tbuckley/cabot-search huggingface dataset:
Outcomes after chemotherapy in early-stage breast cancer (EBC) patients who underwent a 21-gene expression assay.
Authors: Carlos Hernando Barcenas, Arup Kumar Sinha, Akshara Singareeka Raghavendra, Masood Pasha Syed, Limin Hsu, Modesto Patangan, Mariana Chavez-Mac Gregor, Yu Shen, Sharon Hermes Giordano, Naoto T. Ueno, Vicente Valero, Debu Tripathy
Journal: Journal of Clinical Oncology (2016)

559 Background: A recent report from the Trial Assigning Individualized Options for Treatment (TAILORx) study showed that EBC patients who had hormone receptor-positive (HR+), human epidermal growth factor receptor type 2-negative (HER2-), axillary lymph node-negative (LN-) tumors with a recurrence score (RS) of 0-10 in a 21-gene expression assay, had a high rate (93.8%) of invasive disease-free survival (IDFS) at 5 years when treated with endocrine therapy alone. However, outcomes after chemotherapy among patients with a RS of 11-25 were not reported. Methods: We performed a retrospective study of women with HR+ HER2- LN- EBC who received treatment at MD Anderson from 2005-2014 and had a 21-gene expression assay performed at diagnosis. We used a Kaplan-Meier method to estimate the IDFS rate at 5 years, and a multivariable Cox proportional hazards model to calculate a hazard ratio (HR) and 95% confidence interval (CI), assessing the effect of chemotherapy for IDFS, recurrence-free survival (RFS), distant-relapse-free survival (DRFS) and overall survival (OS) among patients with a RS of 11-25. Results: We evaluated 1514 patients with a median age of diagnosis 55 years (interquartile range 48-63). Among all, 40% had a mastectomy, 56% radiation, 92% endocrine therapy and 23% chemotherapy. Tumor characteristics were: 75% stage I, 77% invasive ductal, 23% grade 3. The RS distribution was: 0-10 in 315 (21%), 11-25 in 957 (63%), and ≥ 26 in 242 (16%); a total of 2%, 17% and 74% of patients received chemotherapy, respectively. After a median follow-up of 3.8 years, among those with a RS 11-25, the IDFS rate (95% CI) at 5 years was 93.1% (90.6-95.0%), and was comparable between patients who received chemotherapy (91.7%) and those who did not (93.4%). The HR (95% CI) of the effect of chemotherapy for each outcome was: IDFS 1.18 (0.59-2.36); RFS 0.95 (0.34-2.62); DRFS 0.95 (0.31-2.89); OS 1.92 (0.51-7.30). Among those with RS ≥ 26, all HR were < 1.0, suggesting a benefit from chemotherapy, but statistical significance was not reached. Conclusions: In this cohort of patients with HR+ HER2- LN- EBC, among those who had a RS of 11-25, patients who received chemotherapy had similar outcomes compared to those who did not.
Have patients with oesophagitis got an increased risk of adenocarcinoma? Results from a population-based study
Authors: SJ Murphy, LA Anderson, BT Johnston, DA Fitzpatrick, RGP Watson, P Monaghan, LJ Murray
Journal: Endoscopy (2005)

Aims: Reflux symptoms are associated with an increased risk of oesophageal adenocarcinoma, but it remains unclear if this risk is restricted to patients who develop Barrett's oesophagus or whether oesophagitis per se is a risk factor. We carried out a study to assess the risk of adenocarcinoma in patients with oesophagitis.
Pcarrier: Individual and family distributions of a susceptibility gene for breast and ovarian cancer based on family history.
Authors: Alexandra Lefebvre, Antoine de Pauw, Dominique Stoppa-Lyonnet, Gregory Nuel
Journal: Journal of Clinical Oncology (2017)

e13005 Background: Most of the BRCA1/2 and PALB2 analyses performed in patients with a personal and familial history (FH) of breast/ovarian cancer are negative. In this context, there is no targeted analysis available to identify relatives at high risk (carrier of the causal hypothetical mutated gene). Thus, the recommendations of surveillance to all relatives are based only on the FH of cancer. At the Institut Curie we assess the degree of severity of the FH by calculating the probability of carrying a single autosomal dominant susceptibility gene without taking into account genotyping results but using the LINKAGE software with the parameters of the Claus-Easton model (1993). This reliable but old tool has a slow console interactive interface (roughly 15 min of clinicians time for each assessed family). Methods: We rewrite the model as a Bayesian network combining Mendelian genetics with classical survival analysis. All probabilistic computations are performed through belief propagation (sum-product algorithm) over real numbers or polynomials. The programming language is C++. Results: pCarrier is a modern and efficient implementation of the Claus-Easton model for clinicians with the following features: 1) fast non-interactive command line ( &lt; 1s to process a previously registered family) combined with a graphical user-friendly interface; 2) computations dealing with monozygotic twins or loops without any human intervention (ex: loop breaking); 3) choice between the original discretized model (individual FH into 14 classes) and its continuous version (piecewise constant hazard); 4) marginal individual carrier distribution for all individuals in the pedigree; 5) joint distribution of the number of carriers among any group of individuals (ex: in the entire family, among the living only). Conclusions: pCarrier is experimented since January 2017 in the Institut Curie as a replacement of the existing tool and appears so far to be dramatically faster and easier to use for the clinicians, highly reliable (consistence with the existing tool), and able to provide new useful decision-making probabilities using the distribution of the number of carriers.
Fixed tissue ChIP-seq (FiT-Seq) of archived FFPE clinical bladder cancer (BC) samples to reveal tumor-specific enhancer and super-enhancer profiles.
Authors: Paloma Cejas, Stephanie A. Mullane, Melissa Duarte, Prakash Rao, Anna Orsola, Lewyn Li, Toni K. Choueiri, Matthew L Freedman, Mary-Ellen Taplin, Mark Pomerantz, Henry Long, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2016)

4541 Background: Application of ChIP-seq to the vast majority of clinical tissue samples has not been possible due to the extensive tissue fixation. We developed Fixed-Tissue chromatin immuno-precipitation sequencing (FiT-seq), which reveals the epigenomes of FFPE tissue samples and enables many previously impossible translational studies of chromatin states to be done in archived clinical specimens. No chromatin state maps from primary BC have been described to date. Methods: Using multiple histone marks measured with FiT-seq we generate chromatin state maps for a 10-year old BC sample demonstrating a robust capability to study a wide variety of genomic regions. Six BC tumors were further analyzed with H3K4me2 to identify enhancers. The study was then expanded to a cohort of 24 high grade T1 clinically annotated bladder cancer samples with extreme phenotypes. Results: In the first 6 samples, we observed the existence of a cis-regulatory pattern characteristic for BC that distinguishes it from other tumor types including seminoma, breast, and colorectal. The BC enhancer pattern shows H3K4me2-defined super-enhancers near key bladder-cancer oncogenes, such as GATA3 and CCND1 in the majority of samples. The top-ranked super-enhancer in one case mapped to FGFR3, a driver oncogene in ~12% of bladder cancers. In the expansion cohort of 24 samples, we observed two main clusters in the unsupervised clustering based on the pattern of enhancers. Interestingly, one of the clusters corresponded to a subset of bladder tumors that had specific chromatin features with H3K4me2 marked enhancers at the vicinity of genes that where enriched in the p53 pathway. Conclusions: We show for the first time chromatin state maps from primary BC and describe the enhancer profiles of BC that shows distinct lineage characteristics. Our analysis suggests that histologically similar BC have different chromatin states, which may drive differential biology.
Arrhythmias in a patient with metastatic melanoma treated with targeted therapy and implantable cardioverter defibrillator
Authors: M. Licciardello, M.T. Giura, G. Rozzo, E. Marra, P. Fava, C. Astrua, V. Contu, P. Lista, M.T. Fierro, P. Quaglino, S. Ribero
Journal: British Journal of Dermatology (2017)

Metastatic melanoma is an aggressive and rapidly progressive disease. Heart metastases were shown in over 50% of autopsy. However, these metastases are usually clinically silent and reported in less than 2% of living patients1.2. There are no specific guidelines for the treatment of cardiac metastases as the therapeutic approach varies with the clinical features of the patient.

This article is protected by copyright. All rights reserved.
Abstract 13696: Cardiac-specific Overexpression of Bdh1 Ameliorates Oxidative Stress and Cardiac Remodeling in Pressure Overload Heart Failure
Authors: Motoki Uchihashi, Atsushi Hoshino, Yoshifumi Okawa, Makoto Ariyoshi, Satoshi Kaimoto, Kuniyoshi Fukai, Eri I Kanai, Satoaki Matoba
Journal: Circulation (2013)

Background: The shift of energy substrate from fatty acid to glucose accompanied by myocardial energy compromise is the hallmark of metabolic remodeling in pathological cardiac hypertrophy. However...
An open-label expanded-access study to evaluate the safety, tolerability, and pharmacokinetics of trifluridine/tipiracil in patients with advanced solid tumors and hepatic impairment.
Authors: Wasif M. Saif, Lee S. Rosen, Michelle A. Rudek, Weijing Sun, Dale Randall Shepard, Carlos Becerra, Fumiaki Yamashita, Paul Bebeau, Robert Winkler
Journal: Journal of Clinical Oncology (2017)

2559 Background: The Phase 3 RECOURSE study showed that trifluridine/tipiracil (FTD/TPI) was effective in the treatment of refractory metastatic colorectal cancer (Mayer et al. N Engl J Med 2015;372:1909-19). A Phase 1 open-label study evaluated the safety and pharmacokinetics of FTD/TPI in patients with advanced solid tumors and varying degrees of hepatic impairment to inform dosing recommendations for these patients. Methods: Patients aged ≥18 years with advanced solid tumors, an Eastern Cooperative Oncology Group performance status ≤2, normal hepatic function, and mild, moderate, or severe impaired hepatic function according to the National Cancer Institute criteria were enrolled. Patients received FTD/TPI 35 mg/m 2 orally twice daily on days 1-5 and days 8-12 of each 28-day cycle, except for those with severe impaired hepatic function (dose was to be determined). Results: 24 patients were enrolled to normal (n=8), mild (n=10), and moderate (n=6) groups. Study enrollment was stopped as 5/6 patients in the moderate group experienced elevated bilirubin levels (grade ≥3). The other baseline characteristics were similar across groups. Overall, 12 patients (50%) had at least 1 adverse event leading to study discontinuation: 2 in normal, 5 in mild, and 5 in the moderate hepatic impairment groups. Pharmacokinetic results are summarized in the table. Conclusions: The exposure to FTD or TPI was not increased by hepatic impairment and the patients who experienced grade 3 and 4 increased total bilirubin were not overexposed to FTD or TPI. Clinical trial information: NCT02301104. [Table: see text]
Intradermal Immunization with rAAV1 Vector Induces Robust Memory CD8+ T Cell Responses Independently of Transgene Expression in DCs
Authors: Alexandre Ghenassia, David-Alexandre Gross, Stéphanie Lorain, Fabiola Tros, Dominique Urbain, Sofia Benkhelifa-Ziyyat, Alain Charbit, Jean Davoust, Pascal Chappert
Journal: Molecular Therapy (2017)

Recombinant adeno-associated viral (rAAV) vectors exhibit interesting properties as vaccine carriers for their ability to induce long-lasting antibody responses. However, rAAV-based vaccines have been suggested to trigger functionally impaired long-term memory CD8+ T cell responses, in part due to poor dendritic cell (DC) transduction. Such results, albeit limited to intramuscular immunization, undermined the use of rAAV as vaccine vehicles against intracellular pathogens. We report here that intradermal immunization with a model rAAV2/1-based vaccine drives the development of bona fide long-term memory CD8+ T cell responses. The intradermal route of immunization and the presence of potent major histocompatibility complex (MHC) class II responses showed synergistic effects on the overall quantity and quality of systemic long-term effector memory transgene-specific CD8+ T cells being generated against the transgene. Of key interest, we found that the induction of memory cytotoxic T lymphocytes (CTLs) following intradermal immunization was solely dependent on the cross-presentation of skin-expressed transgene products, which appeared highly enhanced as compared to muscle-expressed transgene products. Overall our results highlight key tissue-specific differences in transgene presentation pathway requirements of importance for the design of rAAV-based T cell-inducing vaccines.
Abstract 268: Improvements in Emergency Department CPR Quality Utilizing Real-Time Audiovisual CPR Feedback
Authors: Christopher Crowe, Tyler Bronnenkant, Annemarie Silver, Marcia Hefner, Tyler Vadeboncoeur, Frank LoVecchio, Uwe Stolz, Daniel Spaite, Bentley Bobrow
Journal: Circulation (2013)

Background: CPR quality is closely linked to outcome in cardiac arrest. The AHA 2010 Guidelines recommend monitoring CPR quality performed by healthcare providers both inside and outside the hospital. However, most EDs currently do not monitor CPR quality. The goal of the present investigation was to assess the quality of CPR performed in an urban ED and determine the influence of training and real-time audiovisual feedback (RTAVF) on CPR quality and patient outcome. Methods: CPR quality was monitored using an R Series defibrillator (ZOLL Medical) during the treatment of adult cardiac resuscitation attempts. During phase 1 (P1; 11/2010-11/2012), real-time audiovisual chest compression feedback was disabled. During phase 2 (P2; 11/2012-3/2013), clinicians underwent a 60 minute didactic/hands-on CPR training session after which the RTAVF and the ECG artifact filtering feature were enabled. CPR quality data (fraction, depth, rate, release, peri-shock pause) were reviewed using Code Review software (ZOLL Medical). Student’s t-test and Wilcoxon-signed rank test were employed. Results: A total of 44 OHCA patients were treated in P1 (mean age 57±18 yrs, 59% male) and 24 in Phase 2 (mean age 63±15 yrs, 88% male). The majority of patients (89% P1; 96% P2) suffered prehospital arrest and were transported to the ED. Chest compression (CC) depth increased from 1.8±0.5 inches in P1 to 2.3±0.4 in P2 (p&lt;0.001), with the percentage of compressions exceeding 2 inches more than doubling from 36% in P1 to 79% in P2 (p&lt;0.001). CC release velocity increased from 1.25±0.36 inch/sec in P1 to 1.69±0.28 in P2 (p&lt;0.001). No significant differences were identified in CC rate (125±12 cpm P1 vs. 121±15 cpm P2, p=0.3) or CC fraction (82% P1 vs. 87% P2, p=0.1). Pre-shock pause (11.5±10.4 sec P1 vs. 8.0±6.2 P2, p=0.4) and post-shock pause (5.2±3.4 sec vs. 3.8±0.6, p=0.9) were statistically similar in P1 and P2. Conclusion: The bundle of real time audiovisual CPR feedback and training were associated with an improvement in chest compression depth and recoil and closer adherence to guidelines for CPR quality in this large urban ED.
Analysis of BRCA1-related functional associations in sporadic triple negative breast cancer: A network-based approach.
Authors: Arcangela De Nicolo, Benjamin Haibe-Kains, Murat Taşan, Michael E. Cusick, Marc Vidal, John Quackenbush, Vladimir Joukov, David M. Livingston
Journal: Journal of Clinical Oncology (2016)

1070 Background: Sporadic triple negative breast cancers (TNBC) are aggressive malignancies that present a yet unaddressed clinical challenge. They are refractory to hormonal and HER2-targeted therapy, leaving chemotherapy as the mainstay of systemic treatment. Their striking resemblance to BRCA1-mutated hereditary breast cancers has led to the speculation that BRCA1 pathway derangement underlies sporadic TNBC and could be exploited therapeutically. BRCA1 has been implicated in multiple cellular processes via interactions with diverse partner proteins. Methods: To search for TNBC-specific aberrations within the complex array of BRCA1-related functional associations, we devised a strategy that takes into account the versatility of the BRCA1 protein and combines database mining, literature curation, network modeling, and transcriptome analysis. Results: We used database- and literature-derived data on protein-protein interactions, co-complex memberships, and biochemical modifications involving BRCA1 to build a BRCA1-centered Interaction network of 157 known BRCA1 partners. We applied functional linkage analysis to add predicted functional links and generate a highly-connected Shell network of 1137 nodes and 2941 edges, directly or indirectly associated with BRCA1. We next used a curated compendium of 14 datasets comprising 2022 uniformly subtyped sporadic primary breast cancers to compute, meta-analytically, the relative expression of the network components in TNBC vs non-TNBC subtypes. Lastly, we derived TNBC-specific subnetworks of significantly hyperactive or suppressed BRCA1-functionally associated genes. Conclusions: Via network analysis, we have identified presumptive signatures of BRCA1 pathway deregulation in sporadic TNBC. We will assess their prognostic/predictive value and potential use for patient stratification. Where relevant, we will also employ them as hypothesis-generating tools to prioritize BRCA1-related genes/proteins and pathways for in-depth analyses and to search for therapeutically exploitable vulnerabilities. These studies can help to inform therapy selection and tailored treatment and, hence, guide clinical trial design.
A new monoclonal antibody detects downregulation of protein tyrosine phosphatase receptor type γ in chronic myeloid leukemia patients
Authors: Marzia Vezzalini, Andrea Mafficini, Luisa Tomasello, Erika Lorenzetto, Elisabetta Moratti, Zeno Fiorini, Tessa L. Holyoake, Francesca Pellicano, Mauro Krampera, Cristina Tecchio, Mohamed Yassin, Nader Al-Dewik, Mohamed A. Ismail, Ali Al Sayab, Maria Monne, Claudio Sorio
Journal: Journal of Hematology & Oncology (2017)

Protein tyrosine phosphatase receptor gamma (PTPRG) is a ubiquitously expressed member of the protein tyrosine phosphatase family known to act as a tumor suppressor gene in many different neoplasms with mechanisms of inactivation including mutations and methylation of CpG islands in the promoter region. Although a critical role in human hematopoiesis and an oncosuppressor role in chronic myeloid leukemia (CML) have been reported, only one polyclonal antibody (named chPTPRG) has been described as capable of recognizing the native antigen of this phosphatase by flow cytometry. Protein biomarkers of CML have not yet found applications in the clinic, and in this study, we have analyzed a group of newly diagnosed CML patients before and after treatment. The aim of this work was to characterize and exploit a newly developed murine monoclonal antibody specific for the PTPRG extracellular domain (named TPγ B9-2) to better define PTPRG protein downregulation in CML patients. TPγ B9-2 specifically recognizes PTPRG (both human and murine) by flow cytometry, western blotting, immunoprecipitation, and immunohistochemistry. Co-localization experiments performed with both anti-PTPRG antibodies identified the presence of isoforms and confirmed protein downregulation at diagnosis in the Philadelphia-positive myeloid lineage (including CD34+/CD38bright/dim cells). After effective tyrosine kinase inhibitor (TKI) treatment, its expression recovered in tandem with the return of Philadelphia-negative hematopoiesis. Of note, PTPRG mRNA levels remain unchanged in tyrosine kinase inhibitors (TKI) non-responder patients, confirming that downregulation selectively occurs in primary CML cells. The availability of this unique antibody permits its evaluation for clinical application including the support for diagnosis and follow-up of these disorders. Evaluation of PTPRG as a potential therapeutic target is also facilitated by the availability of a specific reagent capable to specifically detect its target in various experimental conditions.
Effect of evacuation and displacement on the association between flooding and mental health outcomes: a cross-sectional analysis of UK survey data
Authors: Alice Munro, R Sari Kovats, G James Rubin, Thomas David Waite, Angie Bone, Ben Armstrong, Thomas David Waite, Charles R Beck, Angie Bone, Richard Amlôt, R Sari Kovats, Ben Armstrong, Giovanni Leonardi, G James Rubin, Isabel Oliver
Journal: The Lancet Planetary Health (2017)

Extensive flooding occurred during the winter of 2013-14 in England. Previous studies have shown that flooding affects mental health. Using data from the 2013-14 Public Health England National Study of Flooding and Health, we compared the prevalence of symptoms of depression, anxiety, and post-traumatic stress disorder between participants displaced by flooding and those flooded, but not displaced, 1 year after flooding.In this multivariable ordinal regression analysis, we collected data from a cross-sectional survey collected 1 year after the flooding event from flood-affected postcodes in five counties in England. The analysis was restricted to individuals whose homes were flooded (n=622) to analyse displacement due to flooding. The primary outcome measures were depression (measured by the PHQ-2 depression scale) and anxiety (measured by the two-item Generalised Anxiety Disorder [GAD]-2 anxiety scale), and post-traumatic stress disorder (measured by the Post-Traumatic Stress Disorder Checklist [PCL]-6 scale). We adjusted analyses for recorded potential confounders. We also analysed duration of displacement and amount of warning received.People who were displaced from their homes were significantly more likely to have higher scores on each scale; odds ratio (OR) for depression 1·95 (95% CI 1·30-2·93), for anxiety 1·66 (1·12-2·46), and for post-traumatic stress disorder 1·70 (1·17-2·48) than people who were not displaced. The increased risk of depression was significant even after adjustment for severity of flooding. Scores for depression and post-traumatic stress disorder were higher in people who were displaced and reported receiving no warning than those who had received a warning more than 12 h in advance of flooding (p=0·04 for depression, p=0·01 for post-traumatic stress disorder), although the difference in anxiety scores was not significant.Displacement after flooding was associated with higher reported symptoms of depression, anxiety, and post-traumatic stress disorder 1 year after flooding. The amount of warning received showed evidence of being protective against symptoms of the three mental illnesses studied, and the severity of flooding might be the reason for some, but not all, of the differences between the groups.National Institute for Health Research Health Protection Research Units (HPRU) in Emergency Preparedness and Response at King's College London, Environmental Change and Health at the London School of Hygiene and Tropical Medicine, and Evaluation of Interventions at the University of Bristol, Public Health England.