tbuckley/cabot-search huggingface dataset:
Chemokine signaling and MAPK/ERK pathway for advanced prostate cancer treatment response.
Authors: Yazan Numan, Jonathan Zhao, Song Tang, Youbin Zhang, Qiang Zhang, Borko Jovanovic, David James VanderWeele, Alicia K. Morgans, Massimo Cristofanilli, Jindan Yu, Maha H. A. Hussain
Journal: Journal of Clinical Oncology (2020)

TPS275 Background: Androgen deprivation therapy (ADT) is the backbone of therapy for metastatic hormone sensitive prostate cancer (mHSPC). Despite a high response rate, the majority of patients progress to metastatic castration-resistant prostate cancer (mCRPC). Both disease settings are heterogeneous with variable responses to treatment. While prostate specific antigen is an important biomarker for prognosis and disease monitoring, it has limitations. Biomarkers predictive of disease response and progression are critically needed. Circulating tumor cells (CTCs) are shed from tumors and are found in blood during advanced stages of disease. Serial characterization of CTCs serves as a real-time ‘liquid biopsy’ for molecular profiling of PC. Recent reports suggest that phenotypic &amp; genomic heterogeneity in CTCs and cell-free DNA (cfDNA) is associated with response to AR-targeted therapy highlighting the importance of CTC as a predictive biomarker. In addition, there is a high concordance between mutations in CTCs’ DNA and CRPC tissue through whole cell exome sequencing. We showed that atypical chemokine receptor CXCR7 is up-regulated following AR-targeted therapies, activating MAPK/ERK signaling and resulting in treatment resistance (Li et al., Cancer Res. 2019). To examine the potential of CXCR7/MAPK/ERK signaling in predicting treatment response, we propose to evaluate MAPK/ERK gene signature, pERK and AR level in CRPC or mHSPC patients receiving systemic therapy. Methods: Men with new CRPC or mHSPC are eligible prior to initiating new therapy for the respective disease setting of ADT + AR targeted therapy or chemotherapy. For CRPC arm, we will collect samples at baseline, 3, 6 months &amp; at time of progression. For mHSPC arm, samples are collected at baseline, after 7 months &amp; at progression. We will enroll 120 patients. Collected samples are subjected to identification, isolation, and enumeration of CTCs. Our primary molecular testing will include AR and pERK staining. CfDNA exome and methylome analysis will be performed to evaluate genomic heterogeneity and epigenomic alterations. We will explore pairwise association among biomarkers of interest, stratified by subgroups, using measures of association.
Results from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in muscle invasive bladder cancer (MIBC) undergoing cystectomy.
Authors: Shilpa Gupta, Guru Sonpavde, Christopher J. Weight, Bradley Alexander McGregor, Sumati Gupta, Benjamin Louis Maughan, Xiao X. Wei, Ewan Gibb, Bharat Thyagarajan, David Johnson Einstein, Christopher B. Dechet, William Thomas Lowrance, Paari J Murugan, Kerry L. Kilbridge, Neeraj Agarwal, Elai Davicioni, Markus Eckstein, Matthew Mossanen, Mark A. Preston, Badrinath R. Konety
Journal: Journal of Clinical Oncology (2020)

439 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) in MIBC improves survival which correlates with pathologic response (PaR) at radical cystectomy (RC). The combination of immunotherapy and NAC may improve PaR and outcomes in MIBC. We tested the efficacy and safety of nivolumab (N) with gemcitabine-cisplatin (GC) as neoadjuvant therapy for MIBC in our phase II trial (NCT03294304). Methods: Eligible pts with MIBC (cT2-T4a, N≤1, M0) who were candidates for RC were enrolled. Pts received C (70mg/m2) IV on D1, G (1000mg/m2) on D1,D8 and N (360 mg) IV on D8 every 21 days for 4 cycles followed by RC within 8 weeks. The primary endpoint was PaR (≤pT1,N0). Secondary objectives were safety of GC+N and PFS at 2 years. The correlative objectives based on pre-treatment biopsies were correlation of PaR with 1) WGS 2) molecular subtypes of BC; 3) PD-L1 expression; 4) baseline TILs, CD3, CD8 and CD56.. Evaluable pts. should have received at least 1 dose of N. PaR will be summarized by the PaR rate as estimated by the sample proportion with exact 95% confidence intervals. We specified a null PaR of 0.35 and an alternative hypothesis of 0.55; we will reject the null hypothesis if at least 20 of 41 pts. have a PaR. Results: Between Feb 2018 and June 2019, 41 pts. were enrolled (cT2N0 90%, cT3N0 7%, cT4N1 3%); 2 patients refused surgery but were included in ITT population. PaR was observed in 27/41 pts. (65.8%), including pts with N1 disease. The combination was safe with manageable toxicities and no deaths from treatment. Majority of AEs were from GC; the overall rates of grade 3-4 AEs was 20%, majority being neutropenia, thrombocytopenia and renal insufficiency. Immune related AEs were seen in 3 patients, 2 had "adenitis" which wasymptomatic,1 pt developed Guillian Barre Syndrome after surgery, which resolved with IVIG; and none of them required steroids. There was no delay in time to RC and no unexpected surgical complications from treatment. Patients are being followed for progression and survival. Correlative work is ongoing. Conclusions: Neoadjuvant N+GC is safe and effective in MIBC with significant pathologic downstaging rates and no added toxicities or delay to surgery. Clinical trial information: NCT03294304.
Abstract 408: Predictors of Survival to Hospital Discharge, a Machine Learning Modelfor Out-Of-Hospital Cardiac Arrest in the Young
Authors: Alyssa Vermeulen, Hoang Nguyen, Hai Nguyen, Teri Campbell, Marina Del Rios
Journal: Circulation (2019)

Background: Many efforts in the area of Out of Hospital Cardiac Arrest (OHCA) have been made to enhance diagnosis, interventions, and increase survival; there is little data on OHCA in the young (1-35 years old). Machine learning (ML) enhances medical diagnosis and decision making with recent models allowing clinicians better control and interpretation of their features. Objective: To develop a machine learning model to predict a young patient with OHCA survival to hospital discharge. The ML model will be used to identify important factors contributing to this predictive model. Methods: Utilizing the CARES database in Chicago, IL, from 2013 to 2017, all OHCA in ages 1-35 years were analyzed; the primary outcome of interest is survival to hospital discharge. Eight machine learning techniques were applied to classify survival to hospital discharge. XGBoost was used with decision trees. Synthetic Minority Over-sampling Technique was used to over-sample the under-represented population. All statistics were performed using Python. Results: 744 events were analyzed from 2013 to 2017. Median age was 24.6 years, of these 19.2% were 18 years and younger. The sample was 46% black, 31% caucasian and 19% Hispanic and 68% were male. Presumed cardiac etiology was identified in 61%; 13% had a shockable rhythm; 59% of events were unwitnessed. The model was able to classify survival and death with an accuracy of 90% and AUC of 0.98. Strongest positive correlation of survival to discharge was seen with sustained ROSC, first rhythm type being a shockable rhythm, and use of hypothermia. There was correlation with the year arrest occurred, with positive trend of survival over the study period time. There was a positive trend toward survival with advanced airway and epinephrine use. There was a negative trend toward survival with unwitnessed arrest and location outside of home or healthcare facility. Conclusions: The XGBoost model showed excellent classification of those who survive to discharge and die with OHCA in those 1-35 years old. Most rhythms in this population were not shockable rhythms despite over half of arrests being presumed cardiac in nature. Standard machine learning models can help identify and determine relevant interventions to improve OHCA in the young.
A novel Sprouty4-ERK1/2-Wnt/β-catenin regulatory loop in marrow stromal progenitor cells controls osteogenic and adipogenic differentiation
Authors: Lijie Tian, Hongyan Xiao, Mengyue Li, Xiaowen Wu, Yan Xie, Jie Zhou, Xin Zhang, Baoli Wang
Journal: Metabolism (2020)

Sprouty (SPRY) proteins play critical roles in controlling cell proliferation, differentiation, and survival by inhibiting receptor tyrosine kinase (RTK)-mediated extracellular signal-regulated kinase (ERK) signaling. Recent studies have demonstrated that SPRY4 negatively regulates angiogenesis and tumor growth. However, whether SPRY4 regulates osteogenic and/or adipogenic differentiation of mesenchymal stem cells remains to be explored.In this study, we investigated the expression pattern of Spry4 and found that its expression was regulated during the differentiation of mouse marrow stromal progenitor cells and increased in the metaphysis of ovariectomized mice. In vitro loss-of-function and gain-of-function studies demonstrated that SPRY4 inhibited osteogenic differentiation and stimulated adipogenic differentiation of progenitor cells. In vivo experiments showed that silencing of Spry4 in the marrow of C57BL/6 mice blocked fat accumulation and promoted osteoblast differentiation in ovariectomized mice. Mechanistic investigations revealed the inhibitory effect of SPRY4 on canonical wingless-type MMTV integration site (Wnt) signaling and ERK pathway. ERK1/2 was shown to interact with low-density lipoprotein receptor-related protein 6 (LRP6) and activate the canonical Wnt signaling pathway. Inactivation of Wnt signaling attenuated the inhibition of adipogenic differentiation and stimulation of osteogenic differentiation by Spry4 small interfering RNA (siRNA). Finally, promoter study revealed that β-catenin transcriptionally inhibited the expression of Spry4.Our study for the first time suggests that a novel SPRY4-ERK1/2-Wnt/β-catenin regulatory loop exists in marrow stromal progenitor cells and plays a key role in cell fate determination. It also highlights the potential of SPRY4 as a novel therapeutic target for the treatment of metabolic bone disorders such as osteoporosis.
Prognostic value of novel inflammation index for patients with metastatic castration-resistant prostate cancer.
Authors: Yasutaka Yamada, Shinichi Sakamoto, Junryo Rii, Satoshi Yamamoto, Shuhei Kamada, Yusuke Imamura, Kazuyoshi Nakamura, Akira Komiya, Hiroomi Nakatsu, Tomohiko Ichikawa
Journal: Journal of Clinical Oncology (2020)

212 Background: Inflammation process has been reported to be involved in the development of several types of cancer. Recently, a lung immune prognostic index (LIPI) combining with derived neutrophils/ (leukocytes minus neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) level was proposed as an useful prognostic marker for advanced non-small cell lung cancer. However, the prognostic value of this index has not been evaluated and we aimed to validate its prognostic ability in metastatic castration resistant prostate cancer (mCRPC). Methods: Clinical data of 248 mCRPC patients were retrospectively collected from multi-institutions. We obtained the clinical factors including age, PSA, Gleason score (GS), tumor stage, white blood cell (WBC) count, dNLR, hemoglobin (Hb), LDH, alkaline phosphatase (ALP) and C-reactive protein (CRP) levels. The prognostic index was defined as poor (high dNLR and LDH), intermediate (high dNLR or LDH) and good (low dNLR and LDH) groups. We analyzed the overall survival (OS) after CRPC using Cox proportional hazard models and the Kaplan-Meier methods. Results: The median age at CRPC and baseline PSA level were 75 years and 458.39 ng/ml, respectively. The median OS after CRPC were 31.7 months. In multivariate analysis, dNLR (≥1.48, HR=1.75, P=0.0096), LDH (≥upper limits of normal, HR=1.94, P=0.0015) and ALP (≥310U/l, HR=2.37, P&lt;0.0001) were independent prognostic factors for OS. The good prognostic index group showed significantly longer OS after CRPC compared with the intermediate and poor groups with the median survival of 46.2, 28.9 and 16.6 months, respectively (shown in Table). Conclusions: Novel inflammation index combined with dNLR and LDH was an useful prognostic marker for mCRPC. Further study with a large scale and treatment specific analysis will be required.[Table: see text]
Disease progression among patients who receive available bladder preservation therapies after failure of BCG therapy in the SEER-Medicare data.
Authors: Ashish M. Kamat, Mihaela V. Georgieva, Jinlin Song, Iryna Bocharova, Kun Qian, Amy Guo, Min Yang
Journal: Journal of Clinical Oncology (2020)

453 Background: For patients with high-grade (HG) non-muscle invasive bladder cancer (NMIBC) who recur after Bacillus Calmette-Guérin (BCG) therapy, treatment options other than radical cystectomy have been limited. This study examined real-world utilization and outcomes of current bladder preservation therapies (BPT) after BCG treatment. Methods: We analyzed the SEER-Medicare database and identified patients diagnosed with HG NMIBC between 2008 and 2015 who received at least one BCG induction course (defined as ≥5 weekly instillations). Use of BPT within six months of the last consecutive BCG instillation was identified and included BCG + interferon alpha, docetaxel, doxorubicin, epirubicin, gemcitabine, mitomycin C, nab-paclitaxel, thiotepa, valrubicin, or their combinations. Progression was identified as initiation of treatment for muscle-invasive bladder cancer, radical cystectomy, or presence of metastases. Time to progression (TTP) was defined as time from BPT initiation to progression event. Progression-free survival (PFS) was assessed from BPT initiation and defined as the absence of progression or death due to bladder cancer. TTP and PFS were assessed using Kaplan-Meier analysis. Results: A total of 7,074 patients were diagnosed with HG NMIBC and received ≥ 5 BCG weekly induction instillations. Of these, 8.8% (620 patients) initiated BPT. The most commonly used agents were mitomycin C (66.0%), followed by BCG + interferon alpha (22.9%), valrubicin (4.0%), doxorubicin (2.9%), and gemcitabine (2.1%). Disease progression occurred in 18.7% of patients within 1 year of treatment initiation (40.5% due to metastases), 36.4% within 3 years (50.0% due to metastases), and 45.4% within 5 years (50.2% due to metastases). The rate of PFS was 80.9%, 61.8%, and 52.3% at 1, 3, and 5 years, respectively. Conclusions: High rates of metastatic disease are noted in HG NMIBC following available BPT treatments after failure of BCG therapy. A high unmet need remains for novel bladder-sparing therapies to improve outcomes in this difficult-to-treat population.
Programmable prodrug micelle with size-shrinkage and charge-reversal for chemotherapy-improved IDO immunotherapy
Authors: Liangliang Dai, Xiang Li, Mengjiao Yao, Peiyun Niu, Xichen Yuan, Ke Li, Maowen Chen, Zengxiang Fu, Xianglong Duan, Haibin Liu, Kaiyong Cai, Hui Yang
Journal: Biomaterials (2020)
Effects of Broccoli Sprout Extract Containing High levels of Antioxidant on Allergic Rhinitis
Authors: Joseph Yusin, Vivian Wang, Jivianne Lee, Gail Thames-Washington, Tianyu Qin, Yajing Pan, Jieping Yang, Irina Arnold, Susanne Henning, Zhaoping Li
Journal: Journal of Allergy and Clinical Immunology (2020)
Mining the infant gut microbiota for therapeutic targets against atopic disease
Authors: Rozlyn C. T. Boutin, Hind Sbihi, Melissa Dsouza, Raunaq Malhotra, Charisse Petersen, Darlene Dai, Malcolm R. Sears, Theo J. Moraes, Allan B. Becker, Meghan B. Azad, Piush J. Mandhane, Padmaja Subbarao, B. Brett Finlay, Stuart E. Turvey
Journal: Allergy (2020)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Antibiotic use and risk of colorectal cancer: a meta-analysis of 412 450 participants
Authors: Qian-Yi Wan, Rui Zhao, Yong Wang, Yutao Wu, Xiao-Ting Wu
Journal: Gut (2020)

We read with interest the study by Zhang et al 1 which investigated the associations between oral antibiotic use and risk of colorectal cancer (CRC). The study included 166 057 participants and found that antibiotic use was associated with an increased risk of colon cancer but a reduced risk of rectal cancer. We also noticed another study by Armstrong et al 2 reporting that patients prescribed antibiotics in up to 15 years preceding diagnosis were associated with a higher risk of CRC. However, the study by Armstrong et al did not analyse the risk of colon cancer and rectal cancer, respectively. Considering current studies about antibiotic use and risk of CRC were inconsistent, we conducted this meta-analysis.

The PubMed and Web of Science were …
Unmet needs and behaviour during the Ebola response in Sierra Leone: a retrospective, mixed-methods analysis of community feedback from the Social Mobilization Action Consortium
Authors: Laura A Skrip, Jamie Bedson, Sharon Abramowitz, Mohammed B Jalloh, Saiku Bah, Mohamed F Jalloh, Ollin Demian Langle-Chimal, Nicholas Cheney, Laurent Hébert-Dufresne, Benjamin M Althouse
Journal: The Lancet Planetary Health (2020)

BackgroundThe west African Ebola epidemic (2014–15) necessitated behaviour change in settings with prevalent and pre-existing unmet needs as well as extensive mechanisms for local community action. We aimed to assess spatial and temporal trends in community-reported needs and associations with behaviour change, community engagement, and the overall outbreak situation in Sierra Leone.MethodsWe did a retrospective, mixed-methods study. Post-hoc analyses of data from 12 096 mobiliser visits as part of the Social Mobilization Action Consortium were used to describe the evolution of satisfied and unsatisfied needs (basic, security, autonomy, respect, and social support) between Nov 12, 2014, and Dec 18, 2015, and across 14 districts. Via Bayesian hierarchical regression modelling, we investigated associations between needs categories and behaviours (numbers of individuals referred to treatment within 24 h of symptom onset or deaths responded to with safe and dignified burials) and the role of community engagement programme status (initial vs follow-up visit) in the association between satisfied versus unsatisfied needs and behaviours.FindingsIn general, significant associations were observed between unsatisfied needs categories and both prompt referrals to treatment and safe burials. Most notably, communities expressing unsatisfied capacity needs reported fewer safe burials (relative risk [RR] 0·86, 95% credible interval [CrI] 0·82–0·91) and fewer prompt referrals to treatment (RR 0·76, 0·70–0·83) than did those without unsatisfied capacity needs. The exception was expression of unsatisfied basic needs, which was associated with significantly fewer prompt referrals only (RR 0·86, 95% CrI 0·79–0·93). Compared with triggering visits by community mobilisers, follow-up visits were associated with higher numbers of prompt referrals (RR 1·40, 95% CrI 1·30–1·50) and safe burials (RR 1·08, 1·02–1·14).InterpretationCommunity-based development of locally feasible, locally owned action plans, with the support of community mobilisers, has potential to address unmet needs for more sustained behaviour change in outbreak settings.FundingBill & Melinda Gates, Bill & Melinda Gates Foundation, and National Institutes of Health.
Head-to-head comparison between decipher and prolaris tests: Two commercially available post-prostatectomy genomic tests.
Authors: Mohammed Shahait, Mohammed Alshalalfa, Edward M. Schaeffer, Huei-Chung Huang, Andrea Cronican, Paul L. Nguyen, Ayah el-Fahmawi, Priti Lal, Elai Davicioni, David I. Lee
Journal: Journal of Clinical Oncology (2020)

348 Background: Several post-prostatectomy genomic tests are available; which are used to improve prognostication and to guide additional treatment after radical prostatectomy (RP). There has been no head to head comparison between these tests. The objective of this study is to compare the performance of two genomic tests in predicting oncological outcomes. Methods: 16 patients who underwent RP at the University of Pennsylvania (UPenn) (2013-2018), had adverse pathology (margin, and/or pT3a/b) and had each been tested with both Decipher (D) and Prolaris (P). Pearson correlation was used to compare scores from D and P as well as CCP scores and microarray derived CCP (mCCP). The associations of D and P with biochemical recurrence (BCR) and metastasis (M) was evaluated in survival analysis in a large cohort of RP patients treated at Johns Hopkins University (1992-2010) (JHU). Results: The median follow-up of the UPenn cohort was 24 months. 6 patients developed BCR and two distant M. There was a significant correlation between the D and P score (r=0.67,p=0.004), and between the 10-year BCR risk reported by P and the 5-year M risk reported by D (r=0.69, p=0.003). Each test called 7 patients to be high risk; 5 were in common. Both tests correctly called the 2 M cases as high risk and 4/6 BCR patients to be high risk. A microarray-derived CCP (mCCP) was highly correlated to the CCP scores reported from P (r=0.88, p=6.7e-6) in the UPenn cohort. To compare the prognostic performance of mCCP to D for predicting BCR and M, we used Post-RP cohort from JHU (N=355). Both scores were correlated (r=0.36, p2e-12). D and mCCP were stratified into 5 groups of incremental 20%. When including mCCP groups, D groups, Gleason score, SVI, EPE, LNI, and PSA; D remained independent prognostic variable of BCR (HR 1.16, 95%CI [1.05-1.3], p=0.005) and M (HR 1.3, 95%CI [1.12-1.52], p=0.0005). However, mCCP was not prognostic of BCR (p=0.59) nor M (p=0.62). Conclusions: The findings from this study show that P and D scores post-RP were highly correlated and help in identifying patients who at high risk of progression in this small cohort with short follow up. However, D outperformed mCCP for predicting BCR and M in larger cohorts with longer follow up.