tbuckley/cabot-search huggingface dataset:
Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012
Authors: Maha Hussain, Stephanie Daignault-Newton, Przemyslaw W. Twardowski, Costantine Albany, Mark N. Stein, Lakshmi P. Kunju, Javed Siddiqui, Yi-Mi Wu, Dan Robinson, Robert J. Lonigro, Xuhong Cao, Scott A. Tomlins, Rohit Mehra, Kathleen A. Cooney, Bruce Montgomery, Emmanuel S. Antonarakis, Daniel H. Shevrin, Paul G. Corn, Young E. Whang, David C. Smith, Megan V. Caram, Karen E. Knudsen, Walter M. Stadler, Felix Y. Feng, Arul M. Chinnaiyan
Journal: Journal of Clinical Oncology (2017)

Purpose To determine whether cotargeting poly (ADP-ribose) polymerase-1 plus androgen receptor is superior to androgen receptor inhibition in metastatic castration-resistant prostate cancer (mCRPC) and whether ETS fusions predict response. Patients and Methods Patients underwent metastatic site biopsy and were stratified by ETS status and randomly assigned to abiraterone plus prednisone without (arm A) or with veliparib (arm B). Primary objectives were: confirmed prostate-specific antigen (PSA) response rate (RR) and whether ETS fusions predicted response. Secondary objectives were: safety, measurable disease RR (mRR), progression-free survival (PFS), and molecular biomarker analysis. A total of 148 patients were randomly assigned to detect a 20% PSA RR improvement. Results A total of 148 patients with mCRPC were randomly assigned: arm A, n = 72; arm B, n = 76. There were no differences in PSA RR (63.9% v 72.4%; P = .27), mRR (45.0% v 52.2%; P = .51), or median PFS (10.1 v 11 months; P = .99). ETS fusions did not predict response. Exploratory analysis of tumor sequencing (80 patients) revealed: 41 patients (51%) were ETS positive, 20 (25%) had DNA-damage repair defect (DRD), 41 (51%) had AR amplification or copy gain, 34 (43%) had PTEN mutation, 33 (41%) had TP53 mutation, 39 (49%) had PIK3CA pathway activation, and 12 (15%) had WNT pathway alteration. Patients with DRD had significantly higher PSA RR (90% v 56.7%; P = .007) and mRR (87.5% v 38.6%; P = .001), PSA decline ≥ 90% (75% v 25%; P = .001), and longer median PFS (14.5 v 8.1 months; P = .025) versus those with wild-type tumors. Median PFS was longer in patients with normal PTEN (13.5 v 6.7 months; P = .02), TP53 (13.5 v 7.7 months; P = .01), and PIK3CA (13.8 v 8.3 months; P = .03) versus those with mutation or activation. In multivariable analysis adjusting for clinical covariates, DRD association with PFS remained significant. Conclusion Veliparib and ETS status did not affect response. Exploratory analysis identified a novel DRD association with mCRPC outcomes.
Abstract 16496: Ideal Cardiovascular Health is Inversely Associated With Incident Coronary Heart Disease and Stroke Events in Non-Institutionalized Elderly Subjects. The Three Cities Study
Authors: Bamba Gaye, Marianne Canonico, Marie-Cecile Perier, Cecilia Samieri, Claudine Berr, Jean-François Dartigues, Christophe Tzourio, Alexis Elbaz, Jean-philippe Empana
Journal: Circulation (2016)

Introduction: The promotion of ideal cardiovascular health should concern all segments of the population, still its distribution and its association with outcomes is unknown in the elderly. Hypothe...
Is the concept of clinical equipoise still relevant to research?
Authors: Spencer Phillips Hey, Alex John London, Charles Weijer, Annette Rid, Franklin Miller
Journal: BMJ (2017)

<b>Spencer Hey</b>, <b>Alex John London</b>, and <b>Charles Weijer</b> argue that there is no better framework for justifying patient participation in research. But <b>Annette Rid</b> and <b>Franklin Miller</b> say that it is a mistake to require clinical research ethics to align with the norms of clinical practice
Publisher Correction: TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells
Authors: Nipun Verma, Heng Pan, Louis C. Doré, Abhijit Shukla, Qing V. Li, Bobbie Pelham-Webb, Virginia Teijeiro, Federico González, Andrei Krivtsov, Chan-Jung Chang, Eirini P. Papapetrou, Chuan He, Olivier Elemento, Danwei Huangfu
Journal: Nature Genetics (2017)
Differential PTEN levels and activation of P-Akt and GSK3β detected in Grade II and Grade III Ependymoma: predictors of progression
Authors: Wendy S. McDonough, Christopher O’Barr, Christine Feigal, Stephan W. Coons, Robert Spetzler, Theresa A. Thomas, Michael E. Berens
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

1848 

Ependymomas, the third most common primary brain tumor, are glial tumors that arise from ependymal cells within the CNS. Overall comprising just 2.5% of intracranial gliomas, ependymomas in children represent 10% of all intracranial tumors, and up to 30% in children younger than three years old. In the pediatric population these tumors are poorly manageable, and in adults, markedly different outcomes accompany different grades of ependymoma. The World Health Organization (WHO) classification scheme for these tumors includes 4 Grades: (1) myxopapillary ependymoma, (2) ependymoma, (3) anaplastic ependymoma, and (4) glioblastoma multiforme. Treatment of patients with ependymomas depends upon neurosurgical intervention to facilitate definitive diagnosis and to decrease tumor burden. Postoperative adjuvant therapy can include brain or spine radiation, chemotherapy, and radiosurgery, each compromising quality of life for the patient. Treatment planning is confounded by the lack of good diagnostic markers to distinguish between Grade II and III tumors. Grade II ependymoma is highly curable by surgery while Grade III tumors frequently recur with only 5-15 year survival rates. Definitive histological distinction between Grade II and III tumors is imprecise. In this study we seek to aid in classification of tumor grade at the time of biopsy and hope to improve the outcome of patients with this disease. Reports suggest that pathways related to PTEN may inform the molecular pathology of this tumor. Immunohistochemical analysis of phosphorylated AKT and GS3Kβ were tested for separation of Grade II and Grade III ependymomas. In addition, quantitative PCR of genomic DNA for loss of PTEN from archival FFPE tissue from 25 clinical samples was performed. An inverse correlation between increased IHC staining for P-AKT and GS3Kβ and loss of PTEN copy number was found for 24 out of 25 clinical samples. Surprisingly, clinical data for this small subset of patients revealed that patients with grade 3 ependymoma maintained PTEN expression while those with lower grades I and II had lost PTEN or were heterozygous in copy number. These analyses may prove to be useful diagnostic tools to separate Type II and III ependymal tumors, and to predict tumor behavior of specimens with confounding histology at the time of biopsy.
Cancer Drugs Approved Based on Biomarkers and Not Tumor Type—FDA Approval of Pembrolizumab for Mismatch Repair-Deficient Solid Cancers
Authors: Vinay Prasad, Victoria Kaestner, Sham Mailankody
Journal: JAMA Oncology (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 Oncology 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 Oncology journal
Interest in genomic SNP testing for prostate cancer risk.
Authors: Veda N. Giri, Karen Ruth, David Y. T. Chen, Laura Gross, Michael J. Hall
Journal: Journal of Clinical Oncology (2014)

e12503 Background: Advancements in genetic testing technology have led to the identification of single nucleotide polymorphisms (SNPs) associated with prostate cancer. The clinical utility of SNP tests to evaluate prostate cancer risk is unclear, yet the presence of SNPs has been shown to predict increased risk for prostate cancer above family history alone. Studies have not examined patients’ awareness of genomic SNP tests for prostate cancer risk or interest in a genomic SNP test if it were considered standard-of-care. Methods: Consecutive participants in the Fox Chase Cancer Center (FCCC) Prostate Cancer Risk Assessment Program presenting for annual follow-up (n=40) and unselected men from three surgical urology clinics at FCCC (n=40) completed a one-time survey, with African American men oversampled. Survey items examined interest in genomic single-nucleotide polymorphism (SNP) testing for prostate cancer risk, knowledge, impact of unsolicited findings on interest, and psychosocial factors including health literacy. Results: Knowledge of genomic SNP tests was low in both groups, but interest was higher among PRAP men (p<0.001). The prospect of receiving unsolicited results about ancestral genomic markers increased interest in testing in both groups. A multivariable model identified several predictors of higher interest in a genomic SNP test including higher perceived risk (p=0.025), indicating zero reasons for not wanting testing (vs >1 reason)(p=0.013), and higher health literacy (p=0.016). Conclusions: Knowledge of genomic SNP testing was low in this select sample, but higher among high-risk men. High-risk status may increase interest in novel genomic tests, while negative attitudes and low literacy may lessen interest.
Abstract 14232: Effect of Direct Oral Anticoagulants on Carotid Artery Sclerosis in Patients With Atrial Fibrillation
Authors: Yuta Torii, Hirotsugu Yamada, Kenya Kusunose, Hiromitsu Seno, Yoshihito Saijyo, Yuichiro Okushi, Susumu Nishio, Yukina Hirata, Rie Amano, Masataka Sata
Journal: Circulation (2016)

Introduction: In patients with non-valvular atrial fibrillation (AF), direct oral anticoagulants (DOACs) are at least non-inferior to warfarin for the prevention of stroke and systemic embolism. An...
A phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of oral COH29, a novel ribonucleotide reductase (RNR) inhibitor in adult patients (pts) with advanced solid tumors.
Authors: Joseph Chao, Timothy W. Synold, Paul Henry Frankel, Joanne E. Mortimer, Vincent M. Chung, D. Lynne Smith, Rajiv Nallu, Raju K. Pillai, James Simpson, David Horne, Larry W. Kwak, Linda Malkas
Journal: Journal of Clinical Oncology (2017)

TPS2600 Background: Human RNR catalyzes the rate-limiting step in the formation of deoxyribonucleotide triphosphates (dNTPs) necessary for DNA repair and replication. Rapidly dividing tumor cells are especially sensitive to RNR inhibition due to elevated dNTP requirements. Overexpression of the RNR RRM2 subunit is also associated with neoplasia, metastasis, and poor prognosis. COH29 is an aromatically substituted thiazole compound that is a novel small molecule inhibitor of RNR activity, and exhibits unique mechanisms and target specificity that overcomes the weaknesses of other small molecule RNR inhibitors. Preclinically, it is more potent than hydroxyurea and gemcitabine, and is not associated with iron chelating-related toxicities such as hypoxia. Cell lines deficient in BRCA1 also exhibit greater sensitivity to COH29 than BRCA1 wildtype cell lines, implicating inhibition of DNA repair mechanisms in line with PARP inhibitors. Methods: In this Phase I, single site, dose escalation, safety study pts will receive oral COH29 twice a day for 21 days of a 28-day cycle. Eligible pts are age ≥ 18 years, ECOG ≤ 2, able to take oral medication, have adequate organ and marrow function, and diagnosed with any solid tumor refractory to standard therapies. Dose escalation will be pursued utilizing a Simon’s accelerated titration design, which allows skipping of dose levels (dose doubling) during the accelerated dose-finding phase. Primary objectives are to determine the maximum tolerated dose of COH29, toxicities per CTCAEv4, and PKs. Secondary objectives include assessment of objective response per RECIST 1.1 every 2 cycles. PD assessment includes measurement of plasma CK18 levels to determine degree of cellular apoptosis, evaluation of dNTP pool levels in peripheral blood mononuclear cells (PBMCs) to evaluate RNR inhibition, as well as measurement of PAR expression in PBMCs to assess PARP inhibition. Quantitation of tumor RRM2 expression using dual-color immunohistochemistry will be explored as a predictive biomarker of anti-tumor response to COH29. Clinical trial information: NCT02112565.
Rapid activation of tumor-associated macrophages boosts preexisting tumor immunity
Authors: Sabine Hoves, Chia-Huey Ooi, Carsten Wolter, Hadassah Sade, Stefan Bissinger, Martina Schmittnaegel, Oliver Ast, Anna M. Giusti, Katharina Wartha, Valeria Runza, Wei Xu, Yvonne Kienast, Michael A. Cannarile, Hyam Levitsky, Solange Romagnoli, Michele De Palma, Dominik Rüttinger, Carola H. Ries
Journal: The Journal of Experimental Medicine (2018)

Depletion of immunosuppressive tumor-associated macrophages (TAMs) or reprogramming toward a proinflammatory activation state represent different strategies to therapeutically target this abundant myeloid population. In this study, we report that inhibition of colony-stimulating factor-1 receptor (CSF-1R) signaling sensitizes TAMs to profound and rapid reprogramming in the presence of a CD40 agonist before their depletion. Despite the short-lived nature of macrophage hyperactivation, combined CSF-1R+CD40 stimulation of macrophages is sufficient to create a proinflammatory tumor milieu that reinvigorates an effective T cell response in transplanted tumors that are either responsive or insensitive to immune checkpoint blockade. The central role of macrophages in regulating preexisting immunity is substantiated by depletion experiments, transcriptome analysis of ex vivo sorted TAMs, and gene expression profiling of whole tumor lysates at an early treatment time point. This approach enabled the identification of specific combination-induced changes among the pleiotropic activation spectrum of the CD40 agonist. In patients, CD40 expression on human TAMs was detected in mesothelioma and colorectal adenocarcinoma.
Association of Short-term Exposure to Air Pollution With Mortality in Older Adults
Authors: Qian Di, Lingzhen Dai, Yun Wang, Antonella Zanobetti, Christine Choirat, Joel D. Schwartz, Francesca Dominici
Journal: JAMA (2017)

<h3>Importance</h3> The US Environmental Protection Agency is required to reexamine its National Ambient Air Quality Standards (NAAQS) every 5 years, but evidence of mortality risk is lacking at air pollution levels below the current daily NAAQS in unmonitored areas and for sensitive subgroups. <h3>Objective</h3> To estimate the association between short-term exposures to ambient fine particulate matter (PM<sub>2.5</sub>) and ozone, and at levels below the current daily NAAQS, and mortality in the continental United States. <h3>Design, Setting, and Participants</h3> Case-crossover design and conditional logistic regression to estimate the association between short-term exposures to PM<sub>2.5</sub>and ozone (mean of daily exposure on the same day of death and 1 day prior) and mortality in 2-pollutant models. The study included the entire Medicare population from January 1, 2000, to December 31, 2012, residing in 39 182 zip codes. <h3>Exposures</h3> Daily PM<sub>2.5</sub>and ozone levels in a 1-km × 1-km grid were estimated using published and validated air pollution prediction models based on land use, chemical transport modeling, and satellite remote sensing data. From these gridded exposures, daily exposures were calculated for every zip code in the United States. Warm-season ozone was defined as ozone levels for the months April to September of each year. <h3>Main Outcomes and Measures</h3> All-cause mortality in the entire Medicare population from 2000 to 2012. <h3>Results</h3> During the study period, there were 22 433 862 million case days and 76 143 209 control days. Of all case and control days, 93.6% had PM<sub>2.5</sub>levels below 25 μg/m<sup>3</sup>, during which 95.2% of deaths occurred (21 353 817 of 22 433 862), and 91.1% of days had ozone levels below 60 parts per billion, during which 93.4% of deaths occurred (20 955 387 of 22 433 862). The baseline daily mortality rates were 137.33 and 129.44 (per 1 million persons at risk per day) for the entire year and for the warm season, respectively. Each short-term increase of 10 μg/m<sup>3</sup>in PM<sub>2.5</sub>(adjusted by ozone) and 10 parts per billion (10<sup>−9</sup>) in warm-season ozone (adjusted by PM<sub>2.5</sub>) were statistically significantly associated with a relative increase of 1.05% (95% CI, 0.95%-1.15%) and 0.51% (95% CI, 0.41%-0.61%) in daily mortality rate, respectively. Absolute risk differences in daily mortality rate were 1.42 (95% CI, 1.29-1.56) and 0.66 (95% CI, 0.53-0.78) per 1 million persons at risk per day. There was no evidence of a threshold in the exposure-response relationship. <h3>Conclusions and Relevance</h3> In the US Medicare population from 2000 to 2012, short-term exposures to PM<sub>2.5</sub>and warm-season ozone were significantly associated with increased risk of mortality. This risk occurred at levels below current national air quality standards, suggesting that these standards may need to be reevaluated.
Rescue of GSDIII Phenotype with Gene Transfer Requires Liver- and Muscle-Targeted GDE Expression
Authors: Patrice Vidal, Serena Pagliarani, Pasqualina Colella, Helena Costa Verdera, Louisa Jauze, Monika Gjorgjieva, Francesco Puzzo, Solenne Marmier, Fanny Collaud, Marcelo Simon Sola, Severine Charles, Sabrina Lucchiari, Laetitia van Wittenberghe, Alban Vignaud, Bernard Gjata, Isabelle Richard, Pascal Laforet, Edoardo Malfatti, Gilles Mithieux, Fabienne Rajas, Giacomo Pietro Comi, Giuseppe Ronzitti, Federico Mingozzi
Journal: Molecular Therapy (2017)

Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder caused by a deficiency of glycogen-debranching enzyme (GDE), which results in profound liver metabolism impairment and muscle weakness. To date, no cure is available for GSDIII and current treatments are mostly based on diet. Here we describe the development of a mouse model of GSDIII, which faithfully recapitulates the main features of the human condition. We used this model to develop and test novel therapies based on adeno-associated virus (AAV) vector-mediated gene transfer. First, we showed that overexpression of the lysosomal enzyme alpha-acid glucosidase (GAA) with an AAV vector led to a decrease in liver glycogen content but failed to reverse the disease phenotype. Using dual overlapping AAV vectors expressing the GDE transgene in muscle, we showed functional rescue with no impact on glucose metabolism. Liver expression of GDE, conversely, had a direct impact on blood glucose levels. These results provide proof of concept of correction of GSDIII with AAV vectors, and they indicate that restoration of the enzyme deficiency in muscle and liver is necessary to address both the metabolic and neuromuscular manifestations of the disease.
Loss-of-Function Mutations in Calcitonin Receptor (<i>CALCR</i>) Identify Highly Aggressive Glioblastoma with Poor Outcome
Authors: Jagriti Pal, Vikas Patil, Anupam Kumar, Kavneet Kaur, Chitra Sarkar, Kumaravel Somasundaram
Journal: Clinical Cancer Research (2017)

Purpose: Despite significant advances in the understanding of the biology, the prognosis of glioblastoma (GBM) remains dismal. The objective was to carry out whole-exome sequencing (WES) of Indian glioma and integrate with that of TCGA to find clinically relevant mutated pathways.Experimental Design: WES of different astrocytoma samples (n = 42; Indian cohort) was carried out and compared with that of TCGA cohort. An integrated analysis of mutated genes from Indian and TCGA cohorts was carried out to identify survival association of pathways with genetic alterations. Patient-derived glioma stem-like cells, glioma cell lines, and mouse xenograft models were used for functional characterization of calcitonin receptor (CALCR) and establish it as a therapeutic target.Results: A similar mutation spectrum between the Indian cohort and TCGA cohort was demonstrated. An integrated analysis identified GBMs with defective "neuroactive ligand-receptor interaction" pathway (n = 23; 9.54%) that have significantly poor prognosis (P < 0.0001). Furthermore, GBMs with mutated calcitonin receptor (CALCR) or reduced transcript levels predicted poor prognosis. Exogenously added calcitonin (CT) inhibited various properties of glioma cells and pro-oncogenic signaling pathways in a CALCR-dependent manner. Patient-derived mutations in CALCR abolished these functions with the degree of loss of function negatively correlating with patient survival. WT CALCR, but not the mutant versions, inhibited Ras-mediated transformation of immortalized astrocytes in vitro Furthermore, calcitonin inhibited patient-derived neurosphere growth and in vivo glioma tumor growth in a mouse model.Conclusions: We demonstrate CT-CALCR signaling axis is an important tumor suppressor pathway in glioma and establish CALCR as a novel therapeutic target for GBM. Clin Cancer Res; 24(6); 1448-58. ©2017 AACR.
Protein Stability and Avoidance of Toxic Misfolding Do Not Explain the Sequence Constraints of Highly Expressed Proteins
Authors: Germán Plata, Dennis Vitkup
Journal: Molecular Biology and Evolution (2017)

The avoidance of cytotoxic effects associated with protein misfolding has been proposed as a dominant constraint on the sequence evolution and molecular clock of highly expressed proteins. Recently, Leuenberger et al. developed an elegant experimental approach to measure protein thermal stability at the proteome scale. The collected data allow us to rigorously test the predictions of the misfolding avoidance hypothesis that highly expressed proteins have evolved to be more stable, and that maintaining thermodynamic stability significantly constrains their evolution. Notably, reanalysis of the Leuenberger et al. data across four different organisms reveals no substantial correlation between protein stability and protein abundance. Therefore, the key predictions of the misfolding toxicity and related hypotheses are not supported by available empirical data. The data also suggest that, regardless of protein expression, protein stability does not substantially affect the protein molecular clock across organisms.