tbuckley/cabot-search huggingface dataset:
Abstract 11456: Elevated Lipoprotein(a) is Associated with Statin Resistance
Authors: Gary S Ma, Gregory G Schwartz, Anders G Olsson, Peter Willeit, Sotirios Tsimikas, Calvin Yeang
Journal: Circulation (2021)

Introduction: LDL-C reduction by statins is the mainstay pharmacologic strategy for ASCVD risk reduction. Despite adherence, some patients fail to achieve LDL-C goals, a phenomenon known as statin resistance. Current LDL-C assays include cholesterol content on both lipoprotein(a) [Lp(a)] and LDL particles. Because statins do not lower Lp(a), Lp(a)-cholesterol may represent a statin insensitive pool within LDL-C. Hypothesis: Elevated Lp(a) contributes to statin resistance in patients treated with high-intensity statin therapy. Methods: A secondary analysis was performed on 2338 patients from the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial, randomized to receive atorvastatin 80mg or placebo; baseline and week 16 lipid parameters were analyzed. Results: In the atorvastatin group (n = 1092), mean (SD) baseline LDL-C, absolute LDL-C reduction, median percent LDL-C change from baseline (IQR), and Lp(a) were 123.8 (33.5) mg/dL, 52.2 (36.7) mg/dL, -47.6% (-59.1- -29.9%), and 10.6 (5.1-29.1) mg/dL, respectively. Median (IQR) baseline Lp(a) was higher [12.1 (5.9-38.1) vs 9.2 (4.4-22.4) mg/dL, p &lt; 0.001] in patients with attenuated percent LDL-C reduction compared to group median. The median percent LDL-C reduction on atorvastatin was 42.3% (24.3-52.5%) in patients with baseline Lp(a) between 50 - 99 mg/dL, and 32.6% (11.5-43.7%) with Lp(a) &gt; 100 mg/dL prevalent in ~10% of the population, both significantly attenuated compared to patients with Lp(a) &lt;30 mg/dL (50.4% [33.3-61.1%]), p &lt; 0.001. An LDL-C target of 70 mg/dL or less was achieved in 62.3% of patients with baseline Lp(a) &lt;30 mg/dL, compared to 55.2%, 43.3%, and 24.1% of those with Lp(a) 30 - 49 mg/dL, 50 - 99 mg/dL, and &gt; 100 mg/dL (p &lt; 0.001), respectively [Figure 1]. Conclusions: Elevated Lp(a) is associated with statin resistance and may identify patients who require additional or more potent lipid lowering therapies to achieve LDL-C goals.
Exosomal non-coding RNAs: Emerging roles in bilateral communication between cancer cells and macrophages
Authors: Wenhao Li, Xiaolong Wang, Chen Li, Tong Chen, Qifeng Yang
Journal: Molecular Therapy (2021)

The tumor microenvironment (TME) is a dynamic network of cellular organization that comprises diverse cell types and significantly contributes to cancer development. As pivotal immune stromal cells in the TME, macrophages are extensively heterogeneous and exert both antitumor and protumor functions. Exosomes are nanosized extracellular membranous vesicles with diameters between 30 and 150 nm. By transferring multiple bioactive substances such as proteins, lipids, and nucleic acids, exosomes play an important role in the communication between cells. Recently, growing evidence has demonstrated that non-coding RNAs (ncRNAs) are enriched in exosomes and that exosomal ncRNAs are involved in the crosstalk between cancer cells and macrophages. Furthermore, circulating exosomal ncRNAs can be detected in biofluids, serving as promising noninvasive biomarkers for the early diagnosis and prognostic prediction of cancer. Exosome-based therapies are emerging as potent strategies that can be utilized to alleviate tumor progression. Herein, the present knowledge of exosomal ncRNAs and their vital roles in regulating the interplay between cancer cells and macrophages, as well as their clinical applications are summarized.
Sixty seconds on . . . trust in scientists
Authors: Jacqui Wise
Journal: BMJ (2021)

Indeed. Many scientists have become household names over the past 20 months as they convey complex ideas to the general public. And their efforts have been rewarded. According to a survey of 119 000 people in over 100 countries, 77% of people trust scientists either “a lot” or “some,” up from 72% in 2018.1 In the UK, 60% of people said they …
Abstract 11966: Combined Shear Stress-Molecular Imaging for the Evaluation of Bioresorbable Scaffold: Effect of Strut Thickness on the Endothelial Microenvironment and Early Inflammatory Response
Authors: Sunwon Kim, Hyeong Soo Nam, Hyun-Sang Park, Joon Woo Song, Jae Won Ahn, Yeon Hoon Kim, Hyun Jung Kim, Hongki Yoo, Wang-Yuhl Oh, Kyeongsoon Park, Jin Won Kim
Journal: Circulation (2021)

Introduction: We evaluated local endothelial shear stress (ESS) distribution and arterial healing response of a thin-strut bioresorbable scaffold (BRS, 100μm) compared to 157μm-thickness ABSORB. Hypothesis: Thinner-strut design is known to promote stent healing, however, there has been a lack of in vivo imaging evidence on how strut thickness affect healing process. Methods: BRS and ABSORB were implanted in left anterior descending and circumflex arteries of pigs (n=7). Detailed scaffolded-artery 3D model was reconstructed based on OCT. Scaffold-related inflammation response was serially assessed by OCT-near-infrared fluorescence (OCT-NIRF) molecular imaging using macrophage-mannose receptor-Cy7 as NIRF emitter. Results: On ESS analysis, regions with athero-prone low ESS were significantly greater in ABSORB than in BRS. OCT-NIRF structural-molecular imaging clearly visualized active inflammation at peri-strut regions (Figure). Arterial inflammation, quantified as target-to-background ratio, was significantly lower in thin-strut BRS than ABSORB at 2 weeks (p&lt;0.01). A statistically significant inverse correlation was found between logarithmic transformed ESS and NIRF activity (p&lt;0.0001, Figure), demonstrating direct immune-modulating effect of ESS. Serial imaging showed that inflammation activity decreased more rapidly in thin-strut BRS compared to ABSORB. Ex vivo confocal fluorescence microscopy and immunohistochemical analysis well corroborated the findings in vivo. Conclusions: Thin-strut BRS with favorable ESS profile was associated with less inflammation and rapid resolution of inflammation, demonstrating that strut-related changes in endothelial microenvironment affect early healing by modulating arterial immune response. Our novel imaging strategy enabling comprehensive evaluation of complex biomechanical interaction between scaffold, ESS, and vasculature is expected to enhance understanding of BRS biology.
Abstract 9607: CIED and Non-CIED MRI Imaging; Should Capped or Uncapped Abandoned Leads Remain a Contraindication?
Authors: Loretta Gevenosky, Robert W Biederman
Journal: Circulation (2021)

Introduction: Infrequently, MRI is performed on patients with conventional pacemakers or ICDs. While multiple studies have documented the safety of MRI scans when performed with an approved protocol, retained leads (capped or uncapped) remain a significant concern. Hypothesis: We hypothesize that non-CIED and CIED devices in the presence of capped and uncapped leads, while inherently having no ability to for interrogation, can be performed under a similar MRI-device protocol in a safe and reliable fashion. Methods: Adapting the same MRI-device protocol as for either CIED or non-CIEDs as appropriate, tracking of patient safety to include chest pain, sustained arrhythmias or change in any device setting was performed. Results: A total of 311 pts with CIED (81%) and non-CIED (19%) from 2019-2021 at Allegheny General Hospital incorporating a total of 16 (5%) pts with retained/abandoned/fragmented leads (56% capped and 44% uncapped; p=NS) as well as 3 epicardial leads underwent MRI (GE; EXCITE, 1.5T; WI) of several regions (Brain; 72%, Ortho; 17% and CV; 11%). Repeat imaging was common (12%). Utilizing an established device protocol according to CIED or non-CIED, pts were programmed based on pt-specific pacing requirements. There were no episodes of abnormal vital signs, chest pain, sustained arrhythmias or any clinically significant device setting changes. No significant changes to impedance, amplitude, voltage or sensitivity to RA or RV/LV parameters occurred. There were no differences, naturally, between capped, uncapped or epicardial lead metrics. Likewise, no power-on resets or pacing changes were noted in the primary device system. Altogether, this supports the absence of myocardial or extra-cardiac thermal-induced injury. Infrequent, clinically insignificantly decreased RA sensing, a common natural observation in contemporary interrogation, was infrequently and transiently noted. Conclusions: Following a standard MRI protocol, according to CIED and non-CIED in pts with either capped or uncapped abandoned leads, pts suffered no ill consequences when tracked for CP, arrhythmias or device setting changes supporting a proof-of-concept notion for removing yet another obstacle for often life-changing MRI in patients with PM/ICDs.
Abstract P320: The Gut Microbial Metabolite Butyrate Suppresses Cardiac Hypertrophy Via An Epigenetic Mechanism
Authors: Masahiko Umei, Hiroshi Akazawa, Akiko Saga-Kamo, Hiroki Yagi, Qing Liu, Hiroshi Kadowaki, Ryo Matsuoka, Akito Shindo, Seitaro Nomura, Issei Komuro
Journal: Circulation Research (2021)

Introduction: Short-chain fatty acids (SCFA) are one of the gut microbial metabolites that can influence host health and disease. We previously reported that gut dysbiosis is associated with heart failure, and that the proportion of butyrate-producing bacteria is decreased in the gut of patients with heart failure. Purpose: We investigated the molecular mechanism of butyrate in the development of cardiac hypertrophy. Methods and Results: Single-cell transcriptome analysis and co-expression network analysis revealed that G protein-coupled receptors for short-chain fatty acid receptors were not expressed in cardiomyocytes and that Olfr78 was expressed in vascular smooth muscle cells in the heart. On the other hand, treatment with butyrate inhibited ET1-induced and isoproterenol (ISO)-induced hypertrophic growth in cultured neonatal rat cardiomyocytes. Moreover, butyrate increased the acetylation levels of histone H3, suggesting the inhibitory effect of butyrate on HDAC. In addition, butyrate caused the degradation of HDAC2 and up-regulation of Inpp5f, encoding inositol polyphosphate-5-phosphatase f, leading to a significant decrease in the phosphorylation levels of Akt and glycogen synthase kinase 3β (GSK3β). Finally, intraperitoneal injection of butyrate inhibited ISO-induced cardiac hypertrophy in mice. These results suggest that butyrate protects against hypertrophic responses via suppression of the Akt-GSK3β pathway through HDAC inhibition. Conclusion: In the heart, there were no known short-chain fatty acid receptors in cardiomyocytes. However, butyrate was shown to have an epigenetic mechanism in suppressing effect on cardiomyocyte hypertrophy via suppression of HDAC2-Akt-GSK3β axis. Our results uncover a potential link between dysbiosis of intestinal microbiota and the development of cardiac hypertrophy.
<i>DNMT3A</i> and <i>TET2</i> mutant Clonal Hematopoiesis May Drive a Proinflammatory State and Predict Enhanced Response to Immune Checkpoint Inhibitors
Authors: Abhay Singh Singh, Nuria Mencia-Trinchant, Elizabeth A. Griffiths, Mahesh Swaminathan, Matthew Gravina, Rutaba Tajammal, Mark G. Faber, Marc S. Ernstoff, LunBiao Yan, Eti Sinha, Megan M. Herr, Duane C Hassane, Monica L. Guzman, Amanda Przespolewski, Eunice S. Wang, Swapna Thota
Journal: Blood (2021)
Polatuzumab vedotin plus obinutuzumab and lenalidomide in patients with relapsed or refractory follicular lymphoma: a cohort of a multicentre, single-arm, phase 1b/2 study
Authors: Catherine Diefenbach, Brad S Kahl, Andrew McMillan, Javier Briones, Lalita Banerjee, Raul Cordoba, Fiona Miall, John M Burke, Jamie Hirata, Yanwen Jiang, Joseph N Paulson, Yi Meng Chang, Lisa Musick, Pau Abrisqueta
Journal: The Lancet Haematology (2021)
Leading oncologist who overtreated patients is found to have impaired fitness to practise
Authors: Clare Dyer
Journal: BMJ (2021)

A UK oncologist with a world reputation faces possible striking off or suspension from the medical register next month after a tribunal concluded that his fitness to practise was impaired.

Justin Stebbing, a professor of cancer medicine and oncology at Imperial College London who also has a private practice in Harley Street, faced charges that he overtreated cancer patients at the end of their lives.

Last month a medical practitioners tribunal found …
Abstract 12292: Trends and Outcomes of Cardiac Transplantation in the Lowest Urgency Candidates
Authors: Michael Fuery, Fouad Chouairi, Peter Natov, Jasjit Bhinder, Maya Chiravuri, Lynn Wilson, Katherine Clark, Samuel Reinhardt, Clancy Mullan, Elliott Miller, Joseph G Rogers, Chetan B Patel, Sounok Sen, Arnar Geirsson, Muhammad Anwer, Nihar R Desai, Tariq Ahmad
Journal: Circulation (2021)

Introduction: Due to discrepancies between donor supply and recipient demand, the cardiac transplantation process aims to prioritize the most medically urgent patients. It remains unknown how recipients with the lowest medical urgency compare to others in the allocation process. Methods: We performed a retrospective analysis of the United Network for Organ Sharing database. Patients listed for cardiac transplantation between January 2011 to May 2020 were stratified according to status at time of transplantation. Baseline recipient and donor characteristics, waitlist survival, and post-transplantation outcomes were compared between lower urgency listing and higher urgency listing in the years before and after the 2018 allocation system change. Results: Lower urgency patients in the old system were older (58.5 vs. 56 years) and more likely female (54.4% vs. 23.8%) compared to the highest urgency patients, and these trends persisted in the new system for the lowest urgency patients (59 vs. 55 years; 47.0% vs. 23.9% female; p&lt;0.001, all). Donors for the lowest urgency patients were more likely older, female, or have a history of CMV, hepatitis C, or diabetes (p&lt;0.01, all). The lowest urgency patients had longer waitlist times, and under the new allocation system these patients received organs from shorter distances and with decreased ischemic times (178 vs. 269 miles, 3.1 vs 3.5 hours; p&lt;0,001, all). There was no difference in post-transplantation survival (p&lt;0.01, all). Conclusions: Cardiac transplantation for lower urgency patients has not been well characterized. Our analysis demonstrates that, over the last decade, these patients receive hearts from donors with additional comorbidities compared to higher urgency patients but that outcomes are similar at one year. Our results may support the utility of early listing and less stringent thresholds for organ acceptance to increase access to cardiac transplantation.
Abstract 3618: A Cross Talk Between Stat3 and HSF1 Plays a Critical Role in G-CSF-induced Cardiac Protection Against Ischemia/Reperfusion Injury
Authors: Hong Ma, Yanyan Liang, Hui Gong, Jian Wu, Yuhong Niu, Yunzeng Zou
Journal: Circulation (2009)

Background-Granulocyte colony-stimulating factor (G-CSF) has been reported to protect cardiomyocytes (CM) from ischemic injury through Jak2/Stat3 pathway. Heat shock transcription factor 1 (HSF1), ...
Pan-cancer landscape of<i>CD274</i>(PD-L1) rearrangements in 283,050 patient samples, its correlation with PD-L1 protein expression, and immunotherapy response
Authors: Andrew D Kelly, Karthikeyan Murugesan, Zheng Kuang, Meagan Montesion, Jeffrey S Ross, Lee A Albacker, Richard S P Huang, Douglas I Lin, Umut Demirci, James Creeden
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Immune checkpoint inhibitors (ICIs) benefit patients with multiple cancer types, however, additional predictive biomarkers of response are needed. CD274 (programmed cell death ligand-1, PD-L1) gene rearrangements are positively associated with PD-L1 expression and may confer benefit to ICI, thus a pan-cancer characterization of these alterations is needed. Methods We analyzed 283,050 patient samples across multiple tumor types that underwent comprehensive genomic profiling for activating CD274 rearrangements and other alterations. The DAKO 22C3 Tumor Proportion Scoring (TPS) method was used for PD-L1 immunohistochemistry (IHC) testing in a small subset with available data (n=55,423). A retrospective deidentified real-world clinico-genomic database (CGDB) was examined for ICI treatment outcomes. We also report a detailed case of CD274- rearranged metastatic rectal adenocarcinoma. Results We identified 145 samples with functional rearrangements in CD274 . There were significant enrichments for PIK3CA , JAK2 , PDCD1LG2 , CREBBP , and PBRM1 co-mutations (ORs=2.1, 16.7, 17.8, 3.6, and 3.4, respectively, p&lt;0.01). Genomic human papillomavirus (HPV)-16, Epstein-Barr virus, and mismatch repair genes also co-occurred (OR=6.2, 8.4, and 4.3, respectively, p&lt;0.05). Median tumor mutational burden (TMB) was higher compared with CD274 wild-type samples (7.0 vs 3.5 mutations/Mb, p=1.7e-11), with disease-specific TMB enrichment in non-small cell lung, colorectal, unknown primary, and stomach cancers. PD-L1 IHC skewed toward positivity (N=39/43 samples with ≥1% positivity). Of eight patients from the CGDB, three remained on ICI treatment after 6 months. Separately, one patient with metastatic rectal adenocarcinoma experienced a pathologic complete response on chemoimmunotherapy. Conclusions CD274 gene rearrangements are associated with increased PD-L1 IHC scores, higher TMB, and potential clinical benefit in ICI-treated patients with cancer.
EXTH-01. SECOND GENERATION OF INDUCED NEURAL STEM CELLS TO MIGRATE AND KILL AS AN ADJUVANT TO RADIOTHERAPY IN NON-SMALL CELL LUNG CANCER METASTASIS
Authors: Alison Mercer-Smith, Morrent Thang, Andrew Buckley, Alain Valdivia, Wulin Jiang, Noah Bell, Rashmi Kumar, Hunter Bomba, Alex Woodell, Daniel Luo, Scott Floyd, Shawn Hingtgen
Journal: Neuro-Oncology (2021)

Abstract Non-small cell lung cancer (NSCLC) spread to the leptomeninges is devastating with a median survival of only a few months. Radiation is frequently offered for symptomatic relief but alone does not eliminate leptomeningeal metastases (LMM). With no standard-of-care for patients with LMM, new adjuvant therapies are desperately needed in order to combat this disease. Neural stem cells (NSCs) have shown remarkable promise as drug delivery vehicles in the treatment of brain tumors due to their inherent tumoritropic properties. Using a cell sphere culture-based system, we have transdifferentiated fibroblasts into a second-generation induced neural stem cell (hiNeuroS) secreting the cytotoxic protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to allow for the possibility of readily available, autologous cell carriers. Herein, we provide evidence that hiNeuroS-TRAIL cells can migrate to and suppress growth of NSCLC metastases in combination with radiation. In vitro time-lapse motional analysis and in vivo post-mortem tissue analysis showed that hiNeuroS-TRAIL cells migrate to NSCLC tumors. In vitro co-cultures with isobologram analysis suggests that TRAIL and radiation together have a synergistic cytotoxic effect on NSCLC tumors. In an intratumoral injection model of hiNeuroS-TRAIL, mice treated with the combination therapy of hiNeuroS-TRAIL and 2 Gy together had a small fraction of the mean tumor volume (6.4%) of controls (100%) compared to monotherapies (107.3% radiation-only, 46.6% hiNeuroS-TRAIL only). Only combination-treated mice demonstrated a significant extension in survival, which amounted to a 42% extension compared to controls. In the LMM model with ICV-infused therapy, the combination-treated mice showed significantly smaller tumor volumes (2.0%) compared to control (100%) or 2 Gy (54.9%) treated mice. Mice treated with hiNeuroS-TRAIL-only also showed only 4.6% of the tumor volume of control mice. Combination-treated mice and hiNeuroS-TRAIL-treated mice both showed significant improvements in survival (36.6% and 46.3% median extension in survival, respectively compared to controls).
Effect of PEP flute self-care versus usual care in early covid-19: non-drug, open label, randomised controlled trial in a Danish community setting
Authors: Annette Mollerup, Marius Henriksen, Sofus Christian Larsen, Anita Selmer Bennetzen, Mette Kildevæld Simonsen, Linette Marie Kofod, Jenny Dahl Knudsen, Xiaohui Chen Nielsen, Nina Weis, Berit Lilienthal Heitmann
Journal: BMJ (2021)

Abstract Objective To determine whether positive expiratory pressure (PEP) by PEP flute self-care is effective in reducing respiratory symptoms among community dwelling adults with SARS-CoV-2 infection and early stage covid-19. Design Non-drug, open label, randomised controlled trial. Setting Capital Region and Region Zealand in Denmark from 6 October 2020 to 26 February 2021. Participants Community dwelling adults, able to perform self-care, with a new SARS-CoV-2 infection (verified by reverse transcription polymerase chain reaction tests) and symptoms of covid-19. Intervention Participants were randomised to use PEP flute self-care in addition to usual care or have usual care only. Randomisation was based on permuted random blocks in a 1:1 ratio, stratified for sex and age (&lt;60 or ≥60 years). The PEP self-care group was instructed to use a PEP flute three times per day during the 30 day intervention. Main outcome measures Primary outcome was a change in symptom severity from baseline to day 30, as assessed by the self-reported COPD (chronic obstructive pulmonary disease) assessment test (CAT), which was adjusted for baseline values and stratification factors. Participants completed the CAT test questionnaire every day online. Secondary outcomes were self-reported urgent care visits due to covid-19, number of covid-19 related symptoms, and change in self-rated health, all within 30-days’ follow-up. Results 378 participants were assigned to the PEP flute self-care intervention (n=190) or usual care only (n=188). In the PEP self-care group, the median number of days with PEP flute use was 21 days (interquartile range 13-25). For the intention-to-treat population, a group difference was observed in changes from baseline in CAT scores of −1.2 points (95% confidence interval −2.1 to −0.2; P=0.017) in favour of the PEP flute self-care group. At day 30, the PEP flute self-care group also reported less chest tightness, less dyspnoea, more vigour, and higher level of daily activities, but these differences were small, and no consistent effects were seen on the secondary outcomes. No serious adverse events were reported. Conclusions In community dwelling adults with early covid-19, PEP flute self-care had a significant, yet marginal and uncertain clinical effect on respiratory symptom severity, as measured by CAT scores. Trial registration ClinicalTrials.gov NCT04530435 .