All rights reserved. Contents are the property of the authors and/or journals cited. Cover Image from “Myostatin Inhibition Using mRK35 Produces Skeletal Muscle Growth and Tubular Aggregate Formation in Wild Type and TgACTA1D286G Nemaline Myopathy Mice�
Kevin M. Koch, PhD Associate Professor Vice Chair of Translational Research Department of Radiology Director, Center for Imaging Research Medical College of Wisconsin
I am an imaging physicist specializing in MRI technology development. For over 10 years, I have worked in collaboration with clinical researchers to develop MRI techniques that are capable of assessing disease near total joint replacements. In conventional MRI, the metallic alloys used in orthopedic implants distort MRI and compromise diagnostic capabilities. Multi-spectral MRI is a technique that we developed several years ago to address these problems. Though multi-spectral MRI is now routinely used in the clinic, my research laboratory continues to develop and apply new refinements to this technology.
“Multispectral Diffusion-Weighted Imaging Near Metal Implants” Koch KM, Bhave S, Gaddipati A, et al. Magnetic Resonance in Medicine. 2018;79(2):987-993. Diffusion-weighted imaging (DWI) with MRI can assess how water molecules move in biological tissue. This information can provide important clinical diagnostics. While DWI near metallic implants is becoming increasingly relevant for a variety of clinical diagnostic applications, conventional DWI MRI methods are significantly hindered by metal‐induced image artifacts. In this paper, we present a novel approach relying on multispectral susceptibility artifact reduction techniques to address this unmet need. This approach utilizes a previously unexplored combination of several previously developed MRI technologies. An initial demonstration of this minimal‐artifact multispectral DWI is described and successfully demonstrated on clinical subjects being evaluated for sarcoma recurrence near metal implants. Clinical demonstration of 2D‐MSI diffusion‐weighted acquisition on titanium fixation hardware in the ankle. a: Axial pre‐contrast T1w MAVRIC SL 3D‐MSI. b: sagittal reformat. c and d: Pre‐ and post‐contrast subtractions of T1w images in A‐B. e: Sagittal 2D‐MSI DWI. f: Sagittal apparent diffusion coefficient (ADC) map computed from 2D‐MSI DWI. Elevated ADC is seen in a region of fluid buildup (dashed arrow, bright in T2w), which could be necrosis or hematoma, while reduced ADC (solid arrow) is seen within the region of concern and could be indicative of sarcoma recurrence.
Nirav Shah, MD, MSHP Assistant Professor Department of Medicine Division of Hematology & Oncology Medical College of Wisconsin
I am an Assistant Professor of Medicine in the Division of Hematology and Oncology. I have a clinical practice focusing on patients with lymphomatous malignancies and on those needing cell based therapies, and autologous/allogeneic transplantation. My research focus includes patients with non-Hodgkin lymphoma, and on the development of novel cellular therapies for patients with refractory B-cell malignancies, specifically using CAR-T cell technology.
“R-CHOP Versus Dose-Adjusted R-EPOCH in Frontline Management of Primary Mediastinal B-cell Lymphoma: A Multi-Centre Analysis� Shah NN, Szabo A, Huntington SF, et al. British Journal of Haematology. 2018;180(4):534-544. In this study we evaluated outcomes of two commonly utilized regimens, R-CHOP and R-EPOCH, for the management of Primary Mediastinal B-cell lymphoma (PMBCL), a rare form of nonHodgkin lymphoma. While R-CHOP has been the historical standard, there was emerging data from a non-randomized, single arm study that R-EPOCH may have advantages. In our multi-center, retrospective analysis of patients with PMBCL we found that both overall and progression free survival were similar in both treatment arms. However, there was more use of consolidative radiation therapy after R-CHOP while there were more treatment related complications associated with R-EPOCH. Based on our findings, we recommend that therapy for PMBCL be individualized to the patient with specific consideration to the patient profile and risks associated with each treatment. Figure 2. Overall Survival and Progression Free Survival Graphs
“A Cellular Threshold for Active ERK1/2 Levels Determines Raf/MEK/ERKMediated Growth Arrest Versus Death Responses” Hong SK, Wu PK, Park JI. Cellular Signalling. 2018;42:11-20.
ERK1/2 overexpression switches Raf-induced growth arrest responses to caspasedependent apoptotic death responses. These death responses, however, were reverted to growth arrest responses upon titration of cellular phospho-ERK1/2 levels by the MEK1/2 inhibitor AZD6244. These data suggest that a cellular threshold for active ERK1/2 levels affects the cell fate between death and growth arrest. We also found that death-mediating ability of ERK2 is abolished by the catalytic site-disabling Lys52Arg replacement or significantly attenuated by the F-site recruitment site-disabling Tyr261Asn replacement. These data reveal a mechanism underlying the role of ERK1/2 as a focal point of Raf/MEK/ERK-mediated growth arrest and death signaling.
Seung-Keun Hong, PhD Research Associate Department of Biochemistry
Fabian Yu Project Appointment Department of Pediatrics
“Chronic Lung Injury and Impaired Pulmonary Function in a Mouse Model of Acid Ceramidase Deficiency” Yu FPS, Islam D, Sikora J, et al. American Journal of Physiology. Lung, Cellular, and Molecular Physiology. 2018;314(3):L406-L420. Farber disease (FD) is an ultra-rare lysosomal storage disorder. In its classical form, FD results in multiorgan failure and patients die early in childhood. The most common clinical signs are manifestation of subcutaneous nodules, painful joints, and development of a hoarse voice. Unfortunately, less than 150 cases of FD have been described in the literature and limited research has been done. Our lab developed the first mouse model to better study FD. Within the available cases some patients have developed respiratory symptoms. In this paper we showed that FD mice indeed develop chronic lung injury, significant inflammation, lipid accumulation and surfactant production. Our data provides the first indepth study of lung pathology in FD, and also demonstrates the possible use of partial lung lavage in treating patient symptoms.
“Myostatin Inhibition Using mRK35 Produces Skeletal Muscle Growth and Tubular Aggregate Formation in Wild Type and TgACTA1D286G Nemaline Myopathy Mice” Tinklenberg JA, Siebers EM, Beatka MJ, et al. Human Molecular Genetics. 2018;27(4):638-648.
Nemaline myopathy (NM) is a congenital skeletal muscle disease characterized by weakness and the presence of cytoplasmic rod-like structures (nemaline bodies). To assess whether muscle growth in NM improves strength, we treated the TgACTA1D286G mouse model of NM with a myostatin inhibitor designed to promote muscle growth (mRK35, Pfizer). Treated control and NM mice displayed increases in bodyweight, forelimb grip strength, muscle size, myofiber size, and muscle fiber force, with increases in tubular aggregate structures. These findings suggest that myostatin inhibition could be a beneficial treatment strategy in at least a subset of nemaline myopathy patients.
Jennifer Tinklenberg, MS Graduate Student Department of Physiology
Marie Dreyer, BSBA Medical Student Class of 2018
“Socioeconomic Status and Breast Cancer Treatment” Dreyer MS, Nattinger AB, McGinley EL, Pezzin LE. Breast Cancer Research and Treatment. 2018;167(1):1-8. Evidence suggests substantial disparities in breast cancer survival by socioeconomic status (SES). We examined the extent to which receipt of treatments –a plausible source of disparities in survival –varies by SES among elderly women with early stage breast cancer. Poor and near-poor women were less likely than high SES women to receive sentinel lymph node biopsy and radiation after breast conserving surgery. Near-poor women who initiated hormonal therapy were more likely to use tamoxifen, and less likely to use aromatase inhibitor when compared to poor and high SES women. Our results indicate that SES disparities in the receipt of treatments for incident breast cancer are both pervasive and substantial.
“Setting Up a Clinical Trial for a Novel Disease: A Case Study of the Doxycycline for the Treatment of Nodding Syndrome Trial - Challenges, Enablers and Lessons Learned” Anguzu R, Akun PR, Ogwang R, et al. Global Health Action. 2018;11(1):1431362. Nodding syndrome is an acquired, idiopathic neurological disorder of childhood onset in Sub-Saharan Africa. This paper describes our experiences setting up a randomized controlled trial site testing the first potential treatment and nested case-control investigating its etio-pathogenesis in a remote rural district hospital in Northern Uganda. The main challenges were community fears about nodding syndrome, adverse community experiences from prior research, political involvement, number and delays in protocol approvals. Cold chain for bio-samples may be affected by frequent power fluctuations. These concerns decreased with a pilot community engagement program and may contribute to success of the trial.
Ronald Anguzu, MD, MPH PhD Student, Public & Community Health Institute for Health & Equity
Chuanwu Xia, PhD Research Scientist I Department of Biochemistry
“Structural and Kinetic Studies of Asp632 Mutants and Fully Reduced NADPH-Cytochrome P450 Oxidoreductase Define the Role of Asp632 Loop Dynamics in the Control of NADPH Binding and Hydride Transfer” Xia C, Rwere F, Im S, Shen AL, Waskell L, Kim JP. Biochemistry. 2018;57(6):945-962. NADPH-cytochrome P450 oxidoreductase (CYPOR) transfers electrons from NADPH to various electron acceptors, including cytochromes P450 via enzyme-bound FAD and FMN. We have identified Asp632 loop (G631-N635) is important for NADP(H) binding/release. In this study, structural and kinetic characterizations of D632A, D632F, D632N and D632E show that Asp632 is important for stabilizing the Asp632 loop in a retracted position required for the productive binding of the NADPH. Structures of these mutants and wildtype reduced CYPOR permit us to identify a possible pathway for NADP(H) binding to and release from CYPOR and how the loop initiates CYPOR’s domain movements modulating interflavin electron transfer.
“Spatial Discrimination of Glioblastoma and Treatment Effect with Histologically-Validated Perfusion and Diffusion Magnetic Resonance Imaging Metrics” Prah MA, Al-Gizawiy MM, Mueller WM, et al. Journal of Neuro-Oncology. 2018;136(1):13-21. Standard of care treatment for aggressive brain tumors includes concurrent chemoradiotherapy, where response is evaluated using MRI. On MRI the presence of tumor is highlighted as a bright area after a MRI dye or contrast agent is given. However, the bright area that appears can also be an effect of treatment and not tumor or can result from a mixture of both treatment and tumor. Therefore we performed a study to see if our advanced imaging measurements, such as rCBV (relative cerebral blood volume) can help distinguish between tumor and treatment effect within the bright areas. To accomplish this biopsy samples were spatially matched to rCBV images. Analyses revealed that rCBV could be used to accurately distinguish tumor from treatment effect within the dye-enhanced bright areas on MRI. Application of these results can provide additional spatial information for clinicians and increase confidence in treatment management decisions.
Melissa Prah, BS Engineer II Department of Radiology
Francie Moehring, PhD Postdoctoral Fellow Department of Cell Biology, Neurobiology & Anatomy
“Keratinocytes Mediate Innocuous and Noxious Touch via ATP-P2X4 Signaling” Moehring F, Cowie AM, Menzel AD, et al. eLife. 2018;7:e31684. The first point of the body’s contact with physical objects is the epidermis, the outermost layer of our skin that is largely made up of cells called “keratinocytes.” Here we showed that these keratinocytes play a functional role in sensing gentle and painful touch. Furthermore, we identified ATP as a key signaling molecule between keratinocytes and sensory neurons that convey skin touch information to the spinal cord and brain. Additional studies identified P2X4 as the ion channels on sensory neurons through which ATP signals. Collectively, these data demonstrate that keratinocytes potentiate sensory neuron responses to touch stimuli suggesting that both cell types mutually contribute to normal touch sensation. This study paves the way for future research into skin to sensory neuron communication errors that occur in disorders such as dermatitis or psoriasis.