tbuckley/cabot-search huggingface dataset:
Preliminary immunogenicity, safety, and efficacy of JNJ-64041757 (JNJ-757) in non-small cell lung cancer (NSCLC): Results from two phase 1 studies.
Authors: Julie R. Brahmer, Melissa Lynne Johnson, Manuel Cobo Dols, Santiago Viteri Ramirez, Juan Coves, Ammar Sukari, Mark M. Awad, Ravi Salgia, Vassiliki Papadimitrakopoulou, Arun Rajan, Alicia Jones Allred, Mark Wade, Gary Mason, Enrique Zudaire, Roland Elmar Knoblauch, Nicole L. Stone, Matthew V. Lorenzi, Raffit Hassan
Journal: Journal of Clinical Oncology (2019)

9093 Background: The immunogenicity, safety, and efficacy of JNJ-757, a live attenuated, double-deleted Listeria monocytogenes-based immunotherapy expressing human mesothelin (MSLN), were evaluated in patients (pts) with advanced NSCLC (adenocarcinoma) as monotherapy (phase 1) and in combination with nivolumab (phase 1b/2). Methods: Adult pts with Stage IIIB/IV NSCLC who had received prior systemic therapy (including 1 platinum-based chemotherapy, prior PD-1/PD-L1 therapy allowed) were included. Dose-limiting toxicities, adverse events (AEs), tumor response, T cell response, and JNJ-757 bacterial shedding profile were evaluated in pts treated with JNJ-757 (10 8 or 10 9 colony forming units [CFU]) alone or JNJ-757 (10 9 CFU)+nivolumab 240 mg combination therapy until progression. Results: In the monotherapy trial, 18 pts (median age 63.5 years; women 61%) were treated with JNJ-757 10 8 or 10 9 CFU with a median duration of 1.4 months (range 0-29). Most common AEs were pyrexia (72%) and chills (61%), which were usually mild and resolved within 48 hours, suggesting transient activation of an innate immune response to JNJ-757. Treatment-related grade ≥3 AEs were infrequent (4 [22%]). Induction of peripheral proinflammatory cytokines and lymphocyte activation was observed post-treatment with transient MSLN-specific T cell responses in 10/13 evaluable pts, consistent with the mechanism of action of JNJ-757. With monotherapy, 4/18 response-evaluable pts had stable disease (SD) ≥16 weeks, including 1 pt with a 53% reduction in target lesions. In the combination therapy study, 12 pts were enrolled (median age 63.5 years; women 33%). The most common AEs were pyrexia (67%) and chills (58%); 6 pts had grade ≥3 AEs including 2 cases of treatment-related fatal pneumonitis. Best overall response for the combination was SD in 4/9 evaluable pts. JNJ-757 in combination with nivolumab suggested increased risk of pneumonitis. Conclusions: As monotherapy, JNJ-757 was tolerable with mild infusion-related fever and chills supporting the initiation of the combination therapy study. However, the risk-benefit profile of JNJ-757+nivolumab, did not support proceeding to phase 2. Clinical trial information: NCT02592967, NCT03371381.
Mortality rates among individuals diagnosed with hepatitis C virus (HCV); an observational cohort study, England, 2008 to 2016
Authors: Georgina Ireland, Sema Mandal, Matthew Hickman, Mary Ramsay, Ross Harris, Ruth Simmons
Journal: Eurosurveillance (2019)

BackgroundMonitoring trends in mortality for individuals diagnosed with hepatitis C virus (HCV) infection are important as we expand treatment and move towards World Health Organization elimination targets.AimTo estimate mortality rates for individuals aged ≥ 15 years diagnosed with HCV infection in England 2008-16.MethodsAn observational cohort study whereby death certificate information was linked to the Sentinel Surveillance of Blood Borne Virus Testing in England. Age-sex standardised mortality rates (ASMR) for individuals diagnosed with HCV infection (2008-16) were calculated and compared to the general population.ResultsOf 43,895 individuals with HCV infection, 2,656 (6.3%) died. All-cause ASMRs were 2,834.2 per 100,000 person years (PY), 2.3 times higher than in the general population. In individuals aged 30-69 years, all-cause mortality rates were 1,768.9 per 100,000 PY among individuals with HCV, 4.7 times higher than in the general population. ASMRs had not decreased between 2010 (2,992) and 2016 (2,340; p=0.10), with no change from 2014 (p = 0.058). ASMRs were 441.0 times higher for hepatitis, 34.4 times higher for liver cancer, 8.1 times higher for end stage liver disease and 6.4 times higher for external causes than in the general population.ConclusionsMortality was higher in individuals with diagnosed HCV infection compared to the general population, highlighting health inequalities. There is a need to improve HCV diagnosis, engagement in care and treatment rates. The high mortality from external causes highlights the importance of integrated health and social care strategies and addressing the needs of this vulnerable population.
Medical education: giving feedback to doctors in training
Authors: Emer Kelly, Jeremy B Richards
Journal: BMJ (2019)

### What you need to know

Providing effective feedback is an essential component of being a good teacher. When delivered well, feedback improves doctors’ and students’ skillsets and establishes lifelong learning (fig 1). A 2013 literature review described the characteristics of learners interested in feedback in terms of the self-motives framework (self assessment, self improvement, self enhancement, and self verification) and concluded that feedback‐seeking behaviour is valuable for individuals in work and educational settings as it aids their adaptation, learning, and performance.1



Fig 1 
Clinical learning is an ongoing cycle of progress pivoting on feedback



While the literature about feedback is broad and characterised by a lack of high quality, evidence based guidance or internationally recognised guidelines, consensus opinion and reviews of available quantitative and qualitative results indicate that effective feedback is based on observations, given in a conducive environment, characterised by a non-judgmental approach, focused on specific skills and behaviours, and limited in quantity to avoid overwhelming learners.23

This article is written for clinicians who teach and outlines how to give effective feedback to students and doctors in training, and why it is important. We provide specific strategies and approaches for clinicians and clinician educators to assist in developing and providing effective feedback to medical learners. 

A useful working definition of feedback is “Information describing performance in a given activity that is intended to guide future performance in that same or related activity.”4. Feedback can be either formative or summative in nature.

Formative feedback is provided during or shortly after a specific encounter or experience, with the content focusing constructively on …
Metabolic characterization of inflammatory breast cancer (IBC) with baseline FDG-PET/CT: Relationship with histopathology, hormone receptor status, and pathologic response after neoadjuvant chemotherapy.
Authors: Trisha Youn, Heather A. Jacene, Pamela Dipiro, Yoko Tanaka, Jennifer Ruth Bellon, Faina Nakhlis, Judith Hirshfield-Bartek, Eren Yeh, Beth Overmoyer
Journal: Journal of Clinical Oncology (2013)

1105 Background: Higher metabolic activity on FDG-PET is associated with triple negative (TN) hormone receptor status and invasive ductal histopathology in non-IBC breast cancer. Pts with IBC and a complete pathologic response (pCR) in mastectomy tissue after neoadjuvant chemotherapy (NAC) have a better prognosis compared to pts with residual disease. The objectives were to characterize IBC on baseline FDG-PET with respect to hormone receptor status, tumor grade and to determine if baseline metabolic activity in primary or metastatic lymph nodes (LN) predicts pCR. Methods: This is an IRB-approved retrospective study of 28 pts. SUVmax of primary IBC tumor and local LN metastases were compared between (b/w) pts with pCR versus residual disease, b/w pts with different receptor status (ER, PR, HER2), and b/w pts with different grade tumors (1-3). Results: Baseline SUVmax was higher in 6 pts with TN tumors (median 12.4, range 5.4-29.3) compared with 22 pts with ER+ or PR+ or HER2+ tumors (5.0, 2.0-16.3, p=0.04). SUVmax in local LN metastases tended to be higher in TN tumors vs. others (11.2, 2.7-27.9 vs. 5.4, 2.0-15.5, p=0.06). SUVmax in primary IBC was not different based on tumor grade (p=0.26), but higher SUVmax was seen in metastatic LN in pts with grade 3 vs. 2 tumors (10.5, 2.0-27.9 vs. 4.7, 2.0-10.2, p=0.02). SUVmax of primary IBC tumor was not significantly different b/w pts with pCR (median 10.6, range 2-29.3) vs. residual disease (6.4, 2.5-13.6, p=0.36). No significant difference was seen b/w baseline SUVmax of locally metastatic LN between pts with pCR (9.0, 3.3-27.9) vs. residual disease (6.1, 2.0-16.2, p=0.13). Conclusions: Baseline metabolic activity of primary IBC tumor and locally metastatic LN did not predict pCR at mastectomy. Triple-negative receptor status is associated with higher SUVmax in primary tumor and marginally in metastatic LN suggesting a more aggressive nature. These findings are consistent with data in non-IBC breast cancer.
Phase II trial of a GM-CSF-producing and CD40L-expressing cell line combined with allogeneic tumor antigen as a novel vaccine for metastatic lung adenocarcinoma.
Authors: Ben C. Creelan, Scott Antonia, David Noyes, Terri B. Hunter, George R. Simon, Gerold Bepler, Charles C. Williams, Tawee Tanvetyanon, Eric B. Haura, Michael J. Schell, Sophie Dessureault, Alberto Chiappori
Journal: Journal of Clinical Oncology (2012)

2559 Background: We created a vaccine in which irradiated allogeneic lung adenocarcinoma cells are combined with a bystander K562 cell line transfected with hCD40L and hGM-CSF. By recruiting and activating dendritic cells, we hypothesized the vaccine would induce tumor regression in metastatic lung adenocarcinoma. Methods: Intradermal vaccine was given every 14 days x3, followed by monthly x3. Cyclophosphamide (300 mg/m2 IV) was administered before 1st and 4th vaccines to deplete regulatory T-cells. All-trans retinoic acid was given (150/mg/m2/day) after 1st and 4th vaccines to enhance dendritic differentiation. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and after each vaccination. T-cell activation profiles were analyzed by ELISpot assay and tested by generalized Wilcoxon for correlation to survival. Results: 24 participants were accrued at a single center from 10/2006 to 6/2008, with median age 64 and median of 3 previous lines of chemotherapy prior to entry. 20 were former smokers and 4 had brain metastases. A total of 101 vaccines were administered. Common toxicities of any grade were joint pain (79%) and fatigue (75%). Significant adverse events included a grade 3 hypotension and a grade 3 acute respiratory distress. No confirmed complete or partial radiologic responses were observed. Median overall survival (OS) was 8.0 mo (95% CI 3.5 – 12.5) and median time-to-progression was 2.4 mo (95% CI 0.3 – 4.6). Presence of HLA-A2 conferred reduced risk of progression (HR 0.37, 95% CI 0.14 -0.89, p=0.02) and trend to improved OS (HR 0.59, p = 0.06). Of 14 participants with evaluable PBMCs, 5 demonstrated sustained tumor peptide-specific T-cell activation after vaccination. Ex vivo peptide immune response correlated with improved OS compared to non-responders (23 vs. 7 mo, HR 0.48, p = 0.04). Conclusions: Vaccine administration was feasible and tolerable in a heavily pretreated population of metastatic lung cancer. These data suggest the vaccine has clinical activity in the subset with peptide-induced T-cell immune responses and warrants further investigation. A randomized trial of the vaccine is currently in development.
Roles and Regulation of Long Noncoding RNAs in Hepatocellular Carcinoma
Authors: Lee Jin Lim, Samuel Y.S. Wong, Feiyang Huang, Sheng Lim, Samuel S. Chong, London Lucien Ooi, Oi Lian Kon, Caroline G. Lee
Journal: Cancer Research (2019)

Abstract Next-generation sequencing has uncovered thousands of long noncoding RNAs (lncRNA). Many are reported to be aberrantly expressed in various cancers, including hepatocellular carcinoma (HCC), and play key roles in tumorigenesis. This review provides an in-depth discussion of the oncogenic mechanisms reported to be associated with deregulated HCC-associated lncRNAs. Transcriptional expression of lncRNAs in HCC is modulated through transcription factors, or epigenetically by aberrant histone acetylation or DNA methylation, and posttranscriptionally by lncRNA transcript stability modulated by miRNAs and RNA-binding proteins. Seventy-four deregulated lncRNAs have been identified in HCC, of which, 52 are upregulated. This review maps the oncogenic roles of these deregulated lncRNAs by integrating diverse datasets including clinicopathologic features, affected cancer phenotypes, associated miRNA and/or protein-interacting partners as well as modulated gene/protein expression. Notably, 63 deregulated lncRNAs are significantly associated with clinicopathologic features of HCC. Twenty-three deregulated lncRNAs associated with both tumor and metastatic clinical features were also tumorigenic and prometastatic in experimental models of HCC, and eight of these mapped to known cancer pathways. Fifty-two upregulated lncRNAs exhibit oncogenic properties and are associated with prominent hallmarks of cancer, whereas 22 downregulated lncRNAs have tumor-suppressive properties. Aberrantly expressed lncRNAs in HCC exert pleiotropic effects on miRNAs, mRNAs, and proteins. They affect multiple cancer phenotypes by altering miRNA and mRNA expression and stability, as well as through effects on protein expression, degradation, structure, or interactions with transcriptional regulators. Hence, these insights reveal novel lncRNAs as potential biomarkers and may enable the design of precision therapy for HCC.
Adaptive behaviour and predictive processing accounts of autism
Authors: Kelsey Perrykkad
Journal: Behavioral and Brain Sciences (2019)

Abstract Many autistic behaviours can rightly be classified as adaptive , but why these behaviours differ from adaptive neurotypical behaviours in the same environment requires explanation. I argue that predictive processing accounts best explain why autistic people engage different adaptive responses to the environment and, further, account for evidence left unexplained by the social motivation theory.
The apoptosis-inducing activity of natural plant products involved regulation of events downstream of the p53 pathway
Authors: Laxmi V. Yeruva, J. Abiodun Elegbede, Beau J. Toy, Robert C. Wang
Journal: Cancer Research (2005)

5902  Natural plant products such as perillyl alcohol and their metabolites have been reported to possess anti-tumor and drug related activities against a number of human cancers though the mechanism of action of these compounds is not yet fully known. The p53 tumor suppressor protein is a regulator of cell cycle progression. The P53 gene is mutated in most lung cancer cells resulting in the over- or under-expression of the mutant p53 protein. We studied the effects of the perillyl alcohol metabolite, perillic acid (PA), and methyl jasmonate (MJ), a naturally occurring plant compound, on the proliferation of human lung adenocarcinoma (A549) and squamous cell carcinoma of the lung (NCI-H520 and NCI-H2170) cell lines using cytotoxicity, flow cytometry, enzyme linked immunosorbent assay (ELISA) and western blotting techniques. The expression levels of p53 protein in NCI-H520 and NCI-H2170 cell lines were studied using ELISA and western blotting techniques. Both PA and MJ elicited dose- and kinetic-dependent cytotoxicity against the cell lines. Decreases in the viability of A549, NCI-H520 and NCI-H2170 were observed with the following 72-hr IC50 values: PA (2.8, >3, 2.8 mM) and MJ (1.8, 2.2, 1.25 mM) respectively. DNA content analyses using flow cytometry showed that both PA and MJ caused cell cycle arrest at G0/G1 in A549 cell line, S phase arrest in NCI-H520 cell line and G2-M phase arrest in NCI-H2170 cell line, respectively. The cell cycle arrests were accompanied by significant (p
Cartilage Repair: Injectable Cholesterol‐Enhanced Stereocomplex Polylactide Thermogel Loading Chondrocytes for Optimized Cartilage Regeneration (Adv. Healthcare Mater. 14/2019)
Authors: Chenyu Wang, Naibo Feng, Fei Chang, Jincheng Wang, Baoming Yuan, Yilong Cheng, He Liu, Jiakuo Yu, Jun Zou, Jianxun Ding, Xuesi Chen
Journal: Advanced Healthcare Materials (2019)

Scaffolds are a critical factor of cartilage tissue engineering. In article number 1900312, Yilong Cheng, He Liu, Jun Zou, Jianxun Ding, and co-workers develop a cholesterol-modified stereocomplex thermogel of four-arm poly(ethylene glycol)–polylactide with appropriate critical gelation temperature, mechanical strength, pore size, degradation, and chondrocyte adhesion for optimized cartilage regeneration. Cover design by He Liu and Jianxun Ding.
Treg Cells Promote the SREBP1-Dependent Metabolic Fitness of Tumor-Promoting Macrophages via Repression of CD8+ T Cell-Derived Interferon-γ
Authors: Chang Liu, Maria Chikina, Rahul Deshpande, Ashley V. Menk, Ting Wang, Tracy Tabib, Erin A. Brunazzi, Kate M. Vignali, Ming Sun, Donna B. Stolz, Robert A. Lafyatis, Wei Chen, Greg M. Delgoffe, Creg J. Workman, Stacy G. Wendell, Dario A.A. Vignali
Journal: Immunity (2019)
Clinical Effectiveness of Direct Oral Anticoagulants vs Warfarin in Older Patients With Atrial Fibrillation and Ischemic Stroke
Authors: Ying Xian, Haolin Xu, Emily C. O’Brien, Shreyansh Shah, Laine Thomas, Michael J. Pencina, Gregg C. Fonarow, DaiWai M. Olson, Lee H. Schwamm, Deepak L. Bhatt, Eric E. Smith, Deidre Hannah, Lesley Maisch, Barbara L. Lytle, Eric D. Peterson, Adrian F. Hernandez
Journal: JAMA Neurology (2019)

<h3>Importance</h3> Current guidelines recommend direct oral anticoagulants (DOACs) over warfarin for stroke prevention in patients with atrial fibrillation (AF) who are at high risk. Despite demonstrated efficacy in clinical trials, real-world data of DOACs vs warfarin for secondary prevention in patients with ischemic stroke are largely based on administrative claims or have not focused on patient-centered outcomes. <h3>Objective</h3> To examine the clinical effectiveness of DOACs (dabigatran, rivaroxaban, or apixaban) vs warfarin after ischemic stroke in patients with AF. <h3>Design, Setting, and Participants</h3> This cohort study included patients who were 65 years or older, had AF, were anticoagulation naive, and were discharged from 1041 Get With The Guidelines–Stroke–associated hospitals for acute ischemic stroke between October 2011 and December 2014. Data were linked to Medicare claims for long-term outcomes (up to December 2015). Analyses were completed in July 2018. <h3>Exposures</h3> DOACs vs warfarin prescription at discharge. <h3>Main Outcomes and Measures</h3> The primary outcomes were home time, a patient-centered measure defined as the total number of days free from death and institutional care after discharge, and major adverse cardiovascular events. A propensity score–overlap weighting method was used to account for differences in observed characteristics between groups. <h3>Results</h3> Of 11 662 survivors of acute ischemic stroke (median [interquartile range] age, 80 [74-86] years), 4041 (34.7%) were discharged with DOACs and 7621 with warfarin. Except for National Institutes of Health Stroke Scale scores (median [interquartile range], 4 [1-9] vs 5 [2-11]), baseline characteristics were similar between groups. Patients discharged with DOACs (vs warfarin) had more days at home (mean [SD], 287.2 [114.7] vs 263.0 [127.3] days; adjusted difference, 15.6 [99% CI, 9.0-22.1] days) during the first year postdischarge and were less likely to experience major adverse cardiovascular events (adjusted hazard ratio [aHR], 0.89 [99% CI, 0.83-0.96]). Also, in patients receiving DOACs, there were fewer deaths (aHR, 0.88 [95% CI, 0.82-0.95];<i>P</i> &lt; .001), all-cause readmissions (aHR, 0.93 [95% CI, 0.88-0.97];<i>P</i> = .003), cardiovascular readmissions (aHR, 0.92 [95% CI, 0.86-0.99];<i>P</i> = .02), hemorrhagic strokes (aHR, 0.69 [95% CI, 0.50-0.95];<i>P</i> = .02), and hospitalizations with bleeding (aHR, 0.89 [95% CI, 0.81-0.97];<i>P</i> = .009) but a higher risk of gastrointestinal bleeding (aHR, 1.14 [95% CI, 1.01-1.30];<i>P</i> = .03). <h3>Conclusions and Relevance</h3> In patients with acute ischemic stroke and AF, DOAC use at discharge was associated with better long-term outcomes relative to warfarin.
Normocentric biases taint cognitive neuroscience and intervention of autism
Authors: Laurent Mottron
Journal: Behavioral and Brain Sciences (2019)

Abstract Stepping away from a normocentric understanding of autism goes beyond questioning the supposed lack of social motivation of autistic people. It evokes subversion of the prevalence of intellectual disability even in non-verbal autism. It also challenges the perceived purposelessness of some restricted interests and repetitive behaviors, and instead interprets them as legitimate exploratory and learning-associated manifestations.
Racial differences in attitudes toward molecular testing for personalized cancer therapy.
Authors: Rafeek Adeyemi Yusuf, Deevakar Rogith, Shelly Renee Anstey Hovick, Susan K. Peterson, Allison Michelle Burton-Chase, Bryan Fellman, Yisheng Li, Diana L Urbauer, Carolyn McKinney, Elmer Victor Bernstam, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2013)

6566 Background: We assessed attitudes of breast cancer patients regarding molecular testing for personalized therapy and research. Methods: Female breast cancer patients presenting to a cancer center completed a questionnaire. Associations between demographic, clinical variables and attitudes towards molecular testing were evaluated. Results: 308 patients were approached and 100 completed the survey (32% response rate). If covered by insurance, most patients were willing to undergo molecular testing to assist in selection of both approved drugs (81%) and experimental therapy (59%). Even of testing was covered, non-white patients were less willing to undergo molecular testing for selection of approved drugs (nonwhites vs. whites, OR=0.13; p=0.0004) or experimental drugs (OR=0.26; p=0.0072; see table below). Most patients (75%) were willing to undergo a biopsy to guide therapy, and 46% were willing to undergo research biopsies. Non-white patients were less willing to undergo research biopsies (OR=0.17; p=0.0033). Patients desired return of research results when results had implications for treatment (91%), new cancer risk (90%), and other preventable/treatable diseases (87%). Conclusions: Most patients are willing to undergo molecular testing and minimally invasive procedures to guide approved or experimental therapy. There are significant differences in attitudes towards molecular testing between racial groups. Novel approaches may be needed to prevent disparities in delivery of genomically-informed care and to increase minority participation in biomarker-driven trials. [Table: see text]