Digital Commons Network^™

Regulatory T-Cells And Associated Pathways In Metastatic Renal Cell Carcinoma (Mrcc) Patients Undergoing Dc-Vaccination And Cytokine-Therapy, Adrian Schwarzer, Benita Wolf, Jan L. Fisher, Thomas Schwaab, Sven Olek, Udo Baron, Craig R. Tomlinson, John D. Seigne, Nancy A. Crosby, Jiang Gui, Thomas H. Hampton, Camilo E. Fadul, John A. Heaney, Marc S. Ernstoff

Dartmouth Scholarship

Purpose: To evaluate CD4+CD25+FOXP3+ T regulatory cells (TREG) and associated immune-regulatory pathways in peripheral blood lymphocytes (PBL) of metastatic renal cell carcinoma (mRCC) patients and healthy volunteers. We subsequently investigated the effects of immunotherapy on circulating TREG combining an extensive phenotype examination, DNA methylation analysis and global transcriptome analysis.

Design: Eighteen patients with mRCC and twelve volunteers (controls) were available for analysis. TREG phenotype was examined using flow cytometry (FCM). TREG were also quantified by analyzing the epigenetic status of the FOXP3 locus using methylation specific PCR. As a third approach, RNA of the PBL was hybridized to Affymetrix GeneChip …

Escherichia Coli Recg Functionally Suppresses Human Bloom Syndrome Phenotypes, Michael W. Killen, Dawn M. Stults, William A. Wilson, Andrew J. Pierce

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Defects in the human BLM gene cause Bloom syndrome, notable for early development of tumors in a broad variety of tissues. On the basis of sequence similarity, BLM has been identified as one of the five human homologs of RecQ from Escherichia coli. Nevertheless, biochemical characterization of the BLM protein indicates far greater functional similarity to the E. coli RecG protein and there is no known RecG homolog in human cells. To explore the possibility that the shared biochemistries of BLM and RecG may represent an example of convergent evolution of cellular function where in humans BLM has evolved to …

Mucin (Muc) Expression During Pancreatic Cancer Progression In Spontaneous Mouse Model: Potential Implications For Diagnosis And Therapy., Satyanarayana Rachagani, María P Torres, Sushil Kumar, Dhanya Haridas, Michael J. Baine, Muzafar A. Macha, Sukhwinder Kaur, Moorthy P. Ponnusamy, Parama Dey, Parthasarathy Seshacharyulu, Sonny L. Johansson, Maneesh Jain, Kay-Uwe Wagner, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Pancreatic cancer (PC) is a lethal malignancy primarily driven by activated Kras mutations and characterized by the deregulation of several genes including mucins. Previous studies on mucins have identified their significant role in both benign and malignant human diseases including PC progression and metastasis. However, the initiation of MUC expression during PC remains unknown because of lack of early stage tumor tissues from PC patients.

METHODS: In the present study, we have evaluated stage specific expression patterns of mucins during mouse PC progression in (Kras(G12D);Pdx1-Cre (KC)) murine PC model from pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDAC) …

The Long-Term Impact Of Physical And Emotional Trauma: The Station Nightclub Fire, Jeffrey C. Schneider, Nhi-Ha T. Trinh, Elizabeth Selleck, Felipe Fregni, Sara S. Salles, Colleen M. Ryan, Joel Stein

Physical Medicine and Rehabilitation Faculty Publications

BACKGROUND: Survivors of physical and emotional trauma experience enduring occupational, psychological and quality of life impairments. Examining survivors from a large fire provides a unique opportunity to distinguish the impact of physical and emotional trauma on long-term outcomes. The objective is to detail the multi-dimensional long-term effects of a large fire on its survivor population and assess differences in outcomes between survivors with and without physical injury.

METHODS AND FINDINGS: This is a survey-based cross-sectional study of survivors of The Station fire on February 20, 2003. The relationships between functional outcomes and physical injury were evaluated with multivariate regression models …

Quantifying The Cdk Inhibitor Vmy-1-103'S Activity And Tissue Levels In An In Vivo Tumor Model By Lc-Ms/Ms And By Mri., Paul Sirajuddin, Sudeep Das, Lymor Ringer, Olga C Rodriguez, Angiela Sivakumar, Yi-Chien Lee, Aykut Üren, Stanley T Fricke, Brian Rood, Alpay Ozcan, Sean S Wang, Sana Karam, Venkata Yenugonda, Patricia Salinas, Emanuel Petricoin, Michael Pishvaian, Michael P Lisanti, Yue Wang, Richard Schlegel, Bahram Moasser, Chris Albanese

Kimmel Cancer Center Faculty Papers

The development of new small molecule-based therapeutic drugs requires accurate quantification of drug bioavailability, biological activity and treatment efficacy. Rapidly measuring these endpoints is often hampered by the lack of efficient assay platforms with high sensitivity and specificity. Using an in vivo model system, we report a simple and sensitive liquid chromatography-tandem mass spectrometry assay to quantify the bioavailability of a recently developed novel cyclin-dependent kinase inhibitor VMY-1-103, a purvalanol B-based analog whose biological activity is enhanced via dansylation. We developed a rapid organic phase extraction technique and validated wide and functional VMY-1-103 distribution in various mouse tissues, consistent with …

Thr 163 Phosphorylation Causes Mcl-1 Stabilization When Degradation Is Independent Of The Adjacent Gsk3-Targeted Phosphodegron, Promoting Drug Resistance In Cancer, Shanna K. Nifoussi, Julie A. Vrana, Aaron M. Domina, Alfredo De Biasio, Jingang Gui, Mark A. Gregory, Stephen R. Hann, Ruth W. Craig

Dartmouth Scholarship

The antiapoptotic Bcl-2 family member Mcl-1 is a PEST protein (containing sequences enriched in proline, glutamic acid, serine, and threonine) and is subject to rapid degradation via multiple pathways. Impaired degradation leading to the maintenance of Mcl-1 expression is an important determinant of drug resistance in cancer. Phosphorylation at Thr 163 in the PEST region, stimulated by 12-O-tetradecanoylphorbol acetic acid (TPA)-induced activation of extracellular signal-regulated kinase (ERK), is associated with Mcl-1 stabilization in BL41-3 Burkitt lymphoma cells. This contrasts with the observation that Thr 163 phosphorylation in normal fibroblasts primes glycogen synthase kinase (GSK3)-induced phosphorylation at Ser 159, producing a …

Human Optokinetic Nystagmus: A Stochastic Analysis., J Waddington, Cm Harris

School of Psychology

Optokinetic nystagmus (OKN) is a fundamental gaze-stabilizing response found in almost all vertebrates, in which eye movements attempt to compensate for the optic flow caused by self-motion. It is an alternating sequence of slow compensatory eye movements made in the direction of stimulus motion and fast eye movements made predominantly in the opposite direction. The timing and amplitude of these slow phases (SPs) and quick phases (QPs) are remarkably variable, and the cause of this variability is poorly understood. In this study principal components analysis was performed on OKN data to illustrate that the variability in correlation matrices across individuals …

A Phase Ii Study Of Pulse Dose Imatinib Mesylate And Weekly Paclitaxel In Patients Aged 70 And Over With Advanced Non-Small Cell Lung Cancer, Julie E. Bauman, Keith D. Eaton, Sarah G. Wallace, Laurie L. Carr, Sang-Joon Lee, Dennie V. Jones, Hugo Arias-Pulido, Lisa A. Cerilli, Renato G. Martins

Internal Medicine Faculty Publications

BACKGROUND: In non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR). Antagonizing PDGFR with imatinib may improve intra-tumoral delivery of paclitaxel, increasing response rate (RR).

METHODS: This single-stage, open-label phase II study evaluated pulse dose imatinib and weekly paclitaxel in elderly patients with advanced NSCLC. Eligible patients were aged ≥ 70 with untreated, stage IIIB-IV NSCLC and ECOG performance status 0-2. Primary endpoint was RR. Secondary endpoints included median progression free and overall survival (PFS, OS) and correlatives of PDGFR pathway activation. Baseline Charlson Comorbidity Index …

Cdk Inhibitors (P16/P19/P21) Induce Senescence And Autophagy In Cancer-Associated Fibroblasts, "Fueling" Tumor Growth Via Paracrine Interactions, Without An Increase In Neo-Angiogenesis., Claudia Capparelli, Barbara Chiavarina, Diana Whitaker-Menezes, Timothy G Pestell, Richard Pestell, James Hulit, Sebastiano Andò, Anthony Howell, Ubaldo E. Martinez-Outshoorn, Federica Sotgia, Michael P. Lisanti

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Here, we investigated the compartment-specific role of cell cycle arrest and senescence in breast cancer tumor growth. For this purpose, we generated a number of hTERT-immortalized senescent fibroblast cell lines overexpressing CDK inhibitors, such as p16(INK4A), p19(ARF) or p21(WAF1/CIP1). Interestingly, all these senescent fibroblast cell lines showed evidence of increased susceptibility toward the induction of autophagy (either at baseline or after starvation), as well as significant mitochondrial dysfunction. Most importantly, these senescent fibroblasts also dramatically promoted tumor growth (up to ~2-fold), without any comparable increases in tumor angiogenesis. Conversely, we generated human breast cancer cells (MDA-MB-231 cells) overexpressing CDK inhibitors, …

Rice Consumption And Urinary Arsenic Concentrations In U.S. Children, Matthew A. Davis, Todd A. Mackenzie, Kathryn L. Cottingham, Diane Gilbert-Diamond, Tracy Punshon, Margaret R. Karagas

Dartmouth Scholarship

Background: In adult populations, emerging evidence indicates that humans are exposed to arsenic by ingestion of contaminated foods such as rice, grains, and juice; yet little is known about arsenic exposure among children.

Objectives: Our goal was to determine whether rice consumption contributes to arsenic exposure in U.S. children.

Methods: We used data from the nationally representative National Health and Nutrition Examination Survey (NHANES) to examine the relationship between rice consumption (measured in 0.25 cups of cooked rice per day) over a 24-hr period and subsequent urinary arsenic concentration among the 2,323 children (6–17 years of age) who participated in …

Perlecan Domain V Induces Vegf Secretion In Brain Endothelial Cells Through Integrin Α5Β1 And Erk-Dependent Signaling Pathways., Douglas N Clarke, Abraham Al Ahmad, Boyeon Lee, Christi Parham, Lisa Auckland, Andrezj Fertala, Michael Kahle, Courtney S Shaw, Jill Roberts, Gregory J Bix

Department of Dermatology and Cutaneous Biology Faculty Papers

Perlecan Domain V (DV) promotes brain angiogenesis by inducing VEGF release from brain endothelial cells (BECs) following stroke. In this study, we define the specific mechanism of DV interaction with the α(5)β(1) integrin, identify the downstream signal transduction pathway, and further investigate the functional significance of resultant VEGF release. Interestingly, we found that the LG3 portion of DV, which has been suggested to possess most of DV's angio-modulatory activity outside of the brain, binds poorly to α(5)β(1) and induces less BEC proliferation compared to full length DV. Additionally, we implicate DV's DGR sequence as an important element for the interaction …

Perlecan Domain V Induces Vegf Secretion In Brain Endothelial Cells Through Integrin Α5Β1 And Erk-Dependent Signaling Pathways, Douglas N. Clarke, Abraham Al Ahmad, Boyeon Lee, Christi Parham, Lisa Auckland, Andrezj Fertala, Michael Kahle, Courtney S. Shaw, Jill Roberts, Gregory J. Bix

Sanders-Brown Center on Aging Faculty Publications

Perlecan Domain V (DV) promotes brain angiogenesis by inducing VEGF release from brain endothelial cells (BECs) following stroke. In this study, we define the specific mechanism of DV interaction with the α(5)β(1) integrin, identify the downstream signal transduction pathway, and further investigate the functional significance of resultant VEGF release. Interestingly, we found that the LG3 portion of DV, which has been suggested to possess most of DV's angio-modulatory activity outside of the brain, binds poorly to α(5)β(1) and induces less BEC proliferation compared to full length DV. Additionally, we implicate DV's DGR sequence as an important element for the interaction …

Metabolic Remodeling Of The Tumor Microenvironment: Migration Stimulating Factor (Msf) Reprograms Myofibroblasts Toward Lactate Production, Fueling Anabolic Tumor Growth., Valentina Carito, Gloria Bonuccelli, Ubaldo E Martinez-Outschoorn, Diana Whitaker-Menezes, Maria Cristina Caroleo, Erika Cione, Anthony Howell, Richard G Pestell, Michael P. Lisanti, Federica Sotgia

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Migration stimulating factor (MSF) is a genetically truncated N-terminal isoform of fibronectin that is highly expressed during mammalian development in fetal fibroblasts, and during tumor formation in human cancer-associated myofibroblasts. However, its potential functional role in regulating tumor metabolism remains unexplored. Here, we generated an immortalized fibroblast cell line that recombinantly overexpresses MSF and studied their properties relative to vector-alone control fibroblasts. Our results indicate that overexpression of MSF is sufficient to confer myofibroblastic differentiation, likely via increased TGF-b signaling. In addition, MSF activates the inflammation-associated transcription factor NFκB, resulting in the onset of autophagy/mitophagy, thereby driving glycolytic metabolism (L-lactate …

Development Of Chinese Adolescents: Assessment, Issues, And Intervention, Daniel T. L. Shek, Rachel C. F. Sun, Joav Merrick

Pediatrics Faculty Publications

No abstract.

Cross-Cultural Comparison Of Sensory Behaviors In Children With Autism., Kristina G Caron, Roseann C Schaaf, Teal W. Benevides, Eynat Gal

Department of Occupational Therapy Faculty Papers

Parents of children with autism frequently report that their children exhibit unusual responses to sensory experiences. Little research is available, however, describing how parents' and children's culture and environment might influence parents' reports of their children's behaviors. This study compared the frequency of parent-reported responses to sensory experiences in children from two countries-Israel and the United States. We administered the Short Sensory Profile to primary caregivers of children with autism spectrum disorders (ASD) and typically developing peers. Results indicate that Israeli parents reported unusual responses to sensory experiences less frequently than U.S. parents for both ASD and typically developing children. …

Exosome-Mediated Shuttling Of Microrna-29 Regulates Hiv Tat And Morphine-Mediated Neuronal Dysfunction., Guoku Hu, H Yao, A D. Chaudhuri, Sowmya V. Yelamanchili, H Wen, P D. Cheney, Howard S. Fox, Shilpa J. Buch

Journal Articles: Pharmacology & Experimental Neuroscience

Neuronal damage is a hallmark feature of HIV-associated neurological disorders (HANDs). Opiate drug abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Opiates such as morphine have been shown to enhance HIV transactivation protein Tat-mediated toxicity in both human neurons and neuroblastoma cells. In the present study, we demonstrate reduced expression of the tropic factor platelet-derived growth factor (PDGF)-B with a concomitant increase in miR-29b in the basal ganglia region of the brains of morphine-dependent simian immunodeficiency virus (SIV)-infected macaques compared with the SIV-infected controls. In vitro relevance …

Sarcopenia, Obesity, And Natural Killer Cell Immune Senescence In Aging: Altered Cytokine Levels As A Common Mechanism, Charles T. Lutz, Lebris S. Quinn

Pathology and Laboratory Medicine Faculty Publications

Human aging is characterized by both physical and physiological frailty. A key feature of frailty, sarcopenia is the age-associated decline in skeletal muscle mass, strength, and endurance that characterize even the healthy elderly. Increases in adiposity, particularly in visceral adipose tissue, are almost universal in aging individuals and can contribute to sarcopenia and insulin resistance by increasing levels of inflammatory cytokines known collectively as adipokines. Aging also is associated with declines in adaptive and innate immunity, known as immune senescence, which are risk factors for cancer and all-cause mortality. The cytokine interleukin-15 (IL-15) is highly expressed in skeletal muscle tissue …

Breast Milk From Tanzanian Women Has Divergent Effects On Cell-Free And Cell-Associated Hiv-1 Infection In Vitro, Magdalena A. Lyimo, Matilda Ngarina Mosi, Molly L. Housman, Muhammad Zain-Ul-Abideen, Frederick V. Lee, Alexandra L. Howell, Ruth I. Connor

Dartmouth Scholarship

Transmission of HIV-1 during breastfeeding is a significant source of new pediatric infections in sub-Saharan Africa. Breast milk from HIV-positive mothers contains both cell-free and cell-associated virus; however, the impact of breast milk on HIV-1 infectivity remains poorly understood. In the present study, breast milk was collected from HIV-positive and HIV-negative Tanzanian women attending antenatal clinics in Dar es Salaam. Milk was analyzed for activity in vitro against both cell-free and cell-associated HIV-1. Potent inhibition of cell-free R5 and X4 HIV-1 occurred in the presence of milk from all donors regardless of HIV-1 serostatus. Inhibition of cell-free HIV-1 infection positively …

Subjective Outcome Evaluation Of The Project P.A.T.H.S. (Extension Phase) Based On The Perspective Of Program Implementer, Daniel T. L. Shek, Lu Yu

Pediatrics Faculty Publications

A total of 231 schools participated in the Project P.A.T.H.S. in 2009/2010 school year. After completion of the Tier 1 Program, subjective outcome evaluation data were collected from 3,259 program implementers. Based on the consolidated data with schools as units, results showed that participants had positive perceptions of the program, implementers, and benefits of the program. More than four-fifth of the implementers regarded the program as helpful to the program participants. Multiple regression analyses revealed that perceived qualities of the program and the program implementers predicted perceived effectiveness of the program. Similar to previous studies, compared to implementers' perception about …

Mitochondrial Fission Induces Glycolytic Reprogramming In Cancer-Associated Myofibroblasts, Driving Stromal Lactate Production, And Early Tumor Growth., Carmela Guido, Diana Whitaker-Menezes, Zhao Lin, Richard G Pestell, Anthony Howell, Teresa A Zimmers, Mathew C Casimiro, Saveria Aquila, Sebastiano Ando', Ubaldo E Martinez-Outschoorn, Federica Sotgia, Michael P Lisanti

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Recent studies have suggested that cancer cells behave as metabolic parasites, by inducing oxidative stress in adjacent normal fibroblasts. More specifically, oncogenic mutations in cancer cells lead to ROS production and the "secretion" of hydrogen peroxide species. Oxidative stress in stromal fibroblasts then induces their metabolic conversion into cancer-associated fibroblasts. Such oxidative stress drives the onset of autophagy, mitophagy, and aerobic glycolysis in fibroblasts, resulting in the local production of high-energy mitochondrial fuels (such as L-lactate, ketone bodies, and glutamine). These recycled nutrients are then transferred to cancer cells, where they are efficiently burned via oxidative mitochondrial metabolism (OXPHOS). We …

Hormonal Induction Of Polo-Like Kinases (Plks) And Impact Of Plk2 On Cell Cycle Progression In The Rat Ovary, Feixue Li, Misung Jo, Thomas E. Curry, Jing Liu

Obstetrics and Gynecology Faculty Publications

The highly conserved polo-like kinases (Plks) are potent regulators of multiple functions in the cell cycle before and during mitotic cell division. We investigated the expression pattern of Plk genes and their potential role(s) in the rat ovary during the periovulatory period. Plk2 and Plk3 were highly induced both in intact ovaries and granulosa cells in vivo after treatment with the luteinizing hormone (LH) agonist, human chorionic gonadotropin (hCG). In vitro, hCG stimulated the expression of Plk2 in granulosa cells, but not Plk3. This induction of Plk2 expression was mimicked by both forskolin and phorbol 12 myristate 13-acetate (PMA). Moreover, …

Iron Homeostasis During Cystic Fibrosis Pulmonary Exacerbation, Alex H. Gifford, Lisa A. Moulton, Dana B. Dorman, Gordana Olbina, Mark Westerman, H. Worth Parker, Bruce Stanton, George A. O'Toole

Dartmouth Scholarship

BACKGROUND:

Hypoferremia is a marker of disease severity in cystic fibrosis (CF). The effect of systemic antibiotics on iron homeostasis during CF pulmonary exacerbation (CFPE) is unknown. Our central hypotheses were that, by the completion of treatment, serum iron would increase, serum concentrations of interleukin-6 (IL-6) and hepcidin-25, two mediators of hypoferremia, would decrease, and sputum iron would decrease.

METHODS:

Blood and sputum samples were collected from 12 subjects with moderate-to-severe CF (median percentage-predicted forced expiratory volume in 1 second (FEV(1) %) = 29%; median weight = 56 kg) within 24 hours of starting and completing a course of systemic …

Classroom Misbehavior In The Eyes Of Students: A Qualitative Study, Rachel C. F. Sun, Daniel T. L. Shek

Pediatrics Faculty Publications

Using individual interviews, this study investigated perceptions of classroom misbehaviors among secondary school students in Hong Kong (N = 18). Nineteen categories of classroom misbehaviors were identified, with talking out of turn, disrespecting teacher, and doing something in private being most frequently mentioned. Findings revealed that students tended to perceive misbehaviors as those actions inappropriate in the classroom settings and even disrupting teachers' teaching and other students' learning. Among various misbehaviors, talking out of turn and disrespecting teacher were seen as the most disruptive and unacceptable. These misbehaviors were unacceptable because they disturbed teaching and learning, and violated the values …

Postlecture Evaluation Of A Positive Youth Development Subject For University Students In Hong Kong, Daniel T. L. Shek

Pediatrics Faculty Publications

The purpose of this study was to examine the postlecture evaluation by the students taking a course (Tomorrow's Leaders) that attempted to promote their leadership qualities and intrapersonal competencies at The Hong Kong Polytechnic University in Hong Kong. Except for the last lecture, students were invited to respond to a 12-item postlecture questionnaire after each lecture. Results showed that the students had positive perceptions of the subject, class, and teacher attributes, and they had positive global evaluation of the teacher and the subject. The postlecture evaluation questionnaire was found to possess good psychometric properties. Multiple regression analyses showed that subject, …

Secreted Semaphorin 5a Suppressed Pancreatic Tumour Burden But Increased Metastasis And Endothelial Cell Proliferation., A Sadanandam, S S. Sidhu, S Wullschleger, S Singh, M L. Varney, C-S Yang, A E. Ashour, Surinder K. Batra, Rakesh Singh

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Our earlier reports demonstrated that membrane-bound semaphorin 5A (SEMA5A) is expressed in aggressive pancreatic cancer cells and tumours, and promotes tumour growth and metastasis. In this study, we examine whether (1) pancreatic cancer cells secrete SEMA5A and (2) that secreted SEMA5A modulates certain phenotypes associated with tumour progression, angiogenesis and metastasis through various other molecular factors and signalling proteins.

METHODS AND RESULTS: In this study, we show that human pancreatic cancer cell lines secrete the extracellular domain (ECD) of SEMA5A (SEMA5A-ECD) and overexpression of mouse Sema5A-ECD in Panc1 cells (not expressing SEMA5A; Panc1-Sema5A-ECD; control cells - Panc1-control) significantly increases …

The Proteomics Of Lipid Droplets: Structure, Dynamics, And Functions Of The Organelle Conserved From Bacteria To Humans., Li Yang, Yunfeng Ding, Yong Chen, Shuyan Zhang, Chaoxing Huo, Yang Wang, Jinhai Yu, Peng Zhang, Huimin Na, Huina Zhang, Yanbin Ma, Pingsheng Liu

College of Science & Mathematics Departmental Research

Lipid droplets are cellular organelles that consists of a neutral lipid core covered by a monolayer of phospholipids and many proteins. They are thought to function in the storage, transport, and metabolism of lipids, in signaling, and as a specialized microenvironment for metabolism in most types of cells from prokaryotic to eukaryotic organisms. Lipid droplets have received a lot of attention in the last 10 years as they are linked to the progression of many metabolic diseases and hold great potential for the development of neutral lipid-derived products, such as biofuels, food supplements, hormones, and medicines. Proteomic analysis of lipid …

Systemic Sclerosis Disease Modification Clinical Trials Design: Quo Vadis?, Fabian A. Mendoza, Md, Lynette L Keyes-Elstein, Sergio A. Jimenez

Scleroderma Center Faculty Papers

The purpose of this manuscript is to discuss relevant aspects of clinical trials for Systemic Sclerosis (SSc) and to identify important considerations for the design of SSc disease modification clinical trials. Placebo randomized controlled trials with appropriate identification of SSc patients with diffuse progressive SSc skin involvement of recent onset, along with a rescue strategy for patients with worsening lung and skin involvement are suggested. If change in skin thickening is a major outcome of the study, the selection of patients with recent onset of disease and a predetermined degree of skin involvement are crucial requirements. The trial duration should …

Two-Compartment Tumor Metabolism: Autophagy In The Tumor Microenvironment And Oxidative Mitochondrial Metabolism (Oxphos) In Cancer Cells., Ahmed F Salem, Diana Whitaker-Menezes, Zhao Lin, Ubaldo E. Martinez-Outshoorn, Herbert B Tanowitz, Mazhar Salim Al-Zoubi, Anthony Howell, Richard Pestell, Federica Sotgia, Michael P. Lisanti

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Previously, we proposed a new paradigm to explain the compartment-specific role of autophagy in tumor metabolism. In this model, autophagy and mitochondrial dysfunction in the tumor stroma promotes cellular catabolism, which results in the production of recycled nutrients. These chemical building blocks and high-energy "fuels" would then drive the anabolic growth of tumors, via autophagy resistance and oxidative mitochondrial metabolism in cancer cells. We have termed this new form of stromal-epithelial metabolic coupling: "two-compartment tumor metabolism." Here, we stringently tested this energy-transfer hypothesis, by genetically creating (1) constitutively autophagic fibroblasts, with mitochondrial dysfunction or (2) autophagy-resistant cancer cells, with increased …

Live-Cell Monitoring Of Periodic Gene Expression In Synchronous Human Cells Identifies Forkhead Genes Involved In Cell Cycle Control, Gavin D. Grant, Joshua Gamsby, Viktor Martyanov, Lionel Brooks, Lacy K. George, J. Matthew Mahoney, Jennifer J. Loros, Jay C. Dunlap, Michael L. Whitfield

Dartmouth Scholarship

We developed a system to monitor periodic luciferase activity from cell cycle-regulated promoters in synchronous cells. Reporters were driven by a minimal human E2F1 promoter with peak expression in G1/S or a basal promoter with six Forkhead DNA-binding sites with peak expression at G2/M. After cell cycle synchronization, luciferase activity was measured in live cells at 10-min intervals across three to four synchronous cell cycles, allowing unprecedented resolution of cell cycle-regulated gene expression. We used this assay to screen Forkhead transcription factors for control of periodic gene expression. We confirmed a role for FOXM1 and identified two novel cell cycle …

Associations Between Pathological Gambling And Psychiatric Comorbidity Among Help-Seeking Populations In Hong Kong., Daniel T L Shek, Elda M L Chan, Ryan H Y Wong

Pediatrics Faculty Publications

Problem gambling is complex and often comorbid with other mental health problems. Unfortunately, gambling studies on comorbid psychiatric disorders among Chinese communities are extremely limited. The objectives of this study were to (a) determine the prevalence of comorbid psychiatric disorders among treatment-seeking pathological gamblers; (b) compare the demographic profiles and clinical features of pathological gamblers with and without comorbid psychiatric disorders; (c) explore the associations between pathological gambling and psychiatric disorders and their temporal relationship. Participants (N = 201) who sought gambling counseling were examined by making Axis-I diagnoses including mood disorders, schizophrenia spectrum disorders, substance use disorders, anxiety disorders, …