tbuckley/cabot-search huggingface dataset:
Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer
Authors: Judit Börcsök, Zsofia Sztupinszki, Raie Bekele, Sizhi P. Gao, Miklos Diossy, Amruta S. Samant, Kasia M. Dillon, Viktoria Tisza, Sándor Spisák, Orsolya Rusz, Istvan Csabai, Helle Pappot, Zoë J. Frazier, David J. Konieczkowski, David Liu, Naresh Vasani, James A. Rodrigues, David B. Solit, Jean H. Hoffman-Censits, Elizabeth R. Plimack, Jonathan E. Rosenberg, Jean-Bernard Lazaro, Mary-Ellen Taplin, Gopa Iyer, Søren Brunak, Rita Lozsa, Eliezer M. Van Allen, Dávid Szüts, Kent W. Mouw, Zoltan Szallasi
Journal: Clinical Cancer Research (2020)

Cisplatin-based chemotherapy is a first-line treatment for muscle-invasive and metastatic urothelial cancer. Approximately 10% of bladder urothelial tumors have a somatic missense mutation in the nucleotide excision repair (NER) gene, ERCC2, which confers increased sensitivity to cisplatin-based chemotherapy. However, a significant subset of patients is ineligible to receive cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory ERCC2-mutant cases.We used a series of NER-proficient and NER-deficient preclinical tumor models to test sensitivity to irofulven, an abandoned anticancer agent. In addition, we used available clinical and sequencing data from multiple urothelial tumor cohorts to develop and validate a composite mutational signature of ERCC2 deficiency and cisplatin sensitivity.We identified a novel synthetic lethal relationship between tumor NER deficiency and sensitivity to irofulven. Irofulven specifically targets cells with inactivation of the transcription-coupled NER (TC-NER) pathway and leads to robust responses in vitro and in vivo, including in models with acquired cisplatin resistance, while having minimal effect on cells with intact NER. We also found that a composite mutational signature of ERCC2 deficiency was strongly associated with cisplatin response in patients and was also associated with cisplatin and irofulven sensitivity in preclinical models.Tumor NER deficiency confers sensitivity to irofulven, a previously abandoned anticancer agent, with minimal activity in NER-proficient cells. A composite mutational signature of NER deficiency may be useful in identifying patients likely to respond to NER-targeting agents, including cisplatin and irofulven.See related commentary by Jiang and Greenberg, p. 1833.
Sixty seconds on . . . wobble rooms
Authors: Abi Rimmer
Journal: BMJ (2020)

No, this is a positive story. Wobble rooms are spaces where NHS staff can take a short break when things get too much. They’ve popped up across the country1 this year to offer support during the pandemic.

Yes, exactly! As consultant psychiatrist Richard Duggins at Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust told The BMJ in April, “Wobble rooms provide …
Abstract 16327: Clinical Profiles, Care Patterns, Outcomes and Sex Differences of Patients With STEMI in India: Insights From the North Indian ST-segment Elevation Myocardial Infarction (NORIN STEMI) Registry
Authors: Arman Qamar, Sameer Arora, Puneet Gupta, Michael Hendrickson, Muthiah Vaduganathan, ANKIT BANSAL, Ambarish Pandey, Vishal Batra, Sunil V Rao, Saibal Mukhopadhya, Vimal Mehta, Sripal Bangalore, Girish MP, Deepak L Bhatt, Mohit Gupta
Journal: Circulation (2020)

Background: Although major strides have been made in the care of patients (pts) with STEMI in high-income countries, little is known about the characteristics, practice patterns, outcomes &amp; sex differences of pts with STEMI in India. Methods: The NORIN STEMI registry is an ongoing investigator-initiated prospective cohort study of pts presenting with STEMI at tertiary medical centers in North India. This registry started enrolling pts in January 2019. Results: Of 3,635 participants enrolled to date, 16% were women &amp; the median age was 55 (IQR 45-62) years with 33% aged &lt;50 years. Prior to STEMI, 63% were smokers, 29% had hypertension, 24% diabetes, &amp; 54% were obese or overweight (Figure). Overall, 11% were previously treated with aspirin or statins. Only 2% of these patients had health insurance, &amp; 65% had lower socioeconomic status. Most (93%) initially presented to a non-PCI capable facility. Almost all received aspirin, statin, P2Y12i &amp; heparin on presentation; 66% were treated with PCI (98% femoral access), 15% fibrinolysis alone, 3% both fibrinolysis &amp; PCI, &amp;21% were medically managed; symptom onset to balloon time was 2.9 (0.6-9) days. LVEF was &lt;40% in 46% &amp; mechanical complications occurred in 1.3% (n=35 VSD, n=12 severe MR). 30-day mortality was 9%. Women were less likely to receive PCI (58% vs 67%) &amp; had a 2-fold higher mortality vs men (OR adj 2.1; 1.6-3.0; Figure). Conclusion: In this contemporary registry of pts with STEMI in North India, over a third were younger than 50 years &amp; tobacco smoking was a dominant risk factor. There were significant delays in timely reperfusion therapy with resultant severe LV dysfunction present in over half &amp; high mortality particularly in women. It is critical to identify barriers, increase awareness, and develop strategies to improve STEMI care in India.
Mavacamten Favorably Impacts Cardiac Structure in Obstructive Hypertrophic Cardiomyopathy
Authors: Sara Saberi, Nuno Cardim, Mohamad Yamani, Jeanette Schulz-Menger, Wanying Li, Victoria Florea, Amy J. Sehnert, Raymond Y. Kwong, Michael Jerosch-Herold, Ahmad Masri, Anjali Owens, Neal K. Lakdawala, Christopher M. Kramer, Mark Sherrid, Tim Seidler, Andrew Wang, Farbod Sedaghat-Hamedani, Benjamin Meder, Ofer Havakuk, Daniel Jacoby
Journal: Circulation (2020)
Abstract PO-039: Inhibition of migration, invasion and drug resistance of pancreatic adenocarcinoma cells- Role of Snail, Slug and Twist and small molecule Inhibitors
Authors: Ezgi Kasikci, Esra Aydemir, Omer Faruk Bayrak, Fikrettin Sahin
Journal: Cancer Research (2020)

Abstract Purpose: The main purpose of this study is to demonstrate the effects of epithelial to mesenchymal transition activating transcription factor silencing (EMT-ATF silencing) on migration, invasion, drug resistance and tumor forming abilities of various pancreatic cancer cell lines. Additionally, the contribution of small molecule inhibitors of EMT (SD-208 and CX4945) to the effects of gene silencing was evaluated. Methods: EMT activating transcription factors “Snail, Slug and Twist” were silenced by short hairpins on Panc-1, MIA PaCa-2, BxPC-3, and AsPC-1 pancreatic cancer cell lines. The changes in migration, invasion, laminin attachment, cancer stem-like cell properties and tumor forming abilities were investigated. Chemo sensitivity assays and small molecule inhibitors of EMT were applied to the metastatic pancreatic cancer cell line AsPC-1. Results: EMT-ATF silencing reduce EMT and stem cell-like characteristics of pancreatic cancer cell lines. Following EMT-ATF silencing amongst the four PC cell lines, AsPC-1 showed the best response and was chosen for further chemo resistance and combinational therapy applications. EMT downregulated AsPC-1 cells showed less resistance to selected chemotherapeutics compared to the control group. Both small molecule inhibitors enhanced the outcomes of EMT-ATF silencing. Conclusion: Overall it was found that EMT-ATF silencing, either by EMT-ATF silencing or with the enhancement by small molecules, is a good candidate to treat pancreatic cancer since it simultaneously minimizes metastasis, stem cell properties, and drug resistance. Citation Format: Ezgi Kasikci, Esra Aydemir, Omer Faruk Bayrak, Fikrettin Sahin. Inhibition of migration, invasion and drug resistance of pancreatic adenocarcinoma cells- Role of Snail, Slug and Twist and small molecule Inhibitors [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 PO-039.
Abstract 13951: Safety, Tolerability and Efficacy of Single-dose Amg 890, a Novel Sirna Targeting Lp(a), in Healthy Subjects and Subjects With Elevated Lp(a)
Authors: Michael J Koren, Patrick M Moriarty, Joel Neutel, Seth J Baum, Martha Hernandez-Illas, Howard S Weintraub, Jennifer Hellawell, Tracy Varrieur, Winnie Sohn, Huei Wang, Mary Elliott-Davey, Helina Kassahun, Gerald F Watts
Journal: Circulation (2020)

Introduction: Mendelian and epidemiological randomization studies have identified lipoprotein(a) [Lp(a)] as a risk factor for myocardial infarction and other atherosclerotic events. There are currently no approved medicines that selectively target Lp(a) and have demonstrated reduction in CV events. AMG 890 is a siRNA designed to reduce the production of Lp(a) by targeting mRNA transcribed from the LPA gene. Methods: This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AMG 890. Adults with plasma concentrations of Lp(a) ≥ 70 to ≤ 199 nmol/L (cohorts 1-5), and ≥ 200 nmol/L (cohorts 6-7), were randomized 3:1 to receive a single subcutaneous dose of investigational product (IP; AMG 890 or placebo). The primary endpoints were treatment-emergent adverse events (TEAEs), safety laboratory analytes, vital signs and ECGs. Secondary endpoints included PK parameters and percent reduction from baseline in Lp(a). Results: 64 subjects were administered IP (cohorts 1-5: AMG 890, n=30, doses: 3 mg, 9 mg, 30 mg, 75 mg, 225 mg; placebo, n=10; cohorts 6-7: AMG 890, n=18, doses: 9 mg and 75 mg; placebo, n=6). The most common TEAEs were headache (10% AMG 890; 25% placebo) and upper respiratory tract infection (15% AMG 890; 13% placebo); no safety concerns were identified for AMG 890. In cohorts 1-5, single doses of AMG 890 effectively reduced mean Lp(a) levels from baseline by 71-96% (based on doses) at Day 43, and by 80-94% at Day 113 (cohorts 2-5). In cohorts 6 and 7, single doses of AMG 890 effectively reduced mean Lp(a) levels from baseline by 75% and 89% at Day 43, respectively, and by 61% and 80% at Day 113, respectively. Conclusions: In adults with elevated Lp(a), single-dose treatment of AMG 890 was well-tolerated and significantly reduced Lp(a) with observed maximal percent reductions of &gt; 90% and effects persisting for more than 6 months at doses of 9 mg or higher.
<i>SSBP2-CSF1R</i> is a recurrent fusion in B-lineage acute lymphoblastic leukemia with diverse genetic presentation and variable outcome
Authors: Claire Schwab, Kathryn Roberts, Judith M. Boer, Gudrun Göhring, Doris Steinemann, Ajay Vora, Christine Macartney, Rachael Hough, Zoe Thorn, Richard Dillon, Gabriele Escherich, Giovanni Cazzaniga, Brigitte Schlegelberger, Mignon Loh, Monique L. den Boer, Anthony V. Moorman, Christine J. Harrison
Journal: Blood (2020)
Abstract 9912: The Activation of Natural Killer T Cells Ameliorates Myocardial Ischemia Reperfusion Injury in Mice
Authors: Tsuneaki Homma, Shintaro Kinugawa, Takashi Yokota, Masashige Takahashi, Arata Fukushima, Tadashi Suga, Shingo Takada, Yoshihiro Masaki, Tomoyasu Kadoguchi, Taisuke Ono, Mochamad A Sobirin, Hiroyuki Tsutsui
Journal: Circulation (2011)

Background Natural killer T (NKT) cells play an important role in tissue inflammation in various diseases due to the capacity to produce inflammatory cytokines and orchestrate tissue inflammation. It has been reported that preactivation of NKT cells with α-galactosylceramide (α-GC) protects against hepatic ischemia reperfusion injury. However no previous studies have examined the pathophysiological role of NKT cells in myocardial ischemia reperfusion injury. Methods A 45 minute occlusion of the left coronary artery followed by 24 hours reperfusion (Ischemia/Reperfusion; I/R) or sham operation was performed in male C57BL/6J mice. I/R mice received the single injection of either αGC (100μg/kg body weight, I/R+αGC, n=14), which specifically activates NKT cells, or vehicle (I/R+vehicle, n=16) 30 minutes before reperfusion. Infiltration of inflammatory cells was assessed by immunohistochemical staining and gene expression of inflammatory cytokines such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were quantified by RT-PCR in the left ventricle. Results Hemodynamics such as heart rate and blood pressure were not affected by αGC. The serum and myocardial gene expression levels of IFN-γ did not differ between sham and I/R+vehicle, and they were significantly increased in I/R+αGC in consistent with the activation of NKT cells. Infarct size was significantly smaller in I/R+αGC than I/R+vehicle (infarct size/area at risk: 37.8±2.7 vs 47.1±2.5 %, P &lt;0.05), with no significant changes in area at risk (area at risk/left ventricle: 58.5±2.3 vs 58.9±2.7 %, P =NS). Serum Troponin-I was also lowered in I/R+αGC (5.8±0.8 vs 8.7±0.7 ng/ml, P &lt;0.05). The number of infiltrating CD3 positive cells was lower in I/R+αGC (13.7±2.6 vs 36.3±7.6 cells/HPF, P &lt;0.05). In parallel, mRNA expression of TNF-α and IL-1β were lower in I/R+αGC compared to I/R+vehicle (relative value of sham+vehicle: TNF-α 5.8±0.9 vs 11.8±1.9, P &lt;0.05 and IL-1β 5.3±1.6 vs 30.0±7.8, P &lt;0.05). Conclusions The activation of NKT cells ameliorated myocardial ischemia reperfusion injury in mice possibly through the inhibition of inflammatory cell infiltration and inflammatory cytokine expression within the heart.
Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH
Authors: Rohit Loomba, Mazen Noureddin, Kris V. Kowdley, Anita Kohli, Aasim Sheikh, Guy Neff, Bal Raj Bhandari, Nadege Gunn, Stephen H. Caldwell, Zachary Goodman, Ilan Wapinski, Murray Resnick, Andrew H. Beck, Dora Ding, Catherine Jia, Jen‐Chieh Chuang, Ryan S. Huss, Chuhan Chung, G. Mani Subramanian, Robert P. Myers, Keyur Patel, Brian B. Borg, Reem Ghalib, Heidi Kabler, John Poulos, Ziad Younes, Magdy Elkhashab, Tarek Hassanein, Rajalakshmi Iyer, Peter Ruane, Mitchell L. Shiffman, Simone Strasser, Vincent Wai‐Sun Wong, Naim Alkhouri
Journal: Hepatology (2020)

Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease.In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo-treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3-F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients.In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH.
Abstract 16300: Preoperative Computed Tomography Angiography Reveals Leaflet-specific Contribution to Aortic Stenosis Influenced by Local Coronary Factors
Authors: Ian Y Chen, Vijay Vedula, Sachin B Malik, Tie Liang, Kieran S Chung, Nazish Sayed, Philip S Tsao, John C Giacomini, Alison L Marsden, Joseph C Wu
Journal: Circulation (2020)

Background: Current computed tomography (CT)-based diagnosis of severe aortic stenosis (AS) using aortic valve calcification (AVC) load does not take into account interleaflet differences in calcification and leaflet dysfunction. Objectives: We sought to assess the functional impact of these differences and identify factors that can influence calcification load in a leaflet-specific manner. Methods: We retrospectively reviewed the CT angiograms (CTA) of 170 AS patients being considered for valvular intervention and 20 control normal-valve patients. We quantified AVC load, aortic valve leaflet calcification (AVLC) load, and systolic leaflet excursion (LE sys ), and used regression analysis to investigate their interrelationships. We further performed computer simulation to examine how interleaflet differences in LE sys affect aortic valve area (AVA). Lastly, we used regression analysis to identify contributors of leaflet-specific calcification. Results: We observed significant interleaflet differences in AVLC load in AS patients, with noncoronary cusp (NCC) carrying the most load (342.0 [220.3-603.1] AU), compared to the right coronary cusp (RCC) (278.5 [168.2-492.1] AU; P &lt; 0.001) and the left coronary cusp (LCC) (240.6 [143.1-450.3] AU; P &lt; 0.001). However, LCC, but not NCC, was associated with the least LE sys (43.0 [38.4-49.2] °), compared to both NCC (45.2 [41.2-49.9] °; P = 0.009) and RCC (47.8 [42.1-53.0] °; P &lt; 0.001). Computer simulation of normal valve dynamics revealed that NCC and RCC contributed 10.4 [-1.6-15.7] % more ( P = 0.004) and 10.7 [4.9-20.4] % more ( P &lt; 0.001) to AVA than LCC. In multiple regression analysis, only NCC and RCC AVLC loads predicted LE sys (b = -0.015, P &lt; 0.001; b = -0.020, P &lt; 0.001), but not LCC AVLC load (b = -0.008; P = 0.065). Both ostial/proximal occlusion and ostial height of right coronary artery predicted RCC AVLC load (b = 71.508, P = 0.007; b = 10.252, P = 0.008). Conclusions: NCC and RCC should be given more weight than LCC in the evaluation of AS because of their greater AVC loads, more predictable LE sys -AVLC relationships, and greater contributions to AVA. Ostial/proximal occlusion and large ostial height of RCA should signify risk for disease progression in RCC.
Abstract 262: Consumptive Coagulation in a Porcine Model of Prolonged Out-of-hospital Cardiac Arrest Treated with ECPR
Authors: Joseph E Hill, Stephen L Harvey, Jensyn J VanZalen, Pavel Hala, Emre Gok, Joshua H Jung, Oliva L Pak, Robert H Bartlett, Alvaro Rojas-Peña, Robert W Neumar
Journal: Circulation (2020)

Background: Following prolonged cardiac arrest treated with extracorporeal cardiopulmonary resuscitation (ECPR), recovery of organ function and survival are potentially impaired due to a “no reflow” phenomenon associated with microvascular thrombosis. This study evaluated the effects of antithrombotic interventions on coagulation parameters in a in a porcine model of out-of-hospital cardiac arrest (OHCA). Hypothesis: We hypothesized that anticoagulant therapy (argatroban) during CPR and/or thrombolytic (streptokinase) therapy at onset of ECPR would prevent consumptive coagulopathy after prolonged cardiac arrest. Methods: In a blinded and randomized study, 48 swine (40±5kg) were subjected to 8min of ventricular fibrillation cardiac arrest followed by 30min of goal-directed CPR (gdCPR), and 8hr of ECPR (33°C) with heparin anticoagulation during ECPR titrated to ACT values (200-300s). Animals were randomized to one of 4 groups (n=12) with 350mg/kg argatroban (Arg) or placebo (20mL NSS) administered 12min after arrest and 1.5 MU streptokinase (STK) or placebo (50mL NSS) at ECPR initiation: Group 1 (placebo and placebo); Group 2 (Arg and placebo); Group 3 (placebo and STK); and Group 4 (Arg and STK). Blood samples were drawn at baseline and at 8hr of ECPR (or earlier if the experiment ended). Data was analyzed using t-tests and ANOVA (p&lt;0.05 significant). Results: Average platelet count and fibrinogen levels significantly decreased between baseline and at the end of ECPR ( p =&lt;0.0001) without difference between groups ( p =0.6315 and p =0.7692, respectively). D-dimer levels significantly increased across groups from baseline to the end of ECPR ( p =&lt;0.0001) without difference between groups ( p =0.1881). Discussion: These results indicate that this OHCA model induces consumptive coagulopathy and the effects of antithrombotic therapies did not mitigate it in this porcine model.
Abstract 13758: The Value of Plasma Neutrophil Gelatinase Associated Lipocalin in the Diagnosis of Cardiorenal Syndrome Type 1
Authors: Hao T Phan
Journal: Circulation (2020)

Introduction: The presence of acute kidney injury in the setting of acute heart failure is very common occurrence and was termed cardiorenal syndrome 1 (CRS1). In CRS1 the diagnosis of acute kidney damage is often delayed by creatinine and urine output following KDIGO standards (Kidney Disease Improving Global Outcomes). Neutrophil gelatinase-associated lipocalin (NGAL) in the blood and urine is one of the earliest markers of acute kidney damage due to anemia or nephrotoxicity. Hypothesis: Plasma NGAL has good value in the diagnosis of cardiorenal syndrome type 1. Methods: There were 139 patients with acute heart failure or acute decompensated heart failure (ADHF) in the Department of cardiovascular resuscitation and Interventional cardiology at our hospital from September 2018 to June 2019. This is a prospective cohort study Results: There were 48 cases (rate 34.5%) with CRS1, medium age 66.12 ± 15.77, men accounted for 50.4%. The optimal cut-off for diagnosing NGAL CRS1 is &gt; 353.23 ng/ml, AUC is 0.732 (95% CI 0.65-0.80, p &lt;0.001), sensitivity 74.47%, specificity 68.48%, positive predictive value 54.7%, negative predictive value 84%. Building the optimal regression model by the BMA (Bayesian Model Average) method with 2 variables NGAL and creatinin day 1: Odds Ratio= e^y while y = - 2.39 + 0.0037 x NGAL + 0.17 x CreatininD1. Moreover, a nomogram with 2 variables NGAL and creatinin day 1 was designed to predict the likelihood of CRS1 with AUC 0.79 and validated on a testing set (consiting of 40 % of the data) by 10-cross-validation method with accuracy 79.82%. Ultimately, a confusion matrix was constructed to determine model accuracy 75.93%, sensitivity 76.74%, specificity 72.73%, positive predictive value 91.67%, negative predictive value 44.44%. Conclusions: Plasma NGAL is quite good value in the diagnosis of CRS1 in patients with acute heart failure or ADHF. A predictive model based on NGAL may help early diagnose CRS1 in patients with acute heart failure or ADHF.