tbuckley/cabot-search huggingface dataset:
Identification of novel fumarate hydratase gene alterations in prostate cancer.
Authors: Sherri Z. Millis, Sydney Marsh, Cristina Pecci, Sai-Sridhar Boddupalli, Jeffrey S. Ross, Phil Stephens, Vincent A. Miller, Siraj Mahamed Ali, Jue Wang
Journal: Journal of Clinical Oncology (2017)

11585 Background: Fumarate hydratase (FH), an enzyme involved in the Krebs cycle, plays a crucial role in the generation of energy and oxygenation of cells. Genomic alterations (GAs) of FH, a tumor suppressor gene, have been shown to cause chronic hypoxia that encourages tumor formation and have been linked to hereditary leiomyomatosis and renal cell cancer. Only few reports have associated FH mutations with other cancers, and none in prostate cancer. Methods: Identification of an FH V435M pathogenic alteration, which likely changes fumarate binding kinetics, in a prostate cancer patient, with negative family history for renal cancer and cutaneous leiomyomatosis, led to review of a database of 1781 prostate cancer patients, whose tissue was assayed by hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA: base substitutions, indels, amplifications, copy number alterations, fusions/rearrangements) and targeted therapy opportunities. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb sequenced DNA and reported as mutations/Mb. Results: Profiling identified 49 prostate adenocarcinoma patients (3%) with FH gene alterations, 2 of which harbored the V435M GA identified in the original prostate patient. Ten of 40 alterations were H476_k477 insertions, in the C terminus domain, and 14 were amplifications. The rest were variants of unknown significance (VUS). Conclusions: A FH GA, known to impact other cancers, found in a prostate cancer, led to the discovery of a frequency that suggests deregulation of metabolic pathway activation may contribute to prostate cancer pathogenesis for a subset of patients. The somatic FH GA’s are likely to be substantially more common than germline mutations, and identifying metabolic-enzyme mutations that are pathogenic in prostate cancer could lead to pharmacologic manipulations that are more effective and less toxic than existing therapies. No FDA approved therapies currently exist for this patient’s tumor type nor of any other tumor type with FH GA’s. In our case, alterations in the C-terminal binding domain of FH might inform drug development.
European LeukemiaNet study on the reproducibility of bone marrow features in masked polycythemia vera and differentiation from essential thrombocythemia
Authors: Hans Michael Kvasnicka, Attilio Orazi, Juergen Thiele, Giovanni Barosi, Carlos E. Bueso‐Ramos, Alessandro M. Vannucchi, Robert P. Hasserjian, Jean‐Jacques Kiladjian, Umberto Gianelli, Richard Silver, Tariq I. Mughal, Tiziano Barbui
Journal: American Journal of Hematology (2017)

The purpose of the study was to assess consensus and interobserver agreement among an international panel of six hematopathologists regarding characterization and reproducibility of bone marrow (BM) histologic features used to diagnose early stage myeloproliferative neoplasms, in particular differentiation of so-called masked/prodromal polycythemia vera (mPV) from JAK2-mutated essential thrombocythemia (ET). The six members of the hematopathology panel evaluated 98 BM specimens independently and in a blinded fashion without knowledge of clinical data. The specimens included 48 cases of mPV according to the originally published hemoglobin threshold values for this entity (male: 16.0-18.4 g/dL, female: 15.0-16.4 g/dL), 31 cases with overt PV according to the updated 2016 WHO criteria, and 19 control cases. The latter group included cases of JAK2-mutated ET, primary myelofibrosis, myelodysplastic syndrome, and various reactive conditions. Inter-rater agreement between the panelists was very high (overall agreement 92.6%, kappa 0.812), particularly with respect to separating mPV from ET. Virtually all cases of mPV were correctly classified as PV according to their BM morphology. In conclusion, a central blinded review of histology slides by six hematopathologists demonstrated that highly reproducible specific histological pattern characterize PV and confirmed the notion that there are no significant differences between mPV and overt PV in relation to BM morphology.
Sym015: A Highly Efficacious Antibody Mixture against <i>MET</i>-Amplified Tumors
Authors: Thomas Tuxen Poulsen, Michael Monrad Grandal, Niels Jørgen Østergaard Skartved, Rikke Hald, Lene Alifrangis, Klaus Koefoed, Trine Lindsted, Camilla Fröhlich, Sofie Ellebæk Pollmann, Karsten Wessel Eriksen, Anna Dahlman, Helle Jane Jacobsen, Thomas Bouquin, Mikkel Wandahl Pedersen, Ivan David Horak, Johan Lantto, Michael Kragh
Journal: Clinical Cancer Research (2017)

Purpose: Activation of the receptor tyrosine kinase MET is associated with poor clinical outcome in certain cancers. To target MET more effectively, we developed an antagonistic antibody mixture, Sym015, consisting of two humanized mAbs directed against nonoverlapping epitopes of MET.Experimental Design/Results: We screened a large panel of well-annotated human cancer cell lines and identified a subset with highly elevated MET expression. In particular, cell lines of lung cancer and gastric cancer origin demonstrated high MET expression and activation, and Sym015 triggered degradation of MET and significantly inhibited growth of these cell lines. Next, we tested Sym015 in patient- and cell line-derived xenograft models with high MET expression and/or MET exon 14 skipping alterations, and in models harboring MET amplification as a mechanism of resistance to EGFR-targeting agents. Sym015 effectively inhibited tumor growth in all these models and was superior to an analogue of emibetuzumab, a monoclonal IgG4 antibody against MET currently in clinical development. Sym015 also induced antibody-dependent cellular cytotoxicity (ADCC) in vitro, suggesting that secondary effector functions contribute to the efficacy of Sym015.Retrospectively, all responsive, high MET-expressing models were scored as highly MET-amplified by in situ hybridization, pointing to MET amplification as a predictive biomarker for efficacy. Preclinical toxicology studies in monkeys showed that Sym015 was well tolerated, with a pharmacokinetic profile supporting administration of Sym015 every second or third week in humans.Conclusions: The preclinical efficacy and safety data provide a clear rationale for the ongoing clinical studies of Sym015 in patients with MET-amplified tumors. Clin Cancer Res; 23(19); 5923-35. ©2017 AACR.
Differential Gene Expression of Clinically Resected Colorectal Cancer and Flow Cytometrically Sorted Tumour Cells
Authors: MJ Smith, B Barry, MA Kelly, A Culhane, JH Wang, TG Cotter, HP Redmond
Journal: Endoscopy (2006)

Aims: Datasets generated from microarray experiments are used to infer molecular change during tumour progression, and to develop classifiers which predict cancer outcomes. We aimed to assess the effect of cell population heterogeneity in whole tumour biopsies on the gene expression profile of colorectal cancer.
Determinants of fatigue improvement in outpatient oncology according to baseline categories of fatigue severity.
Authors: Michael Fisch, Fengmin Zhao, Ann M. O'Mara, Xin Shelley Wang, David Cella, Charles S. Cleeland
Journal: Journal of Clinical Oncology (2012)

9112 Background: Understanding the determinants of fatigue response may help distinguish between different fatigue phenotypes and inform trial designs. Methods: Patients with invasive cancer of the breast, prostate, colon/rectum, or lung were enrolled from multiple sites. At baseline and 4-5 weeks later patients rated their symptoms on a 0-10 numerical rating scale. A 2-point change was considered clinically significant for fatigue change. Logistic regression models and ordinal logistic regression models were used to examine the effects of demographic and clinical factors on fatigue change. Separate models were constructed for fatigue deterioration in patients with mild fatigue at baseline and lack of improvement for those with severe fatigue at baseline or any significant change for those with moderate baseline fatigue. Results: 3,106 pts were enrolled at baseline and 3,032 were analyzable for fatigue change. At baseline, 23% had no fatigue, 35% mild, 25% moderate, and 17% severe. Improvement varied by baseline fatigue score with response in 54% with severe fatigue, 31% with moderate, and 9% with mild. Overall, 13 different parameters were significant in these 3 models of fatigue change, but no single parameter was common to all 3 categories of fatigue. Exposure to anxiolytics and duration of current treatment were significant in models of mild and severe fatigue; antidepressant exposure was significant for mild and moderate fatigue, and baseline fatigue level was a significant parameter in moderate and severe fatigue. In colorectal and lung cancer patients, gender was not significant for fatigue change in patients with mild or moderate fatigue, but gender was the strongest predictor fatigue improvement in patients with severe fatigue with men most likely to significantly improve (OR=2.49, 95% CI 1.15-5.41, p=0.021). Conclusions: Clinically significant improvement in fatigue varies between 9% and 54%. Predictors of fatigue change vary depending on categories of baseline fatigue severity. Gender is the strongest predictor for fatigue improvement among lung and colorectal outpatients with severe baseline fatigue. Future trial designs should account for gender and baseline fatigue severity.
Cost-Effectiveness Analysis of Consolidation with Brentuximab Vendotin Versus Active Surveillance in Individuals with High-Risk Hodgkin Lymphoma Undergoing High Dose Chemotherapy with Stem Cell Rescue
Authors: Lucy Hui, Gottfried von Keudell, Rong Wang, Amer M. Zeidan, Steven D. Gore, Xiaomei Ma, Amy J. Davidoff, Scott F Huntington
Journal: Blood (2016)
Conflicts of Interest Reported in an Abbreviated Time Frame
Authors: Anna S. Lok, William G. Powderly
Journal: JAMA Internal Medicine (2017)

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 Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Internal Medicine journal
Annals Graphic Medicine - July Plunge
Authors: Michael Natter
Journal: Annals of Internal Medicine (2017)

Web Exclusives4 July 2017Annals Graphic Medicine - July PlungeFREEMichael Natter, MDMichael Natter, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G17-0008 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Disclosures: The author has disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G17-0008.Author/Illustrator Information: Michael Natter is a recent graduate of Sidney Kimmel Medical College of Thomas Jefferson University in Philadelphia. He will be starting a residency in internal medicine at NYU Langone Medical Center this July. His artwork is inspired by his medical studies, anatomy, and the human condition. A type 1 diabetic, Mr. Natter has highlighted his medical journey on Instagram. (www.instagram.com/mike.natter; e-mail, [email protected]edu.)Author Contributions: Conception and design: M. Natter.Drafting of the article: M. Natter.Critical revision of the article for important intellectual content: M. Natter.Final approval of the article: M. Natter.Provision of study materials or patients: M. Natter.Administrative, technical, or logistic support: M. Natter. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoA Letter to New Interns Darren B. Taichman , Darilyn V. Moyer , and Christine Laine A Letter to New Interns Darren B. Taichman , Darilyn V. Moyer , and Christine Laine Annals Graphic Medicine - Internship Jason Bitterman Metrics Cited byA Letter to New InternsDarren B. Taichman, MD, PhD, Darilyn V. Moyer, MD, and Christine Laine, MD, MPH 4 July 2017Volume 167, Issue 1Page: W1-W2KeywordsConflicts of interestDisclosureGraduate medical educationHealth careResidency ePublished: 4 July 2017 Issue Published: 4 July 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Maternal and Cord Blood Manganese Concentrations and Early Childhood Neurodevelopment among Residents near a Mining-Impacted Superfund Site
Authors: Birgit Claus Henn, David C. Bellinger, Marianne R. Hopkins, Brent A. Coull, Adrienne S. Ettinger, Rebecca Jim, Earl Hatley, David C. Christiani, Robert O. Wright
Journal: Environmental Health Perspectives (2017)

Background: Environmental manganese exposure has been associated with adverse neurodevelopmental outcomes among school-aged children; yet, few studies have evaluated prenatal exposure. Objectives: Our study examines associations between prenatal manganese concentrations and placental transfer of manganese with neurodevelopment in 224 2-y-old children residing near the Tar Creek Superfund Site. Methods: We collected maternal and cord blood at delivery, measured manganese using inductively coupled plasma mass spectrometry, and assessed neurodevelopment using the Bayley Scales of Infant Development-II. Associations between manganese and mental (MDI) and psychomotor (PDI) development indices were estimated in multivariable models. Placental transfer, approximated by cord/maternal manganese ratio, cord/total manganese ratio (total=maternal+cord), and by joint classification according to high or low (above or below median) maternal and cord manganese, was evaluated as a predictor of neurodevelopment. Results: Median levels [interquartile ranges (IQR)] of manganese in maternal and cord blood, respectively, were 24.0 (19.5–29.7) and 43.1 (33.5–52.1) μg/L. Adjusting for lead, arsenic, and other potential confounders, an IQR increase in maternal manganese was associated with −3.0 (95% CI: −5.3, −0.7) points on MDI and −2.3 (95% CI: −4.1, −0.4) points on PDI. Cord manganese concentrations were not associated with neurodevelopment scores. Cord/maternal and cord/total manganese ratios were positively associated with MDI [cord/maternal: β=2.6 (95% Cl: −0.04, 5.3); cord/total: β=22.0 (95% Cl: 3.2, 40.7)] and PDI (cord/maternal: β=1.7 (95% Cl: −0.5, 3.9); cord/total: β=15.6 (95% Cl: 0.3, 20.9)). Compared to mother–child pairs with low maternal and cord manganese, associations with neurodevelopment scores were negative for pairs with either high maternal, high cord, or high maternal and cord manganese. Conclusions: Maternal blood manganese concentrations were negatively associated with early childhood neurodevelopment scores in our study. Findings highlight the importance of understanding maternal exposures during pregnancy and factors influencing placental transfer. https://doi.org/10.1289/EHP925
The role of polymerase proofreading in DNA damage and cell death
Authors: Rina Bhagat, Tina Albertson, Bradley Preston, Varsha Gandhi
Journal: Cancer Research (2007)

1110  Mammalian replicative DNA polymerases δ and ϵ contain proofreading 3’→5’ exonucleases which help maintain genetic stability by removing misincorporated deoxynucleotides from nascent DNA during replication. To determine the role of polymerase proofreading in gemcitabine-induced cellular aberrations, we used a model system consisting of wild type (exo+) and double exonuclease-minus (exo-) mouse embryonic fibroblasts with inactivating point mutations in the exonuclease domains of polymerases δ and ϵ which render the cells exonuclease null but allow normal polymerase function. WT exo+ and mutant exo- cells treated with gemcitabine (3nM for 24 hours) accumulated similar levels of intracellular gemcitabine triphosphate. However, more gemcitabine was incorporated into the DNA of exo- cells, suggesting that polymerase proofreading recognizes and excises gemcitabine residues during DNA synthesis. Paradoxically, in exo- cells there was less inhibition of DNA synthesis and lower sensitivity to gemcitabine compared to exo+ cells, as demonstrated in growth inhibition and clonogenic survival assays. Based on these data, we hypothesize that exonuclease-mediated removal of gemcitabine from DNA leads to cell death by activation of a DNA damage response. To test this hypothesis, we analyzed histone H2AX phosphorylation by flow cytometry, quantified DNA double-strand breaks by neutral COMET assay, and examined activation of Chk1 by immunoblots.  As shown in the table, exonuclease deficiency resulted in increased spontaneous DNA damage and Chk1 phosphorylation. Upon gemcitabine treatment, damage and Chk1 phosphorylation were potentiated in exo+ cells, while minor or no increases were observed in gemcitabine-treated exo- cells above their intrinsic high basal levels. Taken together, these data demonstrate that polymerase proofreading prevents spontaneous DNA breaks and suggest that proofreading by exonuclease may play a role in mediating gemcitabine-induced DNA damage, signaling responses, and cell death.
Pretreatment antigen-specific immunity and regulation - association with subsequent immune response to anti-tumor DNA vaccination
Authors: Laura E. Johnson, Brian M. Olson, Douglas G. McNeel
Journal: Journal for ImmunoTherapy of Cancer (2017)

<h3>Background</h3> Immunotherapies have demonstrated clinical benefit for many types of cancers, however many patients do not respond, and treatment-related adverse effects can be severe. Hence many efforts are underway to identify treatment predictive biomarkers. We have reported the results of two phase I trials using a DNA vaccine encoding prostatic acid phosphatase (PAP) in patients with biochemically recurrent prostate cancer. In both trials, persistent PAP-specific Th1 immunity developed in some patients, and this was associated with favorable changes in serum PSA kinetics. In the current study, we sought to determine if measures of antigen-specific or antigen non-specific immunity were present prior to treatment, and associated with subsequent immune response, to identify possible predictive immune biomarkers. <h3>Methods</h3> Patients who developed persistent PAP-specific, IFNγ-secreting immune responses were defined as immune "responders." The frequency of peripheral T cell and B cell lymphocytes, natural killer cells, monocytes, dendritic cells, myeloid derived suppressor cells, and regulatory T cells were assessed by flow cytometry and clinical laboratory values. PAP-specific immune responses were evaluated by cytokine secretion in vitro, and by antigen-specific suppression of delayed-type hypersensitivity to a recall antigen in an in vivo SCID mouse model. <h3>Results</h3> The frequency of peripheral blood cell types did not differ between the immune responder and non-responder groups. Non-responder patients tended to have higher PAP-specific IL-10 production pre-vaccination (<i>p</i>&nbsp;=&nbsp;0.09). Responder patients had greater preexisting PAP-specific bystander regulatory responses that suppressed DTH to a recall antigen (<i>p</i>&nbsp;=&nbsp;0.016). <h3>Conclusions</h3> While our study population was small (<i>n</i>&nbsp;=&nbsp;38), these results suggest that different measures of antigen-specific tolerance or regulation might help predict immunological outcome from DNA vaccination. These will be prospectively evaluated in an ongoing randomized, phase II trial.
Nicotine from cigarette smoking and diet and Parkinson disease: a review
Authors: Chaoran Ma, Yesong Liu, Samantha Neumann, Xiang Gao
Journal: Translational Neurodegeneration (2017)

Evidence from epidemiological studies suggest a relationship between cigarette smoking and low risk of Parkinson disease (PD). As a major component of tobacco smoke, nicotine has been proposed to be a substance for preventing against PD risk, with a key role in regulating striatal activity and behaviors mediated through the dopaminergic system. Animal studies also showed that nicotine could modulate dopamine transmission and reduce levodopa-induced dyskinesias. However, previous clinical trials yield controversial results regarding nicotine treatment. In this review, we updated epidemiological, preclinical and clinical data, and studies on nicotine from diet. We also reviewed interactions between genetic factors and cigarette smoking. As a small amount of nicotine can saturate a substantial portion of nicotine receptors in the brain, nicotine from other sources, such as diet, could be a promising therapeutic substance for protection against PD.
Chromosomal Microarray Testing for Children With Unexplained Neurodevelopmental Disorders
Authors: Christa Lese Martin, David H. Ledbetter
Journal: JAMA (2017)

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