tbuckley/cabot-search huggingface dataset:
Loss of Perivascular Adipose Tissue on Peroxisome Proliferator–Activated Receptor-γ Deletion in Smooth Muscle Cells Impairs Intravascular Thermoregulation and Enhances Atherosclerosis
Authors: LinChang, LuisVillacorta, RongxiaLi, MiltonHamblin, WeiXu, ChunyanDou, JifengZhang, JiaruiWu, RongZeng, Y. EugeneChen
Journal: Circulation (2012)

Background—Perivascular adipose tissue (PVAT) surrounds most vessels and shares common features with brown adipose tissue (BAT). Although adaptive thermogenesis in BAT increases energy expenditure and is beneficial for metabolic diseases, little is known about the role of PVAT in vascular diseases such as atherosclerosis. We hypothesize that the thermogenic function of PVAT regulates intravascular temperature and reduces atherosclerosis. Methods and Results—PVAT shares similar structural and proteomics with BAT. We demonstrated that PVAT has thermogenic properties similar to BAT in response to cold stimuli in vivo. Proteomics analysis of the PVAT from mice housed in a cold environment identified differential expression in proteins highly related to cellular metabolic processes. In a mouse model deficient in peroxisome proliferator–activated receptor-γ in smooth muscle cells (SMPG KO mice), we uncovered a complete absence of PVAT surrounding the vasculature, likely caused by peroxisome proliferator–activat...
Abstract 2897: Therapeutic efficacy of antibodies targeting domain 1 of HSPG2 in breast cancer
Authors: Vidhi Khanna, Stephen Kalscheuer, Jayanth Panyam, Da Yang, Sihan Li
Journal: Cancer Research (2018)

Abstract Significant advancements in chemotherapy have improved the survival rates of patients presenting with local or regional breast cancer to as high as 99% and 85%, respectively. On the contrary, patients with metastatic breast cancer have a dismal 5-year survival rate of 26%. Thus, there is an urgent need for research strategies directed towards treatment of metastasis. Our lab used a phage display-based cell panning procedure to develop two fully humanized antibodies (Clone 6 and AM6) that are able to bind specifically to breast cancer metastatic cells. Target deconvolution revealed HSPG2/Perlecan Domain 1 as the cell surface antigen bound by the antibodies. Immunohistochemistry studies revealed high HSPG2 expression across various tumor subtypes including melanoma, bladder cancer, glioblastoma and ovarian cancer. There was a significant correlation between high HSPG2 and with poor survival in bladder and ovarian cancers. Interestingly, we observed significant tumor growth inhibition in the triple-negative MDA-MB-231 breast cancer xenograft model. This efficacy was significantly reduced when the tumor growth inhibition studies were repeated in NSG mice, suggesting NK cell-mediated antibody dependent cellular cytotoxicity (ADCC) as the potential mechanism of action. The data presented here point to the relevance of HSPG2 as a novel target for not only breast cancer but also other malignancies. We also show the potential of Clone 6 and AM6 as therapeutic and targeting agents. Further studies are required to understand the significance of HSPG2 overexpression and its correlation with tumor progression as well as to confirm the mechanism of action with Clone 6 and AM6 antibodies. Citation Format: Vidhi Khanna, Stephen Kalscheuer, Jayanth Panyam, Da Yang, Sihan Li. Therapeutic efficacy of antibodies targeting domain 1 of HSPG2 in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2897.
Effects of Permanent Pacemaker and Oral Theophylline in Sick Sinus Syndrome
Authors: PaoloAlboni, CarloMenozzi, MicheleBrignole, NellyPaparella, GermanoGaggioli, GinoLolli, RiccardoCappato
Journal: Circulation (1997)

Background Pacemakers and theophylline are currently being used to relieve symptoms in patients with sick sinus syndrome (SSS). However, the impact of either therapy on the natural course of the disease is unknown. We conducted a randomized controlled trial to prospectively assess the effects of pacemakers and theophylline in patients with SSS. Methods and Results One hundred seven patients with symptomatic SSS (age, 73±11 years) were randomized to no treatment (control group, n=35), oral theophylline (n=36), or dual-chamber rate-responsive pacemaker therapy (n=36). They were followed for up to 48 months (mean, 19±14 months). During follow-up, the occurrence of syncope was lower in the pacemaker group than in the control group (P=.02) and tended to be lower than in the theophylline group (P=.07). Heart failure occurred less often in patients assigned to pacemaker therapy and theophylline than in control patients (both, P=.05), whereas the incidence of sustained paroxysmal tachyarrhythmias, permanent atria...
Comparison of Abdominal and Thoracic Aortic Medial Structure in Mammals
Authors: HarveyWolinsky, SeymourGlagov
Journal: Circulation Research (1969)

Previous studies of adult mammalian thoracic aortas revealed that tension per medial lamellar unit was independent of species and that distribution of medial vasa vasorum, number of medial lamellar units and medial thickness were consistently related. Except for man, a similar pattern prevailed in abdominal aortic segments of all of the ten species studied. The human abdominal aortic media had relatively fewer lamellar units for its diameter than abdominal or thoracic aortas of other species, resulting in a relatively elevated estimated mean tension per lamellar unit. Vasa were normally absent from the human abdominal aortic media, even though its thickness significantly exceeded the thickness of avascular medias of other species and of avascular zones of medias with vasa vasorum. Elevated calculated tension per lamellar unit and excessive avascular thickness may be factors in the increased susceptibility of human abdominal aortas to atherosclerosis.
Abstract LB-047: Novel anti-psychotic drug for pancreatic cancer treatment
Authors: Sharavan Ramachandran, Sanjay K. Srivastava
Journal: Cancer Research (2018)

Abstract Pancreatic cancer is one of the most deadly malignancy with a five-year survival rate of 7%. Despite advances in cancer treatment, this disease is still incurable and the treatment outcomes are limited. Few studies have shown that neuroleptic drugs exert better anti-proliferative effects in pancreatic cancer cells when compared to conventional chemotherapeutic agents gemcitabine and oxaliplatin. In the current study, we evaluated the anti-cancer effects of pimavanserin, an anti-psychotic drug used for the treatment of Parkinson's disease psychosis. Pimavanserin significantly suppressed the proliferation of AsPC1, BxPC3, PANC1, MIAPaCa2 and PO2 pancreatic cancer cells with the IC50 between 3 - 9µM at 24, 48 and 72 hours. Pimavanserin treatment induced 2-5 fold apoptosis in pancreatic cancer cells. Notably, no significant cell death was observed in normal human pancreatic ductal epithelial (HPDE-6) cells by pimavanserin treatment. Furthermore, pimavanserin treatment inhibits the expression of key oncogenic proteins and cancer stem cell markers such as pAkt(S473), pSTAT3(Y705), β-catenin, GLI-1, GLI-2, c-Myc, Oct-4, SOX-2, NANOG and CD44. We further evaluated the efficacy of pimavanserin in two different in vivo tumor models. Oral administration of 10mg/kg pimavanserin suppressed 50% of sub-cutaneously implanted BxPC3 tumors in athymic nude mice. In another setting, 10mg/kg pimavanserin by oral gavage inhibited the growth of orthotopically implanted PANC1 pancreatic tumors by 75%. Moreover, chronic administration of pimavanserin did not show any general signs of toxicity and no apparent changes were observed in the behavioral activity of mice. Further mechanistic studies are in progress. Since pimavanserin is already available in the clinic with established safety profile, our results will accelerate its clinical development for treatment of patients with pancreatic cancer. Our study is the first to demonstrate the anti-cancer effects of pimavanserin. Citation Format: Sharavan Ramachandran, Sanjay K. Srivastava. Novel anti-psychotic drug for pancreatic cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-047.
Amplification of Wild-type <i>KRAS</i> Imparts Resistance to Crizotinib in <i>MET</i> Exon 14 Mutant Non–Small Cell Lung Cancer
Authors: Magda Bahcall, Mark M. Awad, Lynette M. Sholl, Frederick H. Wilson, Man Xu, Stephen Wang, Sangeetha Palakurthi, Jihyun Choi, Elena V. Ivanova, Giulia C. Leonardi, Bryan C. Ulrich, Cloud P. Paweletz, Paul T. Kirschmeier, Masayuki Watanabe, Hideo Baba, Mizuki Nishino, Rebecca J. Nagy, Richard B. Lanman, Marzia Capelletti, Emily S. Chambers, Amanda J. Redig, Paul A. VanderLaan, Daniel B. Costa, Yu Imamura, Pasi A. Jänne
Journal: Clinical Cancer Research (2018)

MET inhibitors can be effective therapies in patients with MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC). However, long-term efficacy is limited by the development of drug resistance. In this study, we characterize acquired amplification of wild-type (WT) KRAS as a molecular mechanism behind crizotinib resistance in three cases of METex14-mutant NSCLC and propose a combination therapy to target it.The patient-derived cell line and xenograft (PDX) DFCI358 were established from a crizotinib-resistant METex14-mutant patient tumor with massive focal amplification of WT KRAS. To characterize the mechanism of KRAS-mediated resistance, molecular signaling was analyzed in the parental cell line and its KRAS siRNA-transfected derivative. Sensitivity of the cell line to ligand stimulation was assessed and KRAS-dependent expression of EGFR ligands was quantified. Drug combinations were screened for efficacy in vivo and in vitro using viability and apoptotic assays.KRAS amplification is a recurrent genetic event in crizotinib-resistant METex14-mutant NSCLC. The key characteristics of this genetic signature include uncoupling MET from downstream effectors, relative insensitivity to dual MET/MEK inhibition due to compensatory induction of PI3K signaling, KRAS-induced expression of EGFR ligands and hypersensitivity to ligand-dependent and independent activation, and reliance on PI3K signaling upon MET inhibition.Using patient-derived cell line and xenografts, we characterize the mechanism of crizotinib resistance mediated by KRAS amplification in METex14-mutant NSCLC and demonstrate the superior efficacy of the dual MET/PI3K inhibition as a therapeutic strategy addressing this resistance mechanism.
Abstract 15609: The Effect of Contrast-induced Acute Kidney Injury in High Risk Patients Undergoing Cardiac Surgery
Authors: Kristen M Tecson, Baron L Hamman, James W Choi, Puja Garg, Oluseun A Olugbode, Jeffrey M Schussler, Robert C Stoler, Anupama Vasudevan, Carlos E Velasco, Peter A McCullough
Journal: Circulation (2016)

Background: Contrast-induced acute kidney injury (CI-AKI) is an acute complication following coronary angiography and is associated with higher rates of AKI in patients who have follow-on cardiac s...
Determination of reference values for IgG antibodies against typical antigens of hypersensitivity pneumonitis - current data of a German multicentre study
Authors: M. Raulf, M. Jöst, I Sander, C. Bittner, F. Hoffmeyer, D. Nowak, U. Ochmann, A. Preisser, J. Schreiber, J. Sennekamp, D. Koschel
Journal: Allergy (2017)
Abstract LB-401: Induction of DISE by tumor suppressive microRNAs
Authors: Quan Q. Gao, William T. Putzbach, Andrea E. Murmann, Siquan Chen, Aishe A. Sarshad, Giovanna Ambrosini, Elizabeth T. Bartom, Markus Hafner, Marcus E. Peter
Journal: Cancer Research (2018)

Abstract Many siRNAs and shRNAs induce a form of cell death in all cancer cells that involves silencing a set of critical survival genes, a process called death induced by survival gene elimination (DISE). Mechanistically a 6mer seed sequence (position 2-7 of the guide strand) is sufficient to confer DISE-inducing activity. We have now performed a strand specific screen testing the toxicity of all 4096 possible 6mer seed sequences in a neutral double stranded siRNA backbone. We found an asymmetric preference for guanine in positions 1-3 of the 6mer seed in the most toxic siRNAs which target survival genes that are GC rich in their 3'UTR. During over 800 million years of evolution miRNAs have evolved to avoid guanine in their seed sequences. However, two tumor suppressive miRNAs were found to be killing cancer cells through DISE using G rich toxic seeds in cells exposed to genotoxic stress: 1) the p53 inducible miR-34 family and most of its cell death inducing activity comes from its 6mer seed; and 2) miR-320a, a noncanonical miRNA that is still expressed in cancer cells when miRNA processing genes are mutated. Ago bound upregulated miR-320a is converted from a poorly to a highly toxic miRNA by removal of two adenine nucleotides from its 5' end. Our data suggest that most miRNAs have evolved to avoid induction of DISE but certain tumor suppressive miRNAs utilize this mechanism to kill cancer cells. Citation Format: Quan Q. Gao, William T. Putzbach, Andrea E. Murmann, Siquan Chen, Aishe A. Sarshad, Giovanna Ambrosini, Elizabeth T. Bartom, Markus Hafner, Marcus E. Peter. Induction of DISE by tumor suppressive microRNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-401.
Abstract 2554: To clone tumor-specific TCRs from a cell-based immunotherapy-benefit cervical cancer patient
Authors: Xiaoling Liang, Shudan Ou, Minjun Ma, Xihe Chen, Xiangjun Zhou, Yanyan Han
Journal: Cancer Research (2018)

Abstract Adoptive transfer of tumor-specific T cell receptor (TCR)-engineered T cells, TCR-T therapy, has shown great efficacy in clinical trials against solid tumors. A cervical cancer patient with bone metastasis was treated with a cell-based immunotherapy, named Multiple-Antigens Stimulating Cellular Therapy (MASCT), which is a combination of multiple tumor antigen peptides loaded dendritic cells (DCs) and autologous T cells stimulated by these DCs. After repeated treatment, the patient showed partially response and remained stable disease for 20 months. Moreover, boosted specific immune responses were detected in patient's periphery blood by IFNγ-Elispot assay against various tumor antigens, such as CEA, RGS5 and HPV18/58. The clinical benefits of this patient indicated that tumor-specific T cells were expanded in vivo and played an important role to control tumor progression. These T cells may be the good sources to isolate tumor-specific TCRs for TCR-T therapies. Given that, patient's PBMCs were stimulated in vitro with selected tumor peptides respectively, such as CEA, RGS5 and HPV18 E7. Tumor-specific T cells were defined as IFNγ-secreting T cells upon peptide stimulation and were further enriched by using magnetic beads. Part of the enriched T cells were analyzed for TCR alpha/beta repertoire via NGS, the other part were sorted into single T cells and analyzed for TCR alpha/beta pairing. The TCR repertoire NGS data revealed that the tumor-specific T cells harbor several hundred unique TCR alpha/beta clonotypes. Some unique TCR alpha/beta clonotypes were considered as tumor-specific TCR candidates, since the copy numbersof these clonotypes were significantly and repeatedly increased after stimulation with CEA, RGS5 or HPV18 E7, and further increased after IFNγ enrichment. After TCR alpha/beta pairing confirmation by single T cell sequencing, alpha and beta chains of these TCRs were sent to synthesis for further investigation. In conclusion we have successfully identified specific TCR clonotypes targeting selected tumor antigens from a MASCT-benefited cervical cancer patient. After functional validations, including epitope specificity, HLA restriction as well as tumor recognition, these tumor-specific TCRs may be good candidates for developing safer and more effective TCR-T therapy targeting multiple tumor antigens. Citation Format: Xiaoling Liang, Shudan Ou, Minjun Ma, Xihe Chen, Xiangjun Zhou, Yanyan Han. To clone tumor-specific TCRs from a cell-based immunotherapy-benefit cervical cancer patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2554.
Evaluation of a Brief Dermatologist-Delivered Intervention vs Usual Care on Sun Protection Behavior
Authors: Kimberly A. Mallett, Rob Turrisi, Elizabeth Billingsley, Bradley Trager, Sarah Ackerman, Racheal Reavy, June K. Robinson
Journal: JAMA Dermatology (2018)

Despite receiving dermatologic care, many patients with or without a history of skin cancer either do not use sun protection or fail to use it in an effective manner.To examine the association of a brief dermatologist-delivered intervention vs usual care with patient satisfaction and sun protection behavior.A longitudinal controlled cohort study among adults receiving dermatology care was conducted from April 25 to November 6, 2017, at 2 dermatologic clinic sites within a Northeastern health care system to compare outcomes associated with the intervention with that of usual care on 1- and 3-month patient outcomes. The sample consisted primarily of non-Hispanic white patients aged 21 to 65 years. Participants were assigned to the intervention group (n = 77) or the control group (n = 82) based on the site location of their dermatologists.The intervention (<3 minutes) was delivered by dermatologists during a skin examination or the suturing phase of skin cancer surgery. The intervention consisted of 6 components targeting sun risk and protective behaviors.First, patient's satisfaction with the dermatologist's communication was assessed. Second, the association of the intervention with changing sun protection behavior of the patient was examined.Patients in the intervention group (46 women and 31 men; mean [SD] age, 52.4 [9.6] years) rated dermatologist-patient communication more positive compared with patients in the control group (59 women and 23 men; mean [SD] age, 51.4 [11.3 years]). Eighteen percent (14 of 77) of patients in the intervention group reported 1 or more sunburns 1 month after the intervention compared with 35% (29 of 82) of patients in the control group (P = .01). No differences in report of sunburns were seen at the 3-month follow-up. Patients in the intervention group reported increased use of sunscreen across 3 months (face: intervention, increased 12% and controls, decreased 4%; P = .001; body: intervention, increased 12% and controls, decreased 1%; P = .02; reapplication: intervention, increased 15% and controls, remained stable; P = .002).The intervention was delivered by dermatologists after minimal standardized training and resulted in a higher level of satisfaction with dermatologist-patient communication and improved sun protection behavior among patients across several months.
Peer-supported self-management for people discharged from a mental health crisis team: a randomised controlled trial
Authors: Sonia Johnson, Danielle Lamb, Louise Marston, David Osborn, Oliver Mason, Claire Henderson, Gareth Ambler, Alyssa Milton, Michael Davidson, Marina Christoforou, Sarah Sullivan, Rachael Hunter, David Hindle, Beth Paterson, Monica Leverton, Jonathan Piotrowski, Rebecca Forsyth, Liberty Mosse, Nicky Goater, Kathleen Kelly, Mel Lean, Stephen Pilling, Nicola Morant, Brynmor Lloyd-Evans
Journal: The Lancet (2018)

BackgroundHigh resource expenditure on acute care is a challenge for mental health services aiming to focus on supporting recovery, and relapse after an acute crisis episode is common. Some evidence supports self-management interventions to prevent such relapses, but their effect on readmissions to acute care following a crisis is untested. We tested whether a self-management intervention facilitated by peer support workers could reduce rates of readmission to acute care for people discharged from crisis resolution teams, which provide intensive home treatment following a crisis.MethodsWe did a randomised controlled superiority trial recruiting participants from six crisis resolution teams in England. Eligible participants had been on crisis resolution team caseloads for at least a week, and had capacity to give informed consent. Participants were randomly assigned to intervention and control groups by an unmasked data manager. Those collecting and analysing data were masked to allocation, but participants were not. Participants in the intervention group were offered up to ten sessions with a peer support worker who supported them in completing a personal recovery workbook, including formulation of personal recovery goals and crisis plans. The control group received the personal recovery workbook by post. The primary outcome was readmission to acute care within 1 year. This trial is registered with ISRCTN, number 01027104.Findings221 participants were assigned to the intervention group versus 220 to the control group; primary outcome data were obtained for 218 versus 216. 64 (29%) of 218 participants in the intervention versus 83 (38%) of 216 in the control group were readmitted to acute care within 1 year (odds ratio 0·66, 95% CI 0·43–0·99; p=0·0438). 71 serious adverse events were identified in the trial (29 in the treatment group; 42 in the control group).InterpretationOur findings suggest that peer-delivered self-management reduces readmission to acute care, although admission rates were lower than anticipated and confidence intervals were relatively wide. The complexity of the study intervention limits interpretability, but assessment is warranted of whether implementing this intervention in routine settings reduces acute care readmission.FundingNational Institute for Health Research.
Calcium Responsiveness in Regional Myocardial Short-term Hibernation and Stunning in the In Situ Porcine Heart
Authors: GerdHeusch, JochenRose, AndreasSkyschally, HeinerPost, RainerSchulz
Journal: Circulation (1996)

Background We tested the hypothesis that decreased calcium responsiveness is responsible for the reduction in contractile function in regional hibernating and stunned myocardium in situ. Methods and Results In 19 anesthetized swine, the left anterior descending coronary artery flow was reduced to decrease anterior myocardial work index (sonomicrometry) by ≈60%. During 90 minutes of hypoperfusion, creatine phosphate recovered (as determined by biopsy specimens and bioluminescence) and no necrosis developed (as determined by staining with triphenyl tetrazolium chloride). In 10 swine, changes in the intracellular calcium concentration were induced by systematic variation of the postextrasystolic time interval at a constant prematurity. In 9 additional swine, a graded IC calcium infusion was performed. Under control conditions, anterior myocardial work increased with a fully compensated postextrasystolic time interval from 380±93 (mean±SD) to 523±98 mm Hg·mm. IC calcium infusion increased anterior myocardial ...