchi CE, McIntosh MW, Kussick SJ, Gown AM. Evaluation of 12 antibodies for distinguishing epithelioid mesothelioma from adenocarcinoma: identification of a three-antibody immunohistochemical panel with maximal sensitivity and specificity. Mod Pathol. 2006 Apr; 19(4):514–523.

Hoksch B, Birken-Bertsch H, Müller JM: Thoracoscopy before Jacobaeus. Ann Thorac Surg 2002; 74:1288-1290.

Beamis Jr JF, Mathur PN, Mehta AC, ed. Interventional Pulmonary Medicine, New York: Marcel Dekker; 2004:411-429.

Rusch VW. A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Mesothelioma Interest Group. Chest. 1995; 108: 1122-8.

Sugarbaker DJ, Flores RM, Jaklitsch MT, Richards WG, Strauss GM, Corson JM, DeCamp MM Jr, Swanson SJ, Bueno R, Lukanich JM, Baldini EH, Mentzer SJ . Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg. 1999 Jan; 117(1):54–63 Stewart AJ, Soren M.Bentzen . "Radiobiological concepts for brachytherapy". In Devlin P. Brachytherapy. Applications and Techniques, 2007.

Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14; 355(24):2542–2550. Erratum in: N Engl J Med. 2007 Jan 18; 356(3):318.

Strizzi L, Catalano A, Vianale G, Orecchia S, Casalini A, Tassi G, Puntoni R, Mutti L, Procopio A . Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J Pathol. 2001 Apr; 193(4):468–475 Krug LM, Curley T, Schwartz L, , Richardson S, Marks P, Chiao J, Kelly WK . Potential role of histone deacetylase inhibitors in mesothelioma: clinical experience with suberoylanilide hydroxamic acid. Clin Lung Cancer. 2006 Jan; 7(4):257–261.

Linda L. Garland, Kari Chansky, Antoinette J. Wozniak, Anne S. Tsao, Shirish M. Gadgeel, Claire F. Verschraegen, Marco A. DaSilva, Mary Redman, and David R. Gandara . Phase II study of erlotinib in patients with malignant pleural mesothelioma: a Southwest Oncology Group Study. J Clin Oncol. 2007 Jun 10; 25(17):2406–2413.

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COMMUNITY ACQUIRED MRSA Dr Namita Bedi Amity Institute of Biotechnology, Amity University grovernamita@yahoo.co.in INTRODUCTION CA-MRSA is a type of Staphylococcus bacteria that is usually manifested as skin infections, similar to a pimple or a boil. CA-MRSA is contracted by individuals who have not been hospitalized or had a medical procedure within the past year. Risk factor for CA-MRSA include: recent antibiotic use, recurrent skin disease and overcrowding. CAMRSA is transmitted primarily through direct skin to skin contact, but can also be spread through contamination of environmental surfaces such as clothing and towels. If left untreated CA-MRSA can infect the blood and bones and can potentially be life threatening .In recent years, there have been cluster of skin and soft tissue infection in certain groups such as prison inmates, sportsmen and kindergarden school kids. However CA-MRSA is not limited to these populations, CA-MRSA outbreak have also occurred in healthy people who come into contact with individuals unaware that they may have the infection.( Vourli et al,2009).

Skin and soft tissue infections are the most common manifestation of CA-MRSA. Invasive CA-MRSA and even death have been increasingly reported (Wang et al, 2007). Some cases developed sepsis with multiple focal infection including pneumonia, pyomyosistis, arthritis or osteomyelitis. Pulmonary septic embolism secondary to primary site infections, often bones or joints, was a common and characteristic manifestation in severe adult and pediatric cases. (Chen et al, 2005).

CHARACTERISTICS STAPHYLOCOCCUS

OF

STAPHYLOCOCCUS

AUREUS

AND

METHICILLIN

RESISTANT

Staphylococcus aureus is a Gram-positive bacterium that can colonise and infect humans. It can be carried harmlessly in the nostrils, throat, and skin (particularly in areas such as the axilla and groin). S. aureus can rapidly colonise broken or abnormal skin, such as superficial wounds, ulcers, psoriasis and eczema. It may not produce any symptoms, but on occasion it produces boils or can enter the bladder or the blood stream resulting in UTI and bacteraemia. S. aureus causes disease either by the production of a toxin that produces tissue destruction or by direct invasion and destruction of tissue. Most S. aureus infections resolve spontaneously or in response to antibiotic treatment, but in recent years there has been increasing concern about the emergence of S. aureus strains that have developed resistance to multiple antibiotics.

Antibiotic resistance first became apparent in S. aureus in the 1950s when strains of bacteria emerged that possessed penicillin destroying Ă&#x;-lactamase enzymes and became widespread. This led to the development and use of semisynthetic penicillins such as methicillin and flucloxacillin that were resistant to the penicillin-destroying enzymes produced by S. aureus and other bacteria. Methicillin resistant Staphylococcus aureus (MRSA) was first described in 1961, almost immediately after the agent was introduced into clinical practice. It is interesting to note that MRSA also emerged in countries where methicillin had not yet been used. Staphylococci would have likely encountered penicillin-producing moulds in various environments over several million years and MRSA resistance probably represents a more primitive type of penicillin resistance compared to the S. aureus penicillin-destroying enzymes that appeared later on.

COMMUNITY-ACQUIRED MRSA It is likely that these strains evolved separately within the community, either associated with the widespread utilization of methicillin in general practice or by random evolution and subsequent spread or occur in the community in patients who have had significant exposure to healthcare. One of the key characteristics of CA-MRSA is that, by contrast with HA-MRSA, it is more prevalent among children and young adults where they cause infections of cuts, wounds and abrasions. One of the main reasons for concern is that unlike HA-MRSA, some S. aureus strains circulating in the community (both CAMRSA and MSSA) strains have acquired the ability to produce the PVL toxin, which can lead to skin and soft tissue infections. In some cases these organisms can cause severe invasive infections such as septic arthritis, bacteraemia, or community-acquired necrotizing pneumonia (Miller et al, 2005). An early skin infection often has the initial appearance of an insect bite. These infections often develop into cellulitis, furuncles, large boils or clusters of boils (up to 10cm in diameter) and deep-seated abscesses often in the thighs or buttocks. If the bacteria gain access to the lungs, fortunately a rare event, a devastating pneumonia that kills more than 40% of patients can result (Frazee, 2005).

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CA-MRSA and PVL gene The PVL toxin was first reported in 1932 and is encoded by a mobile bacteriophage that can transfer the ability to produce the toxin to other strains. PVL is a bicomponent (lukS-PV and lukF-PV), pore-forming exotoxin that targets cells of the immune system such as polymorphonuclear neutrophils. PVL-producing strains including CA-MRSA have preferentially been isolated from furuncles, cutaneous abscesses, and severe necrotic skin infections, suggesting the participation of PVL in the pathological process (Yamasaki et al., 2005).Although most PVL-related infections are uncomplicated skin infections, they bear the risk of developing severe systemic infections such as bacterial endocarditis (Bahrain et al., 2006). Some are primarily fatal owing to necrotizing pneumonia (Gillet et al., 2002) and necrotizing fasciitis (Miller et al., 2005).

In the USA, on the other hand, suggests that PVL-positive CA-MRSA is easily transmissible not only within families but also on a larger scale in community settings such as prisons, schools and sports teams. Skin-to-skin contact (including intact skin) and indirect contact with contaminated objects such as towels, sheets and sport equipment are the primary vehicles of transmission. Johnson et al, 2005 cites risk factors for spread of CA-MRSA as close skin-to-skin contact, cuts and abrasions, shared contaminated items or surfaces, poor hygiene and crowded living conditions.

THE CHAIN OF INFECTION TRANSMISSION IN THE HOME In order to understand the extent of the threat associated with pathogens such as MRSA in the home, it is necessary to first understand the extent to which they are present in our homes and how they are spread, such that family members become exposed and infected. Within the home there is a chain of events that takes place when a family member develops an infectious disease. The chain as applied to the home (see Fig. 1) has five essential links, all of which have to be in place for an infection to pass from its original source to another person. These five links are

Person at risk

Source of germs:

All at risk, but some are at higher risk

people, pets (colonized or infected) Contaminated food or water.

Way in for germs

Way out for germs

Inhaled, ingested, through

faces, vomit, skin, scales, wound

Cuts, wounds, damaged mucous membrane

exudates, droplets of mucous

Spread of germs

:

Via hands, surfaces, cleaning utensils, clothing Personal hygiene items Figure1. The chain of Infection for transmission in the home

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WHY CA-MRSA IS IMPORTANT? CA-MRSA infections have the advantage that they are sensitive to most antibiotics other than methicillin and are thus treatable, provided they are recognized as MRSA. Concerns have been expressed that, if the evolution of MRSA continues, the concepts of hospital and community MRSA strains may become blurred (klutymans,2006; Diederen,2006). Community strains might more resemble hospital strains in terms of antibiotic resistance and thus would be harder to treat. In the same way, HA strains could become more dangerous if they acquire toxin genes, and could cause serious disease in younger, healthier people. There are now concerns, most particularly in the USA that CA-MRSA strains are migrating into the hospital setting following admission of affected patients. While this is under investigation, there is another indication that blurring between CA-MRSA and HA-MRSA is occurring.

Workers in the USA have also reported that CA-MRSA show faster replication rates than HA-MRSA strains when grown in the laboratory.

DIAGNOSTIC TEST FOR MRSA Screening of Staphylococcus spp. from clinical specimens The clinical isolates will be inoculated onto Columbia blood agar (Merck, NJ, USA) plates with 5% sheep blood for 24 h at 37°C. The staphylococcal isolates were identified morphologically and biochemically by standard laboratory procedures . The coagulase plasma test will be performed on organisms that exhibited typical staphylococcal colony morphology, to allow for discrimination of S. aureus from CoNS. Susceptibility testing for methicillin resistance and other antibiotic resistance phenotypes was carried out by the Kirby-Bauer methods (CLSI,2001) MIC of methicillin was determined by E-test kits (AB Biodisk, Solna, Sweden). The results were categorized according to CLSI standards.PCR based molecular analysis will be done for S.aureus and PVL gene.

HOW TO CONTROL MRSA

1. Environmental Cleaning & Disinfecting for MRSA 2. Laboratory testing for MRSA. 3. MRSA Tracking: A full picture of invasive MRSA infections is possible using two complimentary systems: a. Emerging Infections Program (EIP) –surveillance representative of the whole country. b. National Healthcare Safety Network (NHSN) – data entered from hospitals.

INTERNATIONAL AND NATIONAL VIEW OF MRSA Today, MRSA is a major cause of healthcare (hospitals, nursing homes, etc.) associated infections worldwide.

Recently, it has also become an important cause of infections outside of the hospital in the community (Naimi et al, 2003). In late 2007, the Centers for Disease Control and Prevention (CDC) released a study indicating that on an annual basis; approximately 94,000 patients develop serious MRSA infections resulting in 18,650 deaths (Klevens et al, 2007). These numbers are higher than previously estimated. While serious MRSA infections occur more commonly in the hospital, 15% occurred in persons without any exposure to the healthcare setting.

Timothy et al, 2003 from USA studied 1100 MRSA infections, 131 (12%) were community-associated and 937 (85%) were health care–associated; 32 (3%) could not be classified due to lack of information. Skin and soft tissue infections were more common among community-associated cases (75%) than among health care–associated cases (37%) (odds ratio [OR], 4.25; 95% confidence interval [CI], 2.97-5.90). Although community-associated MRSA isolates were more likely to be susceptible to 4 antimicrobial classes (adjusted OR, 2.44; 95% CI, 1.35-3.86), most community-associated infections were initially treated with antimicrobials to which the isolate was nonsusceptible.

Chatterje et al, 2009 had done studies on Community acquired methicillin resistant Staphylococcus aureus (CAMRSA) Colonization rates of MRSA in the community have been reported to range from 0 to 9.2 per cent. The present study was conducted to detect S. aureus nasal colonization and prevalence of MRSA in children (5 to 15 yr) in an Indian community setting of rural, urban and semi-urban slums, as also evaluation of an in-house PCR to detect MRSA. The overall prevalence of S. aureus nasal colonization was 52.3 per cent and that of MRSA 3.89 per cent. CA-MRSA nasal carriage was 3.16 per cent in children without prior exposure to health care settings. PCR detection directly on nasal swabs.

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Miller LG, Perdreau-Remington F, Rieg G, et al.. Necrotising fasciitis caused by community-association methicillin resistant Staphylococcus aureus in Los Angeles. N Engl J Med 2005; 352: 1445-53.

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Naimi, T. S., K. H. LeDell, K. Como-Sabetti, S. M. Borchardt, D. J. Boxrud,J. Etienne, S. K. Johnson, F. Vandenesch, S. Fridkin, C. O’Boyle, R. N.Danila, and R. Lynfield. Comparison of community- and health careassociatedmethicillin-resistant Staphylococcus aureus infection. JAMA ;2003. 290.

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Timothy S, Naimi MD, Kathleen H, LeDell MPH et al.Comparison of Community- and Health Care–Associated Methicillin-Resistant Staphylococcus aureus Infection. JAMA. 2003; 290:2976-2984.

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Vourli S, Vagiakou H, Ganteris G, et al. High rates of community-acquired, Panton-Valentine leukocidin (PVL)- positive methicillinresistant S. aureus (MRSA) infections in adult outpatients in Greece. Eurosurveill. 2009; 14 (2).

Wang R,Braughton KR, Kretschmer D, Bach TH, Queck SY, Li M et al. Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA.Nat Med .2007;13:1510-4.

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Yamasaki O, Kaneko J, Morizane S, Akiyama H, Arata J, Marita S et al. (2005)The association between Staphylococcus aureus strains carrying Panton- Valentine leukocidin genes and the development of deep-seated follicular infection. Clin Infect Dis 40:381–5

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DESIGNER T CELL THERAPY: A NOVEL APPROACH IN CANCER MANAGEMENT 1

Tuhin Rashmi and Tapan K S Chauhan Assistant Professor, Amity Institute of Biotechnology Amity University, Sec 125, Noida, India trashmi@amity.edu, tuhinrashmi@gmail.com

1

Abstract The world is experiencing an alarming and unexplained increase in the incidence of Cancer, a widely spread disease and a major cause of painful deaths all over the world. Cancerous cells have this uncanny ability to evade the immune system, because of which they survive in the patients’ body and eventually manage to bring about gross changes like inflammation, transformations, proliferations, angiogenesis, invasions and metastasis in the patient.

Novel immunotherapies hold the potential to rethink the landscape of cancer treatment and also cancer survival.

Designer T cell for cancer immunotherapy is an emerging area of interest in the oncology community as these immune cells have the ability to recognize and combat malignant tumors. Increased evidence suggests that immunotherapy can result in long term responses across multiple tumor types when combined with traditional therapies. Such combination of treatments may someday allow cancer to become a manageable condition in future.

Key words: Immunotherapy, Designer T cell, Receptor, Ligand INTRODUCTION Cancer is not one disease but a complex of several disorders that share a profound growth dysregulation.

Oncogenesis may be attributed to a wide variety of reasons like chemical exposure, radiation exposure, microbial and viral infections. Age, race, environmental and geographical influences along with hereditary predispositions are also major contributors to the spread and occurrence of this disease. While majority of cancers are sporadic, several are familial. It is characterized by uncontrollable cell growth and proliferation resulting in the formation of neoplastic tumors. A tumor when detectable contains a population of cells which originated from the clonal multiplication of a single cell. Study of such cells reveals that they incur mutations in four classes of important regulatory genes; which are genes for cell growth (proto-oncogenes and tumor suppressor genes), apoptosis and DNA repair. Mutation in a single gene is not reason enough to cause cancer, but a stepwise accumulation of mutations increases the predisposition to malignancy and its progression. In fact, a patients’ total population of tumor cells have been shown to progressively accumulate mutations over a period of time and this makes the cancer patients gradually unresponsive to a variety of traditional anticancer treatments available to patients.

Every attack does not however, result in malignancy because tumor cells are routinely faced with the body’s immune system which recognizes them as non self cells and tries to destroy them. Cell-mediated activities are responsible for antitumor activity where tumor antigens are presented on the cell surface MHC class I molecules and are recognized by CD8+CTLs. However, mechanisms like loss or reduced expression of histocompatibility antigens, selective expression of antigen negative variants or by secretion of immunosuppressive factors by tumor cells they develop the capability to evade immune surveillance of the system and establish themselves.

The treatment of cancer is variable depending upon its type, stage, age, health status, and is governed by physiological as well as psychological factors. Till date, there is no single treatment of cancer and the patients receive a combination of medical therapies and intensive care. Treatment involves procedures like surgery, radiotherapy, chemotherapy, hormone therapy, immune-therapy and gene therapy.

Surgery: It is the oldest and commonest method involving complete removal of the tumor cells or tissues from the patient body.

Radiation: It involves applying specific type of high intensity radiation and rays on tumor cells for killing them.

Chemotherapy: It depends on chemical treatment of cancerous tissue.

Hormone therapy: In hormone therapy, the level of the hormone in the body is altered which results in the elimination of the cancer cells or minimizing the proliferation of tumor cells.

Gene therapy: - In gene therapy, damaged genes are replaced with the working genes.

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Immune-therapy: Immune-therapy aims to boost up the immune system to fight against cancer cells. There are two ways through which the immune-therapy works:1. Local immune-therapy: - Cancer site is eliminated by injecting immune treatment at specific locations so as to kill the proliferation of cells.

2. Systemic immune-therapy: - In systemic immune-therapy, several agents are administered to treat the whole body such as protein interferon alpha that shrinks the cancer cells.

When the disease in question is cancer the objective of a treatment becomes attacking the growth and spread of tumor cells. Using immunotherapy as a tool the immune system of cancer patients can be empowered to fight cancer.

Adoptive immunotherapy by infusion of designer T cells (dTc) engineered with chimeric antigen receptors (CARs) for tumoricidal activity represents a potential and highly specific mode for treatment of cancer (Ma Q et.al, 2013).

Vivian, 2011, is optimistic about the success of this therapy in future.

DESIGNER (FABRICATED) T CELL APPROACH Fabricated T cell therapy has a promising therapeutic value in cancer treatment. This involves the action of modified patient’s T cells by designing the Chimeric Antigen Receptor (CAR) of specific protein or ligand like CD19 in vitro.

In fact, the patients’ T cells found in their blood are genetically re-engineered with a strict agenda to fight tumor cells and kill them. In simple words a key is expressed on the surface of T cells and this fits into a lock which only cancer cells express. Tumor cells with defined antigens have been successfully targeted with adoptively transferred T cells (Rosenberg et al., 2008) and this therapy in which tumor infiltrating lymphocytes (TIL) is used has shown success for specific diseases (Rosenberg et.al., 1986).

Lentiviral vector is extensively used in this gene transfer. It is reportedly safe when experimented on mice, and is reliable and effective in remission of the cancer (Morgan et.al., 2006).

In another technique introduction of scFv receptor on the patient T cells enables them to bind with antibody which in turn binds to the cancerous cell and this competitive binding of antibody to cancer cell and scFv receptor of designer T cell to the antibody results in the elimination of the target cell (Eshhar Z et.al., 1996).

In the clinical trial conducted by researchers at the University of Pennsylvania, a single genetically engineered T-cell which is a type of white blood cell was able to destroy approximately 1,000 cancer cells, multiply itself by 1,000 times and survive for number of months and this progression was found to be sustaining.

CONSTRUCTION OF GENETICALLY MODIFIED T CELLS Peripheral blood is the site of lymphocytes’ isolation from where they are activated before retroviral transduction with a chimeric immune receptor (CIR) gene (Emtage et. al., 2008). The gene which encodes for the specific CAR molecule is inserted into the patient T cells in vitro. The so modified T cells are re-infused back into the patient and these designer T cell (dTc) have specific antitumor activity in patient with the suitable antigen of target tumor (Steven C Katz et.al. , 2013).

The 2nd - and 3rd generation CARs typically consists of a piece of monoclonal antibody, called single-chain variable fragment (scFv), that resides on T-cell membrane (Fig1). It is the scFv which guides cell to its target antigen.

Researchers are still improving CAR T cell production, in addition to testing various delivery vectors and different stimulatory molecules to see which ones can help produce the most potent T cells.

UNIQUE FEATURE OF THE DESIGNER T CELL APPROACH As observed, conventional therapies like chemotherapy, radiation etc, though, most popular treatment option for cancer patients are known to progressively become less and less effective in several cancer patients. They are also often painful with devitalizing side effects on patients.

This therapy only involves modification of patient’s existing T cells to enhance their recognition capacity such that even most evasive, elusive and resistant cancer cells become targets of this empowered immune surveillance.

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Figure 1: Components of second- and third-generation chimeric antigen receptor T cells.

Courtesy: American Association for Cancer Research: Daniel et al., (2010).

CASE STUDY Emily Whitehead, a case of acute lymphoblastic leukemia, was treated with all conventional therapies possible.

Upon enrolling in trial study for T cell therapy at the hospital of Philadelphia under the supervision of Dr Stephan A. Grupp, MD, Emily was infused with these modified T cells. She had an initial complain of flu like high fever along with symptoms suggestive of Rheumatoid arthritis for which she was administered medicines. Once the fever was controlled Emily’s condition improved and she stabilized and recovered. Astonishingly, the bone marrow profile, for estimation of efficiency, performed 3 weeks later revealed complete remission of the disease in Emily. The rheumatoid arthritis was attributed to the cytokine release syndrome associated with this treatment and it was easily taken care of (CHOP ; 2012).

Four year old Nick Wilkins was diagnosed with leukemia which kept coming back even after being given a bone marrow transplant. At 14 years of age, he was enrolled in the clinical trial of genetically modified T cell therapy at the University of Pennsylvania and only 2 months after enrollment he was completely cured (Elizabeth Cohen, 2013).

MAJOR CHALLENGES TO THE THERAPY Three major issues pertaining to this technique need to be addressed before this therapy can become accepted.

1.

These designer cells are unable to differentiate between the malignant B cells and normal B cells. For example, designer T cells expressing the chimeric antigen receptor for CD19 ligand present on the malignant B cells, targets the normal B cells expressing the same ligand on their surface in addition to the desired cancer cells.

2.

There is over-expression of some proteins e.g., several cytokines in patients. .

3.

The random integration of the desired gene of interest in the genome of the patient T cells sometimes results in the non-functioning of the dT cells.

4.

Being in the experimental stages this therapy is very expensive at this stage.

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IMPORTANCE OF STUDY There is a strong possibility that CAR T cell therapy will be the standard therapy for several B cell cancers, like ALL and chronic lymphocytic leukemia as reported in several studies (Kochenderfer and Rosenberg, 2013). Chris, 2013 in his latest studies has shown that the genetically engineered T cells can effectively wipe out tumors in a mouse model of lymphoma. Collective effort from regulatory organizations, biological firms, medical centers and academic institutions would lead to the development of comprehensive approaches to maximize the efficacy of cancer immunotherapy in providing quality life to patients of this deadly disease.

REFERENCES CHOP; (2012) "Emily Whitehead's Story: T cell therapy to treat acute lymphoblastic leukemia"; Children’s hospital of Philadelphia (CHOP).

2. Eshhar Z, Bach N, Fitzer-Attas CJ, Gross G, Lustgarten J,Waks T, Schindler DG; (1996); “The T-body approach: potential for cancer immunotherapy.” Springer Semin Immunopathol”: 18: 199–209 3. Elizabeth Cohen, Senior Medical Correspondent ; (December 9, 2013) ; “Killing cancer like the common cold” ; http://edition.cnn.com 4. Emtage PC, Lo AS, Gomes EM, Liu DL, Gonzalo-Daganzo RM, Junghans RP ; (2008) ; “Second-generation anti-carcinoembryonic antigen designer T cells resist activation-induced cell death, proliferate on tumor contact, secrete cytokines, and exhibit superior antitumor activity in vivo: a preclinical evaluation” ; Clin Cancer Res ,14:8112–8122.

5. Daniel W L, David MB, Crystal M, et. al.,; 2012; “ The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer”. Clin Cancer Res; 18(10); 2780–90.

6. Ma Q, Gomes EM, Lo AS, Junghans RP ; (2013) “Advanced generation anti-prostate specific membrane antigen designer T cells for prostate cancer immunotherapy”; Department of medicine; PMID:24174378 7. Morgan RA, Dudley ME, Wunderlich JR; (2006) “Cancer regression in patients after transfer of genetically engineered lymphocytes.”

Science: 314: 126–9.

8. Rosenberg SA; (2004); “Shedding light on immunotherapy for cancer”; N Engl J Med: 350: 1461–3.

9. Rosenberg SA, Spiess P, Lafreniere R; (1986) ; “A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes.” Science 233:1318–1321.

10. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME; (2008); “Adoptive cell transfer: a clinical path to effective cancer immunotherapy”. Nat Rev Cancer , 8:299–308.

11. Steven CK, Rachel AB, Seema N, Lauren A L, Mitchell T, Doreen O, Cang T N, Joseph NE, Jonathan AF and Richard P J; (2013) “Anti-KIT designer T cells for the treatment of gastrointestinal stromal tumor” ; Journal of Translational Medicine, 11:46 12. Vivan Giang, (2011); “Genetically engineered T cells raise hope for big cancer breakthrough.” Aug-11-2011 ; Business insider.com.

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ROLE OF CANCER STEM CELLS IN BREAST CANCER 1

Sahil Nagpal 1 and Navkiran Kaur* Student, B.Sc (Hons) Medical Biotechnology and *Assistant Professor, Amity Institute of Biotechnology, Amity University, Noida navkirank@amity.edu

INTRODUCTION Two major models of tumor cell initiation have been proposed, namely, the stochastic model, in which each cell contains a low but similar probability to acquire the accidental genetic mutations resulting in the capacity of proliferation and survival and the stem cell model, in which tumor initiation is driven by cancer stem cells (CSC).

The term stem cell is referred to undifferentiated cells that have two basic properties: the capacity to self-renew and the capacity to generate daughter cells that can differentiate in different cell lineages. Normal adult stem cells have relatively long telomeres compared to more differentiated somatic cells, they are usually quiescent or proliferate more slowly than their differentiated progeny, and they have increased longevity; for this reason, they are exposed to more damaging agents than more differentiated cells over time. Thus, they accumulate mutations that are then transmitted to the rapidly proliferating progeny.

The stem cell origin of cancer hypothesis considers that stem cells or other differentiated cells that have acquired self-renewal ability tend to accumulate genetic or epigenetic alterations and evade the strict control of their microenvironment and these cancer stem cells (CSCs) could be responsible for the malignant transformation and the progression of the disease. The CSCs are a population of cells that are more tumourigenic than the bulk tumor population and can be defined mainly through the expression of unique properties, such as specific detoxification enzyme systems, molecular surface markers, and embryonic signaling pathways [1]. The main hallmarks of CSCs are their properties of self-renewal, their ability to generate tumors from very few cells, their slow cell division rate, their ability to give rise to phenotypically diverse progeny, and their selective resistance to radio- and chemotherapy [2] .

MAMMARY GLAND AND MAMMARY STEM CELLS (MaSCs) The human mammary gland is a compound tubuloalveolar gland. Within each breast is a mammary gland, which is a modified sudoriferous or sweat gland, that produces milk. A mammary gland consists of 15-20 lobes separated by a variable amount of adipose tissue. Each lobe is made up of smaller lobules which are composed of milk-secreting glands, termed alveoli, embedded in connective tissue.The mammary epithelium is composed of two lineages of epithelial cells: luminal cells (that differentiates into alveolar and ductal cells) and myoepithelial cells. A small number of ductal basally positioned small undifferentiated cells (also called electron-lucent cells when observed by electron microscopy) represent the normal mammary stem cells. These normal mammary stem cells provide the capacity for extensive cellular expansion associated with pregnancy and also generate differentiated cells that support lactation [3]. The origin of mammary gland based in stem cells has been demonstrated in several experiments that show how one single stem cell can generate the entire mammary gland. The primitive breast stem cells are estrogen receptor negative. These cells generate progenitor cells that finally differentiate into luminal and myoepithelial lineages which are defined by specific sets of markers.

CHARACTERIZATION OF MAMMARY STEM CELLS An exact identification of a human mammary epithelial stem cell has yet to be solidified, but many groups have identified putative mammary epithelial progenitor cells. Technical challenges have arisen due to the complex nature of the hormonal requirements for MaSC differentiation and also for a suitable environment to support growth. Work with human breast stem cells builds on the foundations of experiments investigating the murine population.

Kuperwasser et al., has reported that in the development of a humanized murine fat pad representing the human breast stroma injected with a mixture of irradiated and nonirradiated human mammary epithelial cells allow for the successful engraftment of the stromal cells and for the creation of a humanized environment [4]. More recently, a new model has been described by Eirew et al., where fibroblast and putative mammary stem cells are engrafted in a collagen plug under the murine kidney capsule. The outgrowths observed recapitulate the hierarchal nature of the normal human mammary gland [5]. Through the use of these assays, CD49fhiEpCAM− has been established as the fraction containing the human breast stem cell population. To complement these cell surface markers, a functional marker, aldehyde dehydrogenase 1A1 (ALDH+) (Fig. 1) has been established as a functional marker for mammary stem cells among others [6]. www.giapjournals.org/bioevolution.html

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Fig. 1 The Aldefluor assay The Aldefluor assay is a fluorometric assay that detects the enzymatic activity of aldehyde dehydrogenase 1 (ALDH1) (StemCell Technologies, Vancouver, BC, Canada). Cells are incubated with the intrinsically fluorescent ALDH substrate, BODIPYaminoacetaldehyde (BAAA). BAAA is a neutral molecule and enters the cell through passive diffusion, where it is then converted into BAA− by ALDH and is unable to leave the cell due to its negative charge. The active removal of BAA− by ATP Binding Cassettes is quenched through the use of the assay buffer and through incubation of cells between 2 and 8°C. The resulting fluorescence of the cells is then assessed by flow cytometry, providing single cell analysis of ALDH activity. As a negative control, the activity of ALDH is quenched by the addition of diethylaminobenzaldehyde (DEAB), and the fluorescence of these cells is assessed by flow cytometry. The population observed the DEAB sample is used to create the gate for the ALDH+ cells, whereby cells are only included if they demonstrate higher levels of fluorescence compared to the DEAB sample. Adapted from StemCell Technologies.

BREAST CANCER AND CANCER STEM CELLS (CSCS) Breast cancer may originate from either the glands or the ducts of the breast and is termed lobular or ductal carcinoma respectively. When the cancer extends beyond it’s immediate surroundings, it is known as invasive cancer. Cancer that has not crossed beyond the involved lobule or tubule is called in-situ carcinoma. Types of breast cancers include ductal carcinoma in situ, lobular carcinoma in situ, invasive ductal carcinoma and invasive lobular carcinoma. Less common types of breast cancers include inflammatory breast cancer, triplenegative breast cancer, paget disease of the nipple, phyllodes tumor and angiosarcoma.

The cancer stem cell hypothesis proposes a different model based on a hierarchical organization [7]. According to this hypothesis, a neoplasia originates from the malignant transformation of an adult stem cell through the deregulation of the normally tightly regulated self-renewal program [8]. This model holds that a breast carcinoma may contain genetically and morphologically diverse populations of cells, including primitive stem cells, luminal or basal progenitor cells (also called sometimes transient amplifying cells), and terminally differentiated cells Perhaps, a neoplasia arises from a tumorigenic CSCs rather than from the much larger population of neoplastic progenitor cells. This means that mutations in one stem cell could be transmitted to descendant cells, which can then launch new clonal successions. Conversely, mutation then strikes the genomes of transit-amplifying cells cannot be transmitted further, because these cells only have a limited replicative ability. Therefore, the CSCs represent a minority of the neoplastic cells in tumor masses, while the progenitor and differentiated neoplastic cells represent the majority of the bulk of the tumour. Most cancer cells have only limited proliferative potential, but CSCs have self-renewal capacity that could drive the tumorigenesis process. www.giapjournals.org/bioevolution.html

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In human breast cancer, different reports try to prove how the stem cells are targets for malignant transformation, by the demonstration of mutational changes in genes or in pathways essential for the self-renewal process. BRCA1 gene (Breast Cancer tumor suppressor gene 1), implicated in inherited breast cancer, plays an important role in stem cell self-renewal and in differentiation of a progenitor cell. Because of the BRCA1 gene function in DNA repair and in maintaining chromosome stability, researchers have proposed that the loss of BRCA1 function may produce genetically unstable stem or progenitor cells that serve as prime target for further carcinogenic events [9].

It was proposed that breast carcinogenesis may be initiated by epigenetic changes such as silencing of p16 INK4a.

Since p16INK4a is known to be a downstream target of the polycomb gene BMI1 which regulates stem cell selfrenewal [10].

STEM CELL NICHES Stem cell niches are defined as locations in a tissue which specifically can support the existence of somatic stem cells. These niches contain stromal cells, fibroblasts, and immune cells and these cells maintain the growth and allow repopulation of stem cells in case of depletion of the stem cell compartment.

Recently the mesenchymal stem cells (MSC) have been implicated in the breast CSCs niches. This heterogeneous and multipotent subset of mesenchymal stroma cells have fibroblast-like morphology, form colonies that can differentiate into adypocytes, osteocytes, and chondrocytes; are important in the control of niches through its recruitment from bone-marrow to this niches by the signals of IL-6 and IL-8 and its receptors in the stem cells (CXCL7, CXCR1, respectively). The interaction between MSC and CSC has been demonstrated both in vitro and in in vivo mouse models. The cytokine network involving CSC and the microenvironment stimulates self-renewal of breast CSC and accelerates the growth of human breast cancer, and has focused the attention of investigators to target this novel pathway [11].

It is possible that tumour therapy that disrupts the stem cell niche through ablation of the surrounding differentiated cells could lead to the subsequent death of the cancer stem cells. Alternatively, tumour therapy that depletes stem cells, but does not eradicate the stem cell niche, could lead to repopulation of the stem cell niche with additional cancer stem cells.

IDENTIFICATION OF CANCER STEM CELLS Advances in cell culture approaches have been important in identifying and studying mammary stem cells. In order to validate the method selected as an appropriate technique to isolate CSC, it is crucial to use assays that can assess the stem cell properties of its self-renewal and its differentiation.

Xenograft The xenograft model is based on the orthotopic injection of human cancer cells into the humanized cleared fat pad of immunodeficient mice. It can initiate and maintain the tumor growth upon serial passages. It is presently the most robust model for demonstrating stem cell properties. In addition to self-renewal, CSC also retain the ability to differentiate, albeit abnormally, also generating non-self-renewing cell population that constitutes the bulk of the tumor [12].

In Vitro assays The study of mammary stem cells in vitro has been based upon work identifying neural stem cells through a cell culture assay known as the neurosphere assay, which makes use of serumfree medium supplemented with epidermal growth factor and basic fibroblast growth factor [13, 14]. Application of the neurosphere assay culture conditions has been used to identify undifferentiated human mammary stem cells grown in culture [15] known as mammospheres.

Tumorosphere-initiating cells have stem cell properties including the ability to survive and grow in suspension in serum-free conditions. In contrast, more differentiated tumor cells are anchorage-dependent and undergo anoikis in these conditions [16]. The tumorosphere culture has also been used in different studies to screen for drugs capable of targeting the cancer stem cell populations.

Side Population Technique This method is useful to identify stem cell population in breast cancer cell lines. This method is based on the overexpression of transmembrane transporters, such as the adenosine triphosphate (ATP)-binding cassettes molecule ABCG2/BCRP1 in stem cells. These molecules actively exclude vital dyes such as Hoechst 33342 or Rhodamine 123, a property not found in differentiated cells that retain the dye [17]. www.giapjournals.org/bioevolution.html

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MARKERS USED TO IDENTIFY CSCS Selectable markers are either found on the cell surface or confer functional properties that are characteristics of normal stem cells that have extended to malignant stem cell populations. The current definition of a breast CSC is CD44+CD24- and/or ALDH+.

THE ROLE OF CSCS IN METASTASIS Metastatic cascade consists of a series of processes that move tumor cells from the primary tumor to distant location.

Various factors are involved in intravasation, extravasation, and survival in bloodstream and in the target organ. The induction of epithelial-to-mesenchymal transition in breast cancer cells results in the acquisition of stem-cell properties, including the ability to form mammospheres, resistance to apoptotic signals, facilitates the blood intravasation, and generation of circulating tumor cells. Different studies show that a significant proportion of circulating tumor cells shows stem cell phenotype, such as expression of NOTCH1, ALDH1, and are typically triple negative (estrogen and progesterone receptor-negative and HER2- negative)[20].

The most common site of breast cancer metastasis is the bone, but metastatic lesions are also found in the lymph nodes, liver, lungs, and brain. Interestingly, both HA and osteopontin, common ligands for CD44, are expressed in the bone and other common sites of breast cancer metastasis [21], suggesting a possible adhesive interaction for circulating tumor cell arrest. Experimentally, CD44 has been shown to mediate the attachment of metastatic breast cancer cells to human bone marrow endothelial cells [22]. Additionally, breast cancer cell lines exhibit different levels of C-X-C chemokine receptor type 4 (CXCR4), which appears to correlate with CSC proportions and the tendency to metastasize [19, 23].

BREAST CSCS AND THERAPY RESISTANCE Recent studies have indicated that breast CSCs and other CSCs are more resistant to radiation and chemotherapy as compared to cancer cells. A study in human leukemia revealed that CSCs are often quiescent, and remain in the G0 phase, conferring resistance to many chemotherapy agents as they often target actively replicating cells [24]. Possible mechanisms for this include the expression of cell surface pumps, including ABCG2/BCRP1, capable of expelling chemotherapeutic drugs [25]. Additionally, the presence and activity of ALDH allows CSCs to metabolize cytotoxics such as cyclophosphamide [19]. Other factors potentially prolonging the lifespan of CSCs include the increased expression of anti-apoptotic molecules such as BCL2 and surviving [26, 27]. Furthermore, the radiotherapy resistance of CSCs may be due to the decreased levels of pro-oxidants in the CD44+CD24− population or through Wnt/bcatenin pathway signaling [28]. New therapeutics aimed at eliminating cancer stem cells could also be achieved through a variety of methods: THERAPEUTIC STRATEGIES TO TARGET CSCS Reactive oxygen species (ROS), critical mediators of ionizing radiation-induced cell killing, are shown to be present at lower levels in some subsets of the CSC population in breast cancer. Lower ROS levels in CSCs are associated with an increased expression of free radical scavenging systems predisposing CSCs to develop less DNA damage and preferential sparing after irradiation. Pharmacological depletion of ROS scavengers in CSCs significantly decreases their clonogenicity and results in radiosensitization [29].

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15. Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, Wicha MS: In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 2003, 17:1253-1270.

16. Ponti D, Costa A, Zaffaroni N, et al. (2005) Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 65:5506–5511 17. Kim M, Turnquist H, Jackson J, et al. (2002) The multidrug resistance transporter ABCG2 (breast cancer resistance protein 1) effluxes Hoechst 33342 and is overexpressed in hematopoietic stem cells. Clin Cancer Res 8:22–28 18. Croker AK, Goodale D, Chu J, Postenka C, Hedley BD, Hess DA, Allan AL (2009) High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability. J Cell Mol Med 13 (8B):2236–2252 19. Moreb JS (2008) Aldehyde dehydrogenase as a marker for stem cells. Curr Stem Cell Res Ther 3 (4):237–246 20. Mego M, Mani SA and Cristofanilli M. (2010) Molecular mechanisms of metastasis in breast cancer – clinical applications. Nat Rev Clin Oncol 7: 693–701 21. Brown LF, Berse B, Van de Water L, Papadopoulos-Sergiou A, Perruzzi CA, Manseau EJ, Dvorak HF, Senger DR (1992) Expression and distribution of osteopontin in human tissues: Widespread association with luminal epithelial surfaces. Mol Biol Cell 3 (10):1169–1180 22. Draffin JE, McFarlane S, Hill A, Johnston PG, Waugh DJ (2004) Cd44 potentiates the adherence of metastatic prostate and breast cancer cells to bone marrow endothelial cells. Cancer Res 64 (16):5702–5711. doi:10.1158/0008-5472.CAN-04 0389 64/16/5702 [pii] 23. Dewan MZ, Ahmed S, Iwasaki Y, Ohba K, Toi M, Yamamoto N (2006) Stromal cell-derived factor-1 and cxcr4 receptor interaction in tumor growth and metastasis of breast cancer. Biomed Pharmacother 60 (6):273–276. doi:S0753-3322(06)00086-2 [pii] 10.1016/j.biopha.

2006.06.004 24. Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, Nakamura R, Tanaka T, Tomiyama H, Saito N, Fukata M, Miyamoto T, Lyons B, Ohshima K, Uchida N, Taniguchi S, Ohara O, Akashi K, Harada M, Shultz LD (2007) Chemotherapy-resistant human aml stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 25 (11): 1315–1321. doi:nbt1350 [pii] 10.1038/nbt1350 25. Engelmann K, Shen H, Finn OJ (2008) Mcf7 side population cells with characteristics of cancer stem/progenitor cells express the tumor antigen muc1. Cancer Res 68 (7):2419–2426. doi:68/7/2419 [pii] 10.1158/0008-5472.CAN-07-2249 26. Lee CW, Simin K, Liu Q, Plescia J, Guha M, Khan A, Hsieh CC, Altieri DC (2008) A functional notch-survivin gene signature in basal breast cancer. Breast Cancer Res 10 (6):R97. doi:bcr2200 [pii] 10.1186/bcr2200 56. Madjd Z, Mehrjerdi AZ, Sharifi AM, Molanaei S, Shahzadi SZ, Asadi-Lari M (2009) Cd44+ cancer cells express higher levels of the anti-apoptotic protein bcl-2 in breast tumours. Cancer Immun 9:4. doi:090304 [pii] 27. Dave B, Chang J (2009) Treatment resistance in stem cells and breast cancer. J Mammary Gland Biol Neoplasia 14 (1):79–82. doi:10.1007/s10911-009-9117-9 121.

28. Woodward WA, Chen MS, Behbod F, Alfaro MP, Buchholz TA, Rosen JM (2007) Wnt/betacatenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci USA 104 (2):618–623. doi:0606599104 [pii] 10.1073/pnas.0606599104 29. Diehn, M., Cho, R.W., Lobo, N.A., Kalisky, T., Dorie, M.J., Kulp, A.N., Qian, D., Lam, J.S., Ailles, L.E., Wong, M., Joshua, B., Kaplan, M.J., Wapnir, I., Dirbas, F.M., Somlo, G., Garberoglio, C., Paz, B., Shen, J., Lau, S.K., Quake, S.R., Brown, J.M., Weissman, I.L., and Clarke, M.F. (2009). Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458(7239): 780-783.

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IMPACT OF NANOTECHNOLOGY ON ENVIRONMENT Dr. Arti Goel, Assistant Professor, Amity Institute of Microbial Biotechnology, Amity University, Noida (U.P.). agoel2@amity.edu, peena_agrawal@yahoo.co.in Nanotechnology has direct beneficial applications for medicine and the environment, but like all technologies it may have unintended effects that can adversely impact the environment, both within the human body and within the natural ecosystem. While taking advantage of this new technology for health, environmental, and sustainability benefits, science needs to examine the environmental and health implications. The impact of nanotechnology extends from its medical, ethical, mental, legal and environmental applications, to fields such as engineering, biology, chemistry, computing, materials science, military applications, and communications.

Advances in nanotechnology may be able to provide more sensitive detection systems for air and water quality monitoring, allowing the simultaneous measurement of multiple parameters and real time response capability. Metal oxide nanocatalysts are being developed for the prevention of pollution due to industrial emissions and the photocatalytic properties of titanium dioxide nanoparticles can be exploited to create self-cleaning surfaces that reduce existing pollution. However, while nanotechnology might provide solutions for certain environmental problems, relatively little is known at present about the environmental impact of nanoparticles, though in some cases chemical composition, size and shape have been shown to contribute to toxicological effects. Nanotechnology can assist resource saving through the use of lightweight, high strength materials based on carbon nanotubes and metal oxide frameworks as hydrogen storage materials. Other energy related applications include nanostructured electrode materials for improving the performance of lithium ion batteries and nanoporous silicon and titanium dioxide in advanced photovoltaic cells.

It is important to develop an efficient strategy for the recycling and recovery of nanomaterials and methods are needed to assess whether the potential benefits of nanotechnology outweigh the risks. Life cycle analysis will be a useful tool for assessing the true environmental impacts. The potential positive and negative effects of nanotechnology on the environment are discussed. Advances in nanotechnology may be able to provide more sensitive detection systems for air and water quality monitoring, allowing the simultaneous measurement of multiple parameters and real time response capability. Metal oxide nanocatalysts are being developed for the prevention of pollution due to industrial emissions and the photocatalytic properties of titanium dioxide nanoparticles can be exploited to create self-cleaning surfaces that reduce existing pollution.

However, while nanotechnology might provide solutions for certain environmental problems, relatively little is known at present about the environmental impact of nanoparticles, though in some cases chemical composition, size and shape have been shown to contribute to toxicological effects. Nanotechnology can assist resource saving through the use of lightweight, high strength materials based on carbon nanotubes and metal oxide frameworks as hydrogen storage materials. Other energy related applications include nanostructured electrode materials for improving the performance of lithium ion batteries and nanoporous silicon and titanium dioxide in advanced photovoltaic cells. It is important to develop an efficient strategy for the recycling and recovery of nanomaterials and methods are needed to assess whether the potential benefits of nanotechnology outweigh the risks. Life cycle analysis will be a useful tool for assessing the true environmental impacts.

Nanotechnology's environmental impact can be split into two aspects: the potential for nanotechnological innovations to help improve the environment, and the possibly novel type of pollution that nanotechnological materials might cause if released into the environment.

USE NANOTECHNOLOGY TO 

Help clean up past environmental damage



Correct present environmental problems



Prevent future environmental impacts



Help sustain the planet for future generations

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ENVIRONMENTAL APPLICATIONS OF NANOTECHNOLOGY A strong influence of nanochemistry on waste-water treatment, air purification and energy storage devices is to be expected. Mechanical or chemical methods can be used for effective filtration techniques. One class of filtration techniques is based on the use of membranes with suitable hole sizes, whereby the liquid is pressed through the membrane. Nanoporous membranes are suitable for a mechanical filtration with extremely small pores smaller than 10 nm (“nanofiltration”) and may be composed of nanotubes. Nanofiltration is mainly used for the removal of ions or the separation of different fluids.

Magnetic nanoparticles offer an effective and reliable method to remove heavy metal contaminants from waste water by making use of magnetic separation techniques. Using nanoscale particles increases the efficiency to absorb the contaminants and is comparatively inexpensive compared to traditional precipitation and filtration methods.

Nanoscale iron particles have also shown potential as a detoxifying agent for cleaning environmental contaminents from brownfield sites.

POTENTIAL ENVIRONMENTAL EFFECTS Nanoparticles have higher surface areas than the bulk materials which can cause more damage to the human body and environment compared to the bulk particles. Therefore, concern for the potential risk to the society due to nanoparticles has attracted national and international attentions. Nanoparticles are not only beneficial to tailor the properties of polymeric composite materials and environment in air pollution monitoring, but also to help reduce material consumption and remediation. For example: carbon nanotube and graphene based coatings have been developed to reduce the weathering effects on composites used for wind turbines and aircraft. Graphene has been chosen to be a better nanoscale inclusion to reduce the degradation of UV exposure and salt. By using nanotechnology to apply a nanoscale coating on existing materials, the material will last longer and retain the initial strength longer in the presence of salt and UV exposure. Carbon nanotubes have been used to increase the performance of data information system. However, there are few considerations of potential risks need to be considered using nanoparticles:  The major problem of nanomaterials is the nanoparticle analysis method. As nanotechnology improves, new and novel nanomaterials are gradually developed. However, the materials vary by shape and size which are important factors in determining the toxicity. Lack of information and methods of characterizing nanomaterials make existing technology extremely difficult to detect the nanoparticles in air for environmental protection.  Also, information of the chemical structure is a critical factor to determine how toxic a nanomaterial is, and minor changes of chemical function group could drastically change its properties.  Full risk assessment of the safety on human health and environmental impact need to be evaluated at all stages of nanotechnology. The risk assessment should include the exposure risk and its probability of exposure, toxicological analysis, transport risk, persistence risk, transformation risk and ability to recycle.  Life cycle risk assessment is another factor that can be used to predict the environmental impacts.  Good experimental design in advance of manufacturing a nanotechnology based product can reduce the material waste. Nanoparticles may interact with environment in many ways: it may be attached to a carrier and transported in underground water by bio-uptake, contaminants, or organic compounds. Possible aggregation will allow for conventional transportation to sensitive environments where the nanoparticles can break up into colloidal nanoparticles. There are four ways that nanoparticles or nanomaterials can become toxic and harm the surrounding environment.  Hydrophobic and hydrophilic nanoparticles: Nanocoating researchers are currently working on TiO2 powder as a coating inclusion that will reduce the weathering effects, such as salt rain degradation on composite materials. Ivana Fenoglio, et al expressed their concern that the effect of TiO2 nanoparticles to be assessed when leaked into the environment  Mobility of contaminants: There are two general methods that nanoparticle can be emitted into atmosphere.

Nanoparticles are emitted into air directly from the source called primary emission, and are the main source of the total emissions. However, secondary particles are emitted naturally, such as homogeneous nucleation with ammonia and sulfuric acid presents.

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 Solubility: Nanoparticles are invented and developed in advance of the toxic assessment by scientists. Many of the nanoparticles are soluble in water, and are hard to separate from waste if inappropriately handled.  Disposal: Any waste product, including nanomaterials, can cause environmental concerns/ problems if disposed inappropriately.

POSITIVE EFFECTS ON ENVIRONMENT Nanotechnology offers potential economic, societal and environment benefits. Nanotechnology also has the potential to help reduce the human footprint on the environment by providing solutions for energy consumption, pollution, and green gas emissions. Nanotechnology offers the potential for significant environmental benefits, including:  Cleaner, more efficient industrial processes  Improved ability to detect and eliminate pollution by improving air, water, and soil quality  High precision manufacturing by reducing amount of waste  Clean abundant power via more efficient solar cells  Removal of greenhouse gases and other pollutants from the atmosphere  Decreased need for large industrial plants  Remediating environmental damages NEGATIVE EFFECTS ON ENVIRONMENT Understanding of the environmental effects and risks associated with nanotechnology is very limited and inconsistent. The potential environmental harm through nanotechnology can be summarized as follows:  High energy requirements for synthesizing nanoparticles causing high energy demand  Dissemination of toxic, persistent nanosubstances originating environmental harm  Lower recovery and recycling rates  Environmental implications of other life cycle stages also not clear  Lack of trained engineers and workers causing further concerns.

FORMATION, EMISSION, OCCURRENCE AND FATE OF NANOPARTICLES (NP) IN THE ENVIRONMENT Assessing the risks imposed by the use of nanomaterials in commercial products and environmental applications requires a better understanding of their mobility, bioavailability, and toxicity. For nanomaterials to comprise a risk, there must be both a potential for exposure and a hazard that results after exposure. Release of NP may come from point sources such as production facilities, landfills or wastewater treatment plants or from nonpoint sources such as wear from materials containing NP. Accidental release during production or transport is also possible. In addition to the unintentional release there are also NP released intentionally into the environment. nZVI, for example, is directly injected into groundwater polluted with chlorinated solvents. Whether the particles are released directly into water/soil or the atmosphere, they all end up in soil or water, either directly or indirectly for instance, via sewage treatment plants, waste handling or aerial deposition. In the environment the formation of aggregates and therefore of larger particles that are trapped or eliminated through sedimentation affects the concentrations of free NP. Humans can be either directly influenced by NP through exposure to air, soil or water or indirectly by consuming plants or animals which have accumulated NP. Aggregated or adsorbed NP will be less mobile, but uptake by sediment-dwelling animals or filter feeders is still possible.

SUGGESTED READING 1.

2.

3.

Colvin, V.L. The potential environmental impact of engineered nanomaterials. Nat. Biotechnol. 2003, 21, 1166-1170.

Savage, N. and Diallo, M.S. Nanomaterials and water purification: Opportunities and challenges. J. Nanopart. Res. 2005, 7, 331-342.

Prentice, T. and Reinders, L.T. The world health report 2007: a safer future: global public health security in the 21st century. World Health Organization. 2007, 1-96.

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5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

Frechet, J.M.J.; Tomalia, D.A. Dendrimers and Other Dendrtitic Polymers. Wiley Series in Polymer Science; Wiley: Chichester, England, 2001; pp. 648.

Ottaviani, M.F.; Favuzza, P.; Bigazzi, M.; Turro, N.J.; Jockusch, S.; Tomalia, D.A. A TEM and EPR investigation of the competitive binding of uranyl ions to Starburst dendrimers and liposomes: Potential use of dendrimers as uranyl ion sponges. Langmuir 2000, 16, 73687372.

Lard, M.; Kim, S.H.; Lin, S.; Bhattacharya, P.; Ke, P.C.; Lamm, M.H. Fluorescence resonance energy transfer between phenanthrene and PAMAM dendrimers. Phys. Chem. Chem. Phys. 2010, 12, 9285-9291.

Diallo, M.S. Water treatment by dendrimer enhanced filtration. United States Patent 2008, 11/182,314, 1-40.

Halford, B. Dendrimers branch out. Chemical and Engineering News 2005, 83, 30-36.

Chen, P.; Yang, Y.; Bhattacharya, P.; Wang, P.; Ke, P.C. A tris-dendrimer for hosting diverse chemical species. J. Phys. Chem. C 2011, 115, 12789-12796.

Bhattacharya, P.; Conroy, N.; Rao, A. M.; Powell, B.; Ladner, D. A.; Ke, P. C. PAMAM dendrimer for mitigating humic foulant, RSC Adv. 2012, 2, 7997–8001.

Bhattacharya, P.; Chen, P.; Spano, M.N.; Zhu, L.; Ke, P.C. Copper detection utilizing dendrimer and gold nanowire-induced surface plasmon resonance. J. Appl. Phys. 2011, 109, 014911-1-6.

Bhattacharya, P.; Kim, S. H.; Chen, P.; Chen, R.; Spuches, A. M.; Brown, J. M.; Lamm, M. H.; Ke, P. C. Dendrimer-fullerenol softcondensed nanoassembly. J. Phys. Chem. C 2012, 116, 15775-15781.

Lee, C.C.; MacKay, J.A.; Frechet, J.M.J.; Szoka, F.C. Designing dendrimers for biological applications. Nat. Biotech. 2005, 23, 1517-1526.

Mortimer, M.; Kasemets, K.; Heinlaan, M.; Kurvet, I.; Kahru, A. High throughput kinetic Vibrio fischeri bioluminescence inhibition assay for study of toxic effects of nanoparticles. Toxicology in Vitro 2008, 22, 1412-1417.

Tang, M.X.; Redemann, C.T.; Szoka, F.C. In vitro gene delivery by degraded polyamidoamine dendrimers. Bioconjugate Chem. 1996, 7, 703-714.

Geitner, N. K.; Bhattacharya, P.; Steele, M.; Ladner, D. A.; Ke, P. C. Understanding dendritic polymer-hydrocarbon interaction for oil dispersion. RSC Adv. 2012, Advance Article (DOI: 10.1039/C2RA21602G).

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NANOMATERIAL BASED SENSORS Monika Joshi Assistant Professor, Amity Institute of Nanotechnology Amity University, Noida India mjoshi@amity.edu The word sensor is derived from the Latin word “sentire� which means to perceive [1] A sensor is a device that responds to some stimulus by generating a functionally related output. A sensor is a device that converts a physical quantity into an electrical signal. The change can be measurable by an instrument coupled with Sensor. Once the physical quantity has been converted into an electrical equivalent it could be put as an easily input to a computer or microprocessor for analyzing and displaying the data. Typical sensors are cameras, radiometers, scanners, lasers, thermal devices, seismographs, magnetometers and gravimeters.

A sensor consists of mainly three elements: a nonelectrical input device, processing device that converts a nonelectrical signal into electrical signal and an output device. The output of a sensor depends on the high fidelity mapping of these elements only.

Sensors can model various parameters: Physical parameters such as temperature, displacement, acceleration and chemical and biochemical parameters such as concentration of specie, ions or molecules and their molecular interactions [2]. From recent few years Scientists have been introducing new materials like nanomaterials and their composites to improve the efficiency of sensors.To meet this challenge Nanotechnology is being applied to enabling the development of small, inexpensive and highly efficient sensors.

CHRACTERISTICS OF SENSOR The characteristics of a sensor may be classified as being either static, or dynamic. Static characteristics are those that can be measured after the final or steady state of a sensor has reached. On the other hand dynamic characteristics describe the sensor’s time dependent properties. (i)

Sensitivity: The degree of response of a sensing material under the exposure of input species is known as sensitivity of the sensor.

(ii)

Selectivity: A sensor response to measure a single input in presence of the other inputs is known as selectivity.

(iii)

Repeatability: When all the ambient conditions are same, the repeatability of the sensor is to produce the same results for the same input conditions.

(iv)

Accuracy: An accuracy of a sensor is always comparative against a standard system with some known accuracy. In order to get the accuracy of a sensor the output of the sensor should always be compared against a standard sensor.

(v)

Error: The difference between the true value of the measuring and the value of the measured by the sensor is known as the error of the sensor.

(vi)

Hysteresis: A hysteresis of the sensor is the capability to find the difference between the same input species when approached from lower to higher values or higher to lower values.

(vii)

Response time: The response time of a sensor is expressed as a time period in which it will change its output with respect to the change in input.

(viii)

Noise: Noise of a sensor refers to the sudden changes in the output when the input is not changing.

NANOMATERIAL BASED SENSORS Recent advances in sensor industry have results novel classes of materials known as nanomaterials.A nanomaterials can included a nanoparticles, nanowires, nanorods and nanostructures films. Nanotechnology can enable sensors to detect very small amounts of input species (even of the level of ppb). Various types of detecting elements, such as carbon nanotubes, zinc oxide nanowires or palladium nanoparticles can be used in nanotechnology-based sensors[3].

Nanomaterials can enhance sensing properties via an increased surface area to volume ratio, improving the active sensing area available for the interaction with the target molecules due to its small size (10-9m). Quantum dots of semiconductor nanomaterials like Ag,Au have a possible area to design new class of sensor where strong quantum www.giapjournals.org/bioevolution.html

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confinement effects alters the optical electrical properties by changing simple parameters like layer thickness, materials composition. Additionally, strong photon and phonon quenching and amplification are also observed for such surfaces that cannot be seen in conventional bulk materials. With such alterations the output of the sensor can be drastically changes with the small change in input of the sensor. Surface of nanoparticles can be functionalized for specific sensing applications, which makes a sensor more accurate and selective.

REFERANCES 1.

C. A. Grimes, E. C. Dickey, and M. V. Pishko (2006), Encyclopedia of Scientific Publishers, ISBN 1-58883-056-X

2.

Nylabder, C.; Armgrath, M.; Lundstrom, I. An ammonia detector based on a conducting polymer. Proceedings of the International Meeting on Chemical Sensors, Fukuoka, Japan, 1983, 203-207.

3.

Dubbe, A. Fundamentals of solid state ionic micro gas sensors. Sens. Actuators B 2003, 88, 138-148.

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Sensors (10-Volume Set), American

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CITRIC FROM BIOWASTE: CHALLENGES AND PROSPECTS Seema Raj1 and Nidhee Chaudhary* Amity Institute of Biotechnology, Amity University, Noida-201303, India *nidhee.chaudhary@gmail.com, 1seemaraj1980@yahoo.co.in Abstract Citric acid is an important multifunctional organic acid with a broad range of versatile uses in household and industrial applications that has been produced industrially since the beginning of 20th century. It is a hydroxyl tri-carboxylic acid strong organic (C6H8O7) acid with high solubility in water. It is widely used as it is nontoxic, safe to handle, and easily biodegradable. Several hundred of thousands metric tons of citric acid are produced worldwide every year almost exclusively by fermentation. There is a great worldwide demand for citric acid consumption due to its low toxicity when compared with acidulents used mainly in the pharmaceutical and food industries. The various applications of citric acid can be found in detergent and cleaning products, cosmetics and toiletries, etc. Global production has now reached 1.4 million tons and there is annual growth of 3.5-4.0% in demand /consumption of citric acid. Any increase in citric acid productivity would be potential interest and hence there is an obvious need to consider all possible ways in which this might be achieved. Today, essentially all of the commercial citric acid is produced by fermentation. Surface or submerged fermentation by mold (Aspergillus niger) and submerged fermentation by yeast (e.g. Candida guilliermondii), using a variety of substrates.

I. CITRIC ACID FERMENTATION 1. Different microorganisms used for citric acid fermentation From many centuries scientists have been trying to emulate nature by synthesizing citric acid. In 1784 Swedish chemist C.W. Sheele succeeded in isolating citric acid from lemons. After that it was the work of Currie which opened up the way for successful industrial production of citric acid. In 1916 he found that numerous strains of Aspergillus niger produced significant amount of citric acid. A large number of microorganisms including fungi and bacteria such as, Bacillus licheniformis, Arthrobacter paraffinens, Corynebacterium sp., Aspergillus niger, A. aculeatus, A. carbollarius, A. awamori, A. foetidus, A. fonsecaeus, A. Phoenicis, Penicillium jallthinellum and yeasts such as Candida tropicalis, , C. guilliermondii, C. oleophila, C. citroformans, Hanselula allamola and Yarrowia lipolytica have been employed for citric acid production [1-3]. Most of them, however, are not able to produce commercially acceptable yields due to the fact that citric acid is a metabolite of energy metabolism and its accumulation rises in appreciable amounts only under conditions of drastic imbalances.

Among the mentioned strains, the fungus A. niger is the organism of choice for commercial production because it produces more citric acid per time unit. Easy handling, ability to ferment cheap raw material and high yield are the advantages of A. niger. Other side for citric acid production sector are the improvement of citric acid producing strain, which have been carried out by mutagenesis and selection.

2. Bio waste as a substrate 2.1. Citric acid from fruits and agro waste In the last years, a considerable interest has been shown in using agricultural products as alternative sources of carbon and their wastes such as maize, apple [4, 5] and grape pomace, pineapple, mandarin orange and brewery wastes, citrus, kiwi fruit peel, pumpkin [6], jackfruit [7] and spoiled coconut [8] for citric acid production by Aspergillus niger. The industry is seeking newer cheap and economic process technology. So wheat straw, sugar cane bagasse, corn stover and other agro wastes can be used for citric acid production [9, 10] 2.2. Citric acid from dairy products Large number of Whey is produced world wide as a by-product of cheese and other dairy products manufacturing. Whey in the Middle Eastern region is generally considered a waste and disposed in the sewage system leaving a small amount for drinking for domestic animals. From various studies it come to consideration that production of citric acid by A. niger from cheese whey fortified with different concentrations of sucrose, glucose, fructose, galactose, methanol, tricalcium phosphate and riboflavin in a surface culture process.

2.3. Citric acid from Molasses In the cuisines of the Middle East, molasses is produced from various other materials carob, grape, date, pomegranate, and mulberry. Several raw materials such as hydrocarbons, starchy materials and molasses, have been employed as substrates for commercial submerged citric acid production [11-14], although citric acid is mostly produced from starch or sucrose based medium using submerged fermentation. Molasses is preferably www.giapjournals.org/bioevolution.html

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used as the source of sugar for microbial production of citric acid due to its relatively low cost and high sugar content (40-55%) [15]. It is a by-product of sugar refinery; according to availability of different type molasses it is not necessary that all types are suitable for citric acid production.

II. BIOSYNTHESIS OF CITRIC ACID Citric acid is produced as an overflow product due to the faulty operation of the TCA cycle. Many theories have been proposed regarding the role of TCA cycle with respect to citric acid accumulation [16]. The earlier studies suggested that accumulation of citric acid is possible due to the loss in the activity of aconitase and isocitric

dehydrogenase. Several tracer studies unequivocally showed that citric acid is mainly formed by the glycolytic pathway and subsequent condensation of a C4 and a C2 moiety. Several studies have been done to understand the various aspects of citric acid accumulation.

Citric acid production synthesis by fermentation is the most economical and widely used way of obtaining this product. More than 90% of the citric acid produced in the world is obtained by fermentation. Citric acid production by fermentation can be divided in three phases, which include preparation and inoculation of the raw material, fermentation, and recovery of the product. The industrial citric acid production can be performed in three different ways: by submerged surface and solid-state fermentation or ‘Koji’ process [17, 18]. To obtain the desired product from the fermented broth, in a final form, is one of the most important parts of any fermentation industry. For citric acid recovery, first mycelium is to be separated from the broth and then citric acid is extracted by classical calcium oxide precipitation method or by solvent extraction method.

III. TECHNOLOGY ADVANCES There was some advance technology used for the production of citric acid by A. niger in biochemical aspects, membrane transport and modelling [19]. The hyper productivity of citric acid is also studied by using mutant strain GCBT7 [20]. A manganese resistant mutant [21] of Aspergillus niger (CBS III) both in free or immobilized state have been used for the production of citric acid from molasses [22].

IV. FUTURE PROSPECTS An increase in citric acid productivity would be of potential interest and hence there is an obvious need to approach all possible ways in which this might be achieved. Many by-products and residues of the agro-industry can be used in the production of citric acid. A cost reduction in citric acid production can be achieved by using less expensive substrates. The production by submerged fermentation is still dominating. However, solid-state processes can create new possibilities for producers. The use of agro-industrial wastes as support in solid-state www.giapjournals.org/bioevolution.html

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fermentation is economically important and minimizes environmental problems. If we go through the future perspective and challenges, high citric acid yield giving strains need to be approach. Such innovative strategies can decrease the cost and increase the production of citric acid. The integrated fermentation and product recovery method should be used which we can apply in large scale production of citric acid.

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Soccol , L Vandenberghe P S, Rodri C, et al., Patent Pt. Br. Deinpt/PR 00175, 1999.

Anastassiadis S and Rehm H J, Electronic Journal of Biotechnology, 2005, ISSN 0717-34584.

Hoseyini M, N Asefi and M Mozaffari , Agricultural journal, Vol (6), No ( 5), 2011, 226-230.

Dhillon G, Brar S, Verma M and Tyagi R, Journal of Applied Microbiology, Vol (110), 2011, 1045–1055.

Majumder L, Khalil I, Munshi M K, et al. Europeon J. of Biological Sciences, Vol (2), No (1), 2010, 01-08.

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AN INTRODUCTION TO AIR QUALITY INDEX AND HEALTH CONCERNS Dr. Era Upadhyay Assistant Professor Ansal Institute of Technology & Management, Lucknow (U.P.) era.upadhyay@gmail.com Air pollution arises due to contamination of solid or liquid particles and gases in the environment. The presence of this contamination in the atmosphere in certain quality and for certain duration implies the effect of harm, or expected to be harm to environment, property and health of human, animal & plant life. Contamination in air is the result of discharge of harmful substances from various sources in the atmosphere and may cause to health effects on the population, which might be either chronic or acute depends upon exposure. Other effects of air pollution include agricultural damage, impairment of visibility, and climate change that leads to global warming.

Air pollution results from various reasons including the reasons beyond the human control i.e. natural disasters.

Gaseous and particulate matters emitted from natural calamities like volcanoes, storms, forest fires etc. in the form of ash and toxic fumes into the atmosphere, contribute to air pollution. The explosions of such natural disasters are related to measurable climatic changes. Climate change affects the natural resource systems across the Earth, which disturbs sustainability12,20,21. Increasing frequency and intensity of droughts in many parts of Asia are attributed largely to a rise in temperature, particularly during the summer and normally drier months3,10,16,17,19,20,21,22,23,34. Atmospheric brown clouds, layers of air pollution containing a wide range of aerosol components including black carbon and organic carbon, dust, sulphates and nitrates, have been observed in China and India25. The climatic stimuli are affecting the system adversely and likely to build the Universe more sensitive to the degree to which a system is susceptible, responsible for vulnerability 4,5.

The vulnerability resulted out from the exposure to air pollution causes various types of diseases in human beings, for example asthma, lung cancer, heart diseases, inflammation and infection in the lungs, which leads to chronic obstructive pulmonary disease. Emphysema may also occur due to accumulation of smoke in the lungs.

Recently, long-term health effects of exposure to blast have been observed during wars in Iraq and Afghanistan33. Due to the exposure to blast, many Gulf War veterans have experienced various unexplained symptoms like fatigue, muscle and joint pain, memory loss, and gastrointestinal disorders32. The Institute of Medicine concluded that pollution from the burn pits had caused any long-term health problems due to chemicals released and could lead to cancer, anaemia, and liver, kidney, heart and respiratory problems. The chemicals can also harm the brain and reproductive system.

In Indian context, a number of sources that are directly and indirectly contributed to the particulate pollution, ranging from domestic combustion to transport sector 28. Several studies relating air pollution and health have been conducted in Delhi region1,23and Chronic respiratory morbidity was reported due to PM, SO 2 and NOx6.

Ozone reacts with molecules in the lining of our breathing airways. Short term acute effects of ozone include pulmonary function decrements, increased airway responsiveness and airway inflammation, aggravation of preexisting respiratory diseases like asthma, increase in daily hospital admissions and emergency department visits for respiratory causes, and increased mortality rates26,29. Hence, in polluted urban regions of India health impact of air pollutants is extremely significant. Recently, Centre for Science and Environment assessed air pollution levels in Beijing and Delhi and reported that PM 10 levels of Delhi nearly double that in Beijing. In case of PM2.5 levels, continuous daily average of three months (Nov’2013 – Jan’ 2014), in India shows approximately 240 �g/m3, which is about four times higher than the Indian National Ambient Air Quality standards. During this period the peak level was as high as 575�g/m3 in Delhi, but did not cross 400 �g/m3 in Beijing 31. CSE’s analysis also claims that 39,780 cancer cases in Delhi might occur due to lifetime inhalation and exposure to PAH concentrations.

Therefore, studies show that actual risk depends on the pollutant type and concentration, duration of exposure to the polluted air and current health status.   

Pollutant type and concentration- Particular type and high level of pollutant make hard supply of oxygen to the body; damage of the cells in the respiratory system causes abrupt health problems like cardiovascular and respiratory illness, stress to heart and lungs.

Duration of exposure- Long-term exposure to polluted air could result in permanent health effects like asthma, bronchitis, emphysema, cancer, aging of the lungs, decrease in lung capacity and functioning, reduced life span etc.

Current health status- The patients of heart, lung disease, pregnant women, children, and outdoor workers are most susceptible to health harms due to exposure of air pollution.

Health may be affected either by indoor or outdoor air quality. As per the World Health Organization (WHO), approximately 2 million per year untimely deaths are attributed due to outdoor and indoor air pollution. www.giapjournals.org/bioevolution.html

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Common indoor and outdoor air pollutants, their sources, and health impacts are listed in the tables given as below (Table 1.1 & 1.2)18: TABLE 1.1: COMMON INDOOR AIR POLLUTANTS, THEIR SOURCES, AND HEALTH IMPACTS Indoor Air Pollutants

Pollutant Source(s)

Health Impacts

Cooking processes

Biomass fuels, coal

Headaches, drowsiness, dizziness, respiration problem, vision & brain functioning, nausea, mental confusion and flu

Perfumes, hair sprays, furniture polish, glues, air fresheners, Pesticides, moth repellents, preservatives

Eye, nose, throat irritation, headaches, loss of coordination, confusion, damage to liver, kidneys, and brain

Smoke

Tobacco

Eye, nose and throat irritation, respiratory irritation, Bronchitis and pneumonia, risk of emphysema, lung cancer, and heart disease

Biological substances

Pollen, dust mites, pet hair, fungi, parasites, bacteria

Allergies, asthma, headaches, eye, nose and throat irritation, colds, flu, and pneumonia.

Formaldehyde

Carpets, particle boards, insulation foam

Allergic reactions, eye, nose and throat irritation, headaches, nausea, dizziness, coughing and cancer

Asbestos

Construction

Chest, abdominal and lung cancers and asbestosis

Radon

Radioactive decay of uranium/ radium. In house affects due to poor ventilation

Lung cancer

and

Volatile compounds

burning

organic

SOURCE : IAQ FS2 8/2000

TABLE 1.2: COMMON OUTDOOR AIR POLLUTANTS, THEIR SOURCES, AND HEALTH IMPACTS Outdoor Air Pollutant

Pollutant Source(s)

Major Health Concern

Suspended particulate matter (SPM, PM10, PM2.5)

Organic and inorganic substances in solid / liquid/ mixed form

Disturbed lung’s gas exchange function causes respiratory illness

Ozone (O3), ground level

Formation of photochemical smog produced by the interaction of sunlight and air pollutants

Respiratory infections (colds, pneumonia), breathing difficulties and asthma

Nitrogen dioxide (NO2)

Part of PM2.5 and O3, found in nitrate aerosols, produced by burning fuels, electricity generation and vehicle engines

Long-term intake is toxic, reduces lung function and causes bronchitis in asthmatic children

Sulphur dioxide (SO2)

Burning fossil processes

Decreases pulmonary function. causes eye irritation and respiratory inflammation (coughing, infections, mucus secretion, asthma attacks, bronchitis)

Carbon dioxide (CO2)

Burning coal, oil and natural gases

Lowers oxygen levels, reduces respiratory and brain functions, causes vision defects

Carbon monoxide (CO)

Cigarettes and burning petrol, diesel, and wood

Lowers blood oxygen levels, slows reflexes, increases confusion and sleepiness

Lead (Pb)

Petrol, diesel, lead batteries, paints, and colouring agents

Damages nervous system in children

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fuels

and

industrial

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BioEvolution ISBN 978-81-925781-3-2, May 2014, pg 51-54 SOURCE : HTTP :// HEALTH . INDIA . COM / DISEASES - CONDITIONS / AIR - POLLUTION - URGENT - CAUSE - FOR - CONCERN

To measure the impact of air quality on health, a key tool ‘Air Quality Index (AQI)’is used to provide simple information on local air quality and the health distresses at different levels of air pollutants. The higher the AQI value, the greater will be the level of air pollution, which means the greater the health concerns due to exposure to polluted air. AQI aims to make easier the air quality means to health and divided into six categories with specific colour to each category, corresponds to a different level of health concern (Table 1.3).

TABLE 1.3: AIR QUALITY INDEX AND LEVELS OF HEALTH CONCERN (AQI) Values

Levels of Health Concern

Colour

Health Concern

0 to 50

Good

Green

Satisfactory, may be little or no risk

51 to 100

Moderate

Yellow

Moderate health concern for sensitive Group

101 to 150

Unhealthy Groups

Orange

Sensitive groups may experience health effects.

151 to 200

Unhealthy

Red

Risk to everyone’s health and serious health effects to sensitive group.

201 to 300

Very Unhealthy

Purple

Everyone is more likely to be affected.

301 to 500

Hazardous

Maroon

More serious health effects to everyone

for

Sensitive

S OURCE: HTTP:// AIRNOW . GOV/ INDEX . CFM ? ACTION =AQIBASICS . AQI

AQI calculation-Air quality is monitored on daily basis to record the concentrations of the major pollutants at different locations. This data is then converted into AQI values by using standard formulas developed by Environmental Protection Agency. An AQI value for each pollutant is calculated in the particular area. The highest AQI value for the individual pollutants is the AQI value for that day 2.For example, if today a certain area has AQI values of 85 for PM2.5and 60 for Nitrogen dioxide, the AQI value would be 85 for the pollutant PM2.5 for today. An AQI value of 100 generally corresponds to the National Ambient Air Quality Standard (NAAQS) for the pollutant.

AQI values depend on type of season and time. PM2.5 was observed high concentration in winter and low concentrations in the monsoon due to removal by precipitation and wet deposition14. Another study observed the monthly average maximum concentration in summer was found to be in the range of 62-95 ppb13and exceeds the lower limit of 90ppb on a number of occasions during afternoon 15.During the day ozone concentration observed increasing gradually after sunrise, which attained maximum value during noon time and afterwards decreased27.

Now, the question is how to prevent the diseases arise due to exposure of bad air quality? It is essential to aware the public about the status of air quality and make responsible to take steps to reduce the air pollution. By knowing the Air Quality Status at regional level, the public can make efforts to minimize exposure to poor air quality and Individuals can also contribute to reducing, avoiding, and countering air pollution. General precautions may be taken by each one of us to improve the air quality like outdoor air pollution could be reduced by using public transport, energy-efficient appliances, avoid burning biofuel and cycling & walking to commute etc. Indoor air pollution may be decreased bykeeping house clean without using harmful chemical cleaners so that insects, dust, molds, mildew could be avoided. Keeping proper ventilation and smokeless house may help to control accumulation of poor air in the house. An antioxidants rich diet may also play a major role to prevent from harmful impacts of major air pollutants by boosting immunity in the body. Therefore, involvement of scientific and non-scientific approaches in policy decisions may encourage public participation and effective implementation.

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