tbuckley/cabot-search huggingface dataset:
Targeting Glucose Metabolism Sensitizes Pancreatic Cancer to MEK Inhibition
Authors: Liang Yan, Bo Tu, Jun Yao, Jing Gong, Alessandro Carugo, Christopher A. Bristow, Qiuyun Wang, Cihui Zhu, Bingbing Dai, Ya'an Kang, Leng Han, Ningping Feng, Yanqing Jin, Jason Fleming, Timothy P. Heffernan, Wantong Yao, Haoqiang Ying
Journal: Cancer Research (2021)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal. A critical unmet need exists to explore essential susceptibilities in PDAC and to identify druggable targets to improve PDAC treatment. KRAS mutations dominate the genetic landscape of PDAC and lead to activation of multiple downstream pathways and cellular processes. Here, we investigated the requirement of these pathways for tumor maintenance using an inducible KrasG12D-driven PDAC mouse model (iKras model), identifying that RAF-MEK-MAPK signaling is the major effector for oncogenic KRAS-mediated tumor maintenance. However, consistent with previous studies, MEK inhibition had minimal therapeutic effect as a single agent for PDAC in vitro and in vivo. Although MEK inhibition partially downregulated transcription of glycolysis genes, it failed to suppress glycolytic flux in PDAC cells, which is a major metabolic effector of oncogenic KRAS. Accordingly, an in vivo genetic screen identified multiple glycolysis genes as potential targets that may sensitize tumor cells to MEK inhibition. Inhibition of glucose metabolism with low-dose 2-deoxyglucose in combination with a MEK inhibitor induced apoptosis in KrasG12D-driven PDAC cells in vitro. The combination also inhibited xenograft PDAC tumor growth and prolonged overall survival in a genetically engineered PDAC mouse model. Molecular and metabolic analyses indicated that co-targeting glycolysis and MAPK signaling results in apoptosis via induction of lethal endoplasmic reticulum stress. Together, our work suggests that combined inhibition of glycolysis and the MAPK pathway may serve as an effective approach to target KRAS-driven PDAC. Significance: This study demonstrates the critical role of glucose metabolism in resistance to MAPK inhibition in KRAS-driven pancreatic cancer, uncovering a potential therapeutic approach for treating this aggressive disease.
Circulating tumor DNA as markers of dynamic recurrence risk and adjuvant chemotherapy benefit in resected non-small cell lung cancer.
Authors: Wei Guo, Fan Zhang, Fang Lv, Ying Ji, Yue Peng, Xiaoxi Chen, Hua Bao, Yang Xu, Yang Shao, Fengwei Tan, Qi Xue, Bin Qiu, Shugeng Gao
Journal: Journal of Clinical Oncology (2021)

3028 Background: A significant proportion of non-small cell lung cancer (NSCLC) patients relapse after surgical resection with or without adjuvant therapy. The detection of molecular residual disease (MRD) has great potentials to stratify postoperative risk and facilitate early recurrence diagnosis. Here, we aim to evaluate the clinical utility of serial plasma circulating tumor DNA (ctDNA) in MRD detection, adjuvant therapy guidance, and recurrence risk prediction in resected NSCLC patients. Methods: This prospective cohort study recruited 116 patients with NSCLC following surgery and/or adjuvant therapy. Thirteen patients discontinued, leaving 103 patients for analysis. Tumor samples were obtained at surgery. Plasma samples were collected at baseline, after surgery, after adjuvant therapy and every 3 months thereafter and were analyzed by ultradeep (30000×) next-generation sequencing with molecular barcode and in-silico error correction. Results: Pretreatment ctDNA was detected in 69.8% of patients. ctDNA positivity after surgery and after completion of adjuvant chemotherapy (ACT) were significantly associated with worse recurrence-free survival (RFS) (HR: 4.0; 95% CI: 2.0-8.0; P&lt;.001 and HR:3.2; 95% CI: 1.3-8.2; P &lt;.05, respectively). In stage II-III patients who were positive for ctDNA after surgery, ACT-treated patients had a better RFS than those without ACT ( P&lt;.05), whereas ACT did not confer significant clinical benefits in patients with negative postsurgical ctDNA. During surveillance after definitive therapy, ctDNA positivity was associated with worse RFS (HR: 8.5, 95% CI: 3.7-20, P &lt;.001) and preceded radiological recurrence by a median of 88 days. Using joint modeling of serial ctDNA and time-to-recurrence, we accurately predicted patients’ 12-month and 15-month recurrence status, with areas under receiver-operating characteristics curves (AUROC) of 0.88 and 0.84, respectively. Conclusions: These results indicate that ultradeep ctDNA sequencing could sensitively detect MRD, thus identifying patients with high recurrence risk and guiding the adjuvant therapy decision in resected NSCLC. We also demonstrate that joint modeling of serial ctDNA levels and time to recurrent can provide an accurate dynamic risk prediction for NSCLC patients during surveillance. Clinical trial information: ChiCTR1900024656.
Covid-19: Exponential growth in infections in England is driven by young people
Authors: Jacqui Wise
Journal: BMJ (2021)

Covid-19: Exponential growth in infections in England is driven by young people Jacqui WiseCoronavirus infections in England grew exponentially between 20 May and 7 June, with a doubling time of 11 days and an estimated R number of 1.44, the latest snapshot survey from Imperial College London shows.
Observed survival benefit with limited exposure of durvalumab in unresectable stage III non-small cell lung cancer at a large community-based institution.
Authors: Deepak Vadehra, Christopher R Pallas, Donald Moore, Jeryl Jean Villadolid, Myra M. Robinson, Kathryn Finch Mileham, Daniel R. Carrizosa
Journal: Journal of Clinical Oncology (2021)

e20539 Background: The PACIFIC trial ushered in a paradigm shift in the management of unresectable, non-metastatic non-small cell lung cancer (NSCLC), demonstrating improvement in 12,24,36-month overall survival (OS) and leading to the 2018 FDA approval for durvalumab in unresectable or locally advanced stage III NSCLC. With almost 3 years of FDA approval, we performed a retrospective analysis of patient experiences and outcomes at Levine Cancer Institute analyzing patient data to assess survival and potential points of clinical significance. Methods: Patients over the age of 18, who met criteria similar to the PACIFIC trial (i.e. unresectable or locally advanced stage III NSCLC) from February 2018 through September 2020 were analyzed. Those who were receiving active treatment at the data cutoff were excluded. Patient characteristics, prior treatment, durvalumab administration, immune-related adverse events (irAEs), and efficacy data were summarized and evaluated. OS and progression free survival (PFS) were evaluated with Kaplan Meier methods. Results: A total of 159 patients were evaluated. 40.9% were female and 59.1% were male. The median age was 67 (range 38-83 years). Of note, 86.8% of patients were white, whereas 13.2% were nonwhite. 50.3% patients experienced an irAE. The most common reasons for discontinuation of durvalumab were completion (at least 24 doses), progressive disease, or toxicity (33.3%, 30.8%, 26.4%, respectively). The median number of doses of durvalumab received was 14 (range 1-26 doses). The median PFS was 15.3 months with 12-and 24-month PFS being 54% and 41.1 %, respectively. Median OS was 42 months with 12-and 24-month OS being 78.1% and 67.8%, respectively. Our analysis compared outcomes in those who completed adjuvant durvalumab versus those who did not complete adjuvant therapy (Table). Conclusions: Data shows the best survival in those who completed durvalumab (comparable to historic values) and novel data shows a perceived survival benefit in those completing 12 doses compared to those who did not. Thus, partial treatment may provide a survival advantage. Further multivariate analysis will look for possible correlations to increased immune events and inability to complete therapy. Further investigation will delve into this cohort’s small proportion of non-white patients, evaluating for possible barriers to care that may lead to more patients being diagnosed with stage IV NSCLC.[Table: see text]
Eligibility for mechanical circulatory support devices based on current and past randomised cardiogenic shock trials
Authors: Benedikt Schrage, Benedikt N. Beer, Gianluigi Savarese, Salim Dabboura, Isabell Yan, Jonas Sundermeyer, Peter M. Becher, Hanno Grahn, Moritz Seiffert, Alexander Bernhardt, Holger Thiele, Jacob E. Møller, Stefan Kluge, Hermann Reichenspurner, Paulus Kirchhof, Stefan Blankenberg, Dirk Westermann
Journal: European Journal of Heart Failure (2021)

Mechanical circulatory support devices (MCS) are potentially effective treatments for cardiogenic shock (CS) and are thus evaluated in several randomised controlled trials (RCTs). However, it is not clear how enrolment criteria of these RCTs apply to a real-world CS population. This study aimed to shed light on eligibility to these trials.Pragmatic enrolment criteria for the IABP-SHOCK II, the DanGer-SHOCK, the ECLS-SHOCK and the EURO-SHOCK trials were retrospectively applied to 1305 CS patients admitted to a tertiary care hospital between 2009 and 2019. Based on this, major enrolment criteria were identified and outcome between eligible and ineligible patients was assessed. In this study, 415 (31.8%) patients were eligible for any study. Lowest eligibility was observed for DanGer-SHOCK (11.9%) and the highest for IABP-SHOCK II (26.9%). Over all trials, inclusion criteria were more restrictive than exclusion criteria and absence of CS caused by acute myocardial infarction (AMI) was the primary reason for non-eligibility. However, even in CS caused by AMI, enrolment criteria were only met in 65.4% of patients. Importantly, 30-day mortality was high across all patients/trials, irrespective of eligibility or non-eligibility.The present study highlights that current and past RCTs only reflect about a third of the overall CS population. While enrolment criteria are a necessary aspect of RCTs, their application limits generalisability of the trials' findings. More trials on CS sub-populations not represented by current or past trials, e.g. CS not caused by AMI, are needed, especially as mortality is high irrespective of eligibility status.
Tuning Superfast Curing Thiol‐Norbornene‐Functionalized Gelatin Hydrogels for 3D Bioprinting
Authors: Tobias Göckler, Sonja Haase, Xenia Kempter, Rebecca Pfister, Bruna R. Maciel, Alisa Grimm, Tamara Molitor, Norbert Willenbacher, Ute Schepers
Journal: Advanced Healthcare Materials (2021)

Abstract Photocurable gelatin‐based hydrogels have established themselves as powerful bioinks in tissue engineering due to their excellent biocompatibility, biodegradability, light responsiveness, thermosensitivity and bioprinting properties. While gelatin methacryloyl (GelMA) has been the gold standard for many years, thiol‐ene hydrogel systems based on norbornene‐functionalized gelatin (GelNB) and a thiolated crosslinker have recently gained increasing importance. In this paper, a highly reproducible water‐based synthesis of GelNB is presented, avoiding the use of dimethyl sulfoxide (DMSO) as organic solvent and covering a broad range of degrees of functionalization (DoF: 20% to 97%). Mixing with thiolated gelatin (GelS) results in the superfast curing photoclick hydrogel GelNB/GelS. Its superior properties over GelMA, such as substantially reduced amounts of photoinitiator (0.03% (w/v)), superfast curing (1–2 s), higher network homogeneity, post‐polymerization functionalization ability, minimal cross‐reactivity with cellular components, and improved biocompatibility of hydrogel precursors and degradation products lead to increased survival of primary cells in 3D bioprinting. Post‐printing viability analysis revealed excellent survival rates of &gt; 84% for GelNB/GelS bioinks of varying crosslinking density, while cell survival for GelMA bioinks is strongly dependent on the DoF. Hence, the semisynthetic and easily accessible GelNB/GelS hydrogel is a highly promising bioink for future medical applications and other light‐based biofabrication techniques.
An observed association between conjunctivitis and severity of COVID-19
Authors: Lorenzo Loffredo, Alessandra Oliva, Aurora Paraninfi, Giancarlo Ceccarelli, Federica Orlando, Paolo Ciacci, Fernanda Pacella, Elena Pacella, Silvia Di Bari, Valeria Filippi, Alessia Cruciata, Claudio Maria Mastroianni, Francesco Violi
Journal: Journal of Infection (2021)
Rooting the Animal Tree of Life
Authors: Yuanning Li, Xing-Xing Shen, Benjamin Evans, Casey W Dunn, Antonis Rokas
Journal: Molecular Biology and Evolution (2021)

Abstract Identifying our most distant animal relatives has emerged as one of the most challenging problems in phylogenetics. This debate has major implications for our understanding of the origin of multicellular animals and of the earliest events in animal evolution, including the origin of the nervous system. Some analyses identify sponges as our most distant animal relatives (Porifera-sister hypothesis), and others identify comb jellies (Ctenophora-sister hypothesis). These analyses vary in many respects, making it difficult to interpret previous tests of these hypotheses. To gain insight into why different studies yield different results, an important next step in the ongoing debate, we systematically test these hypotheses by synthesizing 15 previous phylogenomic studies and performing new standardized analyses under consistent conditions with additional models. We find that Ctenophora-sister is recovered across the full range of examined conditions, and Porifera-sister is recovered in some analyses under narrow conditions when most outgroups are excluded and site-heterogeneous CAT models are used. We additionally find that the number of categories in site-heterogeneous models is sufficient to explain the Porifera-sister results. Furthermore, our cross-validation analyses show CAT models that recover Porifera-sister have hundreds of additional categories and fail to fit significantly better than site-heterogenuous models with far fewer categories. Systematic and standardized testing of diverse phylogenetic models suggests that we should be skeptical of Porifera-sister results both because they are recovered under such narrow conditions and because the models in these conditions fit the data no better than other models that recover Ctenophora-sister.
Cardiovascular toxicity incidence following immune checkpoint inhibitors in randomized clinical trials: A systematic review and meta-analysis.
Authors: Camila Bragança Xavier, Carlos Diego Holanda Lopes, Guilherme Harada, Artur Katz, Denis Leonardo Fontes Jardim
Journal: Journal of Clinical Oncology (2021)

2636 Background: Immune checkpoint inhibitors (ICIs) are widely used in oncology and may be associated with a variety of immune-related toxicities. Cardiovascular (CV) adverse effects (AEs) are underreported in randomized clinical trials (RCTs), and the real risk associated with ICIs use has yet to be defined. Therefore, we aimed to investigate the incidence and risk of cardiovascular toxicities in patients receiving ICIs, using an up-to-date meta-analysis of prospective RCTs. Methods: We conducted a systematic search of the literature from January 1st, 2010 until July 1st, 2020 to identify RCTs testing ICIs for solid tumors, either in monotherapy or in combination between them. Our initial search yielded a total of 21,249 relevant publications. For CV AEs incidence estimation, we included phase III RCTs testing PD-1, PD-L1, CTLA-4 inhibitors or any combination of these agents. For relative risk (RR) assessment, we included phase II or phase III RCTs testing the same agents and with placebo or best supportive care (BSC) as the comparator. Data were extracted by independent reviewers following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. CV AEs were categorized based on the Common Toxicity Criteria (CTCAE) and stratified by ICIs type. Analyses were conducted using random effects model. Results: After screening and eligibility assessment, a total of 21,118 patients (67 cohorts from 57 trials) were available for this meta-analysis. We categorized the cohorts by ICIs regimen as monotherapy with a PD-1 inhibitor (35 cohorts; 10,241 patients), PD-L1 inhibitor (12 cohorts; 3,755 patients), CTLA-4 inhibitor (11 cohorts; 4,135 patients), and combination therapy (9 cohorts; 2,987 patients). Incidence measures are described in the table. Deaths from any CV cause occurred in 0.20% of the patients (95%CI 0.10%; 0.20%). For RR analysis, we included 12 cohorts from 11 RCTs. Risk of experiencing all grade AEs was numerically higher among patients who received ICIs than placebo or BSC (RR 1.16; 95%CI 0.98; 1.37; p=0.09). When only grade 3-5 CV AEs were considered, ICIs were associated with increased risk (RR 1.36; 95%CI 1.06; 1.73; p= 0.01). Additional analyses were conducted to estimate the RR of individual CV AEs including arrhythmia, cardiac arrest, heart failure, stroke, hypertension, myocardial infarction, myocarditis, pericardial events, and thromboembolic events. None of the analysis identified a significant additional risk. Conclusions: This meta-analysis corroborates the preclinical rationale of worsen CV risk related to ICIs use.[Table: see text]
Predictive factors for choriocarcinoma syndrome development in high-risk patients with germ cell tumors (GCTs).
Authors: Katarina Rejlekova, Katarina Kalavska, Marek Makovnik, Nikola Hapakova, Michal Chovanec, Valentina De Angelis, Jana Obertova, Patrik Palacka, Zuzana Sycova, Jozef Mardiak, Michal Mego
Journal: Journal of Clinical Oncology (2021)

e17010 Background: Germ cell tumors (GCTs) represent a highly curable cancer. However, a small proportion of patients with super-high-risk characteristics can develop choriocarcinoma syndrome (CS) connected with acute respiratory distress syndrome (ARDS). CS is defined as a syndrome with hemorrhage from metastatic sites in patients with advanced GCTs with high-volume of choriocarcinoma elements, especially those with a choriogonadotropin level over 50,000 IU/l. CS typically develop shortly after the chemotherapy start with high mortality rate. Our retrospective study aimed to determine the risk factors of high-risk GCTs susceptible to CS development. Methods: Using a computerized database and a systematic chart review, we identified the records of 532 patients with GCTs treated in NCI through 2000 to 2018, and 90 eligible patients with high-risk GCTs relying on IGCCCG classification, were identified. All patients were treated with platinum-based induction chemotherapy. Clinicopathological variables were collected and analyzed in correlation to CS development. Results: Nine (10 %) of 90 patients developed CS in a median of 1 day (1- 9 days) after the chemotherapy administration. All patients died shortly after the chemotherapy start with median of 4 days (3-35 days) due to consecutive ARDS development. Predictive factors for CS development were metastatic lung involvement ≥50% of lung parenchyma, choriocarcinoma elements in histology specimen, dyspnea, cough, hemoptysis, ECOG PS ≥2, weight loss and hemoglobin ≤100 g/l at the time of presentation. In multivariate analysis, ECOG PS ≥2 and metastatic lung involvement ≥50% were independently associated with CS. All patients with these two characteristics developed CS compared to 0% with one or zero of these predictive factors (P &lt; 0.000001). Conclusions: In our study we identified predictive factors for CS development. These factors might improve the risk stratification of the patients susceptible to CS development connected with ARDS as well as to find optimal treatment approach for them.
Discovery of a first-in-class inhibitor of sulfide:quinone oxidoreductase that protects against adverse cardiac remodelling and heart failure
Authors: Michael R Jackson, Kristie D Cox, Simon D P Baugh, Luke Wakeen, Adel A Rashad, Patrick Y S Lam, Boris Polyak, Marilyn Schuman Jorns
Journal: Cardiovascular Research (2021)

Hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by post-translational modification (persulfidation) of cysteine residues in upstream protein targets. Heart failure patients with reduced ejection fraction (HFrEF) exhibit low levels of H2S. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling. Here, the aim of this study was to discover a first-in-class inhibitor of human SQOR and evaluate its cardioprotective effect in an animal model of HFrEF.We identified a potent inhibitor of human SQOR (STI1, IC50 = 29 nM) by high-throughput screening of a small-molecule library, followed by focused medicinal chemistry optimization and structure-based design. STI1 is a competitive inhibitor that binds with high selectivity to the coenzyme Q-binding pocket in SQOR. STI1 exhibited very low cytotoxicity and attenuated the hypertrophic response of neonatal rat ventricular cardiomyocytes and H9c2 cells induced by neurohormonal stressors. A mouse HFrEF model was produced by transverse aortic constriction (TAC). Treatment of TAC mice with STI1 mitigated the development of cardiomegaly, pulmonary congestion, dilatation of the left ventricle, and cardiac fibrosis and decreased the pressure gradient across the aortic constriction. Moreover, STI1 dramatically improved survival, preserved cardiac function, and prevented the progression to HFrEF by impeding the transition from compensated to decompensated left ventricle hypertrophy.We demonstrate that the coenzyme Q-binding pocket in human SQOR is a druggable target and establish proof of concept for the potential of SQOR inhibitors to provide a novel therapeutic approach for the treatment of HFrEF.
Variance of HRD score from primary to recurrent in high-grade serous ovarian cancer.
Authors: Xiaoxiang Chen, Jing Ni, Xia Xu, Wenwen Guo, Qian Zhao, Xianzhong Cheng, Rui Zhou, Hongyuan Gu, Chen Chen
Journal: Journal of Clinical Oncology (2021)

e17540 Background: Homologous recombination deficiency (HRD) is an important biomarker of poly (ADP-ribose) polymerase inhibitor (PARPi) in patients with high-grade serous ovarian cancer (HGSOC). The stability of HRD in the recurrent HGSOC and its primary pair from Jiangsu Institute of Cancer Hospital was investigated. Methods: A total of paired 18 samples from 9 HGSOC patients were analyzed. HRD score was evaluated by loss of heterozygosity(LOH) and genetic mutations were also detected from next-generation sequencing.The student t-test evaluated the difference of HRD score between matched tumors. The functional annotation and clustering of affected genes in the recurrent tumor cells were analyzed by the KEGG Orthology (KO) database. Results: The HRD score of recurrent HGSOC tumors was significantly higher than that of the paired primary ones (p = 0.004). A total of 30 new somatic sequence variants at 27 genes presented in the recurrent tumors, were not found in any matched primary tumors. Of which, 19 (63.3%) were copy number variants (CNVs), 3 (10%) variants were rearrangement, and 8 (26.7%) were somatic point mutation. In these17 genes with CNVs, 14 genes had gene amplification variants, among them 50% (7/14) genes associated with the positive regulation of cell proliferation and cellular response to DNA damage stimulus. Four somatic point mutations involved in tumor suppressor pathway. Conclusions: Our data shed first light on the statistically significant changes of HRD score in paired recurrent HGSOC. The HRD score changes over time may imply further instantaneity assay strategy.