tbuckley/cabot-search huggingface dataset:
Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC
Authors: Weihua Li, Lei Guo, Yutao Liu, Lin Dong, Lin Yang, Li Chen, Kaihua Liu, Yang Shao, Jianming Ying
Journal: Journal of Thoracic Oncology (2020)

IntroductionVariable genomic breakpoints have been identified through the application of target-capture DNA next-generation sequencing (NGS) for ALK, ROS1, and RET fusion detection in NSCLC. We investigated whether ALK, ROS1, and RET genomic breakpoint location can predict matched targeted therapy efficacy.MethodsNSCLCs were analyzed by DNA NGS, target-specific RNA NGS, whole-transcriptome sequencing, and immunohistochemistry.ResultsIn total, 3787 NSCLC samples were analyzed. DNA NGS detected ALK, ROS1, and RET fusions in 241, 59, and 76 cases, respectively. These fusions were divided into canonical (single EML4-ALK, CD74/EZR/TPM3/SDC4-ROS1, and KIF5B/CCDC6-RET fusions), noncanonical (single non–EML4-ALK, non–CD74/EZR/TPM3/SDC4-ROS1, and non–KIF5B/CCDC6-RET fusions), and primary/reciprocal (both primary and reciprocal rearrangements were detected) subtypes on the basis of genomic breakpoint position, and noncanonical and primary/reciprocal subtypes were defined as uncommon fusions. Further RNA sequencing and immunohistochemistry revealed that six of 47 (12.8%) uncommon fusions were actually nonproductive rearrangements that generated no aberrant transcripts or proteins. Moreover, genomic breakpoints of canonical ALK and RET, but not ROS1, fusions always predicted breakpoints at the transcript level, whereas 85.4% (35 of 41) of uncommon fusions actually produced canonical fusion transcripts. Patients with uncommon ALK fusion (n = 31) who received first-line crizotinib exhibited shorter median progression-free survival than those with canonical ALK fusion (n = 53, 8.4 mo versus 12.0 mo, p = 0.004). However, no difference in progression-free survival was observed when only ALK RNA or protein-positive cases were analyzed (p = 0.185).ConclusionsUncommon ALK, ROS1, and RET genomic breakpoint is an unreliable predictor of matched targeted therapy efficacy. Functional validation by RNA or protein assay may add value for the accurate detection and interpretation of rare fusions.
Antimetabolite pemetrexed primes a favorable tumor microenvironment for immune checkpoint blockade therapy
Authors: Chia-Sing Lu, Ching-Wen Lin, Ya-Hsuan Chang, Hsuan-Yu Chen, Wei-Chia Chung, Wei-Yun Lai, Chao-Chi Ho, Tong-Hong Wang, Chi-Yuan Chen, Chen-Lin Yeh, Sean Wu, Shu-Ping Wang, Pan-Chyr Yang
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background The immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers, including non-small-cell lung cancer (NSCLC). However, a significant number of patients with NSCLC still fail to respond to ICB due to unfavorable tumor microenvironment. To improve the efficacy, the immune-chemotherapy combination with pemetrexed, cis/carboplatin and pembrolizumab (anti-PD-1) has been recently approved as first-line treatment in advanced NSCLCs. While chemotherapeutic agents exert beneficial effects, the underlying antitumor mechanism(s) remains unclear. Methods Pemetrexed, cisplatin and other chemotherapeutic agents were tested for the potential to induce PD-L1 expression in NSCLC cells by immunoblotting and flow cytometry. The ability to prime the tumor immune microenvironment was then determined by NSCLC/T cell coculture systems and syngeneic mouse models. Subpopulations of NSCLC cells responding differently to pemetrexed were selected and subjected to RNA-sequencing analysis. The key signaling pathways were identified and validated in vitro and in vivo. Results Pemetrexed induced the transcriptional activation of PD-L1 (encoded by CD274 ) by inactivating thymidylate synthase (TS) in NSCLC cells and, in turn, activating T-lymphocytes when combined with the anti-PD-1/PD-L1 therapy. Nuclear factor κB (NF-κB) signaling was activated by intracellular reactive oxygen species (ROSs) that were elevated by pemetrexed-mediated TS inactivation. The TS−ROS−NF-κB regulatory axis actively involves in pemetrexed-induced PD-L1 upregulation, whereas when pemetrexed fails to induce PD-L1 expression in NSCLC cells, NF-κB signaling is unregulated. In syngeneic mouse models, the combinatory treatment of pemetrexed with anti-PD-L1 antibody created a more favorable tumor microenvironment for the inhibition of tumor growth. Conclusions Our findings reveal novel mechanisms showing that pemetrexed upregulates PD-L1 expression and primes a favorable microenvironment for ICB, which provides a mechanistic basis for the combinatory chemoimmunotherapy in NSCLC treatment.
Understanding LV Remodeling Following Myocardial Infarction: Are T1 Maps by CMR the New Guide?⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: Sven Plein, Ananth Kidambi
Journal: JACC. Cardiovascular imaging (2012)
Millions will face surgery delays unless anaesthetic workforce grows, college warns
Authors: Abi Rimmer
Journal: BMJ (2020)

The Royal College of Anaesthetists has urged the government to invest in increasing the number of anaesthetic trainees, after a workforce census found vacancies in most hospitals.

The college gathered data from 145 NHS trusts in England, five trusts in Northern Ireland, 15 health boards in Scotland, and six boards in Wales, with an overall response rate of 97%.1

A report on the census findings said that 90% of anaesthesia …
Successive epidemic waves of cholera in South Sudan between 2014 and 2017: a descriptive epidemiological study
Authors: Forrest K Jones, Joseph F Wamala, John Rumunu, Pinyi Nyimol Mawien, Mathew Tut Kol, Shirlee Wohl, Lul Deng, Lorenzo Pezzoli, Linda Haj Omar, Justin Lessler, Marie-Laure Quilici, Francisco J Luquero, Andrew S Azman
Journal: The Lancet Planetary Health (2020)

BackgroundBetween 2014 and 2017, successive cholera epidemics occurred in South Sudan within the context of civil war, population displacement, flooding, and drought. We aim to describe the spatiotemporal and molecular features of the three distinct epidemic waves and explore the role of vaccination campaigns, precipitation, and population movement in shaping cholera spread in this complex setting.MethodsIn this descriptive epidemiological study, we analysed cholera linelist data to describe the spatiotemporal progression of the epidemics. We placed whole-genome sequence data from pandemic Vibrio cholerae collected throughout these epidemics into the global phylogenetic context. Using whole-genome sequence data in combination with other molecular attributes, we characterise the relatedness of strains circulating in each wave and the region. We investigated the association of rainfall and the instantaneous basic reproduction number using distributed lag non-linear models, compared county-level attack rates between those with early and late reactive vaccination campaigns, and explored the consistency of the spatial patterns of displacement and suspected cholera case reports.FindingsThe 2014 (6389 cases) and 2015 (1818 cases) cholera epidemics in South Sudan remained spatially limited whereas the 2016–17 epidemic (20 438 cases) spread among settlements along the Nile river. Initial cases of each epidemic were reported in or around Juba soon after the start of the rainy season, but we found no evidence that rainfall modulated transmission during each epidemic. All isolates analysed had similar genotypic and phenotypic characteristics, closely related to sequences from Uganda and Democratic Republic of the Congo. Large-scale population movements between counties of South Sudan with cholera outbreaks were consistent with the spatial distribution of cases. 21 of 26 vaccination campaigns occurred during or after the county-level epidemic peak. Counties vaccinated on or after the peak incidence week had 2·2 times (95% CI 2·1–2·3) higher attack rates than those where vaccination occurred before the peak.InterpretationPandemic V cholerae of the same clonal origin was isolated throughout the study period despite interepidemic periods of no reported cases. Although the complex emergency in South Sudan probably shaped some of the observed spatial and temporal patterns of cases, the full scope of transmission determinants remains unclear. Timely and well targeted use of vaccines can reduce the burden of cholera; however, rapid vaccine deployment in complex emergencies remains challenging.FundingThe Bill & Melinda Gates Foundation.
Odorant Receptors for Detecting Flowering Plant Cues Are Functionally Conserved across Moths and Butterflies
Authors: Mengbo Guo, Lixiao Du, Qiuyan Chen, Yilu Feng, Jin Zhang, Xiaxuan Zhang, Ke Tian, Song Cao, Tianyu Huang, Emmanuelle Jacquin-Joly, Guirong Wang, Yang Liu
Journal: Molecular Biology and Evolution (2020)

Odorant receptors (ORs) are essential for plant-insect interactions. However, despite the global impacts of Lepidoptera (moths and butterflies) as major herbivores and pollinators, little functional data are available about Lepidoptera ORs involved in plant-volatile detection. Here, we initially characterized the plant-volatile-sensing function(s) of 44 ORs from the cotton bollworm Helicoverpa armigera, and subsequently conducted a large-scale comparative analysis that establishes how most orthologous ORs have functionally diverged among closely related species whereas some rare ORs are functionally conserved. Specifically, our systematic analysis of H. armigera ORs cataloged the wide functional scope of the H. armigera OR repertoire, and also showed that HarmOR42 and its Spodoptera littoralis ortholog are functionally conserved. Pursuing this, we characterized the HarmOR42-orthologous ORs from 11 species across the Glossata suborder and confirmed the HarmOR42 orthologs form a unique OR lineage that has undergone strong purifying selection in Glossata species and whose members are tuned with strong specificity to phenylacetaldehyde, a floral scent component common to most angiosperms. In vivo studies via HarmOR42 knockout support that HarmOR42-related ORs are essential for host-detection by sensing phenylacetaldehyde. Our work also supports that these ORs coevolved with the tube-like proboscis, and has maintained functional stability throughout the long-term coexistence of Lepidoptera with angiosperms. Thus, beyond providing a rich empirical resource for delineating the precise functions of H. armigera ORs, our results enable a comparative analysis of insect ORs that have apparently facilitated and currently sustain the intimate adaptations and ecological interactions among nectar feeding insects and flowering plants.
Association of CYP2C19 and CYP2D6 Poor and Intermediate Metabolizer Status With Antidepressant and Antipsychotic Exposure
Authors: Filip Milosavljevic, Nikola Bukvic, Zorana Pavlovic, Cedo Miljevic, Vesna Pešic, Espen Molden, Magnus Ingelman-Sundberg, Stefan Leucht, Marin M. Jukic
Journal: JAMA Psychiatry (2020)

Precise estimation of the drug metabolism capacity for individual patients is crucial for adequate dose personalization.To quantify the difference in the antipsychotic and antidepressant exposure among patients with genetically associated CYP2C19 and CYP2D6 poor (PM), intermediate (IM), and normal (NM) metabolizers.PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to June 30, 2020, with no language restrictions.Two independent reviewers performed study screening and assessed the following inclusion criteria: (1) appropriate CYP2C19 or CYP2D6 genotyping was performed, (2) genotype-based classification into CYP2C19 or CYP2D6 NM, IM, and PM categories was possible, and (3) 3 patients per metabolizer category were available.The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for extracting data and quality, validity, and risk of bias assessments. A fixed-effects model was used for pooling the effect sizes of the included studies.Drug exposure was measured as (1) dose-normalized area under the plasma level (time) curve, (2) dose-normalized steady-state plasma level, or (3) reciprocal apparent total drug clearance. The ratio of means (RoM) was calculated by dividing the mean drug exposure for PM, IM, or pooled PM plus IM categories by the mean drug exposure for the NM category.Based on the data derived from 94 unique studies and 8379 unique individuals, the most profound differences were observed in the patients treated with aripiprazole (CYP2D6 PM plus IM vs NM RoM, 1.48; 95% CI, 1.41-1.57; 12 studies; 1038 patients), haloperidol lactate (CYP2D6 PM vs NM RoM, 1.68; 95% CI, 1.40-2.02; 9 studies; 423 patients), risperidone (CYP2D6 PM plus IM vs NM RoM, 1.36; 95% CI, 1.28-1.44; 23 studies; 1492 patients), escitalopram oxalate (CYP2C19 PM vs NM, RoM, 2.63; 95% CI, 2.40-2.89; 4 studies; 1262 patients), and sertraline hydrochloride (CYP2C19 IM vs NM RoM, 1.38; 95% CI, 1.27-1.51; 3 studies; 917 patients). Exposure differences were also observed for clozapine, quetiapine fumarate, amitriptyline hydrochloride, mirtazapine, nortriptyline hydrochloride, fluoxetine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, and venlafaxine hydrochloride; however, these differences were marginal, ambiguous, or based on less than 3 independent studies.In this systematic review and meta-analysis, the association between CYP2C19/CYP2D6 genotype and drug levels of several psychiatric drugs was quantified with sufficient precision as to be useful as a scientific foundation for CYP2D6/CYP2C19 genotype-based dosing recommendations.
Mitigating Inequities and Saving Lives with ICU Triage during the COVID-19 Pandemic
Authors: Douglas B. White, Bernard Lo
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

The burdens of the coronavirus disease (COVID-19) pandemic have fallen disproportionately on disadvantaged groups, including the poor and Black, Latinx, and Indigenous communities. There is substantial concern that the use of existing ICU triage protocols to allocate scarce ventilators and critical care resources-most of which are designed to save as many lives as possible-may compound these inequities. As governments and health systems revisit their triage guidelines in the context of impending resource shortages, scholars have advocated a range of alternative allocation strategies, including the use of a random lottery to give all patients in need an equal chance of ICU treatment. However, both the save-the-most-lives approach and random allocation are seriously flawed. In this Perspective, we argue that ICU triage policies should simultaneously promote population health outcomes and mitigate health inequities. These ethical goals are sometimes in conflict, which will require balancing the goals of maximizing the number of lives saved and distributing health benefits equitably across society. We recommend three strategies to mitigate health inequities during ICU triage: introducing a correction factor into patients' triage scores to reduce the impact of baseline structural inequities; giving heightened priority to individuals in essential, high-risk occupations; and rejecting use of longer-term life expectancy and categorical exclusions as allocation criteria. We present a practical triage framework that incorporates these strategies and attends to the twin public health goals of promoting population health and social justice.
Abstract 10987: Dual Antiplatelet Therapy After Left Atrial Appendage Occlusion With the Watchman Device
Authors: Erika Hutt, Simrat Kaur, Jose Aguilera, Walid I Saliba, Mohamed H Kanj, Khaldoun Tarakji, Mouin S Abdallah, Bryan Baranowski, Daniel J Cantillon, John Rickard, Thomas D Callahan, Thomas J Dresing, Mandeep Bhargava, Bruce D Lindsay, Oussama M Wazni, Ayman Hussein
Journal: Circulation (2019)

Introduction: After Watchman (Boston Scientific) device implantation patients must complete 45 days of anticoagulation (AC) followed by 6 months of dual antiplatelet therapy (DAPT). However, DAPT m...
Real World Experience and Patient Satisfaction Surrounding the Implementation of Daratumumab and Hyaluronidase-Fihj in a Large, Academic Medical Center
Authors: Kathryn T. Maples, Erich Brechtelsbauer, Julia Pendexter, Jonathan L. Kaufman, Nisha Joseph, Leonard Heffner, Craig C Hofmeister, Madhav V. Dhodapkar, Sagar Lonial, Ajay Nooka
Journal: Blood (2020)
Reddish-Brown Hematomalike Annular Plaque in a Healthy Patient’s Axilla
Authors: Vicente Expósito-Serrano, Jorge Romaní de Gabriel, Empar Saez Artacho
Journal: JAMA Dermatology (2020)

A healthy man in his 50s presents with an asymptomatic, reddish hematomalike plaque with a brownish peripheral border in his left axilla, and a biopsy is positive for CD31, CD34, and D2-40 and negative for Wilms tumor 1. What is your diagnosis?
Internet search patterns reveal firearm sales, policies, and deaths
Authors: John S. Brownstein, Adam D. Nahari, Ben Y. Reis
Journal: npj Digital Medicine (2020)

Abstract Firearm-related violence is a leading cause of morbidity and mortality and is at the center of a major public health and policy debate in the United States. Despite the critical role of data in informing this debate, accurate and comprehensive data on firearm sales and ownership is not readily available. In this study, we evaluate the potential of using firearm-related internet search queries as a complementary, freely available, and near-real-time data source for tracking firearm sales and ownership that enables analysis at finer geographic and temporal scales. (Here, we examine data by state and by month to compare with other data sources, but search engine volume can be analyzed by city and by the week or by day). We validate search query volume against available data on background checks in all 50 US states, and find that they are highly correlated over time (Pearson’s r = 0.96, Spearman’s ρ = 0.94) and space (Pearson’s r = 0.78, Spearman’s ρ = 0.76). We find that stratifying this analysis by gun type (long-gun vs. handgun) increases this correlation dramatically, across both time and space. We also find a positive association between firearm-related search query volume and firearm-related mortality (Pearson’s r = 0.87, Spearman’s ρ = 0.90), and a negative association with the strength of state-level firearm control policies (Pearson’s r = −0.82, Spearman’s ρ = −0.83). Based on these findings, we propose a framework for prospective surveillance that incorporates firearm-related internet search volume as a useful complementary data source to inform the public health policy debate on this issue.
Risk stratification in diffuse large B-cell lymphoma using lesion dissemination and metabolic tumor burden calculated from baseline PET/CT†
Authors: A.-S. Cottereau, M. Meignan, C. Nioche, N. Capobianco, J. Clerc, L. Chartier, L. Vercellino, O. Casasnovas, C. Thieblemont, I. Buvat
Journal: Annals of Oncology (2020)
BCR-ABL1 compound mutants: prevalence, spectrum and correlation with tyrosine kinase inhibitor resistance in a consecutive series of Philadelphia chromosome-positive leukemia patients analyzed by NGS
Authors: Simona Soverini, Margherita Martelli, Luana Bavaro, Caterina De Benedittis, Simona Sica, Federica Sorà, Alessandra Iurlo, Massimiliano Bonifacio, Patrizia Pregno, Sara Galimberti, Francesca Lunghi, Francesco Albano, Mariella D’Adda, Monica Crugnola, Isabella Capodanno, Fausto Castagnetti, Gabriele Gugliotta, Cristina Papayannidis, Gianantonio Rosti, Antonio Percesepe, Flavio Mignone, Michele Baccarani, Giovanni Martinelli, Michele Cavo
Journal: Leukemia (2020)
13643 Improvement in specific locations, quality of life, and pruritus after 24 weeks of apremilast in bio-naïve moderate plaque psoriasis patients who failed to achieve a PASI-75 response: Interim results of a real-world prospective study in Greece (APRAISAL)
Authors: Dimitrios Ioannides, Eleftheria Vryzaki, Panagakis Pantelis, Pantelis Panagakis, Andreas Syggros, Eleftheria Tampouratzi, Alexandros Drosos, Rigopoulos Dimitris, Dimitris Rigopoulos, Christina Antoniou, Kalliopi Tomai, Ioannis Bassukas, Markos Papakonstantis
Journal: Journal of the American Academy of Dermatology (2020)
Silver‐Coated Disordered Silicon Nanowires Provide Highly Sensitive Label‐Free Glycated Albumin Detection through Molecular Trapping and Plasmonic Hotspot Formation
Authors: Debadrita Paria, Annalisa Convertino, Valentina Mussi, Luca Maiolo, Ishan Barman
Journal: Advanced Healthcare Materials (2020)

Abstract Glycated albumin (GA) is rapidly emerging as a robust biomarker for screening and monitoring of diabetes. To facilitate its rapid, point‐of‐care measurements, a label‐free surface‐enhanced Raman spectroscopy (SERS) sensing platform is reported that leverages the specificity of molecular vibrations and signal amplification on silver‐coated silicon nanowires (Ag/SiNWs) for highly sensitive and reproducible quantification of GA. The simulations and experimental measurements demonstrate that the disordered orientation of the nanowires coupled with the wicking of the analyte molecules during the process of solvent evaporation facilitates molecular trapping at the generated plasmonic hotspots. Highly sensitive detection of glycated albumin is shown with the ability to visually detect spectral features at as low as 500 × 10 −9 m , significantly below the physiological range of GA in body fluids. Combined with chemometric regression models, the spectral data recorded on the Ag/SiNWs also allow accurate prediction of glycated concentration in mixtures of glycated and non‐glycated albumin in proportions that reflect those in the bloodstream.
16223 Advanced-stage CD30-positive mycosis fungoides: Clinical experience with brentuximab vedotin
Authors: Cristina Vico-Alonso, Juan José Andres-Lencina, Raquel Aragón-Miguel, Alba Calleja-Algarra, Belén Pinilla-Martín, Alba Sanchez-Velazquez, Héctor Muñoz-González, Maria Penalba, Virginia Velasco Tamariz, Concepcion Postigo LLorente, Pablo L. Ortiz-Romero
Journal: Journal of the American Academy of Dermatology (2020)
Priadel: bipolar drug will remain on market after new price is agreed by government
Authors: Elisabeth Mahase
Journal: BMJ (2020)

Priadel, a brand of lithium widely used to treat bipolar disorder, will remain on the market after a new deal was struck between the manufacturer Essential Pharma and the Department for Health and Social Care (DHSC).

The drug company previously announced that it would withdraw Priadel in April 2021. This led the Competition and Markets Authority (CMA) to launch an investigation into whether the company had “abused its dominant position” in order to get patients to …