tbuckley/cabot-search huggingface dataset:
Genome-Wide Mapping of Gene–Phenotype Relationships in Experimentally Evolved Populations
Authors: Laurence D Mueller, Mark A Phillips, Thomas T Barter, Zachary S Greenspan, Michael R Rose
Journal: Molecular Biology and Evolution (2018)

Model organisms subjected to sustained experimental evolution often show levels of phenotypic differentiation that dramatically exceed the phenotypic differences observed in natural populations. Genome-wide sequencing of pooled populations then offers the opportunity to make inferences about the genes that are the cause of these phenotypic differences. We tested, through computer simulations, the efficacy of a statistical learning technique called the "fused lasso additive model" (FLAM). We focused on the ability of FLAM to distinguish between genes which are differentiated and directly affect a phenotype from differentiated genes which have no effect on the phenotype. FLAM can separate these two classes of genes even with relatively small samples (10 populations, in total). The efficacy of FLAM is improved with increased number of populations, reduced environmental phenotypic variation, and increased within-treatment among-replicate variation. FLAM was applied to SNP variation measured in both twenty-population and thirty-population studies of Drosophila subjected to selection for age-at-reproduction, to illustrate the application of the method.
Abstract 12626: Predictors of Initial Revascularization versus Medical Therapy in Patients With Non-ST Segment Elevation Acute Coronary Syndrome Undergoing an Invasive Strategy
Authors: Harindra C Wijeysundera, Mandeep S Sidhu, Maria C Bennell, Feng Qiu, Merril Knudston, Jack V Tu, Dennis T Ko, William E Boden
Journal: Circulation (2015)

Background: Although an invasive strategy is a Class I clinical practice guideline for non-ST-segment elevation acute coronary syndromes (NSTE-ACS), there is wide variation in the proportion of such patients who undergo revascularization despite early angiography. We sought to identify the predictors of early revascularization versus medical therapy alone in NSTE-ACS patients undergoing an invasive strategy and contrast their clinical outcomes. Methods: We assessed revascularization status (PCI or CABG within 7 days of the index angiogram) in all NSTE-ACS patients treated with an invasive strategy at 18 hospitals in Ontario, Canada from October 1st 2008 to October 31st, 2013, using the Cardiac Care Network registry. Follow-up was until December 31st, 2014. The primary outcome was death. Multivariable, hierarchical logistic models were used to identify predictors of revascularization. Multivariable Cox models with treatment strategy as a 3-level time-varying covariate were developed to understand the relationship between revascularization status and clinical outcomes. Results: We identified 50,302 NSTE-ACS patients of whom 34,288 (68.2%) underwent early revascularization (28,011 by PCI; 6,277 by CABG). There was a twofold variation in revascularization rates (Figure). High risk based on the TIMI/GRACE score was a significant predictor of revascularization (OR 1.26; 95% CI 1.18-1.35) as was having the angiogram by an interventional cardiologist (OR 1.76, 95% CI 1.57-1.98) or at a diagnostic only hospital (OR 1.22, 95% CI 1.01-1.48). Compared to patients treated medically, those who were revascularized with either PCI (HR 0.64, 95% CI 0.60-0.69) or CABG (HR 0.53, 95% CI 0.47-0.60) had improved survival. Conclusions: While more than 2/3rds of NSTE-ACS patients who underwent an early invasive approach did receive revascularization, there was wide variation. Those who underwent revascularization had significantly improved clinical outcomes.
Impact of antibiotic administration on blood culture positivity at the beginning of sepsis: a prospective clinical cohort study
Authors: C.S. Scheer, C. Fuchs, M. Gründling, M. Vollmer, J. Bast, J.A. Bohnert, K. Zimmermann, K. Hahnenkamp, S. Rehberg, S.-O. Kuhn
Journal: Clinical Microbiology and Infection (2018)
Applying data analytics to new staging criteria.
Authors: Charlotte Cooper, George Barnes, Nobumasa Kawasaki, Brian Todd, Russell Reeve, Beatriz Callejón, Bettina Schaefer, Cristina Oliva, Joseph D Purvis, Natalia Balko Kotchie, Jeffrey Hodge
Journal: Journal of Clinical Oncology (2018)

e12526 Background: For breast cancer (BC), the most significant change in the 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual – implemented on Jan. 1, 2018 – is the addition of prognostic biologic factors (tumor grade, ER, PR and HER2 status) to anatomic staging. We assess clinical and operational implications of resulting stage changes, and potential impact on patient availability for large clinical trials targeting specific stage groups required for adjuvant therapy. Real-world data (RWD) analytics were performed using proprietary EMR data. Methods: We identified 5726 patients treated between Jan. 1, 2017, and Aug. 31, 2017, with complete clinicopathologic data, including T, N and M categories, in addition to tumor grade, ER, PR and HER2 status. We excluded patients with incomplete clinicopathologic data, stage IV BC and an HER2+ status (~80% BC patients are HER2-). Staging was assessed using AJCC 7th and 8th edition criteria. Cross-tabulations of each patient’s 7th and 8th edition staging were computed. The hypothesis of equal movement up or down was tested using a chi-squared test. Results: Compared with the AJCC 7th edition, the 8th edition upstaged 21.6% of patients and downstaged 23.5%. There was a 19.3% increase in stage IB patients, driven by downstaging of 730 (12.7%) patients from IIA and upstaging of 412 (7.2%) patients from IA. On average, the 8th edition resulted in significant net downstaging on patient pools (p< 0.0001, see Table 1). Conclusions: RWD analytics demonstrated the movement of patient pools using the AJCC 8th edition, which resulted in restaging of 45% of BC patients, impacting patient availability for clinical trials (particularly in groups I and II due to a general trend in downstaging). Similar analyses could inform protocol design and feasibility in any oncology indication covered by AJCC staging criteria. Table 1. Change in staging of BC using AJCC 7th vs. 8th Edition Stage (% of total n) 8th Edition P 0 (0.3%) IA (42.1%) IB (20.0%) IIA (14.4%) IIB (10.4%) IIIA (3.1%) IIIB (6.8%) IIIC (2.9%) 7th Edition 0 (0.4%) 19 - - - - - - - IA (48.6%) - 2375 412 - - - - - < 0.0001 IB (0.7%) - 36 5 - - - - - IIA (25.9%) - - 730 320 432 - - - < 0.0001 IIB (12.2%) - - - 323 162 53 161 - IIIA (7.5%) - - - 179 - 123 51 76 < 0.0001 IIIB (2.6%) - - - - - - 101 50 IIIC (2.1%) - - - - - - 78 40
The Complexities of Advance Care Planning in Individuals With Advanced Dementia
Authors: Nathan E. Goldstein, Harriet Mather
Journal: JAMA Internal Medicine (2018)

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
Chimeric antigen receptor T cell (CAR-T) immunotherapy for solid tumors: lessons learned and strategies for moving forward
Authors: Jian Li, Wenwen Li, Kejia Huang, Yang Zhang, Gary Kupfer, Qi Zhao
Journal: Journal of Hematology & Oncology (2018)

Recently, the US Food and Drug Administration (FDA) approved the first chimeric antigen receptor T cell (CAR-T) therapy for the treatment CD19-positive B cell acute lymphoblastic leukemia. While CAR-T has achieved remarkable success in the treatment of hematopoietic malignancies, whether it can benefit solid tumor patients to the same extent is still uncertain. Even though hundreds of clinical trials are undergoing exploring a variety of tumor-associated antigens (TAA), no such antigen with comparable properties like CD19 has yet been identified regarding solid tumors CAR-T immunotherapy. Inefficient T cell trafficking, immunosuppressive tumor microenvironment, suboptimal antigen recognition specificity, and lack of safety control are currently considered as the main obstacles in solid tumor CAR-T therapy. Here, we reviewed the solid tumor CAR-T clinical trials, emphasizing the studies with published results. We further discussed the challenges that CAR-T is facing for solid tumor treatment and proposed potential strategies to improve the efficacy of CAR-T as promising immunotherapy.
Prevalence of rearrangements in the 22q11.2 region and population-based risk of neuropsychiatric and developmental disorders in a Danish population: a case-cohort study
Authors: Line Olsen, Thomas Sparsø, Shantel M Weinsheimer, Marcelo Bertalan Quintanilha Dos Santos, Wiktor Mazin, Anders Rosengren, Xabier Calle Sanchez, Louise K Hoeffding, Henriette Schmock, Marie Baekvad-Hansen, Jonas Bybjerg-Grauholm, Mark J Daly, Benjamin M Neale, Marianne G Pedersen, Esben Agerbo, Ole Mors, Anders Børglum, Merete Nordentoft, David M Hougaard, Preben Bo Mortensen, Daniel H Geschwind, Carsten Pedersen, Wesley K Thompson, Thomas Werge
Journal: The Lancet Psychiatry (2018)
Development of novel emoji scale to measure patient-reported outcomes in cancer patients.
Authors: Carrie A. Thompson, Paul J Novotny, Alicia Bartz, Kathleen J. Yost, Jeff A. Sloan
Journal: Journal of Clinical Oncology (2018)

174 Background: Patient-reported outcomes (PROs), including physical function and quality of life (QOL), are important outcomes in cancer patients. Emoji are a near-universal, popular form of communication, understandable by diverse populations, including those with low health literacy. We aimed to explore whether emoji could be a valid, reliable scale for assessing PROs in cancer patients. Methods: To develop the emoji scale, 5 emoji faces were selected from the Apple emoji dictionary by study authors. 20 cancer patients participated in a card-sorting exercise to rank the emoji from negative to positive; 19 out of 20 selected the same order, which exceeded Coomb’s criteria for being a valid ordinal scale. Patients were recruited from Mayo Clinic practices. Eligibility included: adult patients with a diagnosis of lymphoma, multiple myeloma, brain, pancreatic, breast, and ovarian cancer within the past 5 years; life expectancy of &gt; 6 months; and own an iPhone version ≥ 5.0. All patients were provided with an Apple Watch and downloaded the study app. Baseline PRO data was collected on the iPhone, including single-item linear analog self-assessments (LASA) and emoji scales for fatigue, physical function, emotional well-being, and overall QOL. Results: From 2/2017-8/2017, 294 eligible patients were recruited. 25% were male, and median age was 53 years (range 20-79). The median time since diagnosis was 8.4 months (range 0-60); 63% were on active therapy, 27% were in observation post-treatment, and 10% had not been treated. All patients were “extremely” confident filling out forms, 99% had used a computer in the past 12 months, and 27% had ever used a smart watch. Emoji responses were significantly associated with validated measures of PROs; the Spearman correlations between the ordinal emoji scales and LASAs were -0.83 for fatigue, 0.72 for physical well-being, 0.72 for emotional well-being, and 0.77 for overall QOL (all p &lt; 0.0001). Of the 75 patients who have completed the study thus far, 92% reported they would use emoji scales again and 89% would recommend that others use emoji scales. Conclusions: A novel ordinal emoji scale is strongly associated with accepted measures of PROs in cancer patients and should be studied further.
Non-disclosed men who have sex with men in UK HIV transmission networks: phylogenetic analysis of surveillance data
Authors: Manon Ragonnet-Cronin, Stéphane Hué, Emma B Hodcroft, Anna Tostevin, David Dunn, Tracy Fawcett, Anton Pozniak, Alison E Brown, Valerie Delpech, Andrew J Leigh Brown
Journal: The Lancet HIV (2018)
Multi-Donor Longitudinal Antibody Repertoire Sequencing Reveals the Existence of Public Antibody Clonotypes in HIV-1 Infection
Authors: Ian Setliff, Wyatt J. McDonnell, Nagarajan Raju, Robin G. Bombardi, Amyn A. Murji, Cathrine Scheepers, Rutendo Ziki, Charissa Mynhardt, Bryan E. Shepherd, Alusha A. Mamchak, Nigel Garrett, Salim Abdool Karim, Simon A. Mallal, James E. Crowe, Lynn Morris, Ivelin S. Georgiev
Journal: Cell Host & Microbe (2018)

Characterization of single antibody lineages within infected individuals has provided insights into the development of Env-specific antibodies. However, a systems-level understanding of the humoral response against HIV-1 is limited. Here, we interrogated the antibody repertoires of multiple HIV-infected donors from an infection-naive state through acute and chronic infection using next-generation sequencing. This analysis revealed the existence of "public" antibody clonotypes that were shared among multiple HIV-infected individuals. The HIV-1 reactivity for representative antibodies from an identified public clonotype shared by three donors was confirmed. Furthermore, a meta-analysis of publicly available antibody repertoire sequencing datasets revealed antibodies with high sequence identity to known HIV-reactive antibodies, even in repertoires that were reported to be HIV naive. The discovery of public antibody clonotypes in HIV-infected individuals represents an avenue of significant potential for better understanding antibody responses to HIV-1 infection, as well as for clonotype-specific vaccine development.
Glypican-3-targeted precision diagnosis of hepatocellular carcinoma on clinical sections with a supramolecular 2D imaging probe
Authors: Hai-Hao Han, Yu-Jiao Qiu, Yuan-Yuan Shi, Wen Wen, Xiao-Peng He, Li-Wei Dong, Ye-Xiong Tan, Yi-Tao Long, He Tian, Hong-Yang Wang
Journal: Theranostics (2018)

The ability of chemical tools to effectively detect malignancy in frozen sections removed from patients during surgery is important for the timely determination of the subsequent surgical program.However, current clinical methods for tissue imaging rely on dye-based staining or antibody-based techniques, which are sluggish and complicated.Methods: Here, we have developed a 2D material-based supramolecular imaging probe for the simple, rapid yet precise diagnosis of hepatocellular carcinoma (HCC).The 2D probe is constructed through supramolecular self-assembly between a water soluble, fluorescent peptide ligand that selectively targets glypican-3 (GPC-3, a specific cell-surface biomarker for HCC) and 2D molybdenum disulfide that acts as a fluorescence quencher as well as imaging enhancer.Results: We show that the 2D imaging probe developed with minimal background fluorescence can sensitively and selectively image cells overexpressing GPC-3 over a range of control cells expressing other membrane proteins.Importantly, we demonstrate that the 2D probe is capable of rapidly (signal became readable within 1 min) imaging HCC tissues over para-carcinoma regions in frozen sections derived from HCC patients; the results are in accordance with those obtained using traditional clinical staining methods.Conclusion: Compared to conventional staining methods, which are laborious (e.g., over 30 min is needed for antibody-based immunosorbent assays) and complex (e.g., diagnosis is based on discrimination of the nucleus morphology of cancer cells from that of normal cells), our probe, with its simplicity and quickness, might become a promising candidate for tumor-section staining as well as fluorescence imaging-guided surgery.
Phase Ib Study of Binimetinib with Paclitaxel in Patients with Platinum-Resistant Ovarian Cancer: Final Results, Potential Biomarkers, and Extreme Responders
Authors: Rachel N. Grisham, Kathleen N. Moore, Michael S. Gordon, Wael Harb, Gwendolyn Cody, Darragh F. Halpenny, Vicky Makker, Carol A. Aghajanian
Journal: Clinical Cancer Research (2018)

Purpose: Epithelial ovarian cancer (EOC) is a molecularly diverse disease. MEK inhibition targets tumors harboring MAPK pathway alterations and enhances paclitaxel-induced apoptosis in EOC. This phase Ib study evaluated the MEK inhibitor binimetinib combined with paclitaxel in patients with platinum-resistant EOC.Patients and Methods: Patients received intravenous weekly paclitaxel with oral binimetinib in three different administration schedules. Outcomes were assessed by RECIST and CGIC CA-125 response criteria. Tumor samples were analyzed using next-generation sequencing.Results: Thirty-four patients received ≥1 binimetinib dose. A 30-mg twice-a-day continuous or 45-mg twice-a-day intermittent binimetinib dose was deemed the recommended phase II dose (RP2D) in combination with 80 mg/m2 i.v. weekly paclitaxel. Rate of grade 3/4 adverse events was 65%. The best overall response rate was 18%-one complete (CR) and four partial responses (PR)-among 28 patients with RECIST-measurable disease. Eleven patients achieved stable disease (SD), yielding a clinical benefit rate (CR+PR+SD) of 57%. Response rates, per both RECIST and CA-125 criteria, were highest in the 45-mg twice-a-day continuous cohort and lowest in the 45-mg twice-a-day intermittent cohort. All four evaluable patients with MAPK pathway-altered tumors experienced clinical benefit.Conclusions: The combination of binimetinib and intravenous weekly paclitaxel was tolerable in this patient population. The RP2D of binimetinib in combination with paclitaxel was 30 mg twice a day as a continuous or 45 mg twice a day as an intermittent dose. Although response rates were modest, a higher clinical benefit rate was seen in patients harboring alterations affecting the MAPK pathway. Clin Cancer Res; 24(22); 5525-33. ©2018 AACR.
Impact of 12 weeks nab-paclitaxel + carboplatin or gemcitabine followed by anthracycline administration according to pCR in triple-negative early breast cancer: Survival results of WSG-ADAPT-TN phase II trial.
Authors: Oleg Gluz, Ulrike Nitz, Cornelia Liedtke, Matthias Christgen, Eva-Maria Grischke, Helmut Forstbauer, Michael Wilhelm Braun, Mathias Warm, John Hackmann, Christoph Uleer, Bahriye Aktas, Claudia Schumacher, Nikola Bangemann, Christoph Lindner, Sherko Kummel, Ronald E. Kates, Rachel Wuerstlein, Hans Heinrich Kreipe, Nadia Harbeck
Journal: Journal of Clinical Oncology (2018)

573 Background: Optimal chemotherapy in TNBC EBC is unclear. ADAPT TN demonstrated higher pCR (46% vs. 29%) and better safety for only 12 weeks nab-paclitaxel/carboplatin vs nab-paclitaxel/gemcitabine (JNCI 2017). Methods: Patients with centrally confirmed TNBC (ER/PR < 1%, HER2-, cT1c-cT4c, cN0/+) were randomized to neoadjuvant A: 4x nab-paclitaxel 125 mg/m2/gemcitabine 1000 mg/m2 d1,8 q3w vs. B: 4x nab-paclitaxel 125 mg/m2/carboplatin AUC2 day 1/8 3-weekly (q3w). Primary endpoint was pCR (ypT0/is/ypN0) after 12 weeks of therapy. Event-free (EFS) -- defined as time from registration to any invasive relapse, secondary malignancy or death of any cause -- and overall survival (OS) were secondary endpoints. Adjuvant anthracycline-based chemotherapy (4xEC) was optional in patients with pCR. Here, we report the per-protocol interim survival analysis recommended by the DSMB after a median follow-up of 3 years. Results: 336 patients were enrolled (48 centers, arms A/B: n = 182/154). Median age was 50 years. At baseline, about 63% had cT2-4c tumors, 26.2% were clinically node-positive. After 36 months median FU, 68 EFS events (A/B: 37/29) and 37 deaths (A/B: 24/13) were observed. pCR (vs. non-pCR) is highly prognostic for EFS (3y EFS: 92% vs. 71%, p < 0.001) and OS (3y OS: 99.1% vs. 81.6%, p < 0.001). Despite the strong impact of carboplatin on pCR, 3y EFS was similar in (77.6% vs. 80.8%) in both arms; OS was numerically higher in Arm B (84.7% vs. 92.2%, p = 0.09). Final analysis regarding anthracycline use and its survival impact will be presented at the meeting. Conclusions: 12w nab-paclitaxel/carboplatin is a tolerable and effective neoadjuvant option in early stage TNBC. In ADAPT TN, the strong impact of carboplatin vs. gemcitabine on pCR seems to be "mitigated" regarding survival by subsequent adjuvant anthracycline/cyclophosphamide therapy. Our findings provide first prospective evidence supporting individualized chemotherapy regimens in early TNBC. Clinical trial information: NCT01815242.
Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With <sup>177</sup>Lu-Dotatate in the Phase III NETTER-1 Trial
Authors: Jonathan Strosberg, Edward Wolin, Beth Chasen, Matthew Kulke, David Bushnell, Martyn Caplin, Richard P. Baum, Pamela Kunz, Timothy Hobday, Andrew Hendifar, Kjell Oberg, Maribel Lopera Sierra, Thomas Thevenet, Ines Margalet, Philippe Ruszniewski, Eric Krenning
Journal: Journal of Clinical Oncology (2018)

Purpose Neuroendocrine tumor (NET) progression is associated with deterioration in quality of life (QoL). We assessed the impact of 177Lu-Dotatate treatment on time to deterioration in health-related QoL. Methods The NETTER-1 trial is an international phase III study in patients with midgut NETs. Patients were randomly assigned to treatment with 177Lu-Dotatate versus high-dose octreotide. European Organisation for Research and Treatment of Cancer quality-of-life questionnaires QLQ C-30 and G.I.NET-21 were assessed during the trial to determine the impact of treatment on health-related QoL. Patients completed the questionnaires at baseline and every 12 weeks until tumor progression. QoL scores were converted to a 100-point scale according to European Organisation for Research and Treatment of Cancer instructions, and individual changes from baseline scores were assessed. Time to QoL deterioration (TTD) was defined as the time from random assignment to the first QoL deterioration ≥ 10 points for each patient in the corresponding domain scale. All analyses were conducted on the intention-to-treat population. Patients with no deterioration were censored at the last QoL assessment date. Results TTD was significantly longer in the 177Lu-Dotatate arm (n = 117) versus the control arm (n = 114) for the following domains: global health status (hazard ratio [HR], 0.406), physical functioning (HR, 0.518), role functioning (HR, 0.580), fatigue (HR, 0.621), pain (HR, 0.566), diarrhea (HR, 0.473), disease-related worries (HR, 0.572), and body image (HR, 0.425). Differences in median TTD were clinically significant in several domains: 28.8 months versus 6.1 months for global health status, and 25.2 months versus 11.5 months for physical functioning. Conclusion This analysis from the NETTER-1 phase III study demonstrates that, in addition to improving progression-free survival, 177Lu-Dotatate provides a significant QoL benefit for patients with progressive midgut NETs compared with high-dose octreotide.