tbuckley/cabot-search huggingface dataset:
Distinct age-associated genomic profiles in acute myeloid leukemia (AML) using FoundationOne heme.
Authors: Katherine Tarlock, Jie He, Shan Zhong, Rhonda E Ries, Mark Bailey, Samantha Morley, Sohail Balasubramanian, Rachel Erlich, Doron Lipson, Geoff Otto, Jo-Anne Vergilio, Tariq I. Mughal, Jeffrey S. Ross, Phil Stephens, Marcel R. M. Van Den Brink, Ross L. Levine, Vincent A. Miller, Soheil Meshinchi
Journal: Journal of Clinical Oncology (2016)

7041 Background: AML is a heterogeneous disease with recurring genomic alterations that define specific disease biology and contribute to variable patient outcomes. New sequencing technologies enable comprehensive interrogation of the AML genome and transcriptome. To gain insight into age-associated variants in AML, we compared comprehensive genomic profiling (CGP) results from pediatric (Pd) and adult (Ad) patient (pt) samples. Methods: CGP was performed on 558 AML specimens (104 Pd (age < 18 years) and 454 Ad), using DNA and RNA integrated next-generation sequencing in a CLIA-certified, CAP-accredited, NYS-approved laboratory. All captured libraries were sequenced to high depth (Illumina HiSeq) averaging 496X for DNA (405 genes) and ~7M on-target unique pairs for RNA (265 genes), enabling sensitive and specific detection of substitutions, indels, copy number alterations and gene rearrangements. A 28-specimen subset was independently validated by orthogonal methodologies, with 100% verification of all clinically annotated variants. Results: Total mutation (mut) prevalence was 1828 muts in 181 genes in the Ad cohort (median age 63) vs. 342 muts in 100 genes in the Pd cohort (median age 9) (Wilcoxon rank sum P < 0.002). A clear age-associated profile, of distinct genomic make-up, was seen for young vs. older pts. Novel transcripts such as NSD1-NUP98, KDM5A-NUP98 and CBFA2T3-GLIS2 were identified in 21 pts, 16 in Pd. Fusions were markedly enriched in Pd vs Ad cohort (62% v. 34%, Fisher’s exact P <0.001). Mutations in epigenetic modifiers occurred almost exclusively in adults (DNMT3A (22%), IDH1/2 (21%) and TET2 (15%)). Mutations in ASXL1 (22%), SRSF2 (14%), and BCOR (9%) were also prevalent in adults, but rare in children. Conclusions: Clinical sequencing via CGP provides insight into the diverse and distinct genomic landscapes of pediatric and adult AML. Our findings inform AML biology, diagnosis, and risk stratification, as well as novel therapeutic approaches that may improve outcomes in clinical care of pts with AML. Gene Freq (Pd) Freq (Ad) P-value IDH1/2 2% 20% 1.99E-07 DNMT3A 2% 20% 3.29E-07 SRSF2 1% 14% 2.36E-05 KDM5A 6% 0% 3.72E-05 ASXL1 6% 21% 1.13E-04 BCOR 0% 8% 6.61E-04 TET2 4% 14% 2.54E-03
Combination versus sequential chemotherapy for metastatic breast cancer: An evaluation of outcomes from a community oncology network.
Authors: M. A. Neubauer, J. L. Espirito, M. Clayton, D. A. Patt
Journal: Journal of Clinical Oncology (2010)

6106 Background: There is wide variability in the treatment of metastatic breast cancer (MBC). Debate exists regarding the relative benefits of combination vs. sequential chemotherapy. Combination therapy may improve response rates, but its effect on overall survival (OS) is not clear. This study evaluated OS for MBC patients receiving combination vs. sequential therapy starting with second-line therapy. Methods: Using the iKnowMed electronic medical record database from the US Oncology network, patients with MBC who initiated second-line chemotherapy between July 2006 and July 2009 were included in this retrospective analysis. Combination therapy was allowed in all patients for first-line therapy only. Group A patients were treated with sequential single-agent chemotherapy (other than first-line). Group B patients received combination chemotherapy at any time beyond first-line. The primary endpoint was OS (from time of initiation of second-line chemotherapy to death). A documented date of death was required for inclusion. Patients with HER2-positive disease were excluded. Patients were characterized with respect to age, Karnofsky performance status, hormone receptor status, visceral vs. bone-only metastases, and lines of therapy. OS was compared using the Kaplan Meier method. Results: 263 patients were included. 135 patients received single-agent therapy (Group A) and 128 patients received combination therapy (Group B). There was a 1.1 month difference in median OS, which was not significant (6.5 months in Group A vs. 7.6 months in Group B; p = 0.1493; hazard ratio = 0.8356; 95% CI = 0.6550 to 1.0665). The groups were well balanced with respect to age, hormone receptor status, and types of metastases. Patients receiving combination therapy tended to have slightly higher performance status. Median number of lines of therapy for MBC was 3 (Group A) vs. 4 (Group B). Conclusions: These findings, incorporating real-world variability in the treatment of MBC, support the concept that combination chemotherapy beyond first-line does not significantly prolong survival compared to sequential monotherapy. Because MBC is incurable, OS, toxicities, and costs are important treatment considerations. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration US Oncology
Posttranscriptional Upregulation of p53 by Reactive Oxygen Species in Chronic Lymphocytic Leukemia
Authors: Jesvin Samuel, Sandrine Jayne, Yixiang Chen, Aneela Majid, Alice Wignall, Timothy Wormull, Hishyar Najeeb, Jin-Li Luo, George D.D. Jones, Salvador Macip, Martin J.S. Dyer
Journal: Cancer Research (2016)

Abstract Chronic lymphocytic leukemia (CLL) cells multiply and become more resistant to immunochemotherapy in “proliferation centers” within tissues, whereas apoptosis occurs in the periphery. Various models recapitulate these microenvironments in vitro, such as stimulation with CD154 and IL4. Using this system, we observed a 30- to 40-fold induction of wild-type p53 protein in 50 distinct human CLL specimens tested, without the induction of either cell-cycle arrest or apoptosis. In contrast, the mRNA levels for p53 did not increase, indicating that its elevation occurred posttranscriptionally. Mechanistic investigations revealed that under the conditions studied, p53 was phosphorylated on residues associated with p53 activation and increased half-life. However, p53 protein induced in this manner could transcriptionally activate only a subset of target genes. The addition of a DNA-damaging agent further upregulated p53 protein levels, which led to apoptosis. p53 induction relied on the increase in intracellular reactive oxygen species observed after CD154 and IL4 stimulation. We propose that chronic oxidative stress is a characteristic of the microenvironment in B-cell “proliferation centers” in CLL that are capable of elevating the basal expression of p53, but to levels below the threshold needed to induce arrest or apoptosis. Our findings suggest that reactivation of the full transcriptional activities of p53 in proliferating CLL cells may offer a possible therapeutic strategy. Cancer Res; 76(21); 6311–9. ©2016 AACR.
Abstract 4677: Control of androgen receptor function by the genomic action of the cochaperone Bag-1L
Authors: Laura Cato, Antje Neeb, Guillaume Adelmant, Scott Ficarro, Thomas Westerling, Jarrod A. Marto, Andrew C. Cato, Myles Brown
Journal: Cancer Research (2015)

Abstract The androgen receptor (AR) is an important determinant of normal and malignant prostate growth and its function is regulated by many factors, including molecular chaperones, cochaperones and coregulators. One such factor is the nuclear-resident cochaperone Bag-1L. Overexpression of Bag-1L and the amplification of its gene have been reported in the hormone-refractory and metastatic stages of prostate cancer and in androgen-independent prostate cancer cells. However the exact mechanism of Bag-1L-mediated regulation of AR action in prostate cancer remains unclear. Here we show that Bag-1L and AR directly interact with one another through two distinct domains in both proteins. While the N-terminus of Bag-1L binds to the AR BF-3 domain via a conserved GARRPR motif, the C-terminal Hsp70/Hsc70-binding domain (BAG) of Bag-1L binds to the tau5 region in the intrinsically disordered AR AF1. The latter interaction is of particular significance as tau5 is a region crucial for the ligand-independent transcriptional activity of the receptor. Understanding the details of this interaction will therefore provide new opportunities of controlling AR action for therapeutic purposes outside of targeting the LBD. We have identified the exact amino acids (K231, K232 and K279) in the BAG domain that are required for the interaction with AR. Amino acid substitution of these residues destroy the interaction of Bag-1L and AR but do not affect the binding to Hsp70/Hsc70. We also observed significant reduction in androgen-dependent cell growth when the BAG-domain mutant is overexpressed in prostate cancer cells in culture and in xenograft mouse models. We further tested the consequence of the BAG-domain mutation on AR transactivation by microarray analysis. We observed repressed expression of multiple genes, including the AR coactivator NCoA2. Correspondingly, we observed multiple changes in the Bag-1L interactome when comparing the wild-type with the BAG mutant; this includes the loss of interaction with the heat shock protein Hsp27 for the mutant Bag-1L protein. Combined these results demonstrate the importance of Bag-1L for AR function and the potential of this protein for therapeutic intervention in prostate cancer. Citation Format: Laura Cato, Antje Neeb, Guillaume Adelmant, Scott Ficarro, Thomas Westerling, Jarrod A. Marto, Andrew C. Cato, Myles Brown. Control of androgen receptor function by the genomic action of the cochaperone Bag-1L. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4677. doi:10.1158/1538-7445.AM2015-4677
What is the origin of dyspnoea in smokers without airway disease?
Authors: Enrico M. Clini, Bianca Beghé, Leonardo M. Fabbri
Journal: European Respiratory Journal (2016)

Dyspnoea is a symptom that affects quality of life, exercise intolerance and prognosis in various chronic conditions (figure 1). As a consequence of dyspnoea, approximately half of all patients with chronic obstructive pulmonary disease (COPD) report a significant degree of disability, losing one or more functions in daily life [1]. Quantification of dyspnoea is therefore essential, and can be achieved through specific instruments (scales and/or questionnaires) that define the intensity rate and relief following pharmacological and nonpharmacological therapies. Several measures pertaining to domains of sensory–perceptual experience (what breathing feels like), affective distress or symptom burden/impact are used [2]. A modified Barthel Index (a scale to assess an individual's general disability) was recently validated to quantify the extent to which functional abilities are limited by dyspnoea in chronic respiratory conditions, including COPD [3]. However, complex physiological mechanisms that generate dyspnoea in single categories of chronic illness are poorly understood. Exertional dyspnoea is a debilitating symptom of smokers; understanding its mechanisms might allow better treatments <http://ow.ly/sbQV3023L9A>
Do we need to fixate a fully covered esophageal metal stent?
Authors: Manon Spaander
Journal: Endoscopy (2016)

Self-expanding metal stents (SEMSs) have been used successfully in both malignant and benign esophageal disease. Esophageal stent placement for malignant disease aims to maintain oral intake and improve the quality of life for patients with malignant obstruction, malignant fistula, or extrinsic compression; while esophageal stent placement for benign upper gastrointestinal (UGI) diseases mainly includes the treatment of refractory benign esophageal strictures and the sealing of benign perforations, fistulas, or leaks [1] [2] [3].
Development of an efficient scoring system for detection of EGFR-T790M mutation in non-small cell lung cancer patients treated with EGFR-tyrosine kinase inhibitors.
Authors: Takahisa Kawamura, Hirotsugu Kenmotsu, Shota Omori, Kazuhisa Nakashima, Kazushige Wakuda, Akira Ono, Tateaki Naito, Haruyasu Murakami, Keita Mori, Yasuhisa Ohde, Masahiro Endo, Toshiaki Takahashi
Journal: Journal of Clinical Oncology (2016)

e20599 Background: Secondary T790M mutation of epidermal growth factor receptor (EGFR) accounts for approximately half of all cases of acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients. However, some third-generation EGFR-TKIs may be able to overcome T790M-mediated resistance. We aimed to develop a scoring method for efficient detection of T790M mutation to enable the effective use of these EGFR-TKIs. Methods: This study was retrospective observational in design. We screened patients with NSCLC harboring EGFR-activating mutations that had experienced disease progression and were rebiopsied between January 2014 and October 2015. We investigated factors associated with T790M status and developed a score based on a multivariate logistic regression model. We assigned scores (1–3 points) for selected factors, and evaluated detection rates of T790M mutation in each scoring group. Results: Among 66 rebiopsied patients in whom T790M status results were available, 26 (39%) had T790M mutations. Imbalanced factors between patients with and without T790M mutation revealed by univariate analysis were tumor staging (postoperative recurrence) (p = 0.01), total duration of treatment with EGFR-TKIs before rebiopsy (p = 0.02), and lesions for rebiopsy (extrathoracic lesions) (p = 0.01). Multivariate analysis confirmed that these three factors were also significantly related to T790M mutation (odds ratios: 5.1 [95%CI: 0.94–40.0], 5.6 [95%CI: 1.3–30.0] and 6.7 [1.2–56.0], respectively). Additionally, EGFR-TKI treatment prior to rebiopsy had a weak effect on T790M status. These four factors were assigned a score: +3, lesions (extrathoracic); +2, total EGFR-TKI duration ( ≥ 720 days); +2, staging (recurrence); and +1, treatment with EGFR-TKI prior to rebiopsy. This scoring system identified T790M in rebiopsy samples as follows: Score 0–1, 21% (8/39); Score 2–3, 64% (9/14); and ≥ Score 4, 81% (9/11). Conclusions: This study suggested that the scoring system can be efficient for detection of T790M mutation. Further clinical studies to evaluate this scoring system are warranted.
Drugs that put older people at risk for fractures are rarely stopped, study finds
Authors: Michael McCarthy
Journal: BMJ (2016)

Most elderly patients who fracture a hip, shoulder, or wrist are taking at least one drug that increases their risk of fracture before their injury, and most continue to take them after hospital discharge, a US study has found.1

Fractures are common in older people: a quarter of men and half of women aged over 50 experience a fracture. Hip fractures in particular are associated with considerable morbidity and mortality, as 44% of patients are readmitted to hospital and 21% die in the first year after the fracture.

In the new study published in JAMA Internal Medicine , Jeffrey …
Age-dependent elastin degradation is enhanced in chronic obstructive pulmonary disease
Authors: Jeffrey T.J. Huang, Charlotte E. Bolton, Bruce E. Miller, Ruth Tal-Singer, Roberto A. Rabinovich, Colin N.A. Palmer, Neil C. Thomson, William MacNee
Journal: European Respiratory Journal (2016)

Chronic obstructive pulmonary disease (COPD) is primarily a lung condition characterised by the presence of persistent airflow limitation resulting from inflammation, remodelling of small airways, and emphysema. It is well-recognised that the impacts of COPD extend beyond the lung with many patients suffering systemic manifestations such as cardiovascular diseases that affect morbidity and mortality [1]. "Accelerated ageing" has been proposed as a mechanism that underlies many of the pulmonary and extrapulmonary consequences of COPD [2, 3]. It is thought that a decline in organ function is a feature of ageing in response to the accumulation of cell and molecular damage, and in the case of COPD, noxious inhalants such as tobacco smoke increase this damage, thus accelerating the ageing process, leading to the development of COPD. With the exception of lung function decline, however, evidence indicating that tobacco smoking or COPD accelerates age-associated deterioration remains scarce. Elastin turnover increases with chronological age and COPD accelerates this process beyond normal ageing <http://ow.ly/7OhE301B9z9> The authors would like to thank Karolina Wrobel in the Biomarker and Drug Analysis Core Facility at University of Dundee, Dundee, UK for technical support.
구연 : 간성 뇌증 환자에서의 영양상태의 평가
Authors: 정지성, 손동균, 조돈현, 김형근, 이영석, 양진모, 조세현, 한준열, 박수헌, 김재광, 정규원, 선희식
Journal: Clinical and Molecular Hepatology (2003)

배경/목적: 간경변환자에서 단백질-칼로리 영양실조가 흔하며, 영양실조의 경우 면역력이 저하되어 감염의 위험성이 높아지며, 또한 예후도 나쁜 것으로 알려져 있다. 현증 간성뇌증 환자의 경우, 단백질 제한이 필수적이지만, 장기간 단백질 제한을 하는 경우 영양실조가 악화될 뿐아니라 예후에도 악영향을 미칠 수 있을 것이다. 영양상태의 평가 지표로서 여러 가지가 알려져 있다. 간성뇌증 환자의 영양상태 평가에 중요한 지표를 알아보기 위하여 본 연구를 시행하였다. 대상과 방법: 만성간질환 환자 79 명을 대상으로 하였다. 만성 간염 환자 28명을 제1군, 식도정맥류나 복수 등의 간경변증의 합병증의 기왕력이나 현증이 있지만 간성뇌증의 기왕력이 없는 환자 27명을 제 2군, 현증 간성 뇌증이나 기왕력이 있는 환자 24명을 제3군으로 분류하여 비교분석하였다. 환자의 영양상태 분석을 위하여 lymphocyte수, 혈청 알부민치 등의 임상검사 결과를 비교하였고, 냉동보관된 혈청을 이용하여 Insulin-like growth factor-I (IGF-I), 성장 호르몬(growth hormone: GH)과 retinol binding protein (RBP)를 측정하여 비교분석하였고, 예후에 대한 의의를 알아보기 위하여 MELD score를 비교하였다. 결과: 1) 총 lymphocyte 수는 1군 1956±658 (×106/L), 2군 1800±797(×10(6)/L), 3군 1256±704(×10(6)/L) (P＜0.001)로 세군간에 의미 있게 감소하였고, albumin은 1군이 3.61±0.58 g/dL, 2군이 3.11±0.68 g/dL,3군이 2.63±0.53 g/dL으로 세 군간에 의미 있는 감소를 보였다.(P＜0.001) 2) retinol binding protein은 1군에서 40.5±31.93 mg/ml, 2군에서 41.4±65.59 mg/mL, 3군에서 41.84±53.75 mg/mL로 세 군에서 차이가 없었다.(P＝0.99) 3) 1군 환자 28명의 IGF-1치는 128.1±49.9 ng/mL, 2군은 70.9±37.8 ng/mL, 3군은 40.2±22.8 ng/mL이었고,성장 호르몬은 1군이 67.8±3.1 ng/mL, 2군이 158.8±7.2 ng/mL, 3군이 126.1±5.7 ng/mL로, IGF-1치는 세 군 환자에서 의미있게 감소하였으며 (P＜0.001) 성장 호르몬은 2군 환자가 1군 환자와 비교하여 의미있게 증가하였으나(P＜0.001) 2군과 3군 환자에서는 차이가 없었다 (p＝0.77) 3) MELD scale은 1군이 6(-2-16), 2군이 12(-5-35), 3군이 17 (-14-48)이었다. 이상을 요약하면, 간성 뇌증 환자에서 간성 뇌증의 기왕력이 없는 환자보다 lymphocyte수와 혈청 알부민치와 IGF-I이 감소되어 있었다. 결론: Lymphocyte수와 혈청 알부민치와 IGF-I level이 간성 뇌증 환자의 영양상태를 반영하는 지표인 것으로 판단되었으며, 향후 간성뇌증 환자의 영양공급과 영양상태의 개선을 반영할 수 있는 지표에 대한 연구가 이루어져야 할 것으로 생각되었다.
Where to Draw the Boundaries for Prenatal Carrier Screening
Authors: Wayne W. Grody
Journal: JAMA (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Safety and Efficacy of Abexinostat, a Pan-Histone Deacetylase (HDAC) Inhibitor, in Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Results of an Ongoing Phase 2 Study
Authors: Vincent Ribrag, Won Seog Kim, Reda Bouabdallah, Soon Thye Lim, Bertrand Coiffier, Zakia Felloussi, Ioana Kloos, Ying Luan, Thorsten Graef, Franck Morschhauser
Journal: Blood (2015)
Biomarkers Predictive of Exacerbations in the SPIROMICS and COPDGene Cohorts
Authors: Jason D. Keene, Sean Jacobson, Katerina Kechris, Gregory L. Kinney, Marilyn G. Foreman, Claire M. Doerschuk, Barry J. Make, Jeffrey L. Curtis, Stephen I. Rennard, R. Graham Barr, Eugene R. Bleecker, Richard E. Kanner, Eric C. Kleerup, Nadia N. Hansel, Prescott G. Woodruff, MeiLan K. Han, Robert Paine, Fernando J. Martinez, Russell P. Bowler, Wanda K. O’Neal
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Rationale: Chronic obstructive pulmonary disease exacerbations are associated with disease progression, higher healthcare cost, and increased mortality. Published predictors of future exacerbations include previous exacerbation, airflow obstruction, poor overall health, home oxygen use, and gastroesophageal reflux.Objectives: To determine the value of adding blood biomarkers to clinical variables to predict exacerbations.Methods: Subjects from the SPIROMICS (Subpopulations and Intermediate Outcomes Measures in COPD Study) (n = 1,544) and COPDGene (Genetic Epidemiology of COPD) (n = 602) cohorts had 90 plasma or serum candidate proteins measured on study entry using Myriad-RBM multiplex panels. We defined total exacerbations as subject-reported worsening in respiratory health requiring therapy with corticosteroids and/or antibiotics, and severe exacerbations as those leading to hospitalizations or emergency room visits. We assessed retrospective exacerbations during the 12 months before enrollment and then documented prospective exacerbations in each cohort. Exacerbations were modeled for biomarker associations with negative binomial regression including clinical covariates (age, sex, percent predicted FEV1, self-reported gastroesophageal reflux, St. George's Respiratory Questionnaire score, smoking status). We used the Stouffer-Liptak test to combine P values for metaanalysis.Measurements and Main Results: Between the two cohorts, 3,471 total exacerbations (1,044 severe) were reported. We identified biomarkers within each cohort that were significantly associated with a history of exacerbation and with a future exacerbation, but there was minimal replication between the cohorts. Although established clinical features were predictive of exacerbations, of the blood biomarkers only decorin and α2-macroglobulin increased predictive value for future severe exacerbations.Conclusions: Blood biomarkers were significantly associated with the occurrence of exacerbations but were not robust between cohorts and added little to the predictive value of clinical covariates for exacerbations.
Direct in Vivo Evidence of Increased Chronic Lymphocytic Leukemia Cell Proliferation in Lymph Nodes Compared to Bone Marrow and Peripheral Blood
Authors: Thomas M. Herndon, Shih-Shih Chen, Michelle Gatmaitan, Claire Emson, Janet Valdez, Nakhle Saba, Nicholas Chiorazzi, Adrian Wiestner
Journal: Blood (2012)