All rights reserved. Contents are the property of the authors and/or journals cited. Cover Image from “Altered CYP19A1 and CYP3A4 Activities Due to Mutations A115V, T142A, Q153R and P284L in the Human P450 Oxidoreductase�
Julie A. Panepinto, MD, MSPH Professor of Pediatrics Hematology Director, Center for Clinical Effectiveness Research Vice Chair of Value, Department of Pediatrics Medical College of Wisconsin
I am a Professor of Pediatric Hematology. As a clinician researcher with a background in public health, I have focused my academic career on understanding and improving the health outcomes of patients and families with chronic disease. My research integrates the perspective of the patient and family in the care of children with chronic disease through the use of patient reported outcomes (PROs). I have also worked with big data to help understand systems of care and acute care utilization. Much of the focus of this research has been in children with sickle cell disease, but more recently I expanded this to other diseases such as cancer, diabetes, and asthma.
“Determining the Longitudinal Validity and Meaningful Differences in HRQL of the PedsQL™ Sickle Cell Disease Module” Panepinto JA, Paul Scott J, Badaki-Makum O, et al. Health and Quality of Life Outcomes. 2017;15(1):124. We conducted a multi-center prospective trial design of children 4-21 years of age with sickle cell disease who presented to the emergency department with acute vaso-occlusive painful crises. The objective of the study was to determine the longitudinal validity of the PedsQLTM Sickle Cell Disease module and the change in health-related quality of life (HRQL) that is meaningful to patients. One hundred and eighty seven patients completed the study. Over 50% of patients improved by at least 1 SEM in Total HRQL score. A HRQL change score of 7–10 in the pain domains represented minimal perceived improvement in HRQL and a HRQL change score of 18 or greater represented moderate to large improvement. The study data establish longitudinal validity and meaningful change parameters for the PedsQLTM Sickle Cell Disease Module. Table. Mean change in PedsQL™ health-related quality of life child report scores from baseline to one week post discharge as categorized by child’s perception of pain within the 7-10 days post discharge No pain since discharge
Much better
A little better
The same or worse
Domain N
Mean change (CI)*
N
Mean change (CI)*
N
Mean change (CI)*
N
Mean change (CI)*
Total Score Pain and Hurt Pain Impact Pain Management and Control and Control
19 18 19 18
20.1 (12.2, 28.0) 28.7 (17.8, 39.6) 33.1 (21.3, 44.9) 18.8 (0.8, 36.7)
59 59 58 58
15.7 (10.6, 20.7) 25.1 (18.2, 32.1) 19.8 (11.7, 28.0) 18.8 (10.9, 26.6)
41 40 42 42
5.8 (1.3, 10.3) 7.5 (1.1, 13.9) 9.1 (3.5, 14.7) 9.8 (-0.3, 20.0)
15 15 15 14
7.0 (0.4, 13.6) 3.9 (-7.0, 14.7) 8.7 (1.7, 15.7) 6.3 (-8.7, 21.2)
PedsQL™ Multidimensional Fatigue Scale Total Score
18
10.8 (3.1, 18.5)
56
10.4 (5.2, 15.5)
41
4.8 (-0.8, 10.4)
14
0.1 (-10.0, 10.3)
PedsQL™ Generic Core Scales Total Score
18
9.5 (0.5, 18.6)
56
10.4 (5.4, 15.3)
39
9.5 (4.9, 14.2)
14
0.3 (-9.3, 9.9)
PedsQL™ Sickle Cell Disease Module
*95% Confidence interval
Erin Doren, MD Assistant Professor Department of Plastic Surgery Medical College of Wisconsin
I am an Assistant Professor in the Department of Plastic Surgery at the Medical College of Wisconsin. I trained at the University of South Florida and completed a microsurgery fellowship at MD Anderson Cancer Center. I specialize in cancer reconstruction and microsurgery. My research interests involve patient reported outcomes as they relate to breast reconstruction. Throughout my career I have developed a strong passion for treating cancer patients and seek to improve care for my patients with my research efforts.
“US Epidemiology of Breast Implant-Associated Anaplastic Large Cell Lymphoma� Doren EL, Miranda RN, Selber JC, et al. Plastic and Reconstructive Surgery. 2017;139 (5):1042-1050. Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare and distinctive type of Tcell lymphoma that arises around breast implants. All known cases with an adequate clinical history have involved a textured (vs. smooth) breast implant. The objective was to determine the U.S. incidence and lifetime prevalence of BIA-ALCL. A review of documented cases in the U.S. revealed 100 cases. The incidence and prevalence was determined based on textured breast implant sales figures. The incidence rate was 1 per 500,000 person-years. Lifetime prevalence was 1 in 30,000 persons with textured breast implants. Although women with a textured breast implant have a low risk of developing BIA-ALCL, we found the current U.S. incidence to be significantly higher (70x) than that of primary ALCL of the breast. Figure 6. U.S. incidence rates of breast implant-associated ALCL per 1 million person-years per year
Louise C. Evans, PhD Assistant Professor Department of Physiology Medical College of Wisconsin
My research is focused on the mechanisms involved in the initiation of salt-sensitive hypertension, with a particular interest in the role of increased oxidative stress and inflammation in the kidney. I use chronic physiological studies in conscious rats to generate a time-course of salt-sensitive hypertension. This approach allows me to identify events which are a primary cause and/or a secondary consequence salt-induced hypertension. I also utilize genetically modified Dahl salt-sensitive rats to determine the role of oxidative stress and renal inflammation in these process. My current work is focused on the role of hydrogen-peroxide in the initiation of renal inflammation and mechanism by which T-cells promote the acceleration of prehypertension to malignancy and chronic kidney disease.
“Increased Perfusion Pressure Drives Renal T-Cell Infiltration in the Dahl Salt-Sensitive Rat” Evans LC, Petrova G, Kurth T, et al. Hypertension. 2017;70(3):543-551. In our recent publication we used our chronic servo control system to determine whether renal T-cell infiltration is a primary cause, or secondary consequence, of increased blood pressure in salt-sensitive hypertension. The unique servo-control system was used to precisely control renal perfusion pressure to the left-kidney of Dahl salt-sensitive rats during 7-days of a high-salt diet. During the same period the right kidney was exposed to a progressive increase in pressure. After 7-days of high-salt, renal immune cell infiltration was assessed by flow-cytometry. Renal inflammation was significantly higher in the hypertensive-right kidney than the servo-controlled left kidney. These data suggest that renal inflammation is a secondary consequence of increased pressure, rather than being an initiating factor.
Figure 1. LEFT: Renal perfusion pressure (RPP) in servo-controlled (n=12) rats during 3 d 0.4% NaCl and 7 d 4.0% NaCl intake. The carotid arterial pressure (gray) represents pressure to the right kidney, whereas the femoral arterial pressure (black) represents pressure to the left kidney. Data are presented as means±SEM for 24-h averages of the day of study. RIGHT: Renal immune cell infiltration in servo-controlled (n=12) rats after 7 d of 4.0% NaCl intake. CD3+ (mature T cells), CD3+CD4+ (helper T cells), CD3+CD8+ (cytotoxic T cells), CD45R+ (B cells), CD11b/c+ (monocytes and macrophages). Data are presented as means±SEM and expressed as total cells per kidney. #Significantly different from the average blood pressure measurement during the control period. #P<0.05, ###P<0.001. *Significantly different from the left kidney in the same group on the same study day, *P<0.05, **P<0.005, ***P<0.001.
Wendy Peltier, MD Associate Professor of Neurology and Medicine Section Head, Palliative Care Medical College of Wisconsin
As an academic neurologist, residency director and clinician-educator, I developed a passion for teaching and end of life care in my daily practice. This led me to pursue further training in Palliative Care, supported by an MCW Faculty Vitality Award, through which I realized my true calling. My experiences as a mid-career Palliative Care physician have fueled my passion for end of life care and work with our team to navigate the interface of holistic palliative care philosophies with highly technical care in a tertiary setting. My research interests include exploration of models of care for early palliative care and advance care planning in high risk populations, and navigating culture change in new models for Palliative Care/ICU integration.
“Initial Experience with "Honoring Choices Wisconsin": Implementation of an Advance Care Planning Pilot in a Tertiary Care Setting” Peltier WL, Gani F, Blissitt J, et al. Journal of Palliative Medicine. 2017;20(9):998-1003. A pilot program of ‘Honoring Choices Wisconsin’ was launched in 2014 with Palliative Care and Gastrointestinal Oncology that involved over 200 patients and their surrogates. HCW is an initiative of the Wisconsin Medical Society designed to increase advocacy and education around advanced care planning using a facilitator model and standardized document. We analyzed patient outcomes of those touched by the pilot and critically reviewed the pilot process. Key findings: 1) Evidence for the potential of facilitated ACP care models to impact end-of-life care planning and ensure care is concordant with individual wishes; 2) Identification of barriers to widespread implementation of a facilitator model which include creating a workforce, navigating culture change and patient/family readiness and 3) Pilot participation enhanced awareness of ACP in our system and spurred implementation of an Epic ACP navigator.
What is ‘Honoring Choices Wisconsin’? The mission of Honoring Choices Wisconsin is to promote the benefits of and improve processes for advance care planning across the state, in health care settings and in the community. Advance Care Planning is the process of understanding, reflecting on, and discussing future medical decisions, including end-of-life preferences. It also involves designating a surrogate decision maker in the event you are unable to express your wishes.
Green indicates counties having active Honoring Choices Wisconsin organizations. Yellow represents the entire service area of those organizations.
F&MCW Honoring Choices Pilot Results
Tammy Kindel, MD, PhD, FACS Assistant Professor Department of Surgery Medical College of Wisconsin
I am an Assistant Professor of Surgery at MCW and a practicing bariatric and minimally invasive surgeon. I received my medical degree from the Ohio State University and completed general surgery residency at Northwestern Memorial Hospital in Chicago followed by a minimally invasive surgery fellowship at the University of Nebraska Medical Center in Omaha. During residency, I obtained a PhD in pathobiology and molecular medicine from the University of Cincinnati working at the Metabolic Diseases Institute studying the mechanisms for glucose homeostasis improvements after bariatric surgery. In my current translational science lab, I study mechanisms for metabolic and cardiac disease improvement after bariatric surgery supported by both an ASMBS research grant and a CTSI\NIH Career Development Award from the National Center for Advancing Translational Sciences.
“Early Weight Loss Independent Effects of Sleeve Gastrectomy on DietInduced Cardiac Dysfunction in Obese, Wistar Rats” Kindel TL, Foster T, Goldspink P, et al. Obesity Surgery. 2017;27(9):2370-2377. In this study, we found that a sleeve gastrectomy significantly improved systolic function in 44% of diet-induced obese rats compared to 0% of pair-fed surgical controls (p=0.03). Sleeve gastrectomy responders had a smaller left ventricular internal diameter in systole and end systolic volume with improved systolic function compared to non-responders. At 10 weeks post-operatively, plasma glucose and B-type natriuretic peptide levels were significantly lower in SG rats compared to PF rats. The systolic function improvements in this study are related to weight-loss independent effects of the surgery on the entero-cardiac axis. These results offer a novel weight-loss independent, metabolic role for bariatric surgery as a potential treatment modality for obesity-associated cardiac dysfunction. Figure 2. Fasting plasma parameters of glucose homeostasis (A: glucose, B: insulin, and D: QUICKI) as well as cardiac function (C: BNP) at 10 weeks after surgery in SG or PF rats. Data are mean ± SD. Statistical significance determined at p<0.05 (*).
Jennifer L. Walsh, PhD Assistant Professor Center for AIDS Intervention Research Department of Psychiatry and Behavioral Medicine Medical College of Wisconsin
I am a developmental psychologist whose primary research interests are HIV prevention, sexual health promotion, and the application of advanced statistical methods to health behavior data. I received my psychology PhD and a MA in statistics from the University of Michigan, completed postdoctoral training at Syracuse University, and was an Assistant Professor at Brown University prior to joining the Center for AIDS Intervention Research at MCW. My current NIH-funded research uses integrative data analysis to combine data from randomized controlled trials of HIV prevention interventions independently conducted at STI clinics to understand factors promoting intervention success. My other research interests include preexposure prophylaxis (PrEP), sexual health and risk among adolescents and emerging adults, and the impact of socioeconomic disadvantage and neighborhood factors on diverse health behaviors.
â&#x20AC;&#x153;Factors Related to Pre-exposure Prophylaxis Prescription by U.S. Primary Care Physiciansâ&#x20AC;? Walsh JL, Petroll AE. American Journal of Preventative Medicine. 2017;52(6):e165-e172. Although pre-exposure prophylaxis (PrEP) reduces risk of HIV infection, use is not widespread enough to impact HIV incidence. Involvement of primary care physicians (PCPs) in PrEP prescription is essential, but previous research has shown low rates of prescription. To identify intervention targets, we tested the Information-Motivation-Behavioral Skills (IMB) model for PrEP discussion and prescription. PCPs from ten cities (N=280) completed a survey. Information items assessed knowledge, motivation items attitudes, and behavioral skills items comfort with behaviors involved in prescribing PrEP. One third of PCPs had discussed and 17% had prescribed PrEP. A structural equation model with good fit supported the IMB model. Information and motivation predicted behavioral skills, and behavioral skills predicted prescription. Results suggest that IMB constructs represent potential targets for PCP-directed interventions to increase PrEP use in high-risk populations. Figure 1. Structural equation model showing associations between information, motivation, and behavioral skills and pre-exposure prophylaxis (PrEP) discussion and prescription in a sample of primary care physicians (PCPs) from 10 U.S. cities (N=280).
“B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection” Darrah EJ, Kulinski JM, Mboko WP, et al. Journal of Virology. 2017;91(19):e01103-17.
Gammaherpesviruses, i.e. Epstein-Barr virus, infect nearly 95% of the adult population. Consequences of poorly controlled chronic infections include development of B cell lymphomas. Using a mouse model, we demonstrate that Ataxia Telangiectasia Mutated (ATM) is a critical host factor which facilitates gammaherpesvirus latency within B cells. This is largely attributed to ATM supporting B cell differentiation through the germinal center. These findings reveal a proviral function, yet, we have previously shown that ATM-deficient hosts are severely susceptible to gammaherpesvirus infections due to impaired adaptive immunity. As such, ATM is central to the delicate balance of host health versus virus-driven disease.
Eric Darrah Graduate Student Department of Microbiology & Immunology
Vikash Kumar, PhD Research Scientist I Department of Physiology
“Inhibition of Mammalian Target of Rapamycin Complex 1 Attenuates SaltInduced Hypertension and Kidney Injury in Dahl Salt-Sensitive Rats” Kumar V, Wollner C, Kurth T, Bukowy JD, Cowley AW Jr. Hypertension. 2017;70(4):813-821. The goal of the present study was to explore the protective effects of mTORC1 inhibition by rapamycin on salt-induced hypertension and kidney injury in SS rats. Daily administration of rapamycin (i.p., 1.5 mg/Kg/day) for 21 days reduced salt-induced hypertension by 23.0 mmHg in SS rats. Compared with vehicle, rapamycin reduced albumin excretion rate in SS rats from 190.0 ± 35.0 to 37.0 ± 5.0 mg/day and reduced the immune cells infiltration in the kidney. We conclude that high salt diet stimulates the mTORC1 pathway which is necessary for the full development of the salt-induced hypertension and kidney injury.
“Cytomegalovirus Late Protein pUL31 Alters Pre-rRNA Expression and Nuclear Organization during Infection” Westdorp KN, Sand A, Moorman NJ, Terhune SS. Journal of Virology. 2017;91(18):e00593-17.
Nucleolar biology is important during human cytomegalovirus infection with nucleolin functioning to maintain the architecture of the viral nuclear replication center. However, the extent of HCMV-mediated regulation of nucleolar biology is not understood. Proteins within nucleoli regulate ribosome biosynthesis and p53-dependent cellular stress responses that can induce cell cycle arrest and/or apoptosis, and are proposed targets for cancer therapies. This study establishes that HCMV protein pUL31 is necessary and sufficient to regulate nucleolar biology involving the reorganization of nucleolar proteins. Understanding these processes will help define approaches to stimulate cellular intrinsic stress responses that are capable of inhibiting HCMV infection.
Kristen Westdorp, PhD Research Associate I Department of Microbiology & Immunology
Hiromi Sato, PhD Research Scientist II Center for Infectious Disease Research Department of Microbiology & Immunology
“Leptospira Interrogans Causes Quantitative and Morphological Disturbances in Adherens Junctions and Other Biological Groups of Proteins in Human Endothelial Cells” Sato H, Coburn J. PLoS Neglected Tropical Diseases. 2017;11(7):e0005830. Pathogenic Leptospira causes the life-threatening infection called leptospirosis. The symptoms range from mild illness to severe illness, such as organ damage, meningitis, and fatal hemorrhagic disease. Invasive species of Leptospira rapidly disseminate to multiple sites where this bacterium damages host endothelial cells, increasing vascular permeability. In this study, human endothelial cells were infected with pathogenic or non-pathogenic Leptospira. Infection with the pathogenic strain most profoundly disturbed the adherensjunction group of proteins that form intercellular connections. This zoonotic agent may damage endothelial cells via adherens-junction-barrier disruption and inflammation, potentially leading to vascular hyperpermeability and severe illness in vivo.
“Steady-State Levels of Phosphorylated Mitogen-Activated Protein Kinase Kinase 1/2 Determined by Mortalin/HSPA9 and Protein Phosphatase 1 Alpha in KRAS and BRAF Tumor Cells” Wu PK, Hong SK, Park JI. Molecular and Cellular Biology. 2017;20(9):998-1003. Although deregulation of MEK/ERK activity is a key feature in cancer, high-magnitude MEK/ERK activity paradoxically induces growth inhibition. Therefore, tumor cells should develop a mechanism to modulate the MEK/ERK activity in favor of their proliferation/survival. We previously reported that mortalin/HSPA9 facilitates proliferation/survival of different BRAF and KRAS tumor cells by regulating MEK/ERK activity. The present study further addresses this regulation by revealing protein phosphatase 1α (PP1α) as a key partner of mortalin in determining the steady-state levels of phosphorylated MEK1/2 in these tumor cells. Because mortalin and PP1α are upregulated in correlation in melanoma and pancreatic cancer, PP1α may play a role in tumorigenesis in concert with mortalin. Our lab continues to determine the significance of these findings.
Pui Kei Wu, PhD Instructor Department of Biochemistry
Sameer S. Udhane, PhD Postdoctoral Research Fellow Department of Pathology
“Altered CYP19A1 and CYP3A4 Activities Due to Mutations A115V, T142A, Q153R and P284L in the Human P450 Oxidoreductase” Udhane SS, Parween S, Kagawa N, Pandey AV. Frontiers in Pharmacology. 2017;8:580. Cytochrome P450 proteins metabolize a wide range of drugs, steroids, and xenobiotics. All cytochromes P450s in the endoplasmic reticulum rely on P450 oxidoreductase (POR) for their catalytic activities. We studied the effect of POR variants on steroid and drug metabolizing enzymes. We found that POR proteins carrying mutations A115V, T142A, Q153R and P284L have variable effect on the activities of both aromatase (CYP19A1) and CYP3A4 enzyme. Our results strongly indicate that detailed analysis of each POR variants with different cytochrome P450s proteins is necessary to accurately determine the genotype-phenotype correlations of POR variants.
Medical College of Wisconsin Office of Research 8701 W Watertown Plank Road Milwaukee, WI 53226-0509 mcw.edu/office-of-research.htm