tbuckley/cabot-search huggingface dataset:
Mendelian Randomization Study of <i>ACLY</i> and Cardiovascular Disease
Authors: Hilma Hólm, Patrick Sulem, Anna Helgadóttir, Vinicius Tragante, Guðmar Þorleifsson, Daníel Guðbjartsson, Kári Stefánsson
Journal: New England Journal of Medicine (2020)

Mendelian Randomization Study of ACLY and Cardiovascular DiseaseTo the Editor: Ference et al. (March 14, 2019, issue) 1 tested the association of plasma low-density lipoprotein (LDL) cholesterol and cardiovascular disease with genetic variants in a 1-millionbase span around the gene encoding ATP citrate lyase (ACLY) and concluded that human genetics validates ACLY as a therapeutic target for cardiovascular disease.Compelling support for this assertion requires that the utilized genetic variants capture inborn variability in the activity of ACLY. 2 However, none of the variants were shown by Ference et al. to affect the quantity or quality of the ACLY gene product.Support for the authors' assertion also requires that the genetic variants reproducibly associate with the exposure (LDL cholesterol). 3Among 99,154 participants in the Veterans Affairs Million Veteran Program, 4 we found that only one of the nine variants was associated with LDL cholesterol levels (see the figure in the Supplementary Appendix, available with the full text of this letter at NEJM.org).Given that the other genetic variants were not associated with LDL cholesterol levels, it is not surprising that we found no association of an aggregate score of these nine variants with coronary heart disease in an independent set of 87,644 case patients with coronary heart disease and 94,463 controls without such disease.This null result for ACLY is in stark contrast to the score of seven variants at the gene encoding proprotein convertase subtilisin-kexin type 9 (PCSK9) reported by Ference et al.Our human genetics findings do not add support to ACLY as a therapeutic target for cardiovascular disease.
The Outcome of Patients with High Risk MDS Achieving Stable Disease after Treatment with 5- Azacitidine. A Retrospective Analysis of the Hellenic (Greek) Mds Study Group
Authors: Sotirios Papageorgiou, Christos K. Kontos, Thomas Tsiambalis, Athina Vyniou, Argiris Symeonidis, Athanasios Galanopoulos, Ioannis Kotsianidis, Vassiliki Pappa
Journal: Blood (2017)
Advances in diagnosis, classification, pathophysiology, and management of trigeminal neuralgia
Authors: Lars Bendtsen, Joanna Maria Zakrzewska, Tone Bruvik Heinskou, Mojgan Hodaie, Paulo Roberto Lacerda Leal, Turo Nurmikko, Mark Obermann, Giorgio Cruccu, Stine Maarbjerg
Journal: The Lancet Neurology (2020)
Are Nonsynonymous Transversions Generally More Deleterious than Nonsynonymous Transitions?
Authors: Zhengting Zou, Jianzhi Zhang
Journal: Molecular Biology and Evolution (2020)

It has been suggested that, due to the structure of the genetic code, nonsynonymous transitions are less likely than transversions to cause radical changes in amino acid physicochemical properties so are on average less deleterious. This view was supported by some but not all mutagenesis experiments. Because laboratory measures of fitness effects have limited sensitivities and relative frequencies of different mutations in mutagenesis studies may not match those in nature, we here revisit this issue using comparative genomics. We extend the standard codon model of sequence evolution by adding the parameter η that quantifies the ratio of the fixation probability of transitional nonsynonymous mutations to that of transversional nonsynonymous mutations. We then estimate η from the concatenated alignment of all protein-coding DNA sequences of two closely related genomes. Surprisingly, η ranges from 0.13 to 2.0 across 90 species pairs sampled from the tree of life, with 51 incidences of η < 1 and 30 incidences of η >1 that are statistically significant. Hence, whether nonsynonymous transversions are overall more deleterious than nonsynonymous transitions is species-dependent. Because the corresponding groups of amino acid replacements differ between nonsynonymous transitions and transversions, η is influenced by the relative exchangeabilities of amino acid pairs. Indeed, an extensive search reveals that the large variation in η is primarily explainable by the recently reported among-species disparity in amino acid exchangeabilities. These findings demonstrate that genome-wide nucleotide substitution patterns in coding sequences have species-specific features and are more variable among evolutionary lineages than are currently thought.
Children’s Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia
Authors: Kimberly P. Dunsmore, Stuart S. Winter, Meenakshi Devidas, Brent L. Wood, Natia Esiashvili, Zhiguo Chen, Nancy Eisenberg, Nikki Briegel, Robert J. Hayashi, Julie M. Gastier-Foster, Andrew J. Carroll, Nyla A. Heerema, Barbara L. Asselin, Karen R. Rabin, Patrick A. Zweidler-Mckay, Elizabeth A. Raetz, Mignon L. Loh, Kirk R. Schultz, Naomi J. Winick, William L. Carroll, Stephen P. Hunger
Journal: Journal of Clinical Oncology (2020)

Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease.From 2007 to 2014, Children's Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/μL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation.The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively (P = .029). Differences between DFS in a four-arm comparison were significant (P = .01), with no interactions between the MTX and nelarabine randomizations (P = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% v 6.9% ± 1.4%, respectively; P = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms.The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.
Estrogen-induced mammary cancer in ACI rats: Role of cytochrome P450s.
Authors: Harini Aiyer, Ramesh Gupta
Journal: Cancer Research (2007)

1648  Estrogen metabolism plays an important role in breast cancer causation. Several cytochrome P450 enzymes are involved in the Phase I metabolism of 17β-estradiol. Of these, the primary extra-hepatic enzymes are CYP1A1 and CYP1B1. Polymorphisms associated with both genes are known to affect breast cancer risk. CYP1B1 predominantly converts estradiol to a 4-hydroxy metabolite. However, recent data suggest that CYP1A1 can also convert estradiol to 4-hydroxy metabolite, in addition to 2-hydroxylation (Cribb AE et al., 2006). We postulate that CYP1A1 may play an important role in estrogen-induced rat mammary tumorigenesis. Female ACI rats (10-week old) were treated with 3-cm silastic implants containing 27 mg 17s-estradiol and were euthanized at 6, 12, 18 and 24 weeks after treatment. This treatment is known to produce mammary tumors in almost 100% of the animals at 24 weeks. The mRNA expression of both CYP1A1 and CYP1B1 was analyzed using quantitative real-time PCR in the mammary tissue of sham- and estrogen-treated rats. The mean fold change for each gene at the four intervals was measured in separate assays. Significant overexpression (51-fold average) of CYP1A1 was found as early as 6 weeks of treatment. The CYP1A1 elevation was maintained subsequently albeit at progressively lower levels (16-, 14- and 7-fold at 12, 18 and 24 weeks, respectively). Conversely, CYP1B1 was under expressed after estrogen treatment at all time points, i.e., 2-, 6-, 8- and 10-fold down regulated at 6, 12, 18 and 24 weeks, respectively. Upon supplementation of diet with black raspberries and blueberries (2.5%, w/w), which significantly diminish estrogen-mediated mammary tumorigenesis in this model, CYP1A1 overexpression was much less pronounced (
Abstract 6448: Oral cancer pain mediators released in exosomes are oncogenes with potential to shape the microenvironment and induce neuronal sensitivity
Authors: Aditi Bhattacharya, Zinaida Dubeykoskaya, Huu Tu Nguyen, Igor Dolgalev, Ratna Veeramachaneni, Brian L. Schmidt, Donna G. Albertson
Journal: Cancer Research (2020)

Abstract Oral cancer patients suffer severe chronic and mechanically-induced pain at the site of the cancer. Patients with metastatic (N+) cancers report greater pain. Cancer pain is attributed to cancer-derived mediators that sensitize neurons and is associated with increased neuronal density. To identify cancer derived mediators of pain and metastasis, we queried an RNA-seq dataset of 19 cancers and 5 normal tissues for genes overexpressed in N+ cancers from patients who reported high pain on the UCSF Oral Cancer Pain Questionnaire (UCSFOCPQ). The 40 candidate pain mediator genes are enriched for functions in extracellular matrix organization and angiogenesis, and are reported to have oncogenic and neuronal functions. Differentially expressed genes encoding neurotrophic and axon guidance molecules were also identified. The pain and metastasis genes encode secreted or membrane proteins. Most of the pain and metastasis genes have been reported in exosomes. A role for exosomes in induction of cancer pain was demonstrated using a mouse paw withdrawal assay. Intraplantar injection of HSC-3 oral tongue cancer cell line conditioned media induced mechanical allodynia and thermal hyperalgesia. By contrast, when conditioned medium depleted of exosomes and extracellular vesicles (EVs) by size exclusion chromatography was injected into the paw, nociceptive behavioral responses to mechanical or thermal stimuli were reduced or abolished, respectively. Nociceptive responses to these stimuli were restored by reconstitution of the EV depleted media with the EV fraction. In conclusion, functional analysis of genes overexpressed in painful N+ cancers highlighted the composition of the N+ oral cancer microenvironment for promotion of angiogenesis and axonogenesis. Preclinical studies implicated cancer-derived exosomes in induction of pain. The autocrine and paracrine actions of identified pain and metastasis genes, as well as communication via exosomes, are potential therapeutic targets for stopping cancer and alleviating pain. Citation Format: Aditi Bhattacharya, Zinaida Dubeykoskaya, Huu Tu Nguyen, Igor Dolgalev, Ratna Veeramachaneni, Brian L. Schmidt, Donna G. Albertson. Oral cancer pain mediators released in exosomes are oncogenes with potential to shape the microenvironment and induce neuronal sensitivity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6448.
Immune Activation in Patients with Locally Advanced Cervical Cancer Treated with Ipilimumab Following Definitive Chemoradiation (GOG-9929)
Authors: Diane M. Da Silva, Danielle M. Enserro, Jyoti S. Mayadev, Joseph G. Skeate, Koji Matsuo, Huyen Q. Pham, Heather A. Lankes, Katherine M. Moxley, Sharad A. Ghamande, Yvonne G. Lin, Russell J. Schilder, Michael J. Birrer, W. Martin Kast
Journal: Clinical Cancer Research (2020)

Abstract Purpose: A phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune-modulation therapy with the checkpoint inhibitor ipilimumab [anti–CTL antigen-4 (anti–CTLA-4)] following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunologic and viral correlates were assessed before, during, and after treatment. Patients and Methods: Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints. Circulating T-cell subsets were evaluated by multiparameter flow cytometry. Cytokines were evaluated by multiplex ELISA. HPV-specific T cells were evaluated in a subset of patients by IFNγ ELISpot. Results: Expression of the activation markers ICOS and PD-1 significantly increased on T-cell subsets following CRT and were sustained or increased following ipilimumab treatment. Combined CRT/ipilimumab treatment resulted in a significant expansion of both central and effector memory T-cell populations. Genotype-specific E6/E7-specific T-cell responses increased post-CRT in 1 of 8 HPV16+ patients and in 2 of 3 HPV18+ patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL6, IL8) post-CRT was significantly associated with worse progression-free survival. Conclusions: Our data indicate that CRT alone and combined with ipilimumab immunotherapy show immune-modulating activity in women with locally advanced cervical cancer and may be a promising therapeutic option for the enhancement of antitumor immune cell function after primary CRT for this population at high risk for recurrence and metastasis. Several key immune biomarkers were identified that were associated with clinical response.
Systemic juvenile xanthogranuloma has a higher frequency of ALK translocations than BRAFV600E mutations
Authors: Jiaosheng Xu, Xin Huang, Yang Wen, Zenggang Pan, Hongyun Lian, Mutong Zhao, Min Li, Zejun Duan, Yanping Zhang, Gaolei Zhang, Xueling Qi, Jianping Tang, Zigang Xu, Zifen Gao, Libing Fu, Lin Ma
Journal: Journal of the American Academy of Dermatology (2020)
Low‐molecular mimetics of nerve growth factor and brain‐derived neurotrophic factor: Design and pharmacological properties
Authors: Tatiana A. Gudasheva, Polina Y. Povarnina, Aleksey V. Tarasiuk, Sergey B. Seredenin
Journal: Medicinal Research Reviews (2020)

To overcome the limitations of the clinical use of neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), scientists have been trying to create their low-molecular-weight mimetics having improved pharmacokinetic properties and lacking side effects of full-sized proteins since the 90s of the last century. The efforts of various research groups have led to the production of peptide and nonpeptide mimetics, being agonists or modulators of the corresponding Trk or p75 receptors that reproduced the therapeutic effects of full-sized proteins. This review discusses different strategies and approaches to the design of such compounds. The relationship between the structure of the mimetics obtained and their action mechanisms and pharmacological properties are analyzed. Special attention is paid to the dipeptide mimetics of individual NGF and BDNF loops having different patterns of activation of Trk receptors signal transduction pathways, phosphoinositide 3-kinase/protein kinase B and mitogen-activated protein kinase/extracellular signal-regulated kinase, which allowed to evaluate the contribution of each pathway to different pharmacological effects. In conclusion, data on therapeutically promising compounds being at different stages of preclinical and clinical studies are summarized.
TSPO PET With 18F-GE-180 to Differentiate Variants of Multiple Sclerosis
Authors: Stefanie Völk, Marcus Unterrainer, Nathalie L. Albert, Joachim Havla, Lisa Ann Gerdes, Minh Schumacher, Matthias Brendel, Lena Kaiser, Kristina Adorjan, Rainer Rupprecht, Peter Bartenstein, Tania Kümpfel, Adrian Danek
Journal: Clinical Nuclear Medicine (2020)

Abstract PET targeting the translocator protein (TSPO) expression is an interesting approach to detect neuroinflammation, as TSPO is upregulated in activated macrophages and microglia. Considering the variable pathophysiology of multiple sclerosis (MS) variants, we compare TSPO PET using 18 F-GE-180 in 3 different demyelinating diseases of the central nervous system: relapsing-remitting MS, tumefactive MS, and Baló’s concentric sclerosis. Visualization of neuroinflammation and its PET patterns in addition to MRI may contribute to accurate distinction and monitoring of central nervous system demyelination.
Depression and Anxiety Are Common Among Patients With Cirrhosis
Authors: Ruben Hernaez, Jennifer R. Kramer, Aisha Khan, Jessica Phillips, Katharine McCallister, Kassie Chaffin, Adriana Portela Hernandez, Hannah Fullington, Cynthia Ortiz, James-Michael Blackwell, Adam Loewen, Yan Liu, Jasmin A. Tiro, Simon C. Lee, Amit G. Singal
Journal: Clinical Gastroenterology and Hepatology (2020)
Using Latent Class Analysis to Identify Hidden Clinical Phenotypes
Authors: Makoto Mori, Harlan M. Krumholz, Heather G. Allore
Journal: JAMA (2020)

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Is cost effective
Authors: G E Mead, A D Parry, P A O'Neill, C N Mccollum
Journal: BMJ (1995)

EDITOR,—Roger N Baird and Mark Lambert are correct in stating that prevention of stroke is an important public health issue.1 There is now good evidence that treating hypertension in older patients, giving anticoagulants to patients with atrial fibrillation, and prescribing aspirin to patients with minor ischaemic stroke and transient ischaemic attacks reduces rates of stroke and costs. Lambert suggests, however, that only 154 strokes are preventable by carotid surgery among the 20500 patients presenting to their …
Abstract 14682: Age, Hypertension, and Exercise Capacity Are Independently Associated With Likelihood of Multi-Vessel Disease in Patients Referred for Exercise Testing
Authors: Maria C Arcineagas Calle, Amanda R Bonikowske, Husam Salah, Christopher G Scott, Hector R Villarraga
Journal: Circulation (2018)

Introduction: Treadmill exercise test (TMET) is a widely used diagnostic tool for CAD. A positive TMET, especially in asymptomatic patients, presents a dilemma in decision-making. Hypothesis: We as...
De novo prediction of cancer-associated T cell receptors for noninvasive cancer detection
Authors: Daria Beshnova, Jianfeng Ye, Oreoluwa Onabolu, Benjamin Moon, Wenxin Zheng, Yang-Xin Fu, James Brugarolas, Jayanthi Lea, Bo Li
Journal: Science Translational Medicine (2020)

A cancer evaluation criterion based on T cell receptors is potentially useful for noninvasive early cancer detection.
DNA methylation profile of a hepatosplenic gamma/delta T-cell lymphoma patient associated with response to interferon-α therapy
Authors: Jaydeep Bhat, Anke K. Bergmann, Silvio Waschina, Christoph Nerl, Christoph Kaleta, Reiner Siebert, Ole Ammerpohl, Dieter Kabelitz
Journal: Cellular and Molecular Immunology (2020)
Mobilizing Carbon Dioxide Stores. An Experimental Study
Authors: Lorenzo Giosa, Mattia Busana, Matteo Bonifazi, Federica Romitti, Francesco Vassalli, Iacopo Pasticci, Matteo Maria Macrì, Rosanna D’Albo, Francesca Collino, Alessandro Gatta, Maria Michela Palumbo, Peter Herrmann, Onnen Moerer, Gaetano Iapichino, Konrad Meissner, Michael Quintel, Luciano Gattinoni
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Understanding the physiology of CO2 stores mobilization is a prerequisite for intermittent extracorporeal CO2 removal (ECCO2R) in patients with chronic hypercapnia.Objectives: To describe the dynamics of CO2 stores.Methods: Fifteen pigs (61.7 ± 4.3 kg) were randomized to 48 hours of hyperventilation (group "Hyper," n = 4); 48 hours of hypoventilation (group "Hypo," n = 4); 24 hours of hypoventilation plus 24 hours of normoventilation (group "Hypo-Baseline," n = 4); or 24 hours of hypoventilation plus 24 hours of hypoventilation plus ECCO2R (group "Hypo-ECCO2R," n = 3). Forty-eight hours after randomization, the current [Formula: see text]e was reduced by 50% in every pig.Measurements and Main Results: We evaluated [Formula: see text]co2, [Formula: see text]o2, and metabolic [Formula: see text]co2 ([Formula: see text]o2 times the metabolic respiratory quotient). Changes in the CO2 stores were calculated as [Formula: see text]co2 - metabolic V̇co2. After 48 hours, the CO2 stores decreased by 0.77 ± 0.17 l kg-1 in group Hyper and increased by 0.32 ± 0.27 l kg-1 in group Hypo (P = 0.030). In group Hypo-Baseline, they increased by 0.08 ± 0.19 l kg-1, whereas in group Hypo-ECCO2R, they decreased by 0.32 ± 0.24 l kg-1 (P = 0.197). In the second 24-hour period, in groups Hypo-Baseline and Hypo-ECCO2R, the CO2 stores decreased by 0.15 ± 0.09 l kg-1 and 0.51 ± 0.06 l kg-1, respectively (P = 0.002). At the end of the experiment, the 50% reduction of [Formula: see text]e caused a PaCO2 rise of 9.3 ± 1.1, 32.0 ± 5.0, 16.9 ± 1.2, and 11.7 ± 2.0 mm Hg h-1 in groups Hyper, Hypo, Hypo-Baseline, and Hypo-ECCO2R, respectively (P < 0.001). The PaCO2 rise was inversely related to the previous CO2 stores mobilization (P < 0.001).Conclusions: CO2 from body stores can be mobilized over 48 hours without reaching a steady state. This provides a physiological rationale for intermittent ECCO2R in patients with chronic hypercapnia.