tbuckley/cabot-search huggingface dataset:
Expression of nectin-4 in bladder cancer with variant histology.
Authors: Jean H. Hoffman-Censits, Woonyoung Choi, Kara Lombardo, Noah M. Hahn, David James McConkey, Bridget McGuire, Vamsi Parimi (Parini), Andres Matoso
Journal: Journal of Clinical Oncology (2020)

546 Background: The antibody-drug conjugate enfortumab vedotin is poised to change the bladder cancer (BC) treatment landscape by targeting Nectin-4, near ubiquitously expressed in urothelial cancer (UC). Less is known about this and other targets in BC with pure or mixed variant histology (VH). Methods: Immunohistochemistry (IHC) was performed on a Ventana Discovery Autostainer (Roche Diagnostics) using an ultraView DAB detection kit (Roche Diagnostics) and a Nectin-4 polyclonal antibody (1:100 dilution; Abcam, Cambridge, UK). The intensity and extent of Nectin-4 expression was determined by the histochemical scoring (H-score) used in preclinical testing, defined as the sum of the products of the staining intensity (score of 0–3) x % of cells (0–100) stained at a given intensity. Specimens were assessed by H score as: negative (0–14), weak (15–99), moderate (100–199), and strong (200–300). Results: Forty UC and VH BC were evaluated for Nectin-4 expression by IHC: 15 small cell (SCBC) (8 pure SCBC, 6 mixed SCBC/UC, 1 SCBC/CIS), 8 carcinosarcomas (CS) (7 pure CS, 1 HGUC/sarcomatoid features), and 17 pure HGUCs. Normal urothelium and stroma were negative. Eight of 8 (100%) pure SCBC were negative for Nectin-4. Six of 7 (85.3%) mixed SCBC+HGUC/CIS had weak staining and 1/7 (14.7%) had moderate staining in the urothelial components (comp) while 7/7 (100%) of the SCBC comp were negative. Seven of 7 (100%) pure CS were negative and 1/1 (100%) mixed CS+HGUC showed weak staining in the HGUC comp while the sarcomatoid comp was negative. Expression in UC was: 1/17 (5.9%) strong, 3/17 (17.6%) moderate, 10/17 (58.8%) weak, and 3/17 (17.6%) negative. Gene expression profiling confirmed Nectin-4 was downregulated in VH compared to UC samples, as was ERBB2 and Trop2. Conclusions: There is heterogeneity of expression of Nectin-4 and other targets in BC with VH compared to UC. This may have therapeutic implications, and highlights need for additional research in VH.[Table: see text]
Effect of Physician Gender and Race on Simulated Patients’ Ratings and Confidence in Their Physicians
Authors: Rachel E. Solnick, Kyle Peyton, Gordon Kraft-Todd, Basmah Safdar
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Women and black physicians encounter workplace challenges because of their gender and race. It is unclear whether these individuals are assessed with lower patient satisfaction or confidence ratings compared with white male physicians. <h3>Objective</h3> To examine whether physician gender and race affect participant ratings in scenarios in which physician competence is challenged. <h3>Design, Setting, and Participants</h3> This randomized trial enrolled a geographically diverse sample of 3592 online respondents in the United States who were recruited from 2 crowdsourcing platforms: Amazon Mechanical Turk (n = 1741) and Lucid (n = 1851). A 2 × 2 factorial design for the gender and race of simulated physicians was conducted between March 9 and July 25, 2018. Participants were excluded before intervention if they were younger than 18 years, were pregnant, or had a history of cancer or abdominal surgical procedures. <h3>Interventions</h3> A clinical vignette was presented to the participant with a picture of the emergency department physician. Participants were randomly assigned to physicians with different gender and race, with 823 assigned to black women, 791 to black men, 828 to white women, and 835 to white men. A contradictory diagnosis from an online symptom checker introduced doubt about the clinical diagnosis. <h3>Main Outcomes and Measures</h3> A composite outcome (range, 0-100, with 0 representing low patient confidence and satisfaction and 100 representing the maximum on the composite scale) measured participant (1) confidence in the physician, (2) satisfaction with care, (3) likelihood to recommend the physician, (4) trust in the physician's diagnosis, and (5) likelihood to request additional tests. <h3>Results</h3> Among 3277 adult participants, complete data were available for 3215 (median age, 49 years [range, 18-89 years]; 1667 [52%] female; 2433 [76%] white). No significant differences were observed in participant satisfaction and physician confidence for the white male physician control physicians (mean composite score, 66.13 [95% CI, 64.76-67.51]) compared with white female (mean composite score, 66.50 [95% CI, 65.19-67.82]), black female (mean composite score, 67.36 [95% CI, 66.03-68.69]), and black male (mean composite score, 66.96 [95% CI, 65.55-68.36]) physicians. Machine learning with bayesian additive regression trees revealed no evidence of treatment effect heterogeneity as a function of participants' race, gender, racial prejudice, or sexism. <h3>Conclusions and Relevance</h3> No significant differences were observed for simulated patients' evaluations of female or black physicians, suggesting that bias in favor of white male physicians is negligible in survey-based measures of patient satisfaction. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT04190901
A New Equation for Calculation of Low-Density Lipoprotein Cholesterol in Patients With Normolipidemia and/or Hypertriglyceridemia
Authors: Maureen Sampson, Clarence Ling, Qian Sun, Roa Harb, Mohmed Ashmaig, Russell Warnick, Amar Sethi, James K. Fleming, James D. Otvos, Jeff W. Meeusen, Sarah R. Delaney, Allan S. Jaffe, Robert Shamburek, Marcelo Amar, Alan T. Remaley
Journal: JAMA Cardiology (2020)

Low-density lipoprotein cholesterol (LDL-C), a key cardiovascular disease marker, is often estimated by the Friedewald or Martin equation, but calculating LDL-C is less accurate in patients with a low LDL-C level or hypertriglyceridemia (triglyceride [TG] levels ≥400 mg/dL).To design a more accurate LDL-C equation for patients with a low LDL-C level and/or hypertriglyceridemia.Data on LDL-C levels and other lipid measures from 8656 patients seen at the National Institutes of Health Clinical Center between January 1, 1976, and June 2, 1999, were analyzed by the β-quantification reference method (18 715 LDL-C test results) and were randomly divided into equally sized training and validation data sets. Using TG and non-high-density lipoprotein cholesterol as independent variables, multiple least squares regression was used to develop an equation for very low-density lipoprotein cholesterol, which was then used in a second equation for LDL-C. Equations were tested against the internal validation data set and multiple external data sets of either β-quantification LDL-C results (n = 28 891) or direct LDL-C test results (n = 252 888). Statistical analysis was performed from August 7, 2018, to July 18, 2019.Concordance between calculated and measured LDL-C levels by β-quantification, as assessed by various measures of test accuracy (correlation coefficient [R2], root mean square error [RMSE], mean absolute difference [MAD]), and percentage of patients misclassified at LDL-C treatment thresholds of 70, 100, and 190 mg/dL.Compared with β-quantification, the new equation was more accurate than other LDL-C equations (slope, 0.964; RMSE = 15.2 mg/dL; R2 = 0.9648; vs Friedewald equation: slope, 1.056; RMSE = 32 mg/dL; R2 = 0.8808; vs Martin equation: slope, 0.945; RMSE = 25.7 mg/dL; R2 = 0.9022), particularly for patients with hypertriglyceridemia (MAD = 24.9 mg/dL; vs Friedewald equation: MAD = 56.4 mg/dL; vs Martin equation: MAD = 44.8 mg/dL). The new equation calculates the LDL-C level in patients with TG levels up to 800 mg/dL as accurately as the Friedewald equation does for TG levels less than 400 mg/dL and was associated with 35% fewer misclassifications when patients with hypertriglyceridemia (TG levels, 400-800 mg/dL) were categorized into different LDL-C treatment groups.The new equation can be readily implemented by clinical laboratories with no additional costs compared with the standard lipid panel. It will allow for more accurate calculation of LDL-C level in patients with low LDL-C levels and/or hypertriglyceridemia (TG levels, ≤800 mg/dL) and thus should improve the use of LDL-C level in cardiovascular disease risk management.
Correction to: Adenovirus-mediated LIGHT gene modification in murine B-cell lymphoma elicits a potent antitumor effect
Authors: Guili Hu, Yang Liu, Hong Li, Dekuang Zhao, Liuqing Yang, Jiangen Shen, Xuejun Hong, Xuetao Cao, Qingqing Wang
Journal: Cellular and Molecular Immunology (2020)
18P Relevance and Prediction of Breast Cancer Phenotype in Primary Tumor and its Positive Lymph Nodes and Later Disease Recurrence (Metastatic Breast Cancer): Results of the Primet-Trial (WSG / Detect)
Authors: R. Wuerstlein, M. Freudenberger, L. Wildenburg, M. Ortmann, C. Liedtke, O. Gluz, R. Kates, T. Fehm, U. Nitz, N. Harbeck
Journal: Annals of Oncology (2012)
Cellulose Nanofibril Hydrogel Promotes Hepatic Differentiation of Human Liver Organoids
Authors: Melanie Krüger, Loes A. Oosterhoff, Monique E. van Wolferen, Simon A. Schiele, Andreas Walther, Niels Geijsen, Laura De Laporte, Luc J. W. van der Laan, Linda M. Kock, Bart Spee
Journal: Advanced Healthcare Materials (2020)

Abstract To replicate functional liver tissue in vitro for drug testing or transplantation, 3D tissue engineering requires representative cell models as well as scaffolds that not only promote tissue production but also are applicable in a clinical setting. Recently, adult liver‐derived liver organoids are found to be of much interest due to their genetic stability, expansion potential, and ability to differentiate toward a hepatocyte‐like fate. The current standard for culturing these organoids is a basement membrane hydrogel like Matrigel (MG), which is derived from murine tumor material and apart from its variability and high costs, possesses an undefined composition and is therefore not clinically applicable. Here, a cellulose nanofibril (CNF) hydrogel is investigated with regard to its potential to serve as an alternative clinical grade scaffold to differentiate liver organoids. The results show that its mechanical properties are suitable for differentiation with overall, either equal or improved, functionality of the hepatocyte‐like cells compared to MG. Therefore, and because of its defined and tunable chemical definition, the CNF hydrogel presents a viable alternative to MG for liver tissue engineering with the option for clinical use.
Effect of the DP2 antagonist, GB001, on asthma worsening in patients with mild-moderate asthma
Authors: Koichiro Asano, Masumi Hirata, Nicola Hanania, Ian Pavord, Harry Southworth, Cindy-ann Tompkins, Gregory Opiteck, Karen Dittrich, Hector Ortega
Journal: Journal of Allergy and Clinical Immunology (2020)
Doublecortin expression in prostate adenocarcinoma and neuroendocrine tumors.
Authors: Shervin Tabrizi, Mohammed Alshalalfa, Brandon Arvin Virgil Mahal, Elai Davicioni, Yang Liu, Kent William Mouw, Felix Y Feng, Paul L. Nguyen, Vinayak Muralidhar
Journal: Journal of Clinical Oncology (2020)

161 Background: Recent work using prostate cancer mouse models implicated doublecortin (DCX)-expressing neural progenitor cells in prostate adenocarcinoma, reporting a strong association between DCX expression and disease progression and outcome. We sought to evaluate the relationship between DCX expression and these outcomes in human prostate cancer. Methods: DCX expression was measured in transcriptome-wide microarray data from 18,501 patients with localized prostate cancer and 290 patients with metastatic castration-resistant prostate cancer (mCRPC). Pairwise comparisons were performed using the Mann–Whitney U test. Metastasis-free survival (MFS) and overall survival (OS) were analyzed using Cox-proportional hazards. Results: DCX expression was not significantly different between normal prostate (n=29), primary prostate cancer (n=131), or metastases (n=19) (p &gt; 0.5), and did not differ across Gleason score in a large cohort of RP samples (n=17,967, p=0.21). The lack of difference persisted after adjusting for stromal contribution using a 141-gene stromal signature. Those with DCX expression above and below the median did not have significant differences in MFS (HR 1.2 [0.84-1.7], p=0.3) or OS (HR 1.15 [0.7-1.84], p =0.56). In a cohort of untreated prostate cancer, DCX expression was higher in neuroendocrine tumors (n=10) compared to Gleason 9-10 prostate adenocarcinoma (n=110) (p=0.007). Similarly, in two cohorts with mCRPC (n=290), DCX expression was higher in lesions with neuroendocrine features than adenocarcinoma (p&lt;0.001). Consistently, in a patient-derived xenograft model subjected to host castration, DCX expression was initially low, but increased significantly once tumors underwent neuroendocrine differentiation and treatment escape. Conclusions: Contrary to recent data using mouse models, DCX expression did not differ by disease state, grade, or outcome in a dataset of human patients with prostate adenocarcinoma. However, DCX expression appeared to correlate with neuroendocrine prostate cancers, a subgroup that can arise de novo or in the castrate-resistant setting. Further work is needed to define the role of DCX expression and its prognostic significance in prostate cancer.
Isotope selection and PSA failure in prostate seed implant: Experience with CS-131 in a community hospital system.
Authors: Jacquelyn G. Booher, Peter Domenig, Paul J. Chuba
Journal: Journal of Clinical Oncology (2020)

375 Background: A recent large single institutional study reported excellent long-term biochemical control and survival for Cs-131 prostate implant. This isotope has short half-life (9.7 days) with clinical advantages including shorter duration of symptoms. We previously showed Cs-131 dosimetry to be quantitatively similar to I-125 with improved homogeneity (mean percent V150 36% for I-125 versus 27% for Cs-131 (p &lt; 0.0001). Our objective was to evaluate PSA failure rates and dosimetric outcomes in a multi-institutional community based setting. Methods: Within an IRB approved retrospective study, we compared outcomes for three groups of permanent prostate implant patients treated at Ascension Macomb Oakland, Ascension Saint John, and Ascension Providence Rochester Hospitals over a 10 year time interval. The comparison groups included isotopes Cs-131 (n = 66; t1/2 9.7 days), I-125 (n = 60; t1/2 60 days), and Pd-103 (n = 60; t1/2 17 days). Kaplan Meier estimates of PSA failure used the nadir plus 2 (Phoenix) definition. Results: Standard permanent implant doses employed were 145 Gy for I-125 monotherapy or 109 Gy for combination therapy. The dose for Cs-131 was 115 Gy for monotherapy and 85 Gy for combination therapy. For Pd-103, the doses employed were 125 Gy and 90 Gy for mono- and combination therapy, respectively. Median age at diagnosis was Cs-131; 69 (range 49-80), I-125; 71 (49-78), and Pd-103; 70 (60-82). Mean pretreatment PSA values were Cs-131 5.73 ng/ml, I-125 6.62 ng/ml, and for Pd-103 8.87 ng/ml. Median PSA follow up was 30 months and the median PSA value at 60 months was 0.11 ng/ml. There was excellent PSA control for all three groups of cases (p = NS), however with fewer failures using Cs-131. Conclusions: Permanent interstitial brachytherapy continues to be an attractive option for treatment early stage prostate cancer. Only a few large single institutional studies have examined PSA failure rates or dosimetric aspects of shorter half-life Cs-131 seed implants. This series confirms wide applicability of Cs-131 permanent prostate seed implant in the community hospital setting.
Disturbed genomic imprinting and its relevance for human reproduction: causes and clinical consequences
Authors: Miriam Elbracht, Deborah Mackay, Matthias Begemann, Karl Oliver Kagan, Thomas Eggermann
Journal: Human Reproduction Update (2020)

Human reproductive issues affecting fetal and maternal health are caused by numerous exogenous and endogenous factors, of which the latter undoubtedly include genetic changes. Pathogenic variants in either maternal or offspring DNA are associated with effects on the offspring including clinical disorders and nonviable outcomes. Conversely, both fetal and maternal factors can affect maternal health during pregnancy. Recently, it has become evident that mammalian reproduction is influenced by genomic imprinting, an epigenetic phenomenon that regulates the expression of genes according to their parent from whom they are inherited. About 1% of human genes are normally expressed from only the maternally or paternally inherited gene copy. Since numerous imprinted genes are involved in (embryonic) growth and development, disturbance of their balanced expression can adversely affect these processes.This review summarises current our understanding of genomic imprinting in relation to human ontogenesis and pregnancy and its relevance for reproductive medicine.Literature databases (Pubmed, Medline) were thoroughly searched for the role of imprinting in human reproductive failure. In particular, the terms 'multilocus imprinting disturbances, SCMC, NLRP/NALP, imprinting and reproduction' were used in various combinations.A range of molecular changes to specific groups of imprinted genes are associated with imprinting disorders, i.e. syndromes with recognisable clinical features including distinctive prenatal features. Whereas the majority of affected individuals exhibit alterations at single imprinted loci, some have multi-locus imprinting disturbances (MLID) with less predictable clinical features. Imprinting disturbances are also seen in some nonviable pregnancy outcomes, such as (recurrent) hydatidiform moles, which can therefore be regarded as a severe form of imprinting disorders. There is growing evidence that MLID can be caused by variants in the maternal genome altering the imprinting status of the oocyte and the embryo, i.e. maternal effect mutations. Pregnancies of women carrying maternal affect mutations can have different courses, ranging from miscarriages to birth of children with clinical features of various imprinting disorders.Increasing understanding of imprinting disturbances and their clinical consequences have significant impacts on diagnostics, counselling and management in the context of human reproduction. Defining criteria for identifying pregnancies complicated by imprinting disorders facilitates early diagnosis and personalised management of both the mother and offspring. Identifying the molecular lesions underlying imprinting disturbances (e.g. maternal effect mutations) allows targeted counselling of the family and focused medical care in further pregnancies.
Sirtuin 5 deficiency increases disease severity in rats with adjuvant-induced arthritis
Authors: Ni Zhang, Hui Zhang, Betty Yuen Kwan Law, Ivo Ricardo De Seabra Rodrigues Dias, Cong Ling Qiu, Wu Zeng, Hu Dan Pan, Jin Yun Chen, Yan Fu Bai, Jing Lv, Li Qun Qu, Xi Chen, Qi Huang, Wei Zhang, Li Jun Yang, Lu Yu, Yu Han, Guo Xin Huang, Hui Miao Wang, Xiao Lei Sun, Yun Zhang, Hu Qiang He, Wei Dan Luo, Yao Xiao, Jian Zhou, Ting Xu, Qing Chun Huang, Min Wu, Zhi Sheng Huang, Wei Liu, Vincent Kam Wai Wong, Liang Liu
Journal: Cellular and Molecular Immunology (2020)
The Prevalence of Food Allergy and Parental Report of Treatment for GERD in the FORWARD Study
Authors: Mary Tobin, Susan Fox, Mahboobeh Mahdavinia, Aame Andy-Nweye, Perry Catlin, Annika Chura, Amal Assa'ad, Adam Robinson, Iman Abdikarim, Hemant Sharma, Amaziah Coleman, Jialing Jiang, Lucy Bilaver, Christopher Warren, Jamie Fierstein, Pamela Newmark, Alexandria Bozen, Olivia Negris, Jacqueline Pongracic, Ruchi Gupta
Journal: Journal of Allergy and Clinical Immunology (2020)
Letter to the editor: Plenty of coronaviruses but no SARS-CoV-2
Authors: Philippe Colson, Bernard La Scola, Vera Esteves-Vieira, Laetitia Ninove, Christine Zandotti, Marie-Thérèse Jimeno, Céline Gazin, Marielle Bedotto, Véronique Filosa, Audrey Giraud-Gatineau, Hervé Chaudet, Philippe Brouqui, Jean-Christophe Lagier, Didier Raoult
Journal: Eurosurveillance (2020)

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MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer
Authors: Ibiayi Dagogo-Jack, Satoshi Yoda, Jochen K. Lennerz, Adam Langenbucher, Jessica J. Lin, Marguerite M. Rooney, Kylie Prutisto-Chang, Audris Oh, Nathaniel A. Adams, Beow Y. Yeap, Emily Chin, Andrew Do, Hetal D. Marble, Sara E. Stevens, Subba R. Digumarthy, Ashish Saxena, Rebecca J. Nagy, Cyril H. Benes, Christopher G. Azzoli, Michael S. Lawrence, Justin F. Gainor, Alice T. Shaw, Aaron N. Hata
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed. Experimental Design: We performed FISH and/or next-generation sequencing on 207 posttreatment tissue (n = 101) or plasma (n = 106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance. Results: MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib (P = 0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid responses to ALK/MET combination therapy. Conclusions: Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET.