tbuckley/cabot-search huggingface dataset:
Interrogating Genomic-Scale Data to Resolve Recalcitrant Nodes in the Spider Tree of Life
Authors: Siddharth Kulkarni, Robert J Kallal, Hannah Wood, Dimitar Dimitrov, Gonzalo Giribet, Gustavo Hormiga
Journal: Molecular Biology and Evolution (2020)

Abstract Genome-scale data sets are converging on robust, stable phylogenetic hypotheses for many lineages; however, some nodes have shown disagreement across classes of data. We use spiders (Araneae) as a system to identify the causes of incongruence in phylogenetic signal between three classes of data: exons (as in phylotranscriptomics), noncoding regions (included in ultraconserved elements [UCE] analyses), and a combination of both (as in UCE analyses). Gene orthologs, coded as amino acids and nucleotides (with and without third codon positions), were generated by querying published transcriptomes for UCEs, recovering 1,931 UCE loci (codingUCEs). We expected that congeners represented in the codingUCE and UCEs data would form clades in the presence of phylogenetic signal. Noncoding regions derived from UCE sequences were recovered to test the stability of relationships. Phylogenetic relationships resulting from all analyses were largely congruent. All nucleotide data sets from transcriptomes, UCEs, or a combination of both recovered similar topologies in contrast with results from transcriptomes analyzed as amino acids. Most relationships inferred from low-occupancy data sets, containing several hundreds of loci, were congruent across Araneae, as opposed to high occupancy data matrices with fewer loci, which showed more variation. Furthermore, we found that low-occupancy data sets analyzed as nucleotides (as is typical of UCE data sets) can result in more congruent relationships than high occupancy data sets analyzed as amino acids (as in phylotranscriptomics). Thus, omitting data, through amino acid translation or via retention of only high occupancy loci, may have a deleterious effect in phylogenetic reconstruction.
Early Noninvasive Cardiac Testing After Emergency Department Evaluation for Suspected Acute Coronary Syndrome
Authors: Aniket A. Kawatkar, Adam L. Sharp, Aileen S. Baecker, Shaw Natsui, Rita F. Redberg, Ming-Sum Lee, Maros Ferencik, Yi-Lin Wu, Ernest Shen, Chengyi Zheng, Visanee V. Musigdilok, Michael K. Gould, Steve Goodacre, Praveen Thokala, Benjamin C. Sun
Journal: JAMA Internal Medicine (2020)

Professional guidelines recommend noninvasive cardiac testing (NIT) within 72 hours of an emergency department (ED) evaluation for suspected acute coronary syndrome. However, there is inexact evidence that this strategy reduces the risk of future death or acute myocardial infarction (MI).To evaluate the effectiveness of early NIT in reducing the risk of death or acute MI within 30 days.This retrospective, multicenter cohort study within the Kaiser Permanente Southern California integrated health care delivery system compared the effectiveness of early noninvasive cardiac testing vs no testing in patients with chest pain and in whom acute MI was ruled out who presented to an ED from January 2015 to December 2017. Patients were followed up for up to 30 days after emergency department discharge.Noninvasive cardiac testing performed within 3 days of an ED evaluation for suspected acute coronary syndrome.The primary outcome was composite risk of death or acute MI, within 30 days of an ED discharge.A total of 79 040 patients were evaluated in this study, of whom 57.7% were female. The mean (SD) age of the cohort was 57 (16) years, and 16 164 patients (21%) had completed early NIT. The absolute risk of death or MI within 30 days was low (<1%). Early NIT had the minor benefit of reducing the absolute composite risk of death or MI (0.4% [95% CI, -0.6% to -0.3%]), and, separately, of death (0.2% [95% CI, -0.2% to -0.1%]), MI (-0.3% [95% CI, -0.5% to -0.1%]), and major adverse cardiac event (-0.5% [95% CI, -0.7% to -0.3%]). The number needed to treat was 250 to avoid 1 death or MI, 500 to avoid 1 death, 333 to avoid 1 MI, and 200 to avoid 1 major adverse cardiovascular event within 30 days. Subgroup analysis revealed a number needed to treat of 14 to avoid 1 death or MI in the subset of patients with elevated troponin.Early NIT was associated with a small decrease in the risk of death or MI in patients admitted to the ED with suspected acute coronary syndrome, but this clinical strategy may not be optimal for most patients given the large number needed to treat.
Prediction of Overall Survival Among Female Patients With Breast Cancer Using a Prognostic Signature Based on 8 DNA Repair–Related Genes
Authors: Dai Zhang, Si Yang, Yiche Li, Jia Yao, Jian Ruan, Yi Zheng, Yujiao Deng, Na Li, Bajin Wei, Ying Wu, Zhen Zhai, Jun Lyu, Zhijun Dai
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Breast cancer (BC), a common malignant tumor, ranks first among cancers in terms of morbidity and mortality among female patients. Currently, identifying effective prognostic models has a significant association with the prediction of the overall survival of patients with BC and guidance of clinicians in early diagnosis and treatment. <h3>Objectives</h3> To identify a potential DNA repair–related prognostic signature through a comprehensive evaluation and to further improve the accuracy of prediction of the overall survival of patients with BC. <h3>Design, Setting, and Participants</h3> In this prognostic study, conducted from October 9, 2019, to February 3, 2020, the gene expression profiles and clinical data of patients with BC were collected from The Cancer Genome Atlas database. This study consisted of a training set from The Cancer Genome Atlas database and 2 validation cohorts from the Gene Expression Omnibus, which included 1096 patients with BC. A prognostic signature based on 8 DNA repair–related genes (DRGs) was developed to predict overall survival among female patients with BC. <h3>Main Outcomes and Measures</h3> Primary screening prognostic biomarkers were analyzed using univariate Cox proportional hazards regression analysis and the least absolute shrinkage and selection operator Cox proportional hazards regression. A risk model was completely established through multivariate Cox proportional hazards regression analysis. Finally, a prognostic nomogram, combining the DRG signature and clinical characteristics of patients, was constructed. To examine the potential mechanisms of the DRGs, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed. <h3>Results</h3> In this prognostic study based on samples from 1096 women with BC (mean [SD] age, 59.6 [13.1] years), 8 DRGs (<i>MDC1</i>,<i>RPA3</i>,<i>MED17</i>,<i>DDB2</i>,<i>SFPQ</i>,<i>XRCC4</i>,<i>CYP19A1</i>, and<i>PARP3</i>) were identified as prognostic biomarkers. The time-dependent receiver operating characteristic curve analysis suggested that the 8-gene signature had a good predictive accuracy. In the training cohort, the areas under the curve were 0.708 for 3-year survival and 0.704 for 5-year survival. In the validation cohort, the areas under the curve were 0.717 for 3-year survival and 0.772 for 5-year survival in theGSE9893data set and 0.691 for 3-year survival and 0.718 for 5-year survival in theGSE42568data set. This DRG signature mainly involved some regulation pathways of vascular endothelial cell proliferation. <h3>Conclusions and Relevance</h3> In this study, a prognostic signature using 8 DRGs was developed that successfully predicted overall survival among female patients with BC. This risk model provides new clinical evidence for the diagnostic accuracy and targeted treatment of BC.
Trials of locoregional therapies inspired by SABR-COMET
Authors: Nikiforos Vasiniotis Kamarinos, Laura A Dawson, Leonard B Saltz, Christopher H Crane, Michael J Overman, Jean-Nicolas Vauthey, Bruno C Odisio, Alban Denys, Thierry de Baère, Philippe L Pereira, Daniel Y Sze, Thomas J Vogl, Martijn R Meijerink, Thomas Helmberger, Hyun S Kim, Stephen B Solomon, Constantinos T Sofocleous
Journal: The Lancet (2020)
Muscle stiffness, gait instability, and liver cirrhosis in Wilson's disease
Authors: Cornelius Kronlage, Martin Hardmeier, Seraina Bally, Marleen Carina Scholz, Heiner C Bucher, Olivia Katharina Müller, Clemens Winterhalder, Michel Mongiat, Jannis Müller, Alexandros Polymeris, Martin Weber, Christina Lausberg, Elianne Kassi, Jens Kuhle, Ludwig Kappos, Wieland Hermann, Christine Bernsmeier, Özgür Yaldizli
Journal: The Lancet (2020)
Effect of cyclo-oxygenase inhibitor use during checkpoint blockade immunotherapy in patients with metastatic melanoma and non-small cell lung cancer
Authors: Shang-Jui Wang, Karishma Khullar, Sinae Kim, Nikhil Yegya-Raman, Jyoti Malhotra, Roman Groisberg, Samuel H Crayton, Ann W Silk, John L Nosher, Michael A Gentile, Janice M Mehnert, Salma K Jabbour
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immune checkpoint inhibitors (ICIs) improve survival outcomes in metastatic melanoma and non-small cell lung cancer (NSCLC). Preclinical evidence suggests that overexpression of cyclo-oxygenase-2 (COX2) in tumors facilitates immune evasion through prostaglandin E2 production and that COX inhibition synergizes with ICIs to promote antitumor T-cell activation. This study investigates whether concurrent COX inhibitor (COXi) use during ICI treatment compared with ICI alone is associated with improved time-to-progression (TTP), objective response rate (ORR) and overall survival (OS) in patients with metastatic melanoma and NSCLC. Methods We retrospectively reviewed 90 metastatic melanoma and 37 metastatic NSCLC patients, treated with ICI between 2011 and 2019. Differences in TTP and OS by ICI+COXi versus ICI alone were compared using Kaplan-Meier and Cox regression. Interaction between ICI+COXi versus ICI alone and pretreatment neutrophil–lymphocyte ratio (NLR) was examined. Independent radiology review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was performed. Results For patients with melanoma, median TTP was significantly prolonged in ICI+COXi versus ICI alone (245 vs 100.5 days, p=0.002). On multivariate analysis, ICI+COXi associated with increased TTP (HR 0.36, 95% CI 0.2 to 0.66, p=0.001), adjusted for age, pretreatment NLR, and gender. For NSCLC patients, ICI+COXi also associated with increased TTP compared with ICI alone on multivariate analysis (HR 0.45; 95% CI 0.21 to 0.97; p=0.042) adjusted for age. ORR at 6 months was significantly higher in patients who received ICI+COXi compared with ICI alone in both melanoma (58.6% vs 19.2%, p=0.0005) and NSCLC (73.7% vs 33.3%, p=0.036) cohorts. In the melanoma cohort, high pretreatment NLR (&gt;5) associated with decreased TTP (HR 3.21, 95% CI 1.64 to 6.3; p=0.0007); however, ICI+COXi significantly associated with increased TTP in high NLR (&gt;5) patients (HR 0.08, 95% CI 0.03 to 0.25), but not in low NLR (≤5) patients (HR 0.65, 95% CI 0.32 to 1.32). Similar outcomes were found in an adjusted melanoma cohort after RECIST review. Conclusions Our study suggests that COXi use concurrently with ICI significantly associated with longer TTP and improved ORR at 6 months in patients with metastatic melanoma and NSCLC compared with ICI alone. Furthermore, COXi use appears to reverse the negative prognostic effect of a high NLR by prolonging TTP in patients with melanoma.
Gene-Level, but Not Chromosome-Wide, Divergence between a Very Young House Fly Proto-Y Chromosome and Its Homologous Proto-X Chromosome
Authors: Jae Hak Son, Richard P Meisel
Journal: Molecular Biology and Evolution (2020)

X and Y chromosomes are usually derived from a pair of homologous autosomes, which then diverge from each other over time. Although Y-specific features have been characterized in sex chromosomes of various ages, the earliest stages of Y chromosome evolution remain elusive. In particular, we do not know whether early stages of Y chromosome evolution consist of changes to individual genes or happen via chromosome-scale divergence from the X. To address this question, we quantified divergence between young proto-X and proto-Y chromosomes in the house fly, Musca domestica. We compared proto-sex chromosome sequence and gene expression between genotypic (XY) and sex-reversed (XX) males. We find evidence for sequence divergence between genes on the proto-X and proto-Y, including five genes with mitochondrial functions. There is also an excess of genes with divergent expression between the proto-X and proto-Y, but the number of genes is small. This suggests that individual proto-Y genes, but not the entire proto-Y chromosome, have diverged from the proto-X. We identified one gene, encoding an axonemal dynein assembly factor (which functions in sperm motility), that has higher expression in XY males than XX males because of a disproportionate contribution of the proto-Y allele to gene expression. The upregulation of the proto-Y allele may be favored in males because of this gene's function in spermatogenesis. The evolutionary divergence between proto-X and proto-Y copies of this gene, as well as the mitochondrial genes, is consistent with selection in males affecting the evolution of individual genes during early Y chromosome evolution.
Matt Morgan: Why Dylan Thomas was wrong—and right
Authors: Matt Morgan
Journal: BMJ (2020)

The blood lands on my left shoe as the needle hits its mark.The adrenaline travels slowly to the heart, sucked onward through the chest's recoil.1-2-3-4-5.1-2-3-4-5.1-2-3-4-5.The compressions continue, pressing out the patient's blood, as well as the pusher's humanity.She is 89.She was a daughter, a mum, a mam-gu (the Welsh word for grandmother), a strong woman, a singer, a real character in life, and then a real character in her nursing home."But the paperwork wasn't completed" is overheard, as the decision to perform CPR is questioned.1-2-3-4-5.1-2-3-4-5.1-2-3-4-5.As I watch, I wonder whether the doctor in training, performing CPR straight out of a textbook, has read Dylan Thomas's poem Do Not Go Gentle Into That Good Night.Writing the poem after his dad's untimely death, Thomas was both right and wrong.As I turned 40, a surprise trip to a spa hotel sent me driving past his boathouse, where he wrote such powerful poetry.Being new to the art of words, I had to stop.I went in, past the gift shop selling fudge and Welsh cakes.In front of me were those words: "Do not go gentle into that good night; Old age should burn and rage at close of day; Rage, rage against the dying of the light."Thomas was right in many ways.In my world of the intensive care unit, the urge is to rage against the dying of the light.Young men with brain injuries, middle aged women with blood in their heads, older men brought back to life after a cardiac arrest out of hospital.Brilliant.My kind of work.And it's why 200 nurses in the critical care unit in Cardiff wake up at 5 am every grey, rainy Welsh morning.But Thomas was also wrong.Consider the patient with end stage chronic disease where drugs prolong death, not life.The granddad with dementia even before his stroke.The 89 year old lady on the ward, not dying from sepsis but dying with it, after 89 long, happy, life filled years.She doesn't want survival at all costs: she wants survivorship.Something that pressing on her breastbone won't achieve.Reading about a similar story, where a nurse working in a care home was recently found at fault for not doing CPR on a patient with severe end stage chronic disease, 1 I hang my head in my hands.I'd rather be sued for doing CPR than for not doing it.And deep down, even watching his dad die, that's what Dylan Thomas was trying to tell us.After the passion, the denial of a finite life, and the love for his dad, he writes: "Though wise men at their end know dark is right . .."The trouble is that those wise men and women are often not the ones doing the CPR-they are the ones having it.
Effect of snoring on respiratory effort measured indirectly by beat to beat blood pressure
Authors: Stradling, C Barbour, B Langford, D M Smith, D J Pitson
Journal: Thorax (1996)

The size of the respiratory swings in blood pressure (pulsus paradoxus) correlate well with the degree of inspiratory effort measured with an oesophageal balloon. To take advantage of this phenomenon to estimate changes in inspiratory effort requires a measure of beat to beat blood pressure. In a respiratory sleep study to identify obstructive sleep apnoea (OSA) and its variants, such measurements are useful to indicate increased inspiratory effort following upper airway narrowing. Our unit has shown that two non-invasive devices, the photoplethysmographic volume clamp (Finapres, Ohmeda) and pulse transit time (RM50, Parametric Recorders) can provide this information. Pulse transit time (PTT) measures BP indirectly because the pulse wave propagation time (eg from heart to finger) is inversely related to arterial wall tension, which in turn depends on blood pressure. This report on snorers, taking part in another study on oral appliances, was done to verify that indirect measurements of PTT could detect the increases in inspiratory effort that usually accompany snoring. In 14 snorers (with no evidence of significant OSA on their diagnostic study) snoring (using a throat microphone), posture, oxygen saturation, thoracic excursions, and indirect blood pressure (PTT) were measured during overnight studies at home. Where available, paired ten minute periods each of continuous regular snoring, and of no snoring, were selected when there was no evidence of accompanying apnoeas, desaturations or hypopnoeas. These periods were during assumed sleep (no body movements on the thoracic excursion tracings) and selected blind of the PTT measurements. The mean size of the respiratory swings in PTT were then calculated for each of the 18 paired data sets available from 13 patients. All but three of the paired data sets showed a rise in respiratory swings during snoring periods, with the means swings being 13.5ms (SD10.5) and 18.6 (SD8.7) silence and snoring respectively. This study shows that swings in PTT can detect the increased inspiratory effort during snoring, even in the absence of any associated apnoeas and hypopnoeas.
Monocytic Myeloid-Derived Suppressor Cells Underpin Resistance to Adoptive T Cell Therapy in Nasopharyngeal Carcinoma
Authors: Richard Hopkins, Wenwei Xiang, Damien Marlier, Veonice Bijin Au, Qianting Ching, Lynn Xue Wu, Rujun Guan, Bernett Lee, Whay-Kuang Chia, Who-Whong Wang, Joseph Wee, Joanna Ng, Rachael Cheong, Shuting Han, Axel Chu, Chit Lai Chee, Timothy Shuen, Michael Podinger, Alexander Lezhava, Han Chong Toh, John E. Connolly
Journal: Molecular Therapy (2020)

Advanced, late-stage Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) is incurable, and its treatment remains a clinical and therapeutic challenge. Results from a phase II clinical trial in advanced NPC patients employing a combined chemotherapy and EBV-specific T cell (EBVST) immunotherapy regimen showed a response rate of 71.4%. Longitudinal analysis of patient samples showed that an increase in EBV DNA plasma concentrations and the peripheral monocyte-to-lymphocyte ratio negatively correlated with overall survival. These parameters were combined into a multivariate analysis to stratify patients according to risk of death. Immunophenotyping at serial time points showed that low-risk individuals displayed significantly decreased amounts of monocytic myeloid-derived suppressor cells postchemotherapy, which subsequently influenced successful cytotoxic T-lymphocyte (CTL) immunotherapy. Examination of the low-risk group, 2 weeks post-EBVST infusion, showed that individuals with a greater overall survival possessed an increased frequency of CD8 central and effector memory T cells, together with higher levels of plasma interferon (IFN)-γ, and cytotoxic lymphocyte-associated transcripts. These results highlight the importance of the rational selection of chemotherapeutic agents and consideration of their impact on both systemic immune responses and downstream cellular immunotherapy outcomes.
Targeting the PI3K/mTOR Pathway Augments CHK1 Inhibitor–Induced Replication Stress and Antitumor Activity in High-Grade Serous Ovarian Cancer
Authors: Tzu-Ting Huang, Ethan Brill, Jayakumar R. Nair, Xiaohu Zhang, Kelli M. Wilson, Lu Chen, Craig J. Thomas, Jung-Min Lee
Journal: Cancer Research (2020)

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in industrialized countries and has limited treatment options. Targeting ataxia-telangiectasia and Rad3-related/cell-cycle checkpoint kinase 1 (CHK1)-mediated S-phase and G2-M-phase cell-cycle checkpoints has been a promising therapeutic strategy in HGSOC. To improve the efficacy of CHK1 inhibitor (CHK1i), we conducted a high-throughput drug combination screening in HGSOC cells. PI3K/mTOR pathway inhibitors (PI3K/mTORi) showed supra-additive cytotoxicity with CHK1i. Combined treatment with CHK1i and PI3K/mTORi significantly attenuated cell viability and increased DNA damage, chromosomal breaks, and mitotic catastrophe compared with monotherapy. PI3K/mTORi decelerated fork speed by promoting new origin firing via increased CDC45, thus potentiating CHK1i-induced replication stress. PI3K/mTORi also augmented CHK1i-induced DNA damage by attenuating DNA homologous recombination repair activity and RAD51 foci formation. High expression of replication stress markers was associated with poor prognosis in patients with HGSOC. Our findings indicate that combined PI3K/mTORi and CHK1i induces greater cell death in HGSOC cells and in vivo models by causing lethal replication stress and DNA damage. This insight can be translated therapeutically by further developing combinations of PI3K and cell-cycle pathway inhibitors in HGSOC. SIGNIFICANCE: Dual inhibition of CHK1 and PI3K/mTOR pathways yields potent synthetic lethality by causing lethal replication stress and DNA damage in HGSOC, warranting further clinical development.