tbuckley/cabot-search huggingface dataset:
Microbiome Profile of Psoriasis and Atopic Dermatitis Using Transcriptome Analysis
Authors: Mira Choi, In Cheol Seo, Dong Hyun Kim, Jeong-Woo Choi, Jung Min Park, Ji Won Oh
Journal: Journal of Allergy and Clinical Immunology (2019)

Many skin diseases are the result of interaction between predisposing genetic susceptibility from the patient and the external environmental factors such as commensal microbiome or physical contacts. Recent advances in analyzing host and microbiome using high-throughput sequencing have enabled analysis of genetic composition and functionality of human health and diseases. In this study, using the transcriptome of the diseased region and non-involved region from patients including information of microbiome transcriptome, we tried to elucidate the interaction between host and microbiome in psoriasis and atopic dermatitis (AD). We used the suitable public RNAseq data of psoriasis and AD from GEO for the analysis of this study. We aligned the data using STAR aligner and used the mapped read for transcriptome analysis. Unmapped sequences are utilized for mapping to bacterial genome by pathseq, leading us to investigate the microbiome profile. Then, we analyzed the interplay between differential expressed genes of host and microbial profiles. We found that their transcriptome from diseased region and heathy region of the patients are quite distinct, showing that immunologic pathways are altered, and cell cycle related genes are highlighted. Based on the analysis of skyline plot, we found that proteobacteria, actinobacteria and firmicutes are relatively common in the psoriasis and AD skin. Using RNAseq, physicians can gather the high throughput information of transcriptome data of diseased area as well as the relevant microbiome data resulted from the disease, which could be used to develop a new approach to the treatment.
IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma
Authors: Alex B. Blair, Jennifer Kleponis, Dwayne L. Thomas, Stephen T. Muth, Adrian G. Murphy, Victoria Kim, Lei Zheng
Journal: Journal of Clinical Investigation (2019)

Pancreatic ductal adenocarcinoma (PDAC) represents an immune quiescent tumor that is resistant to immune checkpoint inhibitors. Previously, our group has shown that a GM-CSF–secreting allogenic pancreatic tumor cell vaccine (GVAX) may prime the tumor microenvironment by inducing intratumoral T cell infiltration. Here, we show that untreated PDACs express minimal indoleamine-2,3-dioxygenase (IDO1); however, GVAX therapy induced IDO1 expression on tumor epithelia as well as vaccine-induced tertiary lymphoid aggregates. IDO1 expression plays a role in regulating the polarization of Th1, Th17, and possibly T regulatory cells in PDAC tumors. IDO1 inhibitor enhanced antitumor efficacy of GVAX in a murine model of PDACs. The combination of vaccine and IDO1 inhibitor enhanced intratumoral T cell infiltration and function, but adding anti–PD-L1 antibody to the combination did not offer further synergy and in fact may have had a negative interaction, decreasing the number of intratumoral effector T cells. Additionally, IDO1 inhibitor in the presence of vaccine therapy did not significantly modulate intratumoral myeloid-derived suppressor cells quantitatively, but diminished their suppressive effect on CD8+ proliferation. Our study supports the combination of IDO1 inhibitor and vaccine therapy; however, it does not support the combination of IDO1 inhibitor and anti–PD-1/PD-L1 antibody for T cell–inflamed tumors such as PDACs treated with vaccine therapy.
Abstract B11: Prostate apoptosis response-4 (PAR4) secretion in breast tumor and normal cell lines cultured in hypoxic conditions
Authors: Simone Aparecida de Bessa Garcia, Irina Gueroldovna Brobovnitchaia, Flavia Rotea Mangone, Maria Aparecida Nagai
Journal: Clinical Cancer Research (2018)

Abstract The prostate apoptosis response-4 (PAR4) gene encodes a 38kDa proapoptotic protein with tumor cell selective action and/or cell sensitization to an additional proapoptotic insult. This selective apoptotic ability is associated with PAR4 nuclear translocation and phosphorylation state. PAR-4 acts through intrinsic and extrinsic apoptotic pathways. PAR-4 can also be secreted by normal/immortalized and cancer cells via the classical ER stress pathway mediated by GRP78. The previous study from our group provided evidence that MCF10A cells cultured in three-dimensional conditions display an increased expression of PAR4 in the center of the acini, where the cells are dying to lumen formation and where the O2 levels are expected to be lower. In the present study, we sought to evaluate the effects of hypoxia on PAR4 secretion in mammary epithelial cells and breast cancer cells. MCF10A (immortalized mammary epithelial cells) and the breast cancer cells MCF7, MDA-MB-231, and SKBR3 were cultured in normoxic and hypoxic (1% O2) conditions. The conditioned medium (CM) was concentrated using Amicon Ultra 10kDA filters and resolved by SDS-PAGE gel electrophoresis in parallel to cell lysate analysis. Cells maintained under hypoxic conditions for 6 h, 24 h, and 48 h showed no alteration in intracellular PAR4 protein levels in relation to cells maintained in normoxia. After 72 h we observed a decrease in intracellular PAR4 protein expression. The GRP78 protein expression did not change in the same time periods. However, Caspase-7 activation could be seen in 24 h, 48 h, and 72 h. Furthermore, we observed an increase (2.7 fold) in PAR4 protein expression in the CM after 72 h under hypoxia. Our results demonstrated for the first time that PAR4 secretion is modulated by hypoxia in normal and tumor breast cells. Further experimental and clinical studies are needed to determine the mechanism and role played by PAR4 secretion in cells' sensitivity to standard chemotherapeutics agents. Supported by FAPESP and CNPq. Citation Format: Simone Aparecida de Bessa Garcia, Irina Gueroldovna Brobovnitchaia, Flavia Rotea Mangone, Maria Aparecida Nagai. Prostate apoptosis response-4 (PAR4) secretion in breast tumor and normal cell lines cultured in hypoxic conditions [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B11.
Estimating Retinal Sensitivity Using Optical Coherence Tomography With Deep-Learning Algorithms in Macular Telangiectasia Type 2
Authors: Yuka Kihara, Tjebo F. C. Heeren, Cecilia S. Lee, Yue Wu, Sa Xiao, Simone Tzaridis, Frank G. Holz, Peter Charbel Issa, Catherine A. Egan, Aaron Y. Lee
Journal: JAMA Network Open (2019)

IMPORTANCEAs currently used, microperimetry is a burdensome clinical testing modality for testing retinal sensitivity requiring long testing times and trained technicians.OBJECTIVE To create a deep-learning network that could directly estimate function from structure de novo to provide an en face high-resolution map of estimated retinal sensitivity.DESIGN, SETTING, AND PARTICIPANTS A cross-sectional imaging study using data collected between January 1, 2016, and November 30, 2017, from the Natural History Observation and Registry of macular telangiectasia type 2 (MacTel) evaluated 38 participants with confirmed MacTel from 2 centers.MAIN OUTCOMES AND MEASURES Mean absolute error of estimated compared with observed retinal sensitivity.Observed retinal sensitivity was obtained with fundus-controlled perimetry (microperimetry).Estimates of retinal sensitivity were made with deep-learning models that learned on superpositions of high-resolution optical coherence tomography (OCT) scans and microperimetry results.Those predictions were used to create high-density en face sensitivity maps of the macula.Training, validation, and test sets were segregated at the patient level.RESULTS A total of 2499 microperimetry sensitivities were mapped onto 1708 OCT B-scans from 63 eyes of 38 patients (mean [SD] age, 74.3 [9.7] years; 15 men [39.5%]).The numbers of examples for our algorithm were 67 899 (103 053 after data augmentation) for training, 1695 for validation, and 1212 for testing.Mean absolute error results were 4.51 dB (95% CI, 4.36-4.65 dB) when using linear regression and 3.66 dB (95% CI, 3.53-3.78dB) when using the LeNet model.Using a 49.9 millionvariable deep-learning model, a mean absolute error of 3.36 dB (95% CI, 3.25-3.48dB) of retinal sensitivity for validation and test was achieved.Correlation showed a high degree of agreement (Pearson correlation r = 0.78).By paired Wilcoxon rank sum test, our model significantly outperformed these 2 baseline models (P < .001). CONCLUSIONS AND RELEVANCEHigh-resolution en face maps of estimated retinal sensitivities were created in eyes with MacTel.The maps were of unequalled resolution compared with microperimetry and were able to correctly delineate functionally healthy and impaired retina.This model may be useful to monitor structural and functional disease progression and has potential as an objective surrogate outcome measure in investigational trials.
STATUS OF EARLY CAREER ACADEMIC CARDIOLOGY: A GLOBAL PERSPECTIVE
Authors: Carl Wei-Chan Tong, Meenakshi Madhur, Anne Rzeszut, Anne Marie Valente, Ravi Hira, Steve Leung, Yoni Bubor, Dmitriy Feldman, Islam Abudayyeh, Melanie Turner, Erica Spatz, Rakesh Gopinathannair, Andrew Freeman
Journal: Journal of the American College of Cardiology (2017)
Precision Medicine vs Preventive Medicine—Reply
Authors: Bruce M. Psaty, Olaf M. Dekkers, Richard S. Cooper
Journal: JAMA (2019)

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A case-control study into risk factors for acute hepatitis E in the Netherlands, 2015–2017
Authors: Anna Dolores Tulen, Harry Vennema, Wilfrid van Pelt, Eelco Franz, Agnetha Hofhuis
Journal: Journal of Infection (2019)

ObjectivesA case-control study was performed (2015–2017) to identify risk factors for acute hepatitis E in the Netherlands.MethodsA questionnaire on potential sources of hepatitis E virus (HEV) exposure, health and socio-demographics was completed by 376 patients with acute hepatitis E, and 1534 controls matched for age, gender and region of residence.ResultsTraditional Dutch dry raw sausages of pork muscle meat, called "cervelaat", "snijworst", and "boerenmetworst" were reported by 72% of the patients, and 46% of controls (aOR 3.0; 95%CI 2.2–4.1), with a population attributable fraction (PAF) of 48%. Direct contact with pigs and working with a septic tank were strong risk factors (aOR 3.1; 95%CI 1.3–7.3 and aOR 6.9; 95%CI 1.2–40.8, respectively), with a low PAF (2% and 1%, respectively). Host risk factors were pre-existing liver disease (aOR 3.8; 95%CI 2.0–7.1), diabetes (aOR 2.1; 95%CI 1.4–3.2), immunosuppressive medication (aOR 2.5; 95%CI 1.5–4.1), and gastric acid inhibitors (aOR 2.3; 95%CI 1.7–3.1).ConclusionsDry raw pork sausages were the major source of HEV infection among our study population. The prevalence and cause of HEV contamination in these pork muscle meat products require further investigation. Infrequently reported, yet strong risk factors were contact with pigs, or a septic tank.
Obinutuzumab for CLL Relapsed and Refractory Patients When New Oral Drugs an Not Available
Authors: Laura Fogliatto, Kamila Grokoski, Ana Segatto, Mirna Philipp, Jorge Vaz Pinto Neto, Eugenio Escovar, Yuri Vasconcelos, Jair Schimidt Filho, Talita Silveira, Tania Hellwig, Christina Fraga
Journal: Blood (2017)
Hand-to-genital and genital-to-genital transmission of human papillomaviruses between male and female sexual partners (HITCH): a prospective cohort study
Authors: Talía Malagón, Karolina Louvanto, Michel Wissing, Ann N Burchell, Pierre-Paul Tellier, Mariam El-Zein, François Coutlée, Eduardo L Franco
Journal: The Lancet Infectious Diseases (2019)
Adjuvant chemotherapy of S-1 versus S-1 plus metformin for resected pancreatic cancer: A multicenter and randomized phase II trial.
Authors: Masato Narita, Masayuki Furukawa, Ichiro Sakamoto, Yutaka Itoh, Hiroshi Nakano, Takuji Naka, Takeshi Sudo, Noboru Yahara, Hideki Aoki, Kouji Oota, Toshifumi Matsumoto, Mototsugu Shimokawa, Terumasa Hisano
Journal: Journal of Clinical Oncology (2019)

TPS474 Background: Adjuvant chemotherapy with S-1 in patients with resected pancreatic ductal adenocarcinoma (PDAC) improved the 5-year survival rate to 44.1% and therefore has been a standard of care in Japan. Recent epidemiologic data has revealed possibility of metformin (a drug for type II diabetes) improving the prognosis of PDAC. In this context, we compare the efficacy and safety of S-1 plus metformin with S-1 alone as adjuvant chemotherapy in patients with resected PDAC. Methods: This multicenter-randomized-phase II study is conducted at 29 institutions in Japan (Registry Number; UMIN000020681). Key eligibility criteria are age 20 years or more with good performance status; histologically proven PDAC of stage I-II without macroscopic residual tumor. Patients receiving preoperative treatment for PDAC and previously treated with DPP-4 inhibitor, GLP-1, and metformin are excluded. After giving written consent to the study, patients are randomly assigned either study group (S-1 plus metformin) or control group (S-1 alone), balancing residual tumor status, nodal status, and institutions. S-1 is given orally for 2 weeks in a 3-week cycle. Cycles are lasted for 6 months. In the study group, metformin is administrated together with S-1 for 2 years. The treatment would be discontinued when the patient has either recurrence or unacceptable toxicity. The primary endpoint is 2-year OS, and the secondary endpoints are relapse-free survival and incidence rate of adverse events. Sample size was calculated based on the data in previous trials, with an expected 2-year survival rate in the control group of 65%. An improvement in 2-year-survival rate from 65% in the control group to 78% in the study group, yielding a hazard ratio of 0.58, is considered clinically relevant in this population. A total of 73 events in each group were required for a power of 80% at a two-sided alpha 20% to detect a difference in OS using an unstratified log-rank test. A total of 160 patients (80 per group) were estimated to achieve the specified number of events in the scheduled follow-up. Duration of this study would be 5 years and it has been started from January 2018. Until September 2018, 17 patients have been enrolled. Clinical trial information: UMIN000020681.
Preclinical Evaluation of Safety and Biodistribution of Red Cell Microparticles (RMP): A Novel Hemostatic Agent
Authors: Ashish Rehni, Vibha Shukla, Hever Navarro-Quero, Carlos Bidot, Conner Haase, Anise Crane, Shivam Patel, Sebastian Koch, Yeon S. Ahn, Wenche Jy, Kunjan Dave
Journal: Blood (2018)
Influence of the Intensity of the Conditioning Regimens on the Risks of Gvhd in Patients Receiving Rituximab Prophylaxis during Allogeneic Stem Cell Transplantation (alloSCT)
Authors: Issa F. Khouri, Denái R. Milton, Celina Ledesma, Elias J. Jabbour, Gheath Alatrash, Paolo Anderlini, Amin M. Alousi, Qaiser Bashir, Stefan O. Ciurea, Sharon Hymes, David Marin, Jeffrey J. Molldrem, Amanda L. Olson, Betul Oran, Uday Popat, Muzaffar H. Qazilbash, Gabriela Rondon, Richard E Champlin, Alison Gulbis
Journal: Blood (2018)
Abstract P5-14-02: Time to treatment discontinuation as a pragmatic endpoint: A U.S. Food and Drug Administration pooled analysis of CDK 4/6 inhibitors
Authors: JJ Gao, Y Gong, J Cheng, RJ Schroeder, L Amiri-Kordestani, S Khozin, P Kluetz, R Sridhara, R Pazdur, G Blumenthal, JA Beaver, TM Prowell
Journal: Cancer Research (2019)

Abstract BACKGROUND: The primary endpoint in many registration trials is progression-free survival (PFS), defined as the time from randomization until objective tumor progression or death. In the clinical setting, however, PFS can be difficult to measure and explain, especially in patient-friendly language. For real-world evidence (RWE) based studies, time to treatment discontinuation (TTD), defined as time from randomization to discontinuation of the investigational study drug, may be a more practical endpoint. We hypothesize TTD will correlate with PFS and analyzed registration trials from recently FDA approved cyclin dependent kinase 4/6 inhibitors (CDKIs) to test this hypothesis. TTD was defined as time from randomization to discontinuation of the CDKI. METHODS: We pooled data from five phase III randomized, controlled, registration trials of CDKIs with an aromatase inhibitor (AI) in the first-line or fulvestrant in the second-line setting. The CDKI discontinuation dates used to calculate TTD were derived from the patient-level datasets. We calculated patient-level correlation between TTD and PFS. We also summarized median TTD and PFS as well as the number of TTD and PFS events. RESULTS: A total of 3017 patients were included in the pooled analysis (n=1899 treated with CDKI, n=1118 with placebo). The median PFS and TTD and the number of events are shown in Table 1. The patient-level Spearman correlation coefficient of TTD and PFS ranged from 0.87-0.95. The trial-level association was approximately R2=0.23. Table 1:Primary ResultsTreatment ArmNPFS EventsTTD EventsMedian PFS, in mo (95% CI)Median TTD, in mo (95% CI)Spearman Correlation CoefficientCDKI1899873138320.7 (19.2-22.2)14.3 (13.6-14.9)0.87Placebo111871488311.7 (11.0-13.6)11.0 (9.7-12.0)0.95 CONCLUSION: Patient-level pooled cross-trial analysis show a relationship between TTD and PFS in registration trials of CDKIs. In all trials, the difference in time between median TTD and median PFS appeared greater in the CDKI arm than the placebo arm. This analysis is limited by the relatively small number of studies included. Further research is needed to determine both whether: 1) TTD can serve as a pragmatic endpoint for analyses of RWE, and 2) is a more meaningful endpoint to patients. Citation Format: Gao JJ, Gong Y, Cheng J, Schroeder RJ, Amiri-Kordestani L, Khozin S, Kluetz P, Sridhara R, Pazdur R, Blumenthal G, Beaver JA, Prowell TM. Time to treatment discontinuation as a pragmatic endpoint: A U.S. Food and Drug Administration pooled analysis of CDK 4/6 inhibitors [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-14-02.
424 ROLE OF THE CIRRHOSIS RISK SCORE FOR THE PREDICTION OF FIBROSIS PROGRESSION IN HEPATITIS C PATIENTS WITH MINIMAL LIVER DISEASE
Authors: P. Pradat, E. Trépo, A. Potthoff, R. Bakshi, B. Young, R. Lagier, C. Moreno, A. Lemmers, T. Gustot, C. Trépo, M. Adler, H. Wedemeyer
Journal: Journal of Hepatology (2009)
Randomized, open-label, perioperative phase II study evaluating nivolumab alone or nivolumab plus ipilimumab in patients with resectable HCC.
Authors: Ahmed Omar Kaseb, Dan G. Duda, Hop Sanderson Tran Cao, Yehia I. Abugabal, Luis M. Vence, Asif Rashid, Roberto Pestana, Jorge M. Blando, Shalini Singh, Jean-Nicolas Vauthey, Manal Hassan, Hesham M. Amin, Aliya Qayyum, Yun Shin Chun, Ching-Wei David Tzeng, Divya Sakamuri, Robert A. Wolff, James C. Yao, James Patrick Allison, Padmanee Sharma
Journal: Journal of Clinical Oncology (2020)

486 Background: In HCC, surgical resection is associated with high recurrence rates, and no effective neoadjuvant or adjuvant therapies currently exist. Immunotherapy using anti-PD-1 antibodies has shown promised but limited increase in survival in advanced disease. To maximize the benefit, we are studying the efficacy and safety of anti–PD-1 (nivolumab) and anti–CTLA-4 (ipilimumab) antibodies against HCC for resectable HCC. Methods: This is a randomized phase II trial of nivolumab (Arm A) or nivolumab + ipilimumab (Arm B) as pre-operative treatment for patients with HCC who are eligible for surgical resection. Pts are given nivolumab 240 mg every 2 weeks (wks) for a total of 6 wks. Pt in Arm B are treated concurrently with ipilimumab 1 mg/kg every 6 wks. Surgical resection occurs within 4 wks after last cycle of therapy. Pts continue adjuvant immunotherapy for up to 2 years after resection. The primary objective is the safety/tolerability of nivolumab +/- ipilimumab. Secondary objectives include overall response rate, complete response rate and time to progression. Exploratory objectives include evaluating the pre- and post-treatment immunological changes in tumor tissues and peripheral blood. Results: Twenty-six patients were enrolled at the time of this interim analysis, of which 20 have evaluable data. Most pts (55%) were between 60-70yo and male (75%). Four pts were HCV-positive, 6 had HBV and 10 had no hepatitis. 20 patients proceeded with resection as planned, surgery was aborted for 5 patients (1 for frozen abdomen and 2 development of contralateral liver nodule). Three are still receiving preoperative therapy. Pathologic complete response (pCR) was observed in 5/20 evaluable patients – 2 in Arm A and 3 Arm B (25% pCR rate). Five patients in Arm B and 1 in Arm A experienced grade 3 or higher toxicity prior to surgery. No grade 4 or higher toxicity were observed. Conclusions: We report a pCR rate of 25% for resectable HCC after preoperative immunotherapy in a randomized phase II pilot trial. Treatment was safe and surgical resection was not delayed. The study is ongoing. These promising results may contribute to a paradigm shift in the perioperative treatment of resectable HCC. Clinical trial information: NCT03510871.