tbuckley/cabot-search huggingface dataset:
Kozak Sequence Acts as a Negative Regulator for De Novo Transcription Initiation of Newborn Coding Sequences in the Plant Genome
Authors: Takayuki Hata, Soichirou Satoh, Naoto Takada, Mitsuhiro Matsuo, Junichi Obokata
Journal: Molecular Biology and Evolution (2021)

The manner in which newborn coding sequences and their transcriptional competency emerge during the process of gene evolution remains unclear. Here, we experimentally simulated eukaryotic gene origination processes by mimicking horizontal gene transfer events in the plant genome. We mapped the precise position of the transcription start sites (TSSs) of hundreds of newly introduced promoterless firefly luciferase (LUC) coding sequences in the genome of Arabidopsis thaliana cultured cells. The systematic characterization of the LUC-TSSs revealed that 80% of them occurred under the influence of endogenous promoters, while the remainder underwent de novo activation in the intergenic regions, starting from pyrimidine-purine dinucleotides. These de novo TSSs obeyed unexpected rules; they predominantly occurred ∼100 bp upstream of the LUC inserts and did not overlap with Kozak-containing putative open reading frames (ORFs). These features were the output of the immediate responses to the sequence insertions, rather than a bias in the screening of the LUC gene function. Regarding the wild-type genic TSSs, they appeared to have evolved to lack any ORFs in their vicinities. Therefore, the repulsion by the de novo TSSs of Kozak-containing ORFs described above might be the first selection gate for the occurrence and evolution of TSSs in the plant genome. Based on these results, we characterized the de novo type of TSS identified in the plant genome and discuss its significance in genome evolution.
Integrative Proteomic Analysis of Multiple Posttranslational Modifications in Inflammatory Response
Authors: Feiyang Ji, Menghao Zhou, Huihui Zhu, Zhengyi Jiang, Qirui Li, Xiaoxi Ouyang, Yiming Lv, Sainan Zhang, Tian Wu, Lanjuan Li
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract Posttranslational modifications (PTMs) of proteins, particularly acetylation, phosphorylation, and ubiquitination, play critical roles in the host innate immune response. PTMs’ dynamic changes and the crosstalk among them are complicated. To build a comprehensive dynamic network of inflammation-related proteins, we integrated data from the whole-cell proteome (WCP), acetylome, phosphoproteome, and ubiquitinome of human and mouse macrophages. Our datasets of acetylation, phosphorylation, and ubiquitination sites helped identify PTM crosstalk within and across proteins involved in the inflammatory response. Stimulation of macrophages by lipopolysaccharide (LPS) resulted in both degradative and non-degradative ubiquitination. Moreover, this study contributes to the interpretation of the roles of known inflammatory molecules and the discovery of novel inflammatory proteins.
Altered network properties in C9ORF72 repeat expansion cortical neurons are due to synaptic dysfunction
Authors: Emma M. Perkins, Karen Burr, Poulomi Banerjee, Arpan R. Mehta, Owen Dando, Bhuvaneish T. Selvaraj, Daumante Suminaite, Jyoti Nanda, Christopher M. Henstridge, Thomas H. Gillingwater, Giles E. Hardingham, David J. A. Wyllie, Siddharthan Chandran, Matthew R. Livesey
Journal: Molecular Neurodegeneration (2021)

Physiological disturbances in cortical network excitability and plasticity are established and widespread in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those harbouring the C9ORF72 repeat expansion (C9ORF72RE) mutation - the most common genetic impairment causal to ALS and FTD. Noting that perturbations in cortical function are evidenced pre-symptomatically, and that the cortex is associated with widespread pathology, cortical dysfunction is thought to be an early driver of neurodegenerative disease progression. However, our understanding of how altered network function manifests at the cellular and molecular level is not clear.To address this we have generated cortical neurons from patient-derived iPSCs harbouring C9ORF72RE mutations, as well as from their isogenic expansion-corrected controls. We have established a model of network activity in these neurons using multi-electrode array electrophysiology. We have then mechanistically examined the physiological processes underpinning network dysfunction using a combination of patch-clamp electrophysiology, immunocytochemistry, pharmacology and transcriptomic profiling.We find that C9ORF72RE causes elevated network burst activity, associated with enhanced synaptic input, yet lower burst duration, attributable to impaired pre-synaptic vesicle dynamics. We also show that the C9ORF72RE is associated with impaired synaptic plasticity. Moreover, RNA-seq analysis revealed dysregulated molecular pathways impacting on synaptic function. All molecular, cellular and network deficits are rescued by CRISPR/Cas9 correction of C9ORF72RE. Our study provides a mechanistic view of the early dysregulated processes that underpin cortical network dysfunction in ALS-FTD.These findings suggest synaptic pathophysiology is widespread in ALS-FTD and has an early and fundamental role in driving altered network function that is thought to contribute to neurodegenerative processes in these patients. The overall importance is the identification of previously unidentified defects in pre and postsynaptic compartments affecting synaptic plasticity, synaptic vesicle stores, and network propagation, which directly impact upon cortical function.
Sapanisertib, a dual mTORC1/2 inhibitor, for <i>TSC1- or TSC2-</i>mutated metastatic urothelial carcinoma (mUC).
Authors: Joseph W. Kim, Matthew I. Milowsky, Noah M. Hahn, David J. Kwiatkowski, Alicia K. Morgans, Nancy B. Davis, Leonard Joseph Appleman, Sumati Gupta, Primo "Lucky" N. Lara, Jean H. Hoffman-Censits, David I. Quinn, Yu Shyr, Patricia LoRusso, Jeffrey Sklar, Daniel Peter Petrylak
Journal: Journal of Clinical Oncology (2021)

431 Background: A mammalian target of rapamycin (mTOR) inhibitor, everolimus, showed activity in patients with metastatic urothelial carcinoma (mUC) including an exceptional objective response in a patient with a deleterious TSC1 mutation. Sapanisertib is a potent inhibitor of mTOR complex 1 and 2. Here, we present the data from a phase II study of sapanisertib in patients with TSC1- or TSC2-mutated mUC. Methods: Eligible mUC patients with a TSC1 or TSC2 mutation received sapanisertib 3mg po daily on days 1 through 28 every 28 days. Primary endpoint was the overall response rate. Tumor samples were submitted for central confirmation of the mutation. A prescreening test for TSC1/2 mutation was available at a central lab for those with unknown mutational status. Results: Tumor samples from 41 patients were submitted for either prescreening (n=24) or confirmation (n=17). Of 24 prescreening patients, 4 (16%) had TSC1 mutation; 2 (8%) had TSC2 mutations. Of 17 confirmatory testing, 16 were confirmed by the central lab. Of 23 potentially eligible patients with a TSC1 or TSC2 mutation, 17 (14 TSC1 and 3 TSC2) were enrolled. Baseline characteristics of these 17 patients are shown. Four patients with TSC1- mutated mUC were deemed non-evaluable for response; two withdrew consent before starting sapanisertib to pursue an alternative therapy, and the other two withdrew consent with an adverse event before completing the first cycle. Of 13 evaluable patients, no objective response was observed. Although 4 patients had stable disease (SD) at their first restaging scan, none were confirmed to have SD with a subsequent scan. Median overall survival is 3.4 months. Four patients withdrew consent due to adverse event. Most common adverse events were hyperglycemia (80%), Cr elevation (53%) and AST increased (46.7%). No treatment-related death was observed. Conclusions: Sapanisertib did not result in any objective response in 13 patients with TSC1- or TSC2-mutated mUC. Given the lack of clinical activity, and problems with tolerance of sapanisertib, the trial was terminated early for futility. Future studies of an mTOR inhibitor or other targeted agent in the mTOR pathway should examine molecular alterations beyond TSC1 or TSC2. Clinical trial information: NCT03047213 . [Table: see text]
Association of Umbilical Cord Management Strategies With Outcomes of Preterm Infants
Authors: Bonny Jasani, Ranjit Torgalkar, Xiang Y. Ye, Sulaiman Syed, Prakesh S. Shah
Journal: JAMA Pediatrics (2021)

It is unclear which umbilical cord management strategy is the best for preventing mortality and morbidities in preterm infants.To systematically review and conduct a network meta-analysis comparing 4 umbilical cord management strategies for preterm infants: immediate umbilical cord clamping (ICC), delayed umbilical cord clamping (DCC), umbilical cord milking (UCM), and UCM and DCC.PubMed, Embase, CINAHL, and Cochrane CENTRAL databases were searched from inception until September 11, 2020.Randomized clinical trials comparing different umbilical cord management strategies for preterm infants were included.Data were extracted for bayesian random-effects meta-analysis to estimate the relative treatment effects (odds ratios [OR] and 95% credible intervals [CrI]) and surface under the cumulative ranking curve values.The primary outcome was predischarge mortality. The secondary outcomes were intraventricular hemorrhage, severe intraventricular hemorrhage, need for packed red blood cell transfusion, and other neonatal morbidities. Confidence in network meta-analysis software was used to assess the quality of evidence and grade outcomes.Fifty-six studies enrolled 6852 preterm infants. Compared with ICC, DCC was associated with lower odds of mortality (22 trials, 3083 participants; 7.6% vs 5.0%; OR, 0.64; 95% CrI, 0.39-0.99), intraventricular hemorrhage (25 trials, 3316 participants; 17.8% vs 15.4%; OR, 0.73; 95% CrI, 0.54-0.97), and need for packed red blood cell transfusion (18 trials, 2904 participants; 46.9% vs 38.3%; OR, 0.48; 95% CrI, 0.32-0.66). Compared with ICC, UCM was associated with lower odds of intraventricular hemorrhage (10 trials, 645 participants; 22.5% vs 16.2%; OR, 0.58; 95% CrI, 0.38-0.84) and need for packed red blood cell transfusion (9 trials, 688 participants; 47.3% vs 32.3%; OR, 0.36; 95% CrI, 0.23-0.53), with no significant differences for other secondary outcomes. There was no significant difference between UCM and DCC for any outcome.Compared with ICC, DCC was associated with the lower odds of mortality in preterm infants. Compared with ICC, DCC and UCM were associated with reductions in intraventricular hemorrhage and need for packed red cell transfusion. There was no significant difference between UCM and DCC for any outcome. Further studies directly comparing DCC and UCM are needed.
PROSPER subgroup analysis by age and region: Overall survival and safety in men with nonmetastatic castration-resistant prostate cancer receiving androgen deprivation therapy plus enzalutamide.
Authors: Ugo De Giorgi, Maha H. A. Hussain, Neal D. Shore, Karim Fizazi, Bertrand Tombal, David F. Penson, Fred Saad, Eleni Efstathiou, Katarzyna Madziarska, Joyce Leta Steinberg, Jennifer Sugg, Xun Lin, Qi Shen, Cora N. Sternberg
Journal: Journal of Clinical Oncology (2021)

84 Background: Previous reports on the PROSPER trial have shown that enzalutamide (ENZA) plus androgen deprivation therapy (ADT) significantly improves metastasis-free survival and overall survival (OS) over placebo (PBO) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) and rapidly rising prostate-specific antigen (PSA) levels. (Hussain et al. N Engl J Med. 2018;378:2465-2474/Sternberg et al. N Engl J Med. 2020;382:2197-2206). To inform decision-making for specific patients, we report here a post hoc analysis of OS and safety in subgroups of PROSPER by age and region. Methods: PROSPER included men with nmCRPC and a PSA doubling time ≤ 10 months. Enrolled men continued ADT and were randomized 2:1 to ENZA 160 mg once daily vs PBO. We performed a multivariable analysis for OS, including age (≤ 70 yrs and &gt; 70 yrs), geographic region, and other variables and further examined exposure-adjusted adverse events (AEs) by age and region. Results: Based on this post hoc analysis, OS benefit with ENZA treatment was similar across geographic regions (table) and for patients aged ≥ 70 yrs (hazard ratio [HR] 0.73; 95% CI 0.58-0.9) and those aged &lt; 70 yrs (HR 0.72, 95% CI 0.5-1.04). In our multivariate analysis, 3 factors emerged as significantly impacting estimated OS: Eastern Cooperative Oncology Group (ECOG) performance status (1 vs 0; HR 1.7; 95% CI 1.4-2.1), log of PSA (HR 1.2; 95% CI 1.1-1.3), and use of subsequent therapy (yes vs no; HR 2.5; 95% CI 2.1-3.1). Overall safety was consistent between age groups and across geographic regions. The proportion of patients reporting any grade treatment-emergent AEs (TEAEs) related to ENZA use was similar between age groups but decreased with increasing age. Conclusions: In men with nmCRPC and rapidly rising PSA, ENZA plus ADT treatment reduced the risk of death, regardless of age or geographic location. Patients reported any grade TEAEs at a similar proportion in both arms. Variables impacting OS included ECOG status, log PSA, and subsequent therapy. Clinical trial information: NCT02003924. [Table: see text]
Abstract IA017: Age against the machine: How the aging tumor microenvironment governs tumor progression
Authors: Ashani Weeraratna
Journal: Cancer Research (2021)

Abstract Cancer is a disease of aging. Most cancers arise after the age of 50, and in our increasingly aging population, this poses a significant public health burden. The molecular mechanisms that underlie the age-induced progression of cancer are not well understood. We have discovered that aged fibroblasts in the tumor microenvironment secrete, or stop secreting, key molecules that affect multiple aspects of tumorigenesis. These include: the loss of molecules that maintain ECM integrity, resulting in changes in mechanotransduction and increased metastasis; the secretion of molecules that increase resistance to targeted therapy; the uptake of macromolecules such as lipids by melanoma cells in the aged microenvironment, affecting tumor cell metabolism; changes in the aged immune tumor microenvironment and the secretion of non-canonical Wnt molecules that affect cell signaling leading to angiogenesis, metastasis, and therapy resistance. These changes drive tumor progression and affect response to therapy in the elderly. Our data suggest that patient age is an important factor in the response to therapy, which is not reflected in most preclinical studies and therapeutic approaches. Citation Format: Ashani Weeraratna. Age against the machine: How the aging tumor microenvironment governs tumor progression [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA017.
Racial disparities in efficacy of first-line abiraterone in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Mallika Marar, Qi Long, Ronac Mamtani, Vivek Narayan, Neha Vapiwala, Ravi Bharat Parikh
Journal: Journal of Clinical Oncology (2021)

20 Background: Prospective studies suggest that abiraterone (Abi) use in mCRPC is associated with improved progression-free survival in African-American (AA) patients (pts) compared to non-Hispanic White (NHW) pts. It is unclear whether racial disparities in Abi effectiveness exist for pts with mCRPC treated in real-world practice. Methods: In this retrospective cohort study, we used the nationwide Flatiron Health electronic health record-derived de-identified database to select pts who received first-line (1L) systemic therapy for mCRPC between January 1, 2012 and December 31, 2018. Propensity score-based inverse probability of treatment weighting (IPTW) was used to address confounding in Kaplan-Meier and Cox regression models of comparative effectiveness, using age, race, comorbidity index, prostate-specific antigen (PSA), baseline steroid or opioid use, insurance status, practice type, practice Abi prescribing rate, and practice region as covariates. The primary exposure was treatment with 1L Abi. Overall survival (OS) was the primary outcome, and time-to-next-treatment (TTNT), using Fine-Gray models with death as a competing risk, was the secondary outcome. Racial disparities between Abi vs. no Abi groups were explored with stratified analyses by race and race-treatment interaction terms. Results: Of 3808 pts, 1729 (45.4%) received 1L Abi, 1255 (33.0%) received 1L enzalutamide, and 549 (14.4%) received 1L docetaxel. The cohort included 2165 (68.7%) NHW and 404 (10.6%) AA pts. Pts receiving Abi were older (mean age 74 vs. 72) and more likely to be treated at academic centers (8% vs. 6%) than pts not receiving Abi. Among pts receiving Abi, AAs had improved OS compared to NHWs (Table). Compared to receipt of a non-Abi regimen, receipt of Abi was not associated with OS among AA pts but was associated with decreased OS among NHW pts. A significant race-by-treatment interaction for OS existed among patients receiving 1L Abi (interaction coeff = 0.27 95% CI = 0.02-0.53). There were no race-based disparities found in TTNT. Conclusions: In a large real-world analysis of pts who received 1L systemic therapy for mCRPC, AAs who received Abi had improved OS compared to NHWs – a finding consistent with ABI-RACE (NCT01940276). Among NHW pts, 1L Abi was associated with decreased OS. These real-world data suggest race-based differences in therapeutic response to Abi and future prospective evidence is needed to assess drivers of differential Abi efficacy in mCRPC. [Table: see text]
Abstract PR-02: Machine learning models to quantify lineage plasticity and neuroendocrine differentiation in high-grade prostate cancer
Authors: Beatrice Knudsen, Isla Garraway, Arkadiusz Gertych, Michael Lewis, Alessandro Ferrero, Ross Whitaker
Journal: Clinical Cancer Research (2021)

Abstract Neuroendocrine differentiation (NED) is a type of lineage plasticity that occurs in multiple cancer types either de-novo, or as a result of treatment-induced selection pressure. NED is identified by different, partially overlapping clinical, morphological and genomic features which include small cell neuroendocrine histomorphology, gene expression signatures of Rb1 loss and lethal tumor behavior. Through the eyes of pathologists, the most extreme form of NED is small cell, neuroendocrine carcinoma (SmCC), a rare cancer type that can arise in many organs. Adenocarcinomas, the most common cancer type in the adult population can harbor clinical and genomic characteristics of SmCC without recognizable morphologic features. Therefore, we determined whether machine learning algorithms can be trained to identify salient morphologic features of NED in adenocarcinoma. Using a cohort of prostate needle biopsies, we trained complementary algorithms to generate NED scores from high-grade prostate cancer regions and tested NED scores for correlation with gene expression and pathway activation from RNA sequencing of the exact same tumor regions. Using this approach as a validation strategy, we observed correlations between NED scores and pathway activation known to be increased in SmCC. In addition, we discovered novel morphologic features through functional interpretations of pathways correlated with NED scores. Finally, we used multi-variate regression analysis to demonstrate that computer generated NED scores predict the risk of lethal prostate cancer in diagnostic prostate needle biopsies. Altogether, we demonstrate the feasibility to quantify NED - lineage plasticity in regular diagnostic H&amp;E stained pathology slides, which can be developed into an impactful, point-of-care clinical assay for the management and treatment of prostate cancer patients. Citation Format: Beatrice Knudsen, Isla Garraway, Arkadiusz Gertych, Michael Lewis, Alessandro Ferrero, Ross Whitaker. Machine learning models to quantify lineage plasticity and neuroendocrine differentiation in high-grade prostate cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PR-02.
Heterologous arenavirus vector prime-boost overrules self-tolerance for efficient tumor-specific CD8 T cell attack
Authors: Weldy V. Bonilla, Nicole Kirchhammer, Anna-Friederike Marx, Sandra M. Kallert, Magdalena A. Krzyzaniak, Min Lu, Stéphanie Darbre, Sarah Schmidt, Josipa Raguz, Ursula Berka, Ilena Vincenti, Mindaugas Pauzuolis, Romy Kerber, Sabine Hoepner, Stephan Günther, Carsten Magnus, Doron Merkler, Klaus K. Orlinger, Alfred Zippelius, Daniel D. Pinschewer
Journal: Cell Reports Medicine (2021)

Therapeutic vaccination regimens inducing clinically effective tumor-specific CD8+ T lymphocyte (CTL) responses are an unmet medical need. We engineer two distantly related arenaviruses, Pichinde virus and lymphocytic choriomeningitis virus, for therapeutic cancer vaccination. In mice, life-replicating vector formats of these two viruses delivering a self-antigen in a heterologous prime-boost regimen induce tumor-specific CTL responses up to 50% of the circulating CD8 T cell pool. This CTL attack eliminates established solid tumors in a significant proportion of animals, accompanied by protection against tumor rechallenge. The magnitude of CTL responses is alarmin driven and requires combining two genealogically distantly related arenaviruses. Vector-neutralizing antibodies do not inhibit booster immunizations by the same vector or by closely related vectors. Rather, CTL immunodominance hierarchies favor vector backbone-targeted responses at the expense of self-reactive CTLs. These findings establish an arenavirus-based immunotherapy regimen that allows reshuffling of immunodominance hierarchies and breaking self-directed tolerance for efficient tumor control.
Abstract IA-10: Machine learning enabled analysis of high content imaging datasets: Progress and prospects
Authors: Mohammad Muneeb Sultan
Journal: Clinical Cancer Research (2021)

Abstract In the last decade deep learning has had a very large impact in the field of image analysis. In this talk, I will discuss several vignettes into how deep learning when applied to biomedical imaging datasets can provide us with insights that can further drug discovery campaigns and uncover new biological insights. In particular, I will show how deep learning can learn a phenotypic manifold that allows us to interrogate the dose response behavior of compounds, measure the phenotypic similarity of compounds, and deconvolute MOAs of new compounds. Citation Format: Mohammad Muneeb Sultan. Machine learning enabled analysis of high content imaging datasets: Progress and prospects [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr IA-10.
Is It Time to Reevaluate Radiotherapy Omission in Older Patients With Favorable Early-Stage Breast Cancer?
Authors: Mudit Chowdhary, Arpit M. Chhabra, Sachin R. Jhawar
Journal: JAMA Oncology (2021)

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