Showing papers by "Kettering University published in 2017"
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Howard Hughes Medical Institute1, Broad Institute2, Massachusetts Institute of Technology3, University of Cambridge4, European Bioinformatics Institute5, Wellcome Trust Sanger Institute6, Harvard University7, Weizmann Institute of Science8, University of Zurich9, Laboratory of Molecular Biology10, Utrecht University11, École Polytechnique Fédérale de Lausanne12, University of Pennsylvania13, Heidelberg University14, German Cancer Research Center15, Ludwig Maximilian University of Munich16, John Radcliffe Hospital17, Newcastle University18, Stanford University19, University of Oxford20, University of California, San Francisco21, Allen Institute for Brain Science22, Karolinska Institutet23, Royal Institute of Technology24, Icahn School of Medicine at Mount Sinai25, University of Cape Town26, University Medical Center Groningen27, Radboud University Nijmegen28, Kettering University29, University of Edinburgh30, Babraham Institute31, New York University32, Netherlands Cancer Institute33, Ragon Institute of MGH, MIT and Harvard34, University of Texas Health Science Center at Houston35, Technische Universität München36, Technical University of Denmark37, University of California, Berkeley38, King's College London39, California Institute of Technology40
TL;DR: An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease.
Abstract: The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body. The Human Cell Atlas Project is an international collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (such as gene expression profiles) and to connect this information with classical cellular descriptions (such as location and morphology). An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas, including a commitment to open data, code, and community.
1,391 citations
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TL;DR: It is demonstrated that directing a CD19-specific CAR to the T- cell receptor α constant (TRAC) locus not only results in uniform CAR expression in human peripheral blood T cells, but also enhances T-cell potency, with edited cells vastly outperforming conventionally generated CAR T cells in a mouse model of acute lymphoblastic leukaemia.
Abstract: Chimeric antigen receptors (CARs) are synthetic receptors that redirect and reprogram T cells to mediate tumour rejection. The most successful CARs used to date are those targeting CD19 (ref. 2), which offer the prospect of complete remission in patients with chemorefractory or relapsed B-cell malignancies. CARs are typically transduced into the T cells of a patient using γ-retroviral vectors or other randomly integrating vectors, which may result in clonal expansion, oncogenic transformation, variegated transgene expression and transcriptional silencing. Recent advances in genome editing enable efficient sequence-specific interventions in human cells, including targeted gene delivery to the CCR5 and AAVS1 loci. Here we show that directing a CD19-specific CAR to the T-cell receptor α constant (TRAC) locus not only results in uniform CAR expression in human peripheral blood T cells, but also enhances T-cell potency, with edited cells vastly outperforming conventionally generated CAR T cells in a mouse model of acute lymphoblastic leukaemia. We further demonstrate that targeting the CAR to the TRAC locus averts tonic CAR signalling and establishes effective internalization and re-expression of the CAR following single or repeated exposure to antigen, delaying effector T-cell differentiation and exhaustion. These findings uncover facets of CAR immunobiology and underscore the potential of CRISPR/Cas9 genome editing to advance immunotherapies.
1,219 citations
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TL;DR: These findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint-blockade-induced immune responses are driven by distinct cellular mechanisms, and that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations.
856 citations
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TL;DR: It is shown that stage I lung adenocarcinoma lesions already harbor significantly altered T cell and NK cell compartments, andaired single-cell analyses thus offer valuable knowledge of tumor-driven immune changes, providing a powerful tool for the rational design of immune therapies.
838 citations
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TL;DR: In this paper, the authors used mass cytometry with extensive antibody panels to perform in-depth immune profiling of samples from 73 clear cell renal cell carcinoma (ccRCC) patients and five healthy controls.
683 citations
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TL;DR: In this paper, the most current trends in the photogrammetry technique (point tracking, digital image correlation, and target-less approaches) are reviewed and compared to other measurement techniques used in structural dynamics (e.g., laser Doppler vibrometry and interferometry).
365 citations
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TL;DR: In this paper, the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue (tumor-normal sequencing) compared with genetic test results based on current guidelines were identified.
Abstract: Importance Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention. Objective To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue (“tumor-normal sequencing”) compared with genetic test results based on current guidelines. Design, Setting, and Participants From January 2014 until May 2016 at Memorial Sloan Kettering Cancer Center, 10 336 patients consented to tumor DNA sequencing. Since May 2015, 1040 of these patients with advanced cancer were referred by their oncologists for germline analysis of 76 cancer predisposition genes. Patients with clinically actionable inherited mutations whose genetic test results would not have been predicted by published decision rules were identified. Follow-up for potential clinical implications of mutation detection was through May 2017. Exposure Tumor and germline sequencing compared with the predicted yield of targeted germline sequencing based on clinical guidelines. Main Outcomes and Measures Proportion of clinically actionable germline mutations detected by universal tumor-normal sequencing that would not have been detected by guideline-directed testing. Results Of 1040 patients, the median age was 58 years (interquartile range, 50.5-66 years), 65.3% were male, and 81.3% had stage IV disease at the time of genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as the most common diagnoses. Of the 1040 patients, 182 (17.5%; 95% CI, 15.3%-19.9%) had clinically actionable mutations conferring cancer susceptibility, including 149 with moderate- to high-penetrance mutations; 101 patients tested (9.7%; 95% CI, 8.1%-11.7%) would not have had these mutations detected using clinical guidelines, including 65 with moderate- to high-penetrance mutations. Frequency of inherited mutations was related to case mix, stage, and founder mutations. Germline findings led to discussion or initiation of change to targeted therapy in 38 patients tested (3.7%) and predictive testing in the families of 13 individuals (1.3%), including 6 for whom genetic evaluation would not have been initiated by guideline-based testing. Conclusions and Relevance In this referral population with selected advanced cancers, universal sequencing of a broad panel of cancer-related genes in paired germline and tumor DNA samples was associated with increased detection of individuals with potentially clinically significant heritable mutations over the predicted yield of targeted germline testing based on current clinical guidelines. Knowledge of these additional mutations can help guide therapeutic and preventive interventions, but whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study. Trial Registration clinicaltrials.gov Identifier: NCT01775072
343 citations
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University of California, Irvine1, University at Buffalo2, Harvard University3, University of Texas MD Anderson Cancer Center4, University of Oklahoma5, Hebron University6, Kettering University7, University of Cincinnati Academic Health Center8, Memorial Sloan Kettering Cancer Center9, Indiana University10, Ohio State University11, Medical University of South Carolina12, University of Pennsylvania13, University of Mississippi Medical Center14, Case Western Reserve University15, Genentech16, University of Washington17, University of Arizona18
TL;DR: In this article, the authors report the prespecified final analysis of the primary objectives, OS and adverse events, assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board.
325 citations
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TL;DR: The role of oxidative stress in mediating separate pathological events that together, ultimately result in cell death in PD is discussed.
Abstract: Parkinson’s disease (PD) is a chronic and progressive neurodegeneration of dopamine neurons in the substantia nigra. The reason for the death of these neurons is unclear; however, studies have demonstrated the potential involvement of mitochondria, endoplasmic reticulum, α-synuclein or dopamine levels in contributing to cellular oxidative stress as well as PD symptoms. Even though those papers had separately described the individual roles of each element leading to neurodegeneration, recent publications suggest that neurodegeneration is the product of various cellular interactions. This review discusses the role of oxidative stress in mediating separate pathological events that together, ultimately result in cell death in PD. Understanding the multi-faceted relationships between these events, with oxidative stress as a common denominator underlying these processes, is needed for developing better therapeutic strategies.
301 citations
University of California, Irvine1, University at Buffalo2, Harvard University3, University of Texas MD Anderson Cancer Center4, University of Oklahoma5, Hebron University6, Kettering University7, University of Cincinnati Academic Health Center8, Memorial Sloan Kettering Cancer Center9, Indiana University10, Ohio State University11, Medical University of South Carolina12, University of Pennsylvania13, University of Mississippi Medical Center14, Case Western Reserve University15, Genentech16, University of Washington17, University of Arizona18
TL;DR: The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups, meeting the prespecified cutoff for final analysis.
Abstract: Summary Background On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events. Methods In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m 2 on day 1 or 2) plus paclitaxel (135 mg/m 2 or 175 mg/m 2 on day 1) or topotecan (0·75 mg/m 2 on days 1–3) plus paclitaxel (175 mg/m 2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062. Findings Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62–0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37–1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66–1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one ( Interpretation The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer. Funding National Cancer Institute.
251 citations
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TL;DR: This Protocol Review discusses the unprecedented opportunity that CRISPR/Cas9 technology offers for investigating and manipulating the epigenome to facilitate further understanding of stem cell biology and engineering of stem cells for therapeutic applications.
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TL;DR: A high-content chemical screen using human pluripotent stem cell-derived cortical neural progenitor cells is performed and it is found that hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ) can inhibit ZIKV infection in hNPCs.
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TL;DR: This review highlights recent advances that have illuminated roles for the RNA exosome and its cofactors in specific biological pathways, alongside studies that attempted to dissect these activities through structural and biochemical characterization of nuclear and cytoplasmic RNAExosome complexes.
Abstract: The eukaryotic RNA exosome is an essential and conserved protein complex that can degrade or process RNA substrates in the 3'-to-5' direction. Since its discovery nearly two decades ago, studies have focused on determining how the exosome, along with associated cofactors, achieves the demanding task of targeting particular RNAs for degradation and/or processing in both the nucleus and cytoplasm. In this review, we highlight recent advances that have illuminated roles for the RNA exosome and its cofactors in specific biological pathways, alongside studies that attempted to dissect these activities through structural and biochemical characterization of nuclear and cytoplasmic RNA exosome complexes.
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TL;DR: A simple, modular protocol for deriving the four main ectodermal lineages from hPSCs by precisely varying FGF, BMP, WNT, and TGFβ pathway activity in a minimal, chemically defined medium is introduced.
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TL;DR: A small-molecule approach for accelerated induction of early-born cortical neurons with functional electrophysiological properties is developed and transplanted into the postnatal mouse cortex, where they are functional and establish long-distance projections.
Abstract: Considerable progress has been made in converting human pluripotent stem cells (hPSCs) into functional neurons. However, the protracted timing of human neuron specification and functional maturation remains a key challenge that hampers the routine application of hPSC-derived lineages in disease modeling and regenerative medicine. Using a combinatorial small-molecule screen, we previously identified conditions to rapidly differentiate hPSCs into peripheral sensory neurons. Here we generalize the approach to central nervous system (CNS) fates by developing a small-molecule approach for accelerated induction of early-born cortical neurons. Combinatorial application of six pathway inhibitors induces post-mitotic cortical neurons with functional electrophysiological properties by day 16 of differentiation, in the absence of glial cell co-culture. The resulting neurons, transplanted at 8 d of differentiation into the postnatal mouse cortex, are functional and establish long-distance projections, as shown using iDISCO whole-brain imaging. Accelerated differentiation into cortical neuron fates should facilitate hPSC-based strategies for disease modeling and cell therapy in CNS disorders.
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TL;DR: This work uses live-cell imaging approaches with single-cell sequencing technologies to measure both the dynamics of lipopolysaccharide-induced NF-κB activation and the global transcriptional response in the same individual cell, establishing a functional role for NF- κB dynamics in determining cellular phenotypes.
Abstract: Signaling proteins display remarkable cell-to-cell heterogeneity in their dynamic responses to stimuli, but the consequences of this heterogeneity remain largely unknown. For instance, the contribution of the dynamics of the innate immune transcription factor nuclear factor κB (NF-κB) to gene expression output is disputed. Here we explore these questions by integrating live-cell imaging approaches with single-cell sequencing technologies. We used this approach to measure both the dynamics of lipopolysaccharide-induced NF-κB activation and the global transcriptional response in the same individual cell. Our results identify multiple, distinct cytokine expression patterns that are correlated with NF-κB activation dynamics, establishing a functional role for NF-κB dynamics in determining cellular phenotypes. Applications of this approach to other model systems and single-cell sequencing technologies have significant potential for discovery, as it is now possible to trace cellular behavior from the initial stimulus, through the signaling pathways, down to genome-wide changes in gene expression, all inside of a single cell.
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TL;DR: The transcriptomic and genetic toolkit reveals in vivo biologic function for the Drosophila m6A pathway, since miCLIP data reveal Sxl as a major intronic m521-B target, and female-specific SxL splicing is compromised in multiple m 6A pathway mutants.
Abstract: The conserved modification N6-methyladenosine (m6A) modulates mRNA processing and activity. Here, we establish the Drosophila system to study the m6A pathway. We first apply miCLIP to map m6A across embryogenesis, characterize its m6A 'writer' complex, validate its YTH 'readers' CG6422 and YT521-B, and generate mutants in five m6A factors. While m6A factors with additional roles in splicing are lethal, m6A-specific mutants are viable but present certain developmental and behavioural defects. Notably, m6A facilitates the master female determinant Sxl, since multiple m6A components enhance female lethality in Sxl sensitized backgrounds. The m6A pathway regulates Sxl processing directly, since miCLIP data reveal Sxl as a major intronic m6A target, and female-specific Sxl splicing is compromised in multiple m6A pathway mutants. YT521-B is a dominant m6A effector for Sxl regulation, and YT521-B overexpression can induce female-specific Sxl splicing. Overall, our transcriptomic and genetic toolkit reveals in vivo biologic function for the Drosophila m6A pathway.
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TL;DR: This paper focuses on the makespan sensitive task assignment problems for the crowdsensing in mobile social networks, where the mobility model is predicable, and the time of sending tasks and recycling results is non-negligible.
Abstract: Mobile crowdsensing is a new paradigm in which a crowd of mobile users exploit their carried smart phones to conduct complex sensing tasks. In this paper, we focus on the makespan sensitive task assignment problems for the crowdsensing in mobile social networks, where the mobility model is predicable, and the time of sending tasks and recycling results is non-negligible. To solve the problems, we propose an Average makespan sensitive Online Task Assignment (AOTA) algorithm and a Largest makespan sensitive Online Task Assignment (LOTA) algorithm. In AOTA and LOTA, the online task assignments are viewed as multiple rounds of virtual offline task assignments. Moreover, a greedy strategy of small-task-first-assignment and earliest-idle-user-receive-task is adopted for each round of virtual offline task assignment in AOTA, while the greedy strategy of large-task-first-assignment and earliest-idle-user-receive-task is adopted for the virtual offline task assignments in LOTA. Based on the two greedy strategies, both AOTA and LOTA can achieve nearly optimal online decision performances. We prove this and give the competitive ratios of the two algorithms. In addition, we also demonstrate the significant performance of the two algorithms through extensive simulations, based on four real MSN traces and a synthetic MSN trace.
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University of Pennsylvania1, University of Verona2, Indiana University3, Johns Hopkins University4, University of Tennessee Health Science Center5, Glasgow Royal Infirmary6, Beth Israel Deaconess Medical Center7, University of Alabama8, Kettering University9, NewYork–Presbyterian Hospital10, University of Pittsburgh11
TL;DR: From this large analysis of pancreatic fistula following DP, CR-POPF occurrence cannot be reliably predicted and opportunities for developing a risk score model are limited for performing risk-adjusted analyses of mitigation strategies and surgeon performance.
Abstract: Objective:To identify a clinical fistula risk score following distal pancreatectomy.Background:Clinically relevant pancreatic fistula (CR-POPF) following distal pancreatectomy (DP) is a dominant contributor to procedural morbidity, yet risk factors attributable to CR-POPF and effective practices to
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TL;DR: Gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity, and treatments that impose the highest fitness threshold will likely prevent the evolution of resistance-causing alterations and merit testing in patients.
Abstract: The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAFamp) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment. The evolutionary selection of BRAFamp was determined by the fitness threshold, the barrier that subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for inhibitors of ERK signaling, suggesting that sequential monotherapy is ineffective and selects for a progressively higher BRAF copy number. Concurrent targeting of the RAF, MEK and ERK kinases, however, imposed a sufficiently high fitness threshold to prevent the propagation of subclones with high-level BRAFamp. When administered on an intermittent schedule, this treatment inhibited tumor growth in 11/11 PDXs of lung cancer or melanoma without apparent toxicity in mice. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose the highest fitness threshold will likely prevent the evolution of resistance-causing alterations and, thus, merit testing in patients.
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TL;DR: It is shown that, in pluripotent stem cells, certain histone marks and stem cell regulators remain associated with specific genomic regions of mitotic chromatin, a phenomenon known as mitotic bookmarking.
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TL;DR: In this article, the performance of conventional 3D DIC and 3D point tracking (3DPT) approaches over the surface of wind turbine blades was evaluated using dynamic spatial data stitching.
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TL;DR: A statistical framework and an analysis tool are presented, RiboDiff, to detect genes with changes in translation efficiency across experimental treatments and performs a statistical test for differential translation efficiency using both mRNA abundance and ribosome occupancy.
Abstract: Motivation: Deep sequencing based ribosome footprint profiling can provide novel insights into the regulatory mechanisms of protein translation. However, the observed ribosome profile is fundamentally confounded by transcriptional activity. In order to decipher principles of translation regulation, tools that can reliably detect changes in translation efficiency in case–control studies are needed. Results: We present a statistical framework and an analysis tool, RiboDiff, to detect genes with changes in translation efficiency across experimental treatments. RiboDiff uses generalized linear models to estimate the over-dispersion of RNA-Seq and ribosome profiling measurements separately, and performs a statistical test for differential translation efficiency using both mRNA abundance and ribosome occupancy. Availability and Implementation: RiboDiff webpage http://bioweb.me/ribodiff. Source code including scripts for preprocessing the FASTQ data are available at http://github.com/ratschlab/ribodiff. Contacts: zhongy@cbio.mskcc.org or raetsch@inf.ethz.ch Supplementary information: Supplementary data are available at Bioinformatics online.
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TL;DR: This work investigates the association between human GATA6 haploinsufficiency and a wide range of clinical phenotypes that include neonatal and adult-onset diabetes using CRISPR/Cas9-mediated genome editing coupled with human pluripotent stem cell (hPSC) directed differentiation and establishes an approach for identifying genetic modifiers of human disease.
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TL;DR: In vivo studies demonstrate the essential role of RBPA, show the effects of RbpA truncations on transcription and cell physiology, and indicate additional functions for Rbp a not evident in vitro, which provides a framework to understand the control of mycobacterial transcription by Rbpa and CarD.
Abstract: RbpA and CarD are essential transcription regulators in mycobacteria. Mechanistic analyses of promoter open complex (RPo) formation establish that RbpA and CarD cooperatively stimulate formation of an intermediate (RP2) leading to RPo; formation of RP2 is likely a bottleneck step at the majority of mycobacterial promoters. Once RPo forms, CarD also disfavors its isomerization back to RP2. We determined a 2.76 A-resolution crystal structure of a mycobacterial transcription initiation complex (TIC) with RbpA as well as a CarD/RbpA/TIC model. Both CarD and RbpA bind near the upstream edge of the -10 element where they likely facilitate DNA bending and impede transcription bubble collapse. In vivo studies demonstrate the essential role of RbpA, show the effects of RbpA truncations on transcription and cell physiology, and indicate additional functions for RbpA not evident in vitro. This work provides a framework to understand the control of mycobacterial transcription by RbpA and CarD.
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TL;DR: In this article, an improved pseudo-two-dimensional (P2D) model is established on basis of partial differential equations (PDEs), since the electrolyte potential is simplified from the nonlinear to linear expression.
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TL;DR: This study provides direct evidence that endogenous Rspo2 and RSPo3 chromosome rearrangements can initiate and maintain tumour development, and indicates a viable therapeutic window for LGK974 treatment of RSPO-fusion cancers.
Abstract: Defining the genetic drivers of cancer progression is a key in understanding disease biology and developing effective targeted therapies. Chromosome rearrangements are a common feature of human malignancies, but whether they represent bona fide cancer drivers and therapeutically actionable targets, requires functional testing. Here, we describe the generation of transgenic, inducible CRISPR-based mouse systems to engineer and study recurrent colon cancer-associated EIF3E-RSPO2 and PTPRK-RSPO3 chromosome rearrangements in vivo. We show that both Rspo2 and Rspo3 fusion events are sufficient to initiate hyperplasia and tumour development in vivo, without additional cooperating genetic events. Rspo-fusion tumours are entirely Wnt-dependent, as treatment with an inhibitor of Wnt secretion, LGK974, drives rapid tumour clearance from the intestinal mucosa without effects on normal intestinal crypts. Altogether, our study provides direct evidence that endogenous Rspo2 and Rspo3 chromosome rearrangements can initiate and maintain tumour development, and indicate a viable therapeutic window for LGK974 treatment of RSPO-fusion cancers.
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TL;DR: The cellular and molecular pathways that appear to be involved in obesity-driven cancer are reviewed and possible therapeutic considerations are described and important unanswered questions in the field are highlighted.
Abstract: Adipocytes have adapted to store energy in the form of lipid and also secrete circulating factors called adipokines that signal to other tissues to coordinate energy homeostasis. These functions are disrupted in the setting of obesity, promoting the development of diseases such as diabetes, cardiovascular disease, and cancer. Obesity is linked to an increased risk of many types of cancer and increased cancer-related mortality. The basis for the striking association between obesity and cancer is not well understood. Here, we review the cellular and molecular pathways that appear to be involved in obesity-driven cancer. We also describe possible therapeutic considerations and highlight important unanswered questions in the field.
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TL;DR: The benefits of sunscreen, different ultraviolet filters, sunscreen regulations and controversies, the importance of broad-spectrum protection, issues of photostability and formulation, and patient education and compliance are discussed.
Abstract: Sunscreens have been widely used by the general public for their photoprotective properties, including prevention of photocarcinogenesis and photoaging and management of photodermatoses. It is important to emphasize to consumers the necessity of broad-spectrum protection, with coverage of both ultraviolet A (320-400 nm) and ultraviolet B (290-320 nm) radiation. This review discusses the benefits of sunscreen, different ultraviolet filters, sunscreen regulations and controversies, the importance of broad-spectrum protection, issues of photostability and formulation, and patient education and compliance.
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TL;DR: Interestingly, an "inverse pattern" of CAR T-cell BLI intensity was observed in control and test tumors, which suggests CAR T cells undergo changes leading to a loss of signal and/or number following hPSMA-specific activation.