tbuckley/cabot-search huggingface dataset:
Efficacy of sequential therapy comprising of docetaxel, abiraterone, enzalutamide, and cabazitaxel in patients with castration-resistant prostate cancer.
Authors: Akiyuki Yamamoto, Masashi Kato, Toyonori Tsuzuki, Momokazu Gotoh, Yushi Naito, Kyosuke Hattori, Kosuke Tochigi, Takuma Yuba, Hideji Kawanishi
Journal: Journal of Clinical Oncology (2020)

239 Background: The sequence of use of life-prolonging therapy (docetaxel, abiraterone, enzalutamide, and cabazitaxel) is unclear in patients with castration-resistant prostate cancer (CRPC). Methods: We retrospectively identified a total of 316 patients diagnosed with CRPC from September 2003 to April 2019 at Nagoya University and its affiliated hospitals. All patients were treated with &gt;2 life-prolonging therapies. We divided these patients into four groups based on the sequence of drug administration. The group of patients who were treated using the sequence of abiraterone to enzalutamide or enzalutamide to abiraterone was termed as AA. The group treated using the sequence of abiraterone or enzalutamide to docetaxel was termed as AD. The group treated using the sequence of docetaxel to abiraterone or enzalutamide was termed as DA. Lastly, the group treated using the sequence of docetaxel to cabazitaxel was termed as DC. We investigated the overall survival (OS) from the time of diagnosis of CRPC. In addition, we estimated combined progression-free survival (combined PFS) defined as the sum of the PFS of each agent. Results: The number of patients in AA, AD, DA, and DC was 106, 69, 130, and 11, respectively. Regarding AA, AD, DA, and DC, the median ages were 72, 70, 68, and 64 years, respectively. The proportion of patients who had de novo distant metastasis was 66%, 65%, 58%, and 73% in AA, AD, DA, and DC, respectively. Further, the median OS was 68.7, 54.5, 68.6, and 22.0 months for AA, AD, DA, and DC, respectively. Notably, no significant differences related to OS were observed between AA and AD ( p = 0.06), AA and DA ( p = 0.24), as well as AD and DA ( p = 0.46). The median combined PFS was 8.6, 10.1, 13.9, and 5.6 months for AA, AD, DA, and DC, respectively. In terms of combined PFS, a significant difference was observed between AA and DA ( p &lt; 0.001) as well as AD and DA ( p = 0.003). OS and combined PFS were significantly poor in DC compared with those in the other groups. Conclusions: No significant differences related to OS were observed regarding the sequence of use of docetaxel, abiraterone, and enzalutamide. Notably, combined PFS was comparatively better in DA than in any other group.
Ineffectual Type 2–to–Type 1 Alveolar Epithelial Cell Differentiation in Idiopathic Pulmonary Fibrosis: Persistence of the KRT8<sup>hi</sup> Transitional State
Authors: Peng Jiang, Rafael Gil de Rubio, Steven M. Hrycaj, Stephen J. Gurczynski, Kent A. Riemondy, Bethany B. Moore, M. Bishr Omary, Karen M. Ridge, Rachel L. Zemans
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
Salivary proteomic profile of patients with renal cell carcinoma.
Authors: Adithya Balasubramanian, Weidong Zhou, Emanuel Petricoin, Charles F. Streckfus, John R Klein, Wei Qiao, Christopher G. Wood, Jose A. Karam, Marisa Lozano, Surena F. Matin
Journal: Journal of Clinical Oncology (2020)

622 Background: We aimed to explore the salivary proteomic profile (SPP) of patients undergoing surgery for suspected renal cell carcinoma (RCC), then evaluate any significant findings in a validation cohort. Methods: Prospective IRB approved trial of consecutive patients with suspected RCC undergoing curative surgery. Saliva was collected pre- and postoperatively, and from healthy volunteers. Saliva was mixed with sodium orthovanadate and protease inhibitor, aliquoted, and frozen at -80 o C. SPP performed using biomarker concentrated saliva via core-shell hydrogel nanoparticles functionalized with molecular baits coupled to high resolution MS/MS electrospray mass spectrometry analysis; output represented as spectral counts. Wilcoxon Rank Sum test was used for comparisons; p-values were adjusted using false discovery rate (FDR) for multiple testing. Results: Exploratory phase: saliva was collected from 27 volunteers and 34 RCC patients (24 clear cell (cc)RCC, 6 chromophobe (ch)RCC, 4 other). Evaluation of cc vs chRCC revealed differential counts for 56 proteins; none were significant after adjustment by FDR. Comparison of matched pre/post-operative SPP in 14 ccRCC patients identified differential counts of 3 proteins: basic salivary proline-rich protein 3 precursor; prolactin-inducible protein precursor; and submaxillary gland androgen-regulated protein 3B precursor. These were not affected by patient age, partial/radical nephrectomy, or tumor size/stage/grade. Validation phase: power analyses indicated a sample size of 38/53 patients = 90% power = effect size of 0.6/0.5, respectively, 2-sided Type 1 error of 0.025. 49 ccRCC patients were enrolled with pre/postop saliva. 611 proteins were identified; none had differential counts after FDR. Conclusions: Using a unique biomarker technology coupled to high resolution MS, interesting SPP’s were seen between RCC subtypes and before/after ccRCC curative resection. We were unable to show significant differences in pre/post-op levels. More research is needed to further study the SPP in RCC patients and the factors impacting their differential expression. In order to aid such efforts, the raw data will be made available for future researchers.
Transient Inhibition of PI3Kδ Enhances the Therapeutic Effect of Intravenous Delivery of Oncolytic Vaccinia Virus
Authors: Mark S. Ferguson, Louisa S. Chard Dunmall, Rathi Gangeswaran, Giulia Marelli, James R. Tysome, Emily Burns, Maria A. Whitehead, Ezra Aksoy, Ghassan Alusi, Crispin Hiley, Jay Ahmed, Bart Vanhaesebroeck, Nicholas R. Lemoine, Yaohe Wang
Journal: Molecular Therapy (2020)

Tumor-targeting oncolytic viruses such as vaccinia virus (VV) are attractive cancer therapeutic agents that act through multiple mechanisms to provoke both tumor lysis and anti-tumor immune responses. However, delivery of these agents remains restricted to intra-tumoral administration, which prevents effective targeting of inaccessible and disseminated tumor cells. In the present study we have identified transient pharmacological inhibition of the leukocyte-enriched phosphoinositide 3-kinase δ (PI3Kδ) as a novel mechanism to potentiate intravenous delivery of oncolytic VV to tumors. Pre-treatment of immunocompetent mice with the PI3Kδ-selective inhibitor IC87114 or the clinically approved idelalisib (CAL-101), prior to intravenous delivery of a tumor-tropic VV, dramatically improved viral delivery to tumors. This occurred via an inhibition of viral attachment to, but not internalization by, systemic macrophages through perturbation of signaling pathways involving RhoA/ROCK, AKT, and Rac. Pre-treatment using PI3Kδ-selective inhibitors prior to intravenous delivery of VV resulted in enhanced anti-tumor efficacy and significantly prolonged survival compared to delivery without PI3Kδ inhibition. These results indicate that effective intravenous delivery of oncolytic VV may be clinically achievable and could be useful in improving anti-tumor efficacy of oncolytic virotherapy. Tumor-targeting oncolytic viruses such as vaccinia virus (VV) are attractive cancer therapeutic agents that act through multiple mechanisms to provoke both tumor lysis and anti-tumor immune responses. However, delivery of these agents remains restricted to intra-tumoral administration, which prevents effective targeting of inaccessible and disseminated tumor cells. In the present study we have identified transient pharmacological inhibition of the leukocyte-enriched phosphoinositide 3-kinase δ (PI3Kδ) as a novel mechanism to potentiate intravenous delivery of oncolytic VV to tumors. Pre-treatment of immunocompetent mice with the PI3Kδ-selective inhibitor IC87114 or the clinically approved idelalisib (CAL-101), prior to intravenous delivery of a tumor-tropic VV, dramatically improved viral delivery to tumors. This occurred via an inhibition of viral attachment to, but not internalization by, systemic macrophages through perturbation of signaling pathways involving RhoA/ROCK, AKT, and Rac. Pre-treatment using PI3Kδ-selective inhibitors prior to intravenous delivery of VV resulted in enhanced anti-tumor efficacy and significantly prolonged survival compared to delivery without PI3Kδ inhibition. These results indicate that effective intravenous delivery of oncolytic VV may be clinically achievable and could be useful in improving anti-tumor efficacy of oncolytic virotherapy.
Association of Long-term Exposure to Elevated Lipoprotein(a) Levels With Parental Life Span, Chronic Disease–Free Survival, and Mortality Risk
Authors: Benoit J. Arsenault, William Pelletier, Yannick Kaiser, Nicolas Perrot, Christian Couture, Kay-Tee Khaw, Nicholas J. Wareham, Yohan Bossé, Philippe Pibarot, Erik S. G. Stroes, Patrick Mathieu, Sébastien Thériault, S. Matthijs Boekholdt
Journal: JAMA Network Open (2020)

Elevated lipoprotein(a) (Lp[a]) levels are associated with atherosclerotic cardiovascular diseases. The association between high Lp(a) levels and human longevity phenotypes is, however, controversial.To examine whether genetically determined Lp(a) levels are associated with parental life span and chronic disease-free survival (health span) and the association between Lp(a) levels and long-term, all-cause mortality risk.In this genetic association study, cross-sectional mendelian randomization (UK Biobank [2006-2010] and LifeGen Consortium) and prospective analyses (European Prospective Investigation Into Cancer and Nutrition (EPIC)-Norfolk [1993-1997, with patients followed up to 2016]) were conducted using individual-level data on 139 362 participants. The association between a weighted genetic risk score of 26 independent single-nucleotide polymorphisms at the LPA locus on parental life span using individual participant data from the UK Biobank, as well as with summary statistics of a genome-wide association study of more than 1 million life spans (UK Biobank and LifeGen), were examined. The association between these single-nucleotide polymorphisms and the age at the end of the health span was tested using summary statistics of a previous genome-wide association study in the UK Biobank. The association between Lp(a) levels and all-cause mortality in the EPIC-Norfolk study was also investigated. Data were analyzed from December 2018 to December 2019.Genetically determined and measured Lp(a) levels.Parental life span, health span, and all-cause mortality.In 139 362 white British participants (mean [SD] age, 62.8 [3.9] years; 52% women) from the UK Biobank, increases in the genetic risk score (weighted for a 50-mg/dL increase in Lp[a] levels) were inversely associated with a high parental life span (odds ratio, 0.92; 95% CI, 0.89-0.94; P = 2.7 × 10-8). Using the Egger-mendelian randomization method, a negative association between LPA single-nucleotide polymorphisms and parental life span (mean [SD] Egger-mendelian randomization slope, -0.0019 [0.0002]; P = 2.22 × 10-18) and health span (-0.0019 [0.0003]; P = 3.00 × 10-13) was noted. In 18 720 participants from EPIC-Norfolk (5686 cases), the mortality risk for those with Lp(a) levels equal to or above the 95th percentile was equivalent to being 1.5 years older in chronologic age (β coefficient [SE], 0.194 [0.064]).The results of this study suggest a potential causal effect of absolute Lp(a) levels on human longevity as defined by parental life span, health span, and all-cause mortality. The results also provide a rationale for trials of Lp(a)-lowering therapy in individuals with high Lp(a) levels.
Deep learning-based approach for automated assessment of PTEN status.
Authors: Tamara Jamaspishvili, Stephanie Harmon, Palak Patel, Thomas Sanford, Isabelle Caven, Rachael Iseman, Sherif Mehralivand, Peter L. Choyke, David Monty Berman, Baris Turkbey
Journal: Journal of Clinical Oncology (2020)

294 Background: PTEN loss is associated with adverse outcomes in prostate cancer and has the potential to be clinically implemented as a prognostic biomarker. Deep learning algorithms applied to digital pathology can provide automated and objective assessment of biomarkers. The objective of this work was to develop an artificial intelligence (AI) system for automated detection and localization of PTEN loss in prostate cancer samples. Methods: Immunohistochemistry (IHC) was used to measure PTEN protein levels on prostate tissue microarrays (TMA) from two institutions (in-house n=272 and external n=125 patients). TMA cores were visually scored for PTEN loss by pathologists and, if present, spatially annotated. In-house cohort (N=1239 cores) were divided into 70/20/10 training/validation/testing sets. Two algorithms were developed: a) Class I=core-based, to label each core for biomarker status and b) Class II=pixel-based, to spatially distinguish areas of PTEN loss within each core. ResNet101 architecture was used to train a multi-resolution ensemble of classifiers at 5x, 10x, and 20x for Class I task and a single classifier at simulated 40x for Class II segmentation. Results: For Class I algorithm, accuracy of PTEN status was 88.3% and 93.4% in validation and testing cohorts, respectively (Table). AI-based probability of PTEN loss was higher in cores with complete loss vs partial loss. Accuracy was improved to 90.7% in validation and 93.5% in test cohorts using the Class II region-based algorithm, with median dice scores 0.833 and 0.831, respectively. Direct application to external set demonstrated a high false positive rate. Loading trained model and conservatively re-training (“fine-tuning”) on 48/320 external cohort cores improved accuracy to 93.4%. Conclusions: Results demonstrate feasibility and robustness for fully automated detection and localization of PTEN loss in prostate cancer tissue samples and possibility for time/cost-effectiveness of sample processing/scoring in research and clinical laboratories.[Table: see text]
RNA Silencing: a Model to Explore the MRGPRX2-pathway in Cultured Human Mast Cells.
Authors: Jessy Elst, Vito Sabato, Margaretha Faber, Christel Mertens, Margo Hagendorens, Luc De Clerck, Diana Campillo-Davo, Viggo Van Tendeloo, Didier Ebo
Journal: Journal of Allergy and Clinical Immunology (2020)
Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer
Authors: Michael Overman, Milind Javle, Richard E Davis, Pankaj Vats, Chandan Kumar-Sinha, Lianchun Xiao, Niharika B Mettu, Edwin R Parra, Al B Benson, Charles D Lopez, Veerendra Munugalavadla, Priti Patel, Lin Tao, Sattva Neelapu, Anirban Maitra
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background The immunosuppressive desmoplastic stroma of pancreatic cancer represents a major hurdle to developing an effective immune response. Preclinical studies in pancreatic cancer have demonstrated promising anti-tumor activity with Bruton tyrosine kinase (BTK) inhibition combined with programmed cell death receptor-1 (PD-1) blockade. Methods This was a phase II, multicenter, open-label, randomized (1:1) clinical trial evaluating the BTK inhibitor acalabrutinib, alone (monotherapy) or in combination with the anti-PD-1 antibody pembrolizumab (combination therapy). Eligible patients were adults with histologically confirmed metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1 who had received at least one prior systemic therapy. Oral acalabrutinib 100 mg twice daily was administered with or without intravenous pembrolizumab 200 mg on day 1 of each 3-week cycle. Peripheral blood was analyzed for changes in immune markers, and tumors from exceptional responders were molecularly analyzed. Results A total of 77 patients were enrolled (37 monotherapy; 40 combination therapy) with a median age of 64 years; 77% had an ECOG PS of 1. The median number of prior therapies was 3 (range 1–6). Grade 3–4 treatment-related adverse events were seen in 14.3% of patients in the monotherapy arm and 15.8% of those in the combination therapy arm. The overall response rate and disease control rate were 0% and 14.3% with monotherapy and 7.9% and 21.1% with combination therapy, respectively. Median progression-free survival was 1.4 months in both arms. Peripheral blood flow analysis demonstrated consistent reductions in granulocytic (CD15+) myeloid-derived suppressor cells (MDSCs) over time. Two exceptional responders were found to be microsatellite stable with low tumor mutation burden, low neoantigen load and no defects in the homologous DNA repair pathway. Conclusions The combination of acalabrutinib and pembrolizumab was well tolerated, but limited clinical activity was seen with either acalabrutinib monotherapy or combination therapy. Peripheral reductions in MDSCs were seen. Efforts to understand and target the pancreatic tumor microenvironment should continue. Trial registration number NCT02362048 .
Isolated nail lichen planus: An expert consensus on treatment of the classical form
Authors: Matilde Iorizzo, Antonella Tosti, Michela Starace, Robert Baran, C. Ralph Daniel, Nilton Di Chiacchio, Sophie Goettmann, Chander Grover, Eckart Haneke, Shari R. Lipner, Phoebe Rich, Bertrand Richert, Dimitris Rigopoulos, Adam I. Rubin, Martin Zaiac, Bianca Maria Piraccini
Journal: Journal of the American Academy of Dermatology (2020)
Glycolipid-mediated basophil activation in alpha-gal allergy
Authors: Onyinye I. Iweala, Shailesh K. Choudhary, Claire T. Addison, Cole J. Batty, Camille M. Kapita, Claire Amelio, Alexander J. Schuyler, Shenglou Deng, Eric M. Bachelder, Kristy M. Ainslie, Paul B. Savage, Patrick J. Brennan, Scott P. Commins
Journal: Journal of Allergy and Clinical Immunology (2020)
Ru@CeO2 yolk shell nanozymes: Oxygen supply in situ enhanced dual chemotherapy combined with photothermal therapy for orthotopic/subcutaneous colorectal cancer
Authors: Xufeng Zhu, Youcong Gong, Yanan Liu, Chunhua Yang, Sijie Wu, Guanglong Yuan, Xian Guo, Jie Liu, Xiuying Qin
Journal: Biomaterials (2020)
RNA Sequencing Analysis of Induced Pluripotent Stem Cell-Derived Cardiomyocytes From Congenital Heart Disease Patients
Authors: Tomoya Kitani, Lei Tian, Tiejun Zhang, Ilanit Itzhaki, Joe Z. Zhang, Ning Ma, Chun Liu, June-Wha Rhee, Anitra W. Romfh, George K. Lui, Joseph C. Wu
Journal: Circulation Research (2020)
Patients with eosinophilic gastrointestinal disorders and hypereosinophilia share common characteristics regardless of single or multi-organ involvement
Authors: Fei Li Kuang, Bryan Curtin, Hawwa Alao, Brent Piligian, Alexis Berry, Nicole Holland-Thomas, Astin Powers, Martha Quezado, Michael Fay, Amy Klion, Sheila Kumar, Paneez Khoury
Journal: Journal of Allergy and Clinical Immunology (2020)
Author Correction: Inducible degradation of lncRNA Sros1 promotes IFN-γ-mediated activation of innate immune responses by stabilizing Stat1 mRNA
Authors: Henan Xu, Yan Jiang, Xiaoqing Xu, Xiaoping Su, Yang Liu, Yuanwu Ma, Yong Zhao, Zhongyang Shen, Bo Huang, Xuetao Cao
Journal: Nature Immunology (2020)
SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients
Authors: Lirong Zou, Feng Ruan, Mingxing Huang, Lijun Liang, Huitao Huang, Zhongsi Hong, Jianxiang Yu, Min Kang, Yingchao Song, Jinyu Xia, Qianfang Guo, Tie Song, Jianfeng He, Hui-Ling Yen, Malik Peiris, Jie Wu
Journal: New England Journal of Medicine (2020)

SARS-CoV-2 Viral Load in Upper Respiratory Specimens The authors report results of an analysis of nasal and throat swabs from 17 patients in Zhuhai, China, who had received a diagnosis of Covid-19....
Single-Pass vs 2-Pass Endoscopic Ultrasound-Guided Fine-Needle Biopsy Sample Collection for Creation of Pancreatic Adenocarcinoma Organoids
Authors: Joseph F. Lacomb, Dennis Plenker, Hervé Tiriac, Juan Carlos Bucobo, Lionel S. D’souza, Asim S. Khokhar, Hardik Patel, Breana Channer, Dimitri Joseph, Maoxin Wu, David A. Tuveson, Ellen Li, Jonathan M. Buscaglia
Journal: Clinical Gastroenterology and Hepatology (2020)
Interim Results of a Phase II Study of Sunitinib and Low Dose Metronomic Cyclophosphamide in Advanced Renal Cell Cancer
Authors: M.A. Khattak, K. Edmonds, K. Khabra, A. Sohaib, K. Pennert, L. Pickering, M.E. Gore, J. Larkin
Journal: Annals of Oncology (2012)
Life as a neurosurgeon
Authors: Jacqui Wise
Journal: BMJ (2020)

Neurosurgeons assess, diagnose, and undertake surgery to treat disorders of the central nervous system, including the brain and spine.The work is varied and challenging.Neurosurgeons deal with patients of all ages, from newborn babies to elderly people, and treat a range of conditions (see box 1).Neurosurgeons increasingly work as part of a large multidisciplinary team.Within the operating theatre they work with other surgeons, anaesthetists, trainee doctors, theatre nurses, and medical students.Outside of theatre they work closely with radiologists who use a range of diagnostic tools, including computed tomography and magnetic resonance imaging scans and other techniques such as brain angiography.They also work with other physicians and surgeons, including neurologists, oncologists, ophthalmologists, and paediatricians.