tbuckley/cabot-search huggingface dataset:
Long-Term Weight Loss With Metformin or Lifestyle Intervention in the Diabetes Prevention Program Outcomes Study
Authors: John W. Apolzan, Elizabeth M. Venditti, Sharon L. Edelstein, William C. Knowler, Dana Dabelea, Edward J. Boyko, Xavier Pi-Sunyer, Rita R. Kalyani, Paul W. Franks, Preethi Srikanthan, Kishore M. Gadde
Journal: Annals of Internal Medicine (2019)

Background: Identifying reliable predictors of long-term weight loss (LTWL) could lead to improved weight management. Objective: To identify some predictors of LTWL. Design: The DPP (Diabetes Prevention Program) was a randomized controlled trial that compared weight loss with metformin, intensive lifestyle intervention (ILS), or placebo. Its Outcomes Study (DPPOS) observed patients after the masked treatment phase ended. (ClinicalTrials.gov: NCT00004992 and NCT00038727) Setting: 27 DPP and DPPOS clinics. Participants: Of the 3234 randomly assigned participants, 1066 lost at least 5% of baseline weight in the first year and were followed for 15 years. Measurements: Treatment assignment, personal characteristics, and weight. Results: After 1 year, 289 (28.5%) participants in the metformin group, 640 (62.6%) in the ILS group, and 137 (13.4%) in the placebo group had lost at least 5% of their weight. After the masked treatment phase ended, the mean weight loss relative to baseline that was maintained between years 6 and 15 was 6.2% (95% CI, 5.2% to 7.2%) in the metformin group, 3.7% (CI, 3.1% to 4.4%) in the ILS group, and 2.8% (CI, 1.3% to 4.4%) in the placebo group. Independent predictors of LTWL included greater weight loss in the first year in all groups, older age and continued metformin use in the metformin group, older age and absence of either diabetes or a family history of diabetes in the ILS group, and higher fasting plasma glucose levels at baseline in the placebo group. Limitation: Post hoc analysis; examination of nonrandomized subsets of randomized groups after year 1. Conclusion: Among persons with weight loss of at least 5% after 1 year, those originally randomly assigned to metformin had the greatest loss during years 6 to 15. Older age and the amount of weight initially lost were the most consistent predictors of LTWL maintenance. Primary Funding Source: National Institutes of Health.
Molecular mechanism by which Dibenzoylmethane (DBM) induces heme oxygenase 1 (HO-1) expression
Authors: Siwang Yu, Ka Cheung, Tin Khor, Avantica Gopalakrishnan, Jung-Hwan Kim, Mou-Tuan Huang, Harold Newmark, Ah-Ng Kong
Journal: Cancer Research (2008)

633  Dibenzoylmethane (DBM) is a minor constituent of licorice (Glycyrrhiza glabra), a herb widely used as an antidote, demulcent and elixir folk medicine in traditional Chinese medicine. Studies in our lab as well as from other groups have shown that DBM exhibits unique cancer-preventive effects against prostate, colon, breast and skin cancers in cell and animal models. It was found that DBM induces the expression of antioxidant and detoxifying enzymes that are important for cancer prevention; however, the underlying molecular mechanism is still unknown. In the present study we delineated the molecular mechanism by which DBM induces the expression of heme oxygenase 1 (HO-1), a major stress response and antioxidant enzyme. DBM potently induced the expression of HO-1 in various cell lines. At the same time, DBM increased nuclear factor-erythroid-related factor2 (Nrf2) protein level concentration- and time-dependently. The induction was diminished in Nrf2 (-/-) mouse embryonic fibroblasts (MEFs). Furthermore, overexpression of dominant-negative form of Nrf2 also inhibited the induction of HO-1 by DBM. Taken together, theses results suggest that the induction of HO-1 by DBM is dependent on Nrf2. On the other hand, DBM activated mitogen-activated protein kinases (MAPKs) and AMP-activated protein kinases, and perturbs intracellular calcium level in cells. Further studies indicate that MAPKs, AMPK and intracellular calcium all contributed to the induction of HO-1 expression by DBM. The presented study investigated an important mechanism underlying the cancer-preventive effects of DBM, and revealed the molecular basis of the induction of HO-1 by DBM. (Supported by NIH R01-CA-94828 R01-CA118947 to A.-N.T. Kong)
Abstract 19213: Burden of Premature Ventricular Complexes on Routine Holter Monitoring is a Predictor of Ventricular Arrhythmias in Hypertrophic Cardiomyopathy
Authors: Tony Chen, Apu Chakrabarti, Maryann Concannon, Adam Helms, Sara Saberi, Sharlene Day
Journal: Circulation (2017)

Nonsustained ventricular tachycardia (NSVT) is a well-established risk factor for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM), but the predictive value of premature ventricular ...
Abstract 1780: Caspase-independent Apoptosis Is Activated In The Late Stage Of Heart Failure In Mice Overexpressing Crma <i>In Vivo</i>
Authors: Soochan Bae, Parco Siu, Sangita Choudhury, Qingen Ke, Young Y Koh, Peter M Kang
Journal: Circulation (2008)

Caspase inhibition is thought to be an effective strategy for inhibiting apoptosis in heart. Recent data, however, suggest that caspase-independent apoptosis might be activated when caspases are inhibited. Here, we examined whether caspase-independent apoptosis involving apoptosis inducing factor (AIF) is important in the development of heart failure in the setting of caspase inhibition in vivo. Method: We created transgenic mice with cardiac specific overexpression of cytokine response modifier A (CrmA), a known inhibitor of caspases, using αMHC promoter (CrmA Tg mice). A single dose of doxorubicin (DOX; 20 mg/kg) was injected i.p. into male mice to generate acute cardiomyopathy. A quantitative analysis of cardiac apoptosis was performed using TUNEL assay. Results: Caspase activity was completely inhibited in CrmA Tg mice hearts 6 days after DOX injection, whereas the WT hearts showed significant caspase activation. We also observed significantly improved survival in CrmA Tg compared to WT mice (81% vs 38%, p&lt;0.05) 6 days after DOX injection. However, at 12 days, CrmA Tg and WT mice had a similar rate of cardiac apoptosis, and the survival benefit did not persist. Further analysis revealed that CrmA Tg but not WT mice hearts were characterized by a significant release of AIF from the mitochondria at 12 days. This evidence of AIF-induced apoptosis suggests a late activation of AIF in the setting of caspase inhibition. CrmA Tg mice were also pre-treated with 4-AN (4-amino-1,8-napthalimide, 3 mg/kg), a potent inhibitor of PARP, and examined 12 days after DOX injection. PARP is an important regulator of AIF-induced apoptosis, and PARP inhibition significantly improved DOX-impaired cardiac function (+91%, p&lt;0.01) and survival compared to CrmA Tg mice without 4-AN (93% vs. 13%, p&lt;0.05). In addition 4-AN pretreatment resulted in a significant inhibition of PARP activity, blockade of AIF released from mitochondria, and less apoptosis compared to CrmA Tg without 4-AN. Conclusion: In the setting of caspase inhibition, apoptosis can be induced through caspase-independent mechanisms, predominately via AIF, in a model of heart failure in vivo . The concurrent inhibition of AIF activation provides a more effective and complete inhibition of apoptosis.
Abstract 17057: Difference of Neoatherosclerosis Pattern in Lesions With In-Stent Restenosis Among Bare-Metal, First and Second Generation Drug-Eluting Stents
Authors: Daisuke Nakamura, Masami Nishino, Keisuke Yasumura, Koji Yasumoto, Akihiro Tanaka, Naoki Mori, Masamichi Yano, Yasuyuki Egami, Ryu Shutta, Jun Tanouchi
Journal: Circulation (2017)

Background: Little is known about difference of the frequency and characteristics of neoatherosclerosis with in-stent restenosis (ISR) among bare-metal stent (BMS), first generation drug-eluting st...
MEDU-14. GENOMIC ANALYSIS OF ETMR GUIDES EFFICACIOUS DFMO DRUG COMBINATIONS
Authors: Austin Goodyke, Elizabeth VanSickle, Joseph Zagorski, Abhinav Beeravally, Giselle Saulnier Sholler
Journal: Neuro-Oncology (2019)

Embryonal tumor with multilayered rosettes (ETMR), formerly termed ETANTR, is a rare pediatric tumor carrying a poor prognosis and occurring primarily in patients less than 4 years of age. The median overall survival of <1 year for patients diagnosed with these primitive neuroectodermal (PNET)-like tumors demands the development of novel treatment regimens. Recent clinical and experimental data shows treatment with the highly tolerated drug DFMO (α-difluoromethylornithine) improves overall survival in neuroblastoma patients; and ETMR patients currently receiving DFMO on our expanded use trial have displayed clinical benefit. In neuroblastoma, DFMO reduces tumor burden through G1 cell cycle arrest, induction of senescence, and targeted cytotoxicity towards cancer stem cells. The effect of DFMO on tumors is mediated through polyamine depletion leading to disruption of the Lin28/Let-7 axis. We hypothesize that; ETMR, characterized by particularly high Lin28 expression, will be responsive to DFMO treatment. We have shown that DFMO treatment of the BT-183 and BIO-296-08 ETMR cell lines leads to a reduced number of viable cells, reducing viable cell number by 50% at 144 hours of exposure (CellTiter Glo). This reduction in viable cells is coupled with a simultaneous reduction in the overall expression of Lin28 as well as a reduction in the proportion and viability of the cancer stem cell subpopulation (flow cytometry). High throughput drug testing of BT-183 and RNA sequencing of six individual ETMR tumors identified temozolomide and the HDAC inhibitor panobinostat as ideal combination agents in treating ETMR cells. Treatment with temozolomide (IC50 2–6µM) and panobinostat (IC50 2-6nM), even in the presence of DFMO, resulted in a potent reduction in ETMR cell viability (CellTiter Glo). These data warrant further work elucidating the mechanism of this therapy and provides rationale for the development of clinical trials incorporating the use of DFMO in this lethal disease.
Medical Students' Handbook: Alcohol and Health
Authors: Debashis Singh
Journal: BMJ (1999)

Marsha Y Morgan and Bruce Ritson

Available from: The Medical Council on Alcoholism, 3 St Andrew's Place, London NW1 4LB; Tel: 0171 487 4445; email mca@medicouncilalcol.demon.co.uk

Price: £3.00 commercially, £2.00 for healthcare workers, £1.00 in bulk, free for medical students

The underground train was busy, which made it all the more surprising when a large woman I had never met before sat on my knee and proposed. She was drunk. Naturally, I graciously declined and briskly walked to the nearest exit. Although this is not a regular occurrence, …
MEDU-10. THERAPEUTIC TARGETING OF STEM CELL SELF-RENEWAL IN CHILDHOOD MEDULLOBLASTOMA: STRATEGIES FOR BLOCKING RECURRENCE
Authors: David Bakhshinyan, Michelle Kameda-Smith, Ashley Adile, Branavan Manoranjan, Chitra Venugopal, Sheila Singh
Journal: Neuro-Oncology (2019)

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Group 3 MB patients face the highest incidence of metastasis and poor overall survival. The early onset and aggressive nature of MB suggest a stem cell origin, where a highly self-renewing transformed cell of the postnatal cerebellum drives MB tumorigenesis. In this work, we explore the therapeutic value of activating WNT signaling and targeting other essential drivers of self-renewal, BMI1 and MSI1. A small molecule BMI1 inhibitor, PTC-028, induced a remarkable decrease in self-renewal, while reducing local and spinal metastatic disease in recurrent MB, which is striking as no prior drug has shown efficacy against recurrent Group 3 MB. Although mouse and human neural stem cells (NSCs) express BMI1 and are mildly sensitive to BMI1 inhibitors, no significant toxicity was observed in NSCs upon PTC-028 treatment, at doses that effectively kill MB cells. Another novel therapeutic paradigm includes activating Wnt signaling in otherwise non-Wnt MB, which abrogates self-renewal and tumorigenicity of these aggressive tumors. For safe and non-toxic activation of Wnt in preclinical models, we identified L807mts, a novel inhibitor that functions through a substrate-to-inhibitor conversion mechanism within the catalytic site of GSK. A final therapeutic strategy lies in the discovery of the targetable MB-specific interactome of the RNA binding protein (RBP) Musashi1. shRNA knockdown of Msi1 decreased the self-renewal capacity of MB stem cells, significantly decreased tumor burden and increased survival in our PDX model. Comparative eCLIP (enhanced cross-linking and immunoprecipitation) of MB stem cells and normal NSCs, combined with mass spectrometry and RNA-sequencing of shMSI1 MB cells has elucidated novel therapeutic targets in interactome of MSI1. Characterization and therapeutic targeting of self-renewal mechanisms may provide an opportunity to limit treatment-resistant stem cell populations from driving patient relapse in Group 3 MB, a disease currently lacking any targeted therapies.
MEDU-04. AN OTX2-PAX GENE NETWORK REGULATES GROUP 3 MEDULLOBLASTOMA DIFFERENTIATION AND TUMOR GROWTH
Authors: Jamie Zagozewski, Ludivine Morrison, Ghazaleh Shahriary, Margaret Stromecki, Agnes Fresnoza, Gareth Palidwor, Christopher Porter, Cynthia Hawkins, Jennifer Chan, Vijay Ramaswamy, Tamra Werbowetski-Ogilvie
Journal: Neuro-Oncology (2019)

Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor. Group 3 has the worst prognosis of the MB subgroups and the pathways driving Group 3 pathogenesis are poorly defined. OTX2 is overexpressed/amplified in 80% of Group 3 tumors and maintains the balance between self-renewal and neuronal differentiation. Here, we evaluated the contribution of the OTX2 gene regulatory network in driving Group 3 MB pathogenesis. We mapped changes in active (H3K4me3) and repressive (H3K27me3) histone modifications following OTX2 silencing in Group 3 MB cells. Neuronal differentiation genes encoding transcription factors (TFs) were associated with loss of H3K27me3 modifications suggesting de-repression in TF expression. Members of the PAX gene family of TFs were significantly de-repressed and their role in Group 3 MB progression is unknown. PAX3 and PAX6 expression is significantly lower in Group 3 MB patients and low expression is correlated with significantly reduced patient survival. Interestingly, OTX2 directly binds to PAX3 and PAX6 and restricts their expression in Group 3 MB cells. Over-expressing PAX3 and PAX6 in Group 3 MB cells reduced tumorsphere number, self-renewal and cell cycle properties while increasing neuronal differentiation. In addition, PAX3 expression significantly increased survival and reduced tumor size following intracerebellar transplantation. RNA-sequencing of tumorspheres over-expressing PAX3 and PAX6 revealed a reduction in Group 3 signatures including GABAergic and glutamatergic signalling. Downregulation of genes involved in mTOR signalling was specifically observed in PAX3 over-expressing tumorspheres, which may contribute to the differential survival observed in vivo. Similar changes in gene signatures were also demonstrated following OTX2 silencing in multiple Group 3 MB cell lines. Our results demonstrate that OTX2 controls cell fate decisions in Group 3 MB by regulating PAX gene expression, and that targeting downstream molecular signatures may reveal novel therapeutic targets for these highly aggressive tumors.
Abstract 18010: Upregulation of Toll-Like Receptors That Underlies Diabetes-Induced Exacerbation of Cardiorenal Syndrome is Attenuated by Canagliflozin, an SGLT-2 Inhibitor
Authors: Yukishige Kimura, Kouhei Ohno, Atsushi Kuno, Masashi Mizuno, Hiroto Ohshima, Toshiyuki Yano, Masaya Tanno, Takayuki Miki, Tetsuji Miura
Journal: Circulation (2017)

Background: Type 1 cardiorenal syndrome (CRS) is defined as acute kidney injury caused by acute cardiac dysfunction, and type 2 diabetes mellitus (T2DM) is an independent risk factor for renal susc...
Hepatitis C Virus Potentially Transmitted by Opioid Drug Diversion from a Nurse — Washington, August 2017–March 2018
Authors: Henry N. Njuguna, Denise Stinson, Patricia Montgomery, Nigel Turner, Marisa D’Angeli, Jason Carr, Sara Podczervinski, Cathy Wasserman, Sumathi Ramachandran, Todd Lucas, Danae Bixler, Kiran Perkins, Isaac Benowitz, Anne Moorman
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

During January 22-March 23, 2018, a local health department in Washington was notified of two patients who received a diagnosis of acute hepatitis C virus (HCV) infection. Neither patient had behavioral risk factors associated with HCV acquisition; however, both had received injectable narcotic (opioid) drugs from the same nurse during separate visits to an emergency department (ED) at a local hospital on December 6 and December 16, 2017. Investigation revealed that the nurse had accessed the automated drug dispensing system at a higher frequency than had other staff members, admitted diverting* patients' injectable narcotic and antihistamine drugs for personal use, and tested positive for HCV antibodies (anti-HCV) on March 19, 2018, but did not have quantifiable HCV RNA. Specimens from both patients were sent to CDC for genetic testing, and HCV viral variants analysis found a significant level of genetically similar HCV variants in both patients, indicating a common source of infection. Further investigation was conducted to confirm the infection source, identify other potentially exposed patients, and treat any new patients who received an HCV diagnosis. Monitoring frequency of access to drug dispensing systems can help identify staff members with abnormal dispensing patterns, including diversion activities (1). U.S. health care facilities are required to prevent, identify, and report any loss, diversion, or theft of controlled substances (2).
Association of <i>PDGFRB</i> Mutations With Pediatric Myofibroma and Myofibromatosis
Authors: Guillaume Dachy, Ronald R. de Krijger, Sylvie Fraitag, Ivan Théate, Bénédicte Brichard, Suma B. Hoffman, Louis Libbrecht, Florence A. Arts, Pascal Brouillard, Miikka Vikkula, Nisha Limaye, Jean-Baptiste Demoulin
Journal: JAMA Dermatology (2019)

Myofibroma is the most frequent fibrous tumor in children. Multicentric myofibroma (referred to as infantile myofibromatosis) is a life-threatening disease.To determine the frequency, spectrum, and clinical implications of mutations in the PDGFRB receptor tyrosine kinase found in sporadic myofibroma and myofibromatosis.In this retrospective study of 69 patients with sporadic myofibroma or myofibromatosis, 85 tumor samples were obtained and analyzed by targeted deep sequencing of PDGFRB. Mutations were confirmed by an alternative method of sequencing and were experimentally characterized to confirm gain of function and sensitivity to the tyrosine kinase inhibitor imatinib.Frequency of gain-of-function PDGFRB mutations in sporadic myofibroma and myofibromatosis. Sensitivity to imatinib, as assessed experimentally.Of the 69 patients with tumor samples (mean [SD] age, 7.8 [12.7] years), 60 were children (87%; 29 girls [48%]) and 9 were adults (13%; 4 women [44%]). Gain-of-function PDGFRB mutations were found in samples from 25 children, with no mutation found in samples from adults. Mutations were particularly associated with severe multicentric disease (13 of 19 myofibromatosis cases [68%]). Although patients had no familial history, 3 of 25 mutations (12%) were likely to be germline, suggesting de novo heritable alterations. All of the PDGFRB mutations were associated with ligand-independent receptor activation, and all but one were sensitive to imatinib at clinically relevant concentrations.Gain-of-function mutations of PDGFRB in myofibromas may affect only children and be more frequent in the multicentric form of disease, albeit present in solitary pediatric myofibromas. These alterations may be sensitive to tyrosine kinase inhibitors. The PDGFRB sequencing appears to have a high value for diagnosis, prognosis, and therapy of soft-tissue tumors in children.
Initial Results of KD025-208: A Phase 2a Open Label Trial of KD025 for Steroid-Dependent Chronic Graft Versus Host Disease
Authors: Aleksandr Lazaryan, Stephanie J Lee, Amandeep Salhotra, Madan Jagasia, James Essell, Alexandra Zanin-Zhorov, Beth Mac Gillivray, Olivier Schueller, David Eiznhamer, Bruce Blazar, John L. Ryan
Journal: Blood (2017)
Social Parasitism in the Honeybee (Apis mellifera) Is Not Controlled by a Single SNP
Authors: Matthew J Christmas, Nicholas M A Smith, Benjamin P Oldroyd, Matthew T Webster
Journal: Molecular Biology and Evolution (2019)

Abstract The Cape bee (Apis mellifera capensis) is a subspecies of the honeybee, in which workers commonly lay diploid unfertilized eggs via a process known as thelytoky. A recent study aimed to map the genetic basis of this trait in the progeny of a single capensis queen where workers laid either diploid (thelytokous) or haploid (arrhenotokous) eggs. A nonsynonymous single nucleotide polymorphism (SNP) in a gene of unknown function was reported to be strongly associated with thelytoky in this colony. Here, we analyze genome sequences from a global sample of A. mellifera and identify populations where the proposed thelytoky allele at this SNP is common but thelytoky is absent. We also analyze genome sequences of three capensis queens produced by thelytoky and find that, contrary to predictions, they do not carry the proposed thelytoky allele. The proposed SNP is therefore neither sufficient nor required to produce thelytoky in A. mellifera.
Impact of a Pre-Operative Exercise Intervention on Breast Cancer Proliferation and Gene Expression: Results from the Pre-Operative Health and Body (PreHAB) Study
Authors: Jennifer A. Ligibel, Deborah Dillon, Anita Giobbie-Hurder, Anne McTiernan, Elizabeth Frank, MacIntosh Cornwell, Matthew Pun, Nancy Campbell, Ryan J.O. Dowling, Martin C. Chang, Sara Tolaney, Anees B. Chagpar, Rachel L. Yung, Rachel A. Freedman, Laura S. Dominici, Mehra Golshan, Esther Rhei, Krishan Taneja, Ying Huang, Myles Brown, Eric P. Winer, Rinath Jeselsohn, Melinda L. Irwin
Journal: Clinical Cancer Research (2019)

Exercise after breast cancer diagnosis is associated with lower cancer-specific mortality, but the biological mechanisms through which exercise impacts breast cancer are not fully understood. The Pre-Operative Health and Body (PreHAB) Study was a randomized window-of-opportunity trial designed to test the impact of exercise on Ki-67, gene expression, and other biomarkers in women with breast cancer.Inactive women with newly diagnosed breast cancer were randomized to an exercise intervention or mind-body control group, and participated in the study between enrollment and surgery (mean 29.3 days). Tumor and serum were collected at baseline and surgery.Forty-nine women were randomized (27 exercise, 22 control). At baseline, mean age was 52.6, body mass index was 30.2 kg/m2, and exercise was 49 minutes/week. Exercise participants significantly increased exercise versus controls (203 vs. 23 minutes/week, P < 0.0001). There were no differences in changes of expression of Ki-67, insulin receptor, and cleaved caspase-3 in exercise participants versus controls. KEGG pathway analysis demonstrated significant upregulation of 18 unique pathways between the baseline biopsy and surgical excision in exercise participants and none in control participants (q < 0.1). Top-ranked pathways included several implicated in immunity and inflammation. Exploratory analysis of tumor immune infiltrates demonstrated a trend toward a decrease in FOXP3+ cells in exercise versus control participants over the intervention period (P = 0.08).A window-of-opportunity exercise intervention did not impact proliferation but led to alterations in gene expression in breast tumors, suggesting that exercise may have a direct effect on breast cancer.See related commentary by Koelwyn and Jones, p. 5179.