Translational Medical Research Commons^™

Hmgcs2 Is A Key Ketogenic Enzyme Potentially Involved In Type 1 Diabetes With High Cardiovascular Risk., Sanket Kumar Shukla, Weijing Liu, Kunal Sikder, Sankar Addya, Amrita Sarkar, Yidong Wei, Khadija Rafiq

Center for Translational Medicine Faculty Papers

Diabetes increases the risk of Cardio-vascular disease (CVD). CVD is more prevalent in type 2 diabetes (T2D) than type 1 diabetes (T1D), but the mortality risk is higher in T1D than in T2D. The pathophysiology of CVD in T1D is poorly defined. To learn more about biological pathways that are potentially involved in T1D with cardiac dysfunction, we sought to identify differentially expressed genes in the T1D heart. Our study used T1D mice with severe hyperglycemia along with significant deficits in echocardiographic measurements. Microarray analysis of heart tissue RNA revealed that the T1D mice differentially expressed 10 genes compared to …

Mir-181a Increases Foxo1 Acetylation And Promotes Granulosa Cell Apoptosis Via Sirt1 Downregulation., Mei Zhang, Qun Zhang, Yali Hu, Lu Xu, Yue Jiang, Chunxue Zhang, Lijun Ding, Ruiwei Jiang, Jianxin Sun, Haixiang Sun, Guijun Yan

Center for Translational Medicine Faculty Papers

Oxidative stress impairs follicular development by inducing granulosa cell (GC) apoptosis, which involves enhancement of the transcriptional activity of the pro-apoptotic factor Forkhead box O1 (FoxO1). However, the mechanism by which oxidative stress promotes FoxO1 activity is still unclear. Here, we found that miR-181a was upregulated in hydrogen peroxide (H

Ixazomib Enhances Parathyroid Hormone-Induced Β-Catenin/T-Cell Factor Signaling By Dissociating Β-Catenin From The Parathyroid Hormone Receptor., Yanmei Yang, Hong Lei, Ya-Wei Qiang, Bin Wang

Center for Translational Medicine Faculty Papers

The anabolic action of PTH in bone is mostly mediated by cAMP/PKA and Wnt-independent activation of β-catenin/T-cell factor (TCF) signaling. β-Catenin switches the PTH receptor (PTHR) signaling from cAMP/PKA to PLC/PKC activation by binding to the PTHR. Ixazomib (Izb) was recently approved as the first orally administered proteasome inhibitor for the treatment of multiple myeloma; it acts in part by inhibition of pathological bone destruction. Proteasome inhibitors were reported to stabilize β-catenin by the ubiquitin-proteasome pathway. However, how Izb affects PTHR activation to regulate β-catenin/TCF signaling is poorly understood. In the present study, using CRISPR/Cas9 genome-editing technology, we show that …

Obesity-Induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction And Promotes Acute Lung Injury, Dilip Shah, Freddy Romero, Zhi Guo, Jianxin Sun, Jonathan C. Li, Caleb Kallen, Ulhas P. Naik, Ross Summer

Center for Translational Medicine Faculty Papers

Conclusion

• Lung endothelial dysfunction in DIO mice coincides with increased endoplasmic reticulum (ER) stress.
• Fatty acids in obese serum induce ER stress in the pulmonary endothelium leading to pulmonary endothelial cell dysfunction.
• Reducing protein load in the endoplasmic reticulum of pulmonary endothelial cells might protect against ARDS in obese individuals.

Bitter Taste Receptor Agonists Mitigate Features Of Allergic Asthma In Mice., Pawan Sharma, Roslyn Yi, Ajay P Nayak, Nadan Wang, Francesca Tang, Morgan J. Knight, Shi Pan, Brian Oliver, Deepak A. Deshpande

Department of Medicine Faculty Papers

Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in …

Autophagy And Airway Fibrosis: Is There A Link?, Pawan K. Sharma, Anudeep Kota, Deepak A. Deshpande, Mehra Haghi, Brian G. Oliver

Center for Translational Medicine Faculty Papers

In the past decade, an emerging process named “autophagy” has generated intense interest in many chronic lung diseases. Tissue remodeling and fibrosis is a common feature of many airway diseases, and current therapies do not prevent or reverse these structural changes. Autophagy has evolved as a conserved process for bulk degradation and recycling of cytoplasmic components to maintain basal cellular homeostasis and healthy organelle populations in the cell. Furthermore, autophagy serves as a cell survival mechanism and can also be induced by chemical and physical stress to the cell. Accumulating evidence demonstrates that autophagy plays an essential role in vital …

Endothelium In The Pharyngeal Arches 3, 4 And 6 Is Derived From The Second Heart Field., Xia Wang, Dongying Chen, Kelley Chen, Ali Jubran, Annjosette Ramirez, Sophie Astrof

Center for Translational Medicine Faculty Papers

Oxygenated blood from the heart is directed into the systemic circulation through the aortic arch arteries (AAAs). The AAAs arise by remodeling of three symmetrical pairs of pharyngeal arch arteries (PAAs), which connect the heart with the paired dorsal aortae at mid-gestation. Aberrant PAA formation results in defects frequently observed in patients with lethal congenital heart disease. How the PAAs form in mammals is not understood. The work presented in this manuscript shows that the second heart field (SHF) is the major source of progenitors giving rise to the endothelium of the pharyngeal arches 3 - 6, while the endothelium …

Small Rna Zippers Lock Mirna Molecules And Block Mirna Function In Mammalian Cells., Lingyu Meng, Cuicui Liu, Jinhui Lü, Qian Zhao, Shengqiong Deng, Guangxue Wang, Jing Qiao, Chuyi Zhang, Lixiao Zhen, Ying Lu, Wenshu Li, Yuzhen Zhang, Richard G. Pestell, Huiming Fan, Yi-Han Chen, Zhongmin Liu, Zuoren Yu

Department of Cancer Biology Faculty Papers

MicroRNAs (miRNAs) loss-of-function phenotypes are mainly induced by chemically modified antisense oligonucleotides. Here we develop an alternative inhibitor for miRNAs, termed 'small RNA zipper'. It is designed to connect miRNA molecules end to end, forming a DNA-RNA duplex through a complementary interaction with high affinity, high specificity and high stability. Two miRNAs, miR-221 and miR-17, are tested in human breast cancer cell lines, demonstrating the 70∼90% knockdown of miRNA levels by 30-50 nM small RNA zippers. The miR-221 zipper shows capability in rescuing the expression of target genes of miR-221 and reversing the oncogenic function of miR-221 in breast cancer …

The Mitochondrial Ca(2+) Uniporter: Structure, Function, And Pharmacology., Jyotsna Mishra, Bong Sook Jhun, Stephen Hurst, Jin O-Uchi, György Csordás, Shey-Shing Sheu

Center for Translational Medicine Faculty Papers

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex.

Neural Crest Cell-Autonomous Roles Of Fibronectin In Cardiovascular Development., Xia Wang, Sophie Astrof

Department of Medicine Faculty Papers

The chemical and mechanical properties of extracellular matrices (ECMs) modulate diverse aspects of cellular fates; however, how regional heterogeneity in ECM composition regulates developmental programs is not well understood. We discovered that fibronectin 1 (Fn1) is expressed in strikingly non-uniform patterns during mouse development, suggesting that regionalized synthesis of the ECM plays cell-specific regulatory roles during embryogenesis. To test this hypothesis, we ablated Fn1 in the neural crest (NC), a population of multi-potent progenitors expressing high levels of Fn1. We found that Fn1 synthesized by the NC mediated morphogenesis of the aortic arch artery and differentiation of NC cells into …

Fibronectin Signals Through Integrin Α5Β1 To Regulate Cardiovascular Development In A Cell Type-Specific Manner., Dongying Chen, Xia Wang, Dong Liang, Julie Gordon, Ashok Mittal, Nancy Manley, Karl Degenhardt, Sophie Astrof

Department of Medicine Faculty Papers

Fibronectin (Fn1) is an evolutionarily conserved extracellular matrix glycoprotein essential for embryonic development. Global deletion of Fn1 leads to mid-gestation lethality from cardiovascular defects. However, severe morphogenetic defects that occur early in embryogenesis in these embryos precluded assigning a direct role for Fn1 in cardiovascular development. We noticed that Fn1 is expressed in strikingly non-uniform patterns during mouse embryogenesis, and that its expression is particularly enriched in the pharyngeal region corresponding with the pharyngeal arches 3, 4, and 6. This region bears a special importance for the developing cardiovascular system, and we hypothesized that the localized enrichment of Fn1 in …

Akt Kinase C-Terminal Modifications Control Activation Loop Dephosphorylation And Enhance Insulin Response., Tung O. Chan, Jin Zhang, Brian C. Tiegs, Brian Blumhof, Linda Yan, Nikhil Keny, Morgan Penny, Xue Li, John M. Pascal, Roger S. Armen, Ulrich Rodeck, Raymond B. Penn

Center for Translational Medicine Faculty Papers

The Akt protein kinase, also known as protein kinase B, plays key roles in insulin receptor signalling and regulates cell growth, survival and metabolism. Recently, we described a mechanism to enhance Akt phosphorylation that restricts access of cellular phosphatases to the Akt activation loop (Thr(308) in Akt1 or protein kinase B isoform alpha) in an ATP-dependent manner. In the present paper, we describe a distinct mechanism to control Thr(308) dephosphorylation and thus Akt deactivation that depends on intramolecular interactions of Akt C-terminal sequences with its kinase domain. Modifications of amino acids surrounding the Akt1 C-terminal mTORC2 (mammalian target of rapamycin …

Isoform-Specific Dynamic Translocation Of Pkc By Α1-Adrenoceptor Stimulation In Live Cells., Jin O-Uchi, Jaime Sorenson, Bong Sook Jhun, Jyotsna Mishra, Stephen Hurst, Kaleef Williams, Shey-Shing Sheu, Coeli M.B. Lopes

Center for Translational Medicine Faculty Papers

Protein kinase C (PKC) plays key roles in the regulation of signal transduction and cellular function in various cell types. At least ten PKC isoforms have been identified and intracellular localization and trafficking of these individual isoforms are important for regulation of enzyme activity and substrate specificity. PKC can be activated downstream of Gq-protein coupled receptor (GqPCR) signaling and translocate to various cellular compartments including plasma membrane (PM). Recent reports suggested that different types of GqPCRs would activate different PKC isoforms (classic, novel and atypical PKCs) with different trafficking patterns. However, the knowledge of isoform-specific activation of PKC by each …

New Functions For Alpha-Catenins In Health And Disease: From Cancer To Heart Regeneration., Alexia Vite, Jifen Li, Glenn L. Radice

Center for Translational Medicine Faculty Papers

Strong cell-cell adhesion mediated by adherens junctions is dependent on anchoring the transmembrane cadherin molecule to the underlying actin cytoskeleton. To do this, the cadherin cytoplasmic domain interacts with catenin proteins, which include α-catenin that binds directly to filamentous actin. Originally thought to be a static structure, the connection between the cadherin/catenin adhesion complex and the actin cytoskeleton is now considered to be dynamic and responsive to both intercellular and intracellular signals. Alpha-catenins are mechanosensing proteins that undergo conformational change in response to cytoskeletal tension thus modifying the linkage between the cadherin and the actin cytoskeleton. There are three α-catenin …

Shape And Position Of The Node And Notochord Along The Bilateral Plane Of Symmetry Are Regulated By Cell-Extracellular Matrix Interactions., Maria Pulina, Dong Liang, Sophie Astrof

Center for Translational Medicine Faculty Papers

The node and notochord (and their equivalents in other species) are essential signaling centers, positioned along the plane of bilateral symmetry in developing vertebrate embryos. However, genes and mechanisms regulating morphogenesis of these structures and their placement along the embryonic midline are not well understood. In this work, we provide the first evidence that the position of the node and the notochord along the bilateral plane of symmetry are under genetic control and are regulated by integrin α5β1 and fibronectin in mice. We found that the shape of the node is often inverted in integrin α5-null and fibronectin-null mutants, and …

Jefferson Interprofessional Clinical Rounding Project: An Innovative Approach To Patient Care, Kevin J. Lyons Phd, Gerald Isenberg Md, Facs, Elizabeth Speakman Edd, Rn, Cde, Anef, Reena Antony Bsn, Mph

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

Jefferson Hosts Third Interprofessional Education Conference, Kevin Lyons Phd, Christine Arenson Md, Elizabeth Speakman Rn, Phd, Carolyn Giordano Phd

Population Health Matters (Formerly Health Policy Newsletter)

No abstract provided.

The Effects Of A Group Visit Program On Outcomes Of Diabetes Care In An Urban Family Practice., Jeffrey A Reitz, Mona Sarfaty, James Diamond, Brooke Salzman

Department of Family & Community Medicine Faculty Papers

Diabetes mellitus is a prevalent chronic health condition associated with significant morbidity and mortality. Those with diabetes must acquire self-efficacy in the tasks necessary for them to successfully manage their disease. In this study, a controlled pre- and post-design was used to determine the effect of an adult support and education group visit program embedded in an urban academic family medicine practice on weight and the achievement of treatment goals for hemoglobin A1C, low-density lipoprotein (LDL) blood concentration, and blood pressure (BP) several months after it was implemented. Participants in the program were matched to a comparison group based on …

Community-Based Partnerships For Improving Chronic Disease Management, James Plumb, Laura Carson Weinsten, Rickie Brawer, Kevin Scott

Department of Family & Community Medicine Faculty Papers

With the growing burden of chronic disease, the medical and public health communities are re-examining their roles and opportunities for more effective prevention and clinical interventions. The potential to significantly improve chronic disease prevention and have an impact on morbidity and mortality from chronic conditions is enhanced by adopting strategies that incorporate a social ecology perspective, realigning the patient-physician relationship, integrating population health perspectives into the Chronic Care Model, and effectively engaging communities using established principles of community engagement.

Copyright © 2012 Elsevier Inc. All rights reserved.

The Career Support Network (Csn): Workforce Programming Through A New Lens, Rickie Brawer, Mph, Phd, James D. Plumb Md, Mph, Stephen Kern, Phd, Otr/L, Faota

Department of Family & Community Medicine Faculty Papers

Challenges:

Loss of Earn center as referral source

Multiple IRB submissions

Training/orientation at Philadelphia Prison System for working with pre-release prisoners

Service team organization/scheduling

Coordinating of cohorts at various stages of enrollment

Sepa-Reads: Cardiovascular Health Literacy Coalition, Rickie Brawer, Mph, Phd, James D. Plumb Md, Mph, Rob Simmons Drph,Mph,Ches, Martha Romney Rn,Ms,Jd,Mph, Patricia Yurchick, Rn, Mba, Cphq, Leslie Stearns

Department of Family & Community Medicine Faculty Papers

Poster includes:

Health literacy definition

Factors that contribute to health literacy

Extent of the literacy problem

What do we know from a decade of research?

Readmission rates

Evaluation: long and short term outcomes

And much more.

Vaccine-Preventable Diseases And Foreign-Born Populations, Marc Altshuler, Md, Giang Nguyen, Md

Department of Family & Community Medicine Faculty Papers

Foreign-born individuals account for over 12% of the U.S. population, according to the most recent census data. Since many vaccine-preventable outbreaks in the U.S. have been correlated with disease importation, Congress has mandated vaccinations for numerous immigrant populations. It is essential for primary care physicians to be knowledgeable on the unique immunization-related needs of foreign-born individuals, to recognize some of the cultural and linguistic challenges that immigrants have accessing healthcare, and remember to use each medical encounter as an opportunity to provide necessary vaccinations.

Obesity And Other Predictors Of Absenteeism In Philadelphia School Children., Elizabeth B Rappaport, Constantine Daskalakis, Jocelyn Andrel

Department of Family & Community Medicine Faculty Papers

BACKGROUND: Limited data indicate that obese children are absent from school more than their normal-weight peers. We analyzed administrative data from a large urban school district to investigate the association of obesity and student sociodemographic characteristics with absenteeism.

METHODS: We analyzed 291,040 records, representing 165,056 unique students (grades 1-12). Obesity status was classified according to Centers for Disease Control and Prevention age- and sex-specific percentiles for body mass index (BMI) and analyses were based on negative binomial regression.

RESULTS: Overall rates of overweight and obesity were 17% and 20%, respectively, and the estimated absence rate was 17 absences per 180 …

Obesity And Cancer Screening According To Race And Gender., Heather Bittner Fagan, Richard Wender, Ronald E Myers, Nicholas Petrelli

Department of Family & Community Medicine Faculty Papers

The relationship between obesity and cancer screening varies by screening test, race, and gender. Most studies on cervical cancer screening found a negative association between increasing weight and screening, and this negative association was most consistent in white women. Recent literature on mammography reports no association with weight. However, some studies show a negative association in white, but not black, women. In contrast, obese/overweight men reported higher rates of prostate-specific antigen (PSA) testing. Comparison of prostate cancer screening, mammography, and Pap smears implies a gender difference in the relationship between screening behavior and weight. In colorectal cancer (CRC) screening, the …

End-Of-Life Care For Hospitalized Patients With Lung Cancer: Utilization Of A Palliative Care Service., Barbara Reville, M.S., Achpn, Marshal N Miller, B.S., Richard W Toner, M.S., Joanne Reifsnyder, Ph.D., Achpn

Department of Family & Community Medicine Faculty Papers

PURPOSE: High symptom burden and hospital mortality among patients with lung cancer argues for early palliative care intervention. Patient characteristics and discharge dispositions in hospitalized patients with lung cancer receiving usual care were compared to those referred to a new palliative care service.

METHODS: A retrospective database review of all lung cancer discharges receiving usual care (UC) and palliative care service (PCS) consultation was conducted. Demographics, length of stay, discharge disposition, and mortality were described and compared. Palliative Performance Scale scores were described according to discharge disposition in the PCS group. Disposition of all patients receiving either chemotherapy or surgery …

Transforming Chronic Care Education: A Longitudal Interprofessional Mentorship Curriculum, Lauren G. Collins, Md, Christine A. Arenson, Md, Christine Jerpbak, Md, Elena Umland, Pharmd, Stephen B. Kern, Phd, Otr/L, Faota, Leigh Ann Hewston, Pt, Med

Department of Family & Community Medicine Faculty Papers

Rationale:

Future state of academic medicine demands preparing students for collaborative, team-based practice.

Interprofessional education (IPE) is widely advocated as a key element to promote an effective redesigned healthcare system

Evidence and curricular resources describing effective IPE remain limited

Obesity And Cancer, Rickie Brawer, Phd, Mph, Nancy Brisbon, Md, James Plumb, Md

Department of Family & Community Medicine Faculty Papers

Obesity has become the second leading preventable cause of disease and death in the United States, trailing only tobacco use. Weight control, dietary choices, and levels of physical activity are important modifiable determinants of cancer risk. If multi-factorial approaches to prevention and management are not implemented, obesity will likely become the leading modifiable cause of death in the coming years. Physicians have a key role in integrating these approaches into clinical care and advocating for systemic prevention efforts. This article provides: 1) an introduction to the epidemiology and magnitude of childhood and adult obesity; 2) the relationship of overweight/obesity to …

Persistent Nodular Rash In An Elderly Patient, Daniel Dejoseph, Md, James Studdiford, Md, Amber Stonehouse, Md, Beth Careyva, Md

Department of Family & Community Medicine Faculty Papers

A 62yo white male presented to same day clinic with an erythematous nodular rash. He was initially treated with antibiotics for a furunculosis, but the rash worsened and he was eventually found to have secondary syphilis. He is an MSM who had a prior history of syphilis, putting him at high risk for STI’s and HIV, and should have been undergoing annual screening. He was found to be HIV positive. The rates of STI’s and HIV are increasing in older Americans. Despite this, physicians do not regularly screen this population for unsafe sexual behavior. This case emphasizes the importance of …

The Physician's Response To Climate Change., Mona Sarfaty, Safiya Abouzaid

Department of Family & Community Medicine Faculty Papers

Climate change will have an effect on the health and well-being of the populations cared for by practicing physicians. The anticipated medical effects include heat- and cold-related deaths, cardiovascular illnesses, injuries and mental harms from extreme weather events, respiratory illnesses caused by poor air quality, infectious diseases that emanate from contaminated food, water, or spread of disease vectors, the injuries caused by natural disasters, and the mental harm associated with social disruption. Within several years, such medical problems are likely to reach the doorsteps of many physicians. In the face of this reality, physicians should assume their traditional roles as …

Intracerebral Hemorrhage For The Palliative Care Provider: What You Need To Know., B Brent Simmons, Susan M Parks

Department of Family & Community Medicine Faculty Papers

Intracerebral hemorrhage (ICH) makes up 10%-30% of all strokes. Palliative care providers are often asked to get involved with ICH cases to aid with development of short-term and long-term goals. Prognosis can be calculated using the ICH score (based on Glasgow Coma Score score, ICH volume, presence of intraventricular hemorrhage, age, and location of origin) or the Essen score (based on age, NIH Stroke Scale [NIHSS], and level of consciousness). Do-not-resuscitate (DNR) status is important to discuss with families. Expert consensus states DNR is appropriate if the patient has two of the following: severe stroke, life-threatening brain damage, or significant …