tbuckley/cabot-search huggingface dataset:
Abstract IA-17: Mechanisms of pancreatic cancer-induced cachexia
Authors: Benjamin Pryce, Nivedita Ratnam, Erin E. Talbert, Mary Dilhoff, Carl R. Schmidt, David J. Wang, Denis C. Guttridge
Journal: Cancer Research (2020)

Abstract Cachexia is a debilitating syndrome that results in severe, involuntary weight loss due to the depletion of skeletal muscle mass. Currently, no effective therapy exists to combat this malignant disorder. For pancreatic cancer, 85% of patients lose on average 14% of their pre-illness weight, and cachexia dramatically limits their ability to tolerate surgery, chemo- or radiotherapy. New therapies will likely evolve from an enhanced understanding of the mechanisms leading to muscle wasting and tumor development. Our laboratory has been examining the role of the NF-κB signaling pathway in tumorigenesis for several decades and that interest led us to discover the connection between NF-κB and muscle wasting in cancer cachexia and more recently in pancreatic cancer. We view the pathway as playing two separate functions in pancreatic cancer-induced cachexia. The first occurs at the level of skeletal muscle, or more preciously in skeletal muscle stem cells. We have found that during cancer progression, skeletal muscle undergoes a type of injury response leading to the activation of resident stem cells to engage in a regeneration program. NF-κB is activated in these stem cells and functions to inhibit regeneration, which contributes to the overall wasting process in cachexia. New data reveal that NF-κB activity in progenitor cells also regulates a local muscle inflammatory environment that might also contribute to skeletal muscle catabolism. The mechanism of this regulation will be discussed in more details. The second function of NF-κB signaling that we are pursuing focuses in the tumor microenvironment of pancreatic cancer. Using orthotopic mouse models of pancreatic cancer, we showed that NF-κB plays a critical role in protecting tumor cells from the surveillance property of anti-tumor macrophages. This occurs through the direct transcriptional regulation of the immunosuppressive cytokine, GDF15. Interestingly, circulating levels of GDF15 are elevated in cachectic patients and recent studies indicate that this cytokine might be an attractive therapeutic target in cancer cachexia. Together, we speculate that NF-κB functions in cancer cachexia by acting in muscle stem cells to block muscle repair, as well as promoting pancreatic cancer through the production of immunosuppressive genes such as GDF15. Citation Format: Benjamin Pryce, Nivedita Ratnam, Erin E. Talbert, Mary Dilhoff, Carl R. Schmidt, David J. Wang, Denis C. Guttridge. Mechanisms of pancreatic cancer-induced cachexia [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-17.
Targeting Telomerase with an HLA Class II-Restricted TCR for Cancer Immunotherapy
Authors: Pierre Dillard, Hakan Köksal, Solrun Melkorka Maggadottir, Anna Winge-Main, Sylvie Pollmann, Mathilde Menard, Marit Renée Myhre, Gunhild M. Mælandsmo, Vivi Ann Flørenes, Gustav Gaudernack, Gunnar Kvalheim, Sébastien Wälchli, Else Marit Inderberg
Journal: Molecular Therapy (2020)

T cell receptor (TCR)-engineered T cell therapy is a promising cancer treatment approach. Human telomerase reverse transcriptase (hTERT) is overexpressed in the majority of tumors and a potential target for adoptive cell therapy. We isolated a novel hTERT-specific TCR sequence, named Radium-4, from a clinically responding pancreatic cancer patient vaccinated with a long hTERT peptide. Radium-4 TCR-redirected primary CD4+ and CD8+ T cells demonstrated in vitro efficacy, producing inflammatory cytokines and killing hTERT+ melanoma cells in both 2D and 3D settings, as well as malignant, patient-derived ascites cells. Importantly, T cells expressing Radium-4 TCR displayed no toxicity against bone marrow stem cells or mature hematopoietic cells. Notably, Radium-4 TCR+ T cells also significantly reduced tumor growth and improved survival in a xenograft mouse model. Since hTERT is a universal cancer antigen, and the very frequently expressed HLA class II molecules presenting the hTERT peptide to this TCR provide a very high (>75%) population coverage, this TCR represents an attractive candidate for immunotherapy of solid tumors. T cell receptor (TCR)-engineered T cell therapy is a promising cancer treatment approach. Human telomerase reverse transcriptase (hTERT) is overexpressed in the majority of tumors and a potential target for adoptive cell therapy. We isolated a novel hTERT-specific TCR sequence, named Radium-4, from a clinically responding pancreatic cancer patient vaccinated with a long hTERT peptide. Radium-4 TCR-redirected primary CD4+ and CD8+ T cells demonstrated in vitro efficacy, producing inflammatory cytokines and killing hTERT+ melanoma cells in both 2D and 3D settings, as well as malignant, patient-derived ascites cells. Importantly, T cells expressing Radium-4 TCR displayed no toxicity against bone marrow stem cells or mature hematopoietic cells. Notably, Radium-4 TCR+ T cells also significantly reduced tumor growth and improved survival in a xenograft mouse model. Since hTERT is a universal cancer antigen, and the very frequently expressed HLA class II molecules presenting the hTERT peptide to this TCR provide a very high (>75%) population coverage, this TCR represents an attractive candidate for immunotherapy of solid tumors.
Abstract 14540: Preliminary Efficacy and Feasibility of an Emotion Regulation Intervention on Physical Activity and Depressive and Anxious Symptoms in Individuals in Cardiac Rehabilitation
Authors: Kelly L Wierenga, David M Fresco, Megan Alder, Shirley M Moore
Journal: Circulation (2020)

Cardiac rehabilitation (CR) is an important part of overcoming an acute cardiac event, but can be undermined by debilitating levels of depression and anxiety, which can leave cardiac patients at risk for diminished functional capacity. The purpose of this randomized control trial was to evaluate the development and early efficacy testing of a theoretically based emotion regulation treatment (RENEwS) designed to assist people in CR to optimize recovery following acute cardiac events. CR participants (n=30, 83% men) were randomized to 5 one-hour, in-person group sessions of RENEwS or a phone-based active-control group. Participants completed measures of depression and anxiety symptoms at three timepoints. PA was objectively measured for 7 days at each time point using waist-worn actigraphy monitors. Between-group differences were calculated using linear mixed models to evaluate initial efficacy. Qualitative data were collected during RENEwS sessions and analyzed using content analysis with a directed approach to assess intervention feasibility and acceptability. Compared to active-control participants, RENEwS participants showed greater reductions in depression (Cohen’s f = .34) and anxiety symptoms (Cohen’s f = .40) but only modest improvements in PA from baseline to 5 months (Cohen’s f = .08). Descriptive exploratory analysis of within-group changes in the RENEwS group reveals individuals with above mean depressive symptoms and individuals with above mean anxiety symptoms experienced clinically meaningful decreases in psychological symptoms and increases in PA at 5 months. Qualitative analysis of feasibility indicated strengths in acceptability, demand, adaptation, integration, and implementation. Findings show that RENEwS is a promising emotion regulation intervention for CR patients, though revisions are needed to address practicality, expansion, and efficacy.
Abstract 15151: The Prevalence of Covid-19 on the Door to Balloon Time in Patients With St-elevation Myocardial Infarction
Authors: yuki matsubara, Takeshi Yamada, Soichiro Washimi, Akihiko Takahashi, Tetsuya Hata, Shunsuke Nakajima, Norimasa Taniguchi, Sho Hashimoto
Journal: Circulation (2020)

Background: Patients with ST-elevation myocardial infarction (STEMI) should undergo primary PCI (percutaneous coronary intervention) as a standard of care. However, with the increase in the prevalence of COVID-19, all patients with suspected STEMI should be treated as possible COVID-19 cases. Therefore, more time may be needed to establish an acute MI diagnosis and to perform a COVID-19 status assessment. There has been a paucity of data regarding its influence on the primary PCI procedure. Objective: We sought to evaluate the impact of the prevalence of COVID-19 on the door-to-balloon time and clinical outcome in patient with STEMI. Method: Between January 2019 and May 2020, 157 patients with STEMI underwent primary PCI in 3 Japanese PCI centers. Mean age of patients was 70.4±12.9 years, and 71.6% were male. Right distal radial artery access was used in 110 patients (94.8%). We divided these patients into two groups: a group before the COVID -19 outbreak and another group during the pandemic, and were retrospectively analyzed. The following patients’ baseline characteristics were obtained: door-to-balloon time, duration in the emergency department, finding of CT scan if conducted, peak CK, 30-day mortality rate. Results: We evaluated patients with STEMI who underwent PCI between January 2019 and January 2020 (before the pandemic) and between February 2020 and May 2020 (during the pandemic). The number of patients was 119 before pandemic and 37 during pandemic. Mean door-to-balloon time was 35.8 ± 24.5 min before the pandemic and 41.2 ± 20.8 min after the outbreak (p&lt;0.05). Induration at the emergency department was 22.6 ± 18.6 min before the pandemic and 21.3 ± 13.3 min after the outbreak (p=0.329). CT evaluation was performed before PCI was conducted in 41 patients (34.5%) and 14 patients (37.8%) (p=0.699). The peak CPK was 1956.2 ±2141.9 U/L and 2801.1 ± 2982.5 U/L (P=0.006). There was no significant difference in a 30-day mortality rate (5% vs 0%; P=0.699). Of the 37 patients after the outbreak, no patient underwent PCR examination for COVID-19 virus. Conclusion: The COVID-19 pandemic changed the diagnostic procedure in the emergency department and affected door-to-balloon time in patients with STEMI.
Abstract 13438: The Role and Mechanism of Chronic Beta3-Adrenergic Receptor Blockade on the Progression of Heart Failure in a Rat Model
Authors: Xiaoqiang Sun, Che Cheng, Jing Cao, Zhi Zhang, Tiankai Li, Xiaowei Zhang, Heng Jie Cheng
Journal: Circulation (2020)

Background: The negative inotrope and up-regulation of β 3 -adrenergic receptors (AR) in human and animal failing hearts suggest a direct and contributing role of cardiac β 3 -AR activation on the progression of congestive heart failure (CHF). However, its precise role is still being debated. We hypothesize that up-regulation of cardiac β 3 -AR is detrimental and chronic β 3 -AR blockade may prevent CHF-caused intrinsic defects of left ventricular (LV) myocyte force-generating capacity and relaxation and improve β-AR regulation, thereby limiting the progression of CHF. Methods: We compared the alterations of LV and myocyte functional responses and [Ca 2+ ] i transient ([Ca 2+ ] iT ) in SD rats divided into 3 groups (8/group): 1) CHF 3 months after isoproterenol (ISO) (170 mg/kg, sq, for 2 days); 2) ISO/β 3 -ANT , 2 months after receiving ISO, a selective β 3 -AR antagonist (ANT), L-748,337, was initiated (10 -7 M/kg/day, sq. by mini-pump) and was given for 1 month; and 3) Sham controls . Results: Compared with controls, the animals that received ISO treatment had CHF onset at 1 month and progressed to severe HF at 3 months after ISO. Plasma norepinephrine (NE) (1295 vs 259 pg/ml) increased 5-fold; whereas, stroke volume (SV) (39 vs 91 μl) and ejection fraction (EF) (39 vs 62%) significantly decreased, and LV end-diastolic pressure (P ED ) (13.9 vs 6.0 mmHg) was doubled. These changes were paralleled with about 50% reductions in cell contraction (dL/dt max , 93 vs 186 μm/s) and relaxation (dR/dt max , 96 vs 159 μm/s) associated with a significant decrease in the peak systolic [Ca 2+ ] iT , (0.17 vs 0.26). In addition, superfusion of ISO (10 -8 M) caused much less increases in dL/dt max (39 vs 68%), dR/dt max (23 vs 54%), and [Ca 2+ ] IT (14 vs 28%). Treatment with β 3 -ANT increased SV (89 μl) and EF (60%), decreased P ED more than 90% from ISO-treated values, and corrected the elevation of plasma NE (301 pg/ml), dL/dt max (184 μm/s), dR/dt max (152 μm/s), and [Ca 2+ ] iT (0.24). ISO-induced increase in dL/dt max and [Ca 2+ ] iT also returned close to control levels. Conclusion: Chronic β 3 -ANT treatment after CHF significantly improves LV and myocyte contractile function and [Ca 2+ ] i regulation and limits the development of CHF. Thus, β 3 -AR blocker may provide a new therapeutic strategy for the treatment of CHF.
Machine-learning-based prediction models for high-need high-cost patients using nationwide clinical and claims data
Authors: Itsuki Osawa, Tadahiro Goto, Yuji Yamamoto, Yusuke Tsugawa
Journal: npj Digital Medicine (2020)

Abstract High-need, high-cost (HNHC) patients—usually defined as those who account for the top 5% of annual healthcare costs—use as much as half of the total healthcare costs. Accurately predicting future HNHC patients and designing targeted interventions for them has the potential to effectively control rapidly growing healthcare expenditures. To achieve this goal, we used a nationally representative random sample of the working-age population who underwent a screening program in Japan in 2013–2016, and developed five machine-learning-based prediction models for HNHC patients in the subsequent year. Predictors include demographics, blood pressure, laboratory tests (e.g., HbA1c, LDL-C, and AST), survey responses (e.g., smoking status, medications, and past medical history), and annual healthcare cost in the prior year. Our prediction models for HNHC patients combining clinical data from the national screening program with claims data showed a c-statistics of 0.84 (95%CI, 0.83–0.86), and overperformed traditional prediction models relying only on claims data.
Abstract 14931: Low-Dose Prasugrel Has Prognostic Superiority to Clopidogrel in High-Bleeding Risk Patients Undergoing Contemporary Percutaneous Coronary Intervention
Authors: Takuro Abe, Kentaro Jujo, Takehiro Hata, KAZUHO KAMISHIMA, Hiroshi Koganei, Tomohiro Sakamoto, Junichi Yamaguchi, Nobuhisa Hagiwara
Journal: Circulation (2020)

Introduction: The combination of aspirin and P2Y12 receptor antagonist is the standard antiplatelet therapy after percutaneous coronary intervention (PCI). Previous trials reported that prasugrel reduced the risk of ischemic events, but increased bleeding events compared to clopidogrel. Hypothesis: The prognostic impact of low-dose prasugrel (3.75 mg/day), which the dose was determined by phase II trial, is different from that of clopidogrel, depending on patient’s bleeding risk. Methods: This study is a subanalysis from the TWINCRE registry that is a multicentral prospective cohort including patients who underwent PCI. We analyzed 1,001 patients who received the combination of aspirin and prasugrel or clopidogrel after PCI. The primary endpoint was a composite of major bleeding event and major adverse cardiovascular and cerebrovascular events (MACCE) including any death, acute coronary syndrome, stent thrombosis, stroke and heart failure hospitalization. Results: There were 490 patients with high bleeding risk (HBR) and 511 patients with low bleeding risk (LBR), based on ARC-HBR criteria. In HBR patients, the Low-dose prasugrel group had significantly lower rates of MACCE (Log-rank, p=0.003) and the composite endpoint than the Clopidogrel group (p=0.001). While, in LBR patients, there was no significant difference in rates of MACCE or the composite endpoint between the groups (p=0.76, p=0.15, respectively), and a higher rate of major bleeding event in the Low-dose prasugrel group (p=0.002). With Cox proportional hazards analysis, low-dose prasugrel has still retained the superiority to clopidogrel regarding with the composite endpoint in HBR patients, even after adjusting with diverse covariates (hazard ratio: 0.33, 95% confidence interval: 0.16-0.65). Conclusion: In the multicenter cohort study in Japan, low-dose prasugrel showed a long-term prognostic superiority to clopidogrel only in HBR patients undergoing contemporary PCI.
Children Are Not Little Adults When Prescribing Opioids
Authors: Adam C. Alder, Dai H. Chung
Journal: JAMA Surgery (2020)

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Abstract 15949: Post-transcriptional Regulation of Cardiac Pathological Remodeling-- Role of Cytosolic Rbfox1c
Authors: Chen Gao, Zhaojun xiong, Jianfang Liu, Menglong Wang, Yun-Hua Hsiao, Shuxun Ren, Christoph D Rau, Katelyn Li, Thomas M Vondriska, Yibin Wang, Yi Xing
Journal: Circulation (2020)

Post-transcriptional regulation plays a key role in transcriptome reprogramming during cardiac development and pathogenesis. In previous study, we have identified that loss of RBFox1 is a molecular hallmark associated with cardiac pathological hypertrophy and heart failure. We further demonstrate that RBFox1 regulates cardiac gene expression and function at post-transcriptional level through targeted RNA splicing in nuclei. However, RBFox1 gene also generates a cytosolic isoform RBFox1c, suggesting that it might also regulate other aspects of post-transcriptional regulation in heart. We detected that RBFox1c mRNA constituted 40% of total RBFox1 level in normal adult heart but repressed in diseased heart. In RBFox1-cKO mice, enhanced cardiac fibrosis was associated with loss of cardiac function following MI or TAC. Restoration of RBFox1c expression (RBFox1c-TG) significantly reduced cardiac fibrosis. RNA sequencing in RBFox1c expressing cardiomyocytes showed that RBFox1c specifically suppressed the expression of pro-inflammatory genes. The pro-inflammatory genes were induced in the RBFox1 deficient hearts but suppressed upon cardiomyocyte specific RBFox1c expression. In vitro, RBFox1c expression in NRVM suppressed PE induced proinflammatory genes and significantly blocked the effects of the conditioned media on fibroblast proliferation. De novo motif discovery identified a significant enrichment of the conserved RBFox1 binding motif in the 3’UTRs of the RBFox1c dependent genes. RNA-CLIP analysis further demonstrated a direct binding of RBFox1c to the pro-inflammatory gene 3’UTR. We characterized the interactome of RBFox1c and found RBFox1c specifically interacted with a component of the RNA non-sense mediated decay machinery-Upf1. RBFox1c interaction with Upf1 in cardiomyocytes was diminished upon hypertrophic stress. By inactivation of Upf1 via siRNA, we demonstrated that RBFox1c mediated repression of proinflammatory genes was Upf1 dependent. Finally, by temporally induced expression of RBFox1c in post-TAC heart, we provided proof-of-concept evidence that targeted expression of RBFox1c was sufficient to ameliorate pathological remodeling and progression of heart failure as a potential gene-based therapy.
Prone position in ARDS patients: why, when, how and for whom
Authors: Claude Guérin, Richard K. Albert, Jeremy Beitler, Luciano Gattinoni, Samir Jaber, John J. Marini, Laveena Munshi, Laurent Papazian, Antonio Pesenti, Antoine Vieillard-Baron, Jordi Mancebo
Journal: Intensive Care Medicine (2020)
Abstract 13082: The Impact of Specific Therapy on Glucose Metabolism in Pulmonary Arterial Hypertension Patients - Follow Up Study
Authors: Remigiusz Kazimierczyk, Piotr Szumowski, Stephan Nekolla, Piotr Blaszczak, Lukasz A Malek, Marcin Hladunski, Bozena Sobkowicz, Janusz Mysliwiec, Ryszard Grzywna, Wlodzimierz J Musial, Karol Kaminski
Journal: Circulation (2020)

Introduction: Right ventricular (RV) function is a major determinant of survival in patients with pulmonary arterial hypertension (PAH). In our previous study, we confirmed that increased RV fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) (presented as higher ratio of FDG uptake of RV to LV) was associated with progressive RV dysfunction and preceded hemodynamic and clinical deterioration in PAH patients. Now, we obtained second PET/MRI assessments of the study group after 2-years of PAH-targeted treatment. Hypothesis: Altered cardiac glucose uptake in severe PAH patients may change after PAH specific treatment. Methods: Twenty-eight PAH patients (51.32±15.91 years) had simultaneous PET/MRI scans performed during baseline visit. Second PET/MRI assessments were done after 2 years in the group of twenty patients (four deaths, four patients did not agree to perform additional scans). Results: After follow-up period, we observed significant change of MRI-derived RV ejection fraction (45±10% to 51.2±12.7%, p=0.03), and improvement in hemodynamic parameters obtained from right heart catheterization e.g. mean pulmonary artery pressure, mPAP (48.5±17.2 to 41.8±17.1 mmHg, p=0.01) and pulmonary vascular resistance, PVR (8.7±5.3 to 7.0±4.2 WU, p=0.04). Follow-up SUVRV/SUVLV ratio was lower than baseline (0.84±0.57 vs 1.02±0.75, p=0.05) and significantly correlated with follow-up RV hemodynamic parameters confirming relationship between RV function and metabolic alterations. Interestingly, patients who had improvement in SUVRV/SUVLV (lower follow-up value than baseline, n=11) had significantly higher mPAP at baseline visit (58.9±18.7 vs 40.3±11.8 mmHg, p=0.02), suggesting that RV FDG accumulation in advanced PAH may decrease after the specific PAH-treatment in accordance with the degree of reduction in the pulmonary vascular resistance. Conclusions: Impaired RV function is associated with increased glucose uptake of RV myocytes estimated by FDG PET in PAH patients. Targeted treatment may improve RV function and thus affect previously altered cardiac glucose uptake.