tbuckley/cabot-search huggingface dataset:
Chronically elevated branched chain amino acid levels are pro-arrhythmic
Authors: Vincent Portero, Thomas Nicol, Svitlana Podliesna, Gerard A Marchal, Antonius Baartscheer, Simona Casini, Rafik Tadros, Jorien L Treur, Michael W T Tanck, I Jane Cox, Fay Probert, Tertius A Hough, Sara Falcone, Leander Beekman, Martina Müller-Nurasyid, Gabi Kastenmüller, Christian Gieger, Annette Peters, Stefan Kääb, Moritz F Sinner, Andrew Blease, Arie O Verkerk, Connie R Bezzina, Paul K Potter, Carol Ann Remme
Journal: Cardiovascular Research (2021)

Abstract Aims Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke, and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach. Methods and results We employed a phenotype-driven N-ethyl-N-nitrosourea mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6–9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4–5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs—leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to electrocardiogram indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs), and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation. Conclusions Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome, and heart failure.
Reply to Trey Durdin, Alvin Goh, and Eugene Pietzak. Can an Imaging-guided Pathway Replace the Current Paradigm for Muscle-invasive Bladder Cancer?
Authors: Richard T. Bryan, James W.F. Catto, Kieran P. Jefferson, Prashant Patel, Nicholas D. James, None on behalf of the BladderPath Trial Management Group
Journal: European Urology (2021)
Evaluation of same day pegfilgrastim (PFG) or PFG-cbqv prophylaxis of chemotherapy induced (Febrile) neutropenia (CIN/FN) in bendamustine plus rituximab (BR) and CHOP+/-R regimens in patients with lymphoma and chronic lymphocytic leukemia (CLL): Real-world, single-center experience.
Authors: Ali McBride, Neda AlRawashdh, Trace Bartels, Logan Moore, Daniel O Persky, Ivo Abraham
Journal: Journal of Clinical Oncology (2021)

e19541 Background: BR and CHOP+/-R regimens are considered an intermediate FN risk (10-20%) per guidelines. Patients (pts) receiving these regimens need to be assessed for FN prophylaxis using specific risk factors. Current guidelines suggest waiting 24 hours post chemotherapy (CTX) to administer PFG due to an increased FN risk. Studies have shown equivocal outcomes between same day (D1) and next day (D2) administration. We evaluated real-world outcomes associated with D1 and D2 PFG administration in pts with lymphoma and CLL treated with these two regimens. Methods: Retrospective chart review of lymphoma or CLL pts treated with CHOP+/-R or BR and PFG or a biosimilar from 11/2013 through 11/2020 at the University of Arizona Cancer Center was conducted. Two pt cohorts were analyzed based on D1 vs D2 PFG administration timing. Outcomes of interest were the incidence of FN across all CTX cycles and after cycle 1, CIN grade 3/4, hospitalizations, antibiotics administration, and CTX dose reduction or delay. A secondary analysis compared the incidence of FN in pts receiving CHOP+/-R in our study with published studies (Burris et al, 2010 and Cheng et al, 2014) of D1 PFG in lymphoma pts. Results: Of the 116 pts meeting inclusion criteria, 103 received PFG on D1 and 13 on D2 of CTX. As shown in the Table, the incidence of 1st cycle FN was 6% vs 8% (P&gt;0.05), FN across all cycles was 4% vs 5% (P&gt;0.05), CIN grade 3/4, hospitalization, anti-biotic administration and dose delays/reductions incidences were 11% vs 16% (P&gt;0.05), 8% vs 11% (P&gt;0.05), 6% vs 32% (P=0.001), 11% vs 5% (P&gt;0.05) for D1 vs D2, respectively. The incidence of 1 st cycle FN in D1 cohort was 6% vs 19% (P=0.15) and 11% (P=0.67) in our study vs Burris et al and Cheng et al, respectively. While the incidence of FN across all cycles in D1 group was 5% vs 9% (P=0.03) and 17% (P=0.001) in our study vs Burris et al and Cheng et al, respectively. Conclusions: This data provides evidence that D1 PFG/PFG-cbqv does not increase FN or delayed engraftment risk as compared to previously published studies in lymphoma and may be safe to use after CTX has been administered.[Table: see text]
Phosphorylation of TRIP13 at Y56 induces radiation resistance but sensitizes head and neck cancer to cetuximab
Authors: Rajat Banerjee, Min Liu, Emily Bellile, Ligia B. Schmitd, Mitsuo Goto, Marsha-Kay N.D. Hutchinson, Priyanka Singh, Shuang Zhang, Dilna P.V. Damodaran, Mukesh K. Nyati, Matthew E. Spector, Brent Ward, Gregory Wolf, Keith Casper, Michelle Mierzwa, Nisha J. D’Silva
Journal: Molecular Therapy (2021)

Radiation therapy, a mainstay of treatment for head and neck cancer, is not always curative due to the development of treatment resistance; additionally, multi-institutional trials have questioned the efficacy of concurrent radiation with cetuximab, the epidermal growth factor receptor (EGFR) inhibitor. We unraveled a mechanism for radiation resistance; that is, radiation induces EGFR, which phosphorylates TRIP13 (thyroid hormone receptor interactor 13) on tyrosine 56. Phosphorylated (phospho-)TRIP13 promotes non-homologous end joining (NHEJ) repair to induce radiation resistance. NHEJ is the main repair pathway for radiation-induced DNA damage. Tumors expressing high TRIP13 do not respond to radiation but are sensitive to cetuximab or cetuximab combined with radiation. Suppression of phosphorylation of TRIP13 at Y56 abrogates these effects. These findings show that EGFR-mediated phosphorylation of TRIP13 at Y56 is a vital mechanism of radiation resistance. Notably, TRIP13-pY56 could be used to predict the response to radiation or cetuximab and could be explored as an actionable target. Radiation therapy, a mainstay of treatment for head and neck cancer, is not always curative due to the development of treatment resistance; additionally, multi-institutional trials have questioned the efficacy of concurrent radiation with cetuximab, the epidermal growth factor receptor (EGFR) inhibitor. We unraveled a mechanism for radiation resistance; that is, radiation induces EGFR, which phosphorylates TRIP13 (thyroid hormone receptor interactor 13) on tyrosine 56. Phosphorylated (phospho-)TRIP13 promotes non-homologous end joining (NHEJ) repair to induce radiation resistance. NHEJ is the main repair pathway for radiation-induced DNA damage. Tumors expressing high TRIP13 do not respond to radiation but are sensitive to cetuximab or cetuximab combined with radiation. Suppression of phosphorylation of TRIP13 at Y56 abrogates these effects. These findings show that EGFR-mediated phosphorylation of TRIP13 at Y56 is a vital mechanism of radiation resistance. Notably, TRIP13-pY56 could be used to predict the response to radiation or cetuximab and could be explored as an actionable target.
Exploration of the TMB and hypermutation landscape in Chinese pan-cancer patient by next-generation sequencing.
Authors: Shuo Wang, Jiasheng Xu, Jian Sun, Deng Wei, Xinsheng Zhang, Danhua Wang, Tonghui Ma
Journal: Journal of Clinical Oncology (2021)

e14575 Background: Among a variety of malignant tumors, the level of the patient's TMB was currently an important criterion for clinical judgment whether to adopt immunotherapy. Hypermutation could produce many nearby mutation sites at the same time, which seriously damages genetic material and may cause cancer. Therefore, performing TMB detection on cancer patients and understanding the occurrence of hypermutation in pan-cancer patients will help clinical researchers to further understand the disease characteristics of cancer patients and helped the choice of treatment methods. Previously, TMB and Hypermutation had been tested and studied in pan-cancer patients in the United States and Europe, but rare research was reported in China. In this study, we explored the TMB and hypermutation landscape in Chinese pan-cancer patient by next-generation sequencing. Methods: A total of 8,361 cancer patients from multiple cancer hospitals and research centers in China were included in the study. We sequenced 8,361 Chinese cancer patients from 8 cancer types using the oncopanscan product of Genetron Health Co., Ltd. and calculated the tumor mutation burden of the patients. We separately analyzed the tumor mutation burden of patients in 8 cancer types and analyzed the relationship between the occurrence of hypermutation and the patient's age and gender. Results: The results showed that in pan-cancer, hypermutation patients accounted for 16.97%, and ultrahypermutation patients accounted for 0.78%. Among them, patients with lung cancer have the highest proportion of hypermutation, reaching 27.72%, and patients with colorectal cancer have the highest proportion of ultrahypermutation, reaching 2.86%. Correlation analysis between TMB and age and gender was carried out on 8336 patients. The results showed that in the patients with intrahepatic bile duct cancer, the proportion of men and women was the same. Among the other cancer types, hypermutation patients were more male, and the proportion of men with liver cancer was the largest, with 90 percent. We further explored the correlation between the TMB of pan-cancer patients and the patient’s age, and found that in gastric cancer, liver cancer, and melanoma, the older patients have higher TMB; however, the younger the patients in brain cancer, the higher the TMB ( P&lt;0.05). Conclusions: In this study, we explored the TMB and hypermutation landscape in Chinese pan-Cancer patient for the first time. We found that among Chinese cancer patients, lung cancer patients have the highest proportion of hypermutation. In a variety of cancers, hypermutation patients account for a higher proportion of men, and the older the patient, the higher the TMB.
Capmatinib in <i>MET</i> exon 14-mutated, advanced NSCLC: Updated results from the GEOMETRY mono-1 study.
Authors: Juergen Wolf, Edward B. Garon, Harry J.M. Groen, Daniel Shao-Weng Tan, Anna Robeva, Sylvie Le Mouhaer, Mariana Carbini, Andrea Chassot-Agostinho, Rebecca Suk Heist
Journal: Journal of Clinical Oncology (2021)

9020 Background: Capmatinib, a selective MET inhibitor, is approved in the USA and Japan for the treatment of patients (pts) with MET exon 14 skipping mutation ( METex14) advanced non-small-cell lung cancer (NSCLC) based on the multi-cohort phase II GEOMETRY mono-1 study. This is the first report on expansion Cohort 7 in first line (1L) METex14 NSCLC pts, with updates to previously reported results (Wolf et al, NEJM 2020) for METex14 pts. Methods: In GEOMETRY mono-1, pts were assigned to cohorts based on previous lines of therapy and MET status ( METex14 or MET amplification). This efficacy analysis includes patients with METex14 NSCLC who were treatment-naive (Cohort 5b and 7) and those who had previously received 1L or 2L of therapy (expansion Cohort 6 and Cohort 4) for their advanced disease (data cutoff: Sep 18, 2020). Evaluated outcomes included overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS), all by BIRC; and overall survival (OS). The safety analysis includes all patients enrolled. Results: In total, 160 pts with METex14 who received capmatinib 400 mg BID were analyzed. ORR of 65.6% (95% CI 46.8-81.4) for the treatment-naive expansion Cohort 7 was in line with that previously reported for Cohort 5b (Table). Though Cohort 7 data are still immature, median PFS was 10.8 mo (95% CI 6.87-not estimable [NE]). Mature median OS was 20.8 mo (95% CI 12.4-NE) in Cohort 5b and 13.6 mo (95% CI 8.6-22.2) in Cohort 4. Median OS for Cohorts 6 and 7 and DOR for Cohort 7 are not yet reached. The safety profile remained unchanged across all study cohorts (N = 373): 98.4% of pts reported AEs (68.6% Grade [G] 3/4) regardless of causality and 16.1% reported AEs leading to discontinuation (10.5% G3/4). The most common AEs (≥20% all G) were peripheral edema (54.2%), nausea (45.0%), vomiting (28.2%), increased blood creatinine (26.5%), dyspnea (23.3%), fatigue (22.3%), and decreased appetite (21.2%). Conclusions: Results of Cohort 7 confirm those previously reported for Cohort 5b showing higher efficacy of capmatinib when used as 1L in METex14 NSCLC pts. A clinically meaningful median OS of 20.8 mo in 1L (Cohort 5b) and of 13.6 mo in relapse (Cohort 4) was also observed and, together with the continued manageable toxicity profile, the data support capmatinib as a valuable targeted treatment option for METex14 NSCLC pts. Clinical trial information: NCT02414139. [Table: see text]
ROS‐Responsive Boronate‐Stabilized Polyphenol–Poloxamer 188 Assembled Dexamethasone Nanodrug for Macrophage Repolarization in Osteoarthritis Treatment
Authors: Xinxin Li, Xinyu Wang, Qingfeng Liu, Junjie Yan, Donghui Pan, Lizhen Wang, Yuping Xu, Fang Wang, Yuhang Liu, Xiaotian Li, Min Yang
Journal: Advanced Healthcare Materials (2021)

Abstract Osteoarthritis (OA) is a disabling joint disease associated with chronic inflammation. The polarization of macrophages plays the key role in inflammatory microenvironment of joint which is a therapeutic target for OA treatment. Herein, a boronate‐stabilized polyphenol–poloxamer assembled dexamethasone nanodrug with reactive oxygen species (ROS)‐responsive drug release behavior and ROS scavenging ability is prepared. Thanks to that, the nanodrug can efficiently inhibit the ROS and nitric oxide production in lipopolysaccharide‐activated RAW264.7 macrophages and modulate macrophages M2 polarization at a much lower concentration than free drug dexamethasone. Furthermore, the monosodium iodoacetate‐induced OA mice treated with this nanodrug is very similar with the normal mice with the evaluation of body weight and scores including clinical arthritis scores, claw circumference, and kinematics score. The inflammation associated angiogenesis is also reduced which revealed by 68 Ga‐labeled arginine‐glycine‐aspartic acid peptide micro‐positron emission tomography imaging. Cartilage degradation and bone erosion in the joints are also inhibited by the nanodrug, along with the inhibition of proinflammatory cytokines. In addition, the biosafety of this nanodrug is also verified. This nanodrug with excellent immunomodulation properties can be used not only for OA therapy but also for other inflammatory diseases associated with excess oxidative stress and macrophage polarization.
Surgical Debulking for Refractory Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma
Authors: Vinod Solipuram, Marina Baretti, Alexander Y. Kim, Lucy X. Chen, Jill A. Fahrner, Meral Gunay‐Aygun, Xiao P. Peng, Dylan Hardenbergh, Anna Ferguson, Paige Griffith, Yuxuan Wang, Madelena Brancati, Harish Gopalakrishna, Tomoaki Kato, Chris Shubert, Daniel Laheru, Mark Yarchoan
Journal: Hepatology (2021)
Abstract GMM-059: SHEAR STRESS DOWNREGULATION OF MIR-199A-3P DRIVES CHEMORESISTANCE IN OVARIAN CANCER CELLS
Authors: Shan-Shan Li, Carman K. M. Ip, Ho-Cheung Shum, Alice S. T. Wong
Journal: Clinical Cancer Research (2019)

Abstract Ovarian cancer is leading cause of deaths among all gynecological malignancies. The presence of intrinsic and acquired drug resistance are major challenges in the treatment and clinical management of ovarian cancer. Ovarian cancer cells typically cluster into tumor spheroids and float in the ascitic fluid, which are characteristic of the aggressiveness of these tumor cells. We have recently developed a three-dimensional microfluidic platform with tumor spheroids and continuous fluidic flow to closely emulate the physiological condition in the ascites of ovarian cancer patients. Using this model, we showed for the first time that clinically relevant levels of ascitic shear stress induced drug resistance in ovarian tumor spheroids. Such chemoresistance was mediated through the increased expression of ABC-binding cassette transporter G2 and P-glycoprotein. By profiling the microRNAs (miRNAs) expression patterns under flow conditions, we identified miR-199a-3p as a critical mechanosensitive miRNA that was downregulated under shear stress through regulating the miRNA biogenesis machinery. miR-199a-3p expression was found to be inversely correlated with enhanced drug resistance properties and chemoresistant ovarian cancer sublines. Ectopic expression of miRNA-199a-3p could reverse the shear stress-induced expression of ABC-binding cassette transporter G2 and P-glycoprotein in ovarian tumor spheroids, confirming that the effect was miR-199a-3p specific. Taken together, these findings highlight the importance of shear stress-mediated decrease of miR-199a-3p in the regulation of drug response in ovarian cancer, which provide new insights in the understanding of cancer biology and potential effective treatment. Citation Format: Shan-Shan Li, Carman K. M. Ip, Ho-Cheung Shum, Alice S. T. Wong. SHEAR STRESS DOWNREGULATION OF MIR-199A-3P DRIVES CHEMORESISTANCE IN OVARIAN CANCER CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-059.
Phase I expansion study of the first-in-class monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL).
Authors: Sarah E. R. Halford, Harriet Walter, Pamela McKay, William Townsend, Kim Linton, Kathrin Heinzmann, Ilaria Dragoni, Laura Brotherton, Gareth Veal, Alexandros Siskos, Hector C Keun, Chris Bacon, Steve Wedge, Martin J.S. Dyer, Elizabeth Ruth Plummer
Journal: Journal of Clinical Oncology (2021)

3115 Background: Tumours rely on lactate transporters (MCT1-4) to maintain glycolytic flux and avoid intracellular acidification. In haematological tumours the MCT1 transporter acts as a lactate and pyruvate exporter. AZD3965 is a potent and specific inhibitor of MCT1 causing intracellular lactate accumulation. In vivo efficacy was observed in xenografts of DLBCL and BL, expressing high levels of MCT1 and no or low levels of MCT4. In the AZD3965 phase I (NCT01791595) dose-escalation an oral recommended phase 2 dose (RP2D) of 10mg twice-daily (bd) was determined. Pharmacokinetic (PK) showed exposure estimated to produce a minimum MCT1 occupancy of 90% (based on modelling). DLTs were primarily on-target dose-dependent, reversible, asymptomatic alterations in retinal function seen on ERG. Methods: This expansion cohort enrolled patients with relapsed/refractory DLBCL and BL. Expression of MCT1/MCT4 was assessed by immunohistochemistry. Pharmacokinetic (PK) sampling was performed and pharmacodynamic assessments included [ 18 F]FDG-PET/CT imaging and plasma/urine metabolomics. Results: 11 DLBCL patients were treated with AZD3965 10mg bd. PK showed exposure to be broadly in line with the escalation cohort. No significant ERG changes were observed. One patient experienced a dose-limiting SUSAR of Troponin I increase. MCT1 is expressed in erythrocytes, however no serious events of anaemia were seen, with one non-clinically significant episode of grade 3 anaemia reported. Urine analysis showed increased excretion of lactate and ketone bodies post AZD3965 treatment consistent with renal target engagement. No alteration was detected in plasma. Ongoing stable disease at cycle 5 was observed in one patient and an additional patient had a confirmed complete response (CR) lasting 15 months, with no significant toxicity. In the patient showing CR a reduction in tumour FDG uptake was observed on day 3 of cycle 1. The other four patients who consented to research imaging did not have a clinical response and no changes were observed on FDG-PET. Conclusions: AZD3965 can be safely administered at 10mg bd. In one DLBCL patient monotherapy activity was observed with changes in FDG-PET providing evidence indicative of proof of mechanism. These changes in FDG uptake as early as on day 3 in the responding patient warrant further investigation of FDG-PET as a predictive biomarker. Further biomarker analysis and preclinical studies are ongoing to understand the biology and explore effective combinations with other agents targeting tumour cell metabolism Clinical trial information: NCT01791595.
Post-COVID-19 symptoms 6 months after acute infection among hospitalized and non-hospitalized patients
Authors: Maddalena Peghin, Alvisa Palese, Margherita Venturini, Maria De Martino, Valentina Gerussi, Elena Graziano, Giulia Bontempo, Francesco Marrella, Alberto Tommasini, Martina Fabris, Francesco Curcio, Miriam Isola, Carlo Tascini
Journal: Clinical Microbiology and Infection (2021)
Parameters associated with outcomes in pretreated MSI/dMMR metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI): Subgroup analysis of a prospective cohort.
Authors: Raphael Colle, Marine Cachanado, Alexandra Rousseau, Magali Svrcek, Yves Menu, Romain Cohen, Thierry Andre
Journal: Journal of Clinical Oncology (2021)

3580 Background: Immune checkpoint inhibitors (ICI) have demonstrated efficacy in patients (pts) with MSI/dMMR mCRC. We aimed to evaluate clinical, pathological and molecular factors associated with progression-free survival (PFS) and overall survival (OS) in ICI-treated pretreated mCRC patients (pts). Methods: Pts are drawn from a prospective cohort of all patients treated with ICI for MSI/dMMR mCRC at Saint-Antoine Hospital, Paris, France. All MSI/dMMR mCRC pts with disease progression after ≥ 1 prior systemic treatment (fluoropyrimidine and oxaliplatin or irinotecan ± targeted therapy) were included. MSI/dMMR status was centrally reviewed. Lynch syndrome or sporadic status was determined according to MMR gene germline mutational testing, MLH1 methylation status and BRAF V600E mutation. PFS and objective response rate (ORR) were assessed using iRECIST criteria. The impact of Lynch syndrome on PFS was analyzed apart from the multivariate analysis due to the interaction with the BRAF V600E mutation status. Results: Of 130 included pts, 66 received anti-PD1 alone, 1 anti-PDL1 alone and 63 anti-PD1 plus anti-CTLA4. 71% have had at least 2 prior lines of treatment. 33 patients (25%) have BRAF V600E mutation (mt) and 49 (38%) RASmt. The ORR for the whole population was 62.8 % IC95% [53.8; 71.1]. Median follow-up was 21.0 months, median PFS and OS were not reached. Results of PFS unadjusted and adjusted analysis are displayed in the table. BRAF V600E and RAS mutation were not associated with PFS and OS in multivariate analyses. After adjustment for the treatment type, Hazard Ratio (HR) for PFS between patients with proven Lynch syndrome (N=44) and patients with proven sporadic tumors (n= 44) was 0.57 (95%IC 0.26 -1.26). Conclusions: In this cohort, main known clinical, pathological and molecular factors do not influence the efficacy of ICI in pre-treated MSI/dMMR mCRC.[Table: see text]