tbuckley/cabot-search huggingface dataset:
Prenatal Risk Factors and Perinatal and Postnatal Outcomes Associated With Maternal Opioid Exposure in an Urban, Low-Income, Multiethnic US Population
Authors: Romuladus E. Azuine, Yuelong Ji, Hsing-Yuan Chang, Yoona Kim, Hongkai Ji, Jessica DiBari, Xiumei Hong, Guoying Wang, Gopal K. Singh, Colleen Pearson, Barry Zuckerman, Pamela J. Surkan, Xiaobin Wang
Journal: JAMA Network Open (2019)

The opioid epidemic increasingly affects pregnant women and developing fetuses, resulting in high rates of neonatal abstinence syndrome. However, longitudinal studies that prospectively observe newborns with neonatal abstinence syndrome or with maternal opioid use and examine their long-term physical and neurodevelopmental outcomes are lacking.To examine prenatal risk factors associated with maternal opioid use during pregnancy and the short-term and long-term health consequences on their children.This cohort study analyzed data from the Boston Birth Cohort, an urban, low-income, multiethnic cohort that enrolled mother-newborn pairs at birth at Boston Medical Center (Boston, Massachusetts) starting in 1998, and a subset of children were prospectively observed at Boston Medical Center pediatric primary care and subspecialty clinics from birth to age 21 years. Data analysis began in June 2018 and was completed in May 2019.In utero opioid exposure was defined as maternal self-reported opioid use and/or clinical diagnosis of neonatal abstinence syndrome.Pregnancy outcomes, postnatal child physical health, and major neurodevelopmental disabilities, documented in maternal and child medical records.This study included 8509 Boston Birth Cohort mother-newborn pairs for prenatal and perinatal analyses. Of those, 3153 children continued to receive pediatric care at Boston Medical Center and were included in assessing postnatal outcomes. Overall, 454 of the 8509 children (5.3%) in the Boston Birth Cohort had in utero opioid exposure. At birth, opioid exposure was associated with higher risks of fetal growth restriction (odds ratio [OR], 1.87; 95% CI, 1.41-2.47) and preterm birth (OR, 1.49; 95% CI, 1.19-1.86). Opioid exposure was associated with increased risks of lack of expected physiological development (OR, 1.80; 95% CI, 1.17-2.79) and conduct disorder/emotional disturbance (OR, 2.13; 95% CI, 1.20-3.77) among preschool-aged children. In school-aged children, opioid exposure was associated with a higher risk of attention-deficit/hyperactivity disorder (OR, 2.55; 95% CI, 1.42-4.57).In this sample of urban, high-risk, low-income mother-child pairs, in utero opioid exposure was significantly associated with adverse short-term and long-term outcomes across developmental stages, including higher rates of physical and neurodevelopmental disorders in affected children. Efforts to prevent the opioid epidemic and mitigate its health consequences would benefit from more intergenerational research.
Design of vaccine efficacy trials during public health emergencies
Authors: Natalie E. Dean, Pierre-Stéphane Gsell, Ron Brookmeyer, Victor De Gruttola, Christl A. Donnelly, M. Elizabeth Halloran, Momodou Jasseh, Martha Nason, Ximena Riveros, Conall H. Watson, Ana Maria Henao-Restrepo, Ira M. Longini
Journal: Science Translational Medicine (2019)

This Perspective describes key considerations for the design and analysis of candidate vaccine trials during public health emergencies.
Cost-effectiveness of next-generation sequencing minimal residual disease testing during maintenance treatment for multiple myeloma.
Authors: Josh John Carlson, Benjamin Eckert, Marita Zimmerman
Journal: Journal of Clinical Oncology (2019)

e19529 Background: MRD testing is part of the response evaluation criteria for MM, and clinical guidelines recommend MRD testing with technologies that detect malignant cells at a level of at least 1/100,000. Deep MRD negativity correlates with improved health outcomes for MM pts, and MRD status may inform treatment (tx) continuation decisions during MM maintenance therapy. We evaluated the potential cost-effectiveness of NGS MRD (clonoSEQ) vs. no MRD testing in the maintenance MM setting. Methods: We developed a Markov model with 6 health states: MRD+ or MRD- on or off tx, relapsed, or dead and compared yearly NGS MRD to no MRD testing over a lifetime horizon. The model assumed tx stops after an MRD- result; otherwise, tx continued until disease progression. Progression-free survival (PFS) and overall survival (OS) data for MRD- and MRD+ and hazard ratios for on/off tx were applied based on peer-reviewed literature. MRD- pts were assumed to have the same PFS/OS rates on and off tx, which were varied in sensitivity analyses. On tx, 2%/month of MRD+ pts became MRD-. Health state utilities were based on peer-reviewed literature and included an adverse event (AE) disutility. The cost of NGS MRD was $1,800 + $1,836 for specimen collection, with maintenance tx at $21,168/month and tx for relapsed pts at $27,422/month. We used a US health system perspective and a 3% discount rate. Results: MRD testing saved $1,156,600 over patients remaining lifetime. Health outcomes were similar and slightly favored MRD testing vs no testing (0.01 quality-adjusted life-years [QALYs]) from lower AE risk over time, suggesting a potentially dominant strategy, i.e., less costly with improved health outcomes. This result was most sensitive to the probability of MRD+ to MRD- transition and the cost of maintenance tx. Conclusions: NGS MRD testing is cost-saving, with potential QALY gains due to avoidance of tx-related AEs compared with no testing for MM patients on maintenance therapy. Further studies are needed to determine the health outcomes of MRD testing during MM maintenance tx. [Table: see text]
Higher expression of ERBB2, KRAS and down-regulation of APC, NF1 genes in colorectal cancer
Authors: H. Javed, M. Faisal, J. Khan, H. Anwar, A. Mahmood, H. Muzaffar, J. Aslam, J. Hussain, H. Nazeer, M. Rahman, N. Aslam, L. Majeed, A. Roobi
Journal: Annals of Oncology (2019)
Abstract 3466: The oncogenic roles of ANXA1 in gastrointestinal tract cancer
Authors: Motonobu Saito
Journal: Cancer Research (2019)

Abstract Annexin A1 (ANXA1) is a calcium-dependent phospholipid-linked protein that is associated with anti-inflammatory effects, regulation of cellular proliferation, and apoptosis and, therefore, ANXA1 is associated with cancer development and metastasis. We have previously reported that ANXA1 was upregulated in gastrointestinal cancer and associated with venous invasion (P=0.023) and lymph node metastasis (P=0.042). We also performed in vitro cell experiments and revealed that elevated ANXA1 expression was induced resistance to 5-FU in the colon cancer cells. So next, we have evaluated the association between ANXA1 and cancer related genes, including p53 by immunohistochemical (IHC) staining in two independent gastric cancer cohorts (n=200 and n=220). The percentage of positive ANXA1 was significantly higher in p53 positive tumors compared with p53 negative tumors (P=0.023 and P=0.022, respectively). We also evaluated the association with ARID1A, the chromatin remodeler AT-Rich interactive 1A, that is frequently mutated in gastric cancer and is considered as a candidate therapeutic target by synthetic lethality. Although it was reported that the expression of ANXA1 was upregulated in ARID1A mutated breast cancer cases, significant association between ANXA1 and ARID1A expressions was not found in gastric cancer. We next performed IHC staining for ANXA1 and p53 in three human gastric cancer cell lines (MKN7, NUGU4, KATOIII). Positive staining for both ANXA1 and p53 was detected in cells with TP53 missense mutation. On the other hand, weak positive staining for ANXA1 and negative staining for p53 was found in NUGC4 cells with TP53 wild-type and KATOIII cells with TP53 truncating mutation. These results suggested that ANXA1 expression may be induced by aberrant p53 protein, resulting cancer progression and resistance to 5-FU. Our results also provide a possible strategy to overcome 5-FU resistance by modulating ANXA1 expression. Note: This abstract was not presented at the meeting. Citation Format: Motonobu Saito. The oncogenic roles of ANXA1 in gastrointestinal tract cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3466.
Abstract 353: Genetic Mutation of ALDH2 Enhances Cardiomyocyte Tolerance to Oxidative Stress as a Result of Hormetic Response to Aldehydes
Authors: Jin Endo, Motoaki Sano, Takaharu Katayama, Satori Tokudome, Shinsuke Yuasa, Mitsushige Murata, Shinji Makino, Takeshi Adachi, Makoto Suematsu, Hiroki Nakanishi, Ryo Taguchi, Ikurou Ohsawa, Shigeo Ohta, Satoshi Ogawa, Keiichi Fukuda
Journal: Circulation (2007)

[Introduction]Aldehyde dehydrogenases (ALDH) play a major role in the detoxification of aldehydes produced by lipid peroxidation under oxidative stress. The single nucleotide polymorphism of ALDH2 ...
Abstract 2641: Transactivation of EGFR and mTOR pathway by H2Sin cancer cells
Authors: Jillian L. Higgins, Aileen K. Kraus, Dominic T. Arruda, Hao Guo, Mattew Lautato, Christopher Lautato, Eliana DaCunha, Ashley Chen, Ricky Yao, Dongqin Yang, Yinsheng Wan
Journal: Cancer Research (2019)

Abstract Hydrogen sulfide regulates a variety of physiological and pathological processes. Previous studies have suggested that H2S plays a significant role as a secondary messenger in cellular signaling. Interestingly, it has been found that this unique gaseous molecule, or gasotransmitter, is capable of producing both pro- and anti- apoptotic activity in cultured cells. It has been speculated that these gasotransmitters are endogenously generated in mammalian systems through enzymatic catalysis. Our pursuits focus on comparing the effects of H2S on various lines of cancer cells (CaOV3-ovarian cancer cells, A375-melanoma cells, HeLa-cervical cancer cells, and WM 266-4-melanoma cells). Using a water-soluble, slow-releasing H2S donor, GYY4137 (200 μM), we studied how both concentration and time affect cell viability and investigated further whether H2S causes pro- or anti- apoptotic activity. Existing data have indicated that GYY4137 may activate molecular targets, including EGFR, ERK and JNK. We hypothesize that GYY4137 activates mTOR (mammalian target of rapamycin) with result of phosphorylation of S6, leading to either cell death or cell proliferation. By monitoring various proteins through Western blot analysis and confocal microscopy we studied the activation of EGFR/mTOR pathway in response to GYY4137 treatment. Our data showed that the longer the treatment the more prevalent phosphor S6 and phosphor-EGFR are. Noticeably, we observed a significant difference between 15 minutes and 30 minutes, suggesting that GYY4137 has the largest effect after 30 minutes of treatment. We further studied cell growth and viability using MTT assay to investigate the effects of various concentrations of GYY4137 on the cells. Our data indicated that the stronger the concentration is, the lower the cell viability. Similarly, we used Mitotracker ® Red dye to stain for mitochondrial activity in CaOV3 and WM 266-4 cells treated at various time points. Overall, mitochondrial activity increased when cells were exposed to GYY4137, suggesting that H2S may cause anti-apoptotic activity, and instead favor cell growth at the concentration we used. Collectively, our data suggests that the H2S donor, GYY4137 has a significant effect on cell proliferation and survival in several cancerous cells likely mediated by transactivation of EGFR and mTOR pathways. Note: This abstract was not presented at the meeting. Citation Format: Jillian L. Higgins, Aileen K. Kraus, Dominic T. Arruda, Hao Guo, Mattew Lautato, Christopher Lautato, Eliana DaCunha, Ashley Chen, Ricky Yao, Dongqin Yang, Yinsheng Wan. Transactivation of EGFR and mTOR pathway by H2Sin cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2641.
Investigating acute kidney injury in primary care
Authors: Indre K Semogas, Amy Davis, Imran Rafi, Christopher Anderson, Nicholas M P Annear
Journal: BMJ (2019)

### What you need to know

A 65 year old obese man with diabetes, hypertension, osteoarthritis, and a two month history of persistent lower urinary tract symptoms attended his general practice with general malaise. Regular medications included metformin, gliclazide, ramipril, and ibuprofen. On examination, his blood pressure was 150/96 mm Hg. Digital rectal examination revealed a smooth enlarged prostate. Urine analysis showed 2+ proteinuria. Blood tests revealed a serum creatinine concentration of 160 µmol/L, compared with 78 µmol/L three weeks earlier; his prostate specific antigen (PSA) level had been 6 µg/L.

Acute kidney injury (AKI) is a syndrome characterised by a sudden decline in renal function. To standardise AKI classification, international guidelines were published in 2012 (table 1).1

View this table:

Table 1 
KDIGO classification of acute kidney injury (AKI)1



Population incidence of AKI is as high as 0.2%,2 and between 8.4% and 17.6% among hospital inpatients.34 Around two thirds of AKI cases identified in hospital develop in the community before hospitalisation.5 AKI is associated with longer inpatient admissions, increased risk of progression to chronic kidney disease (CKD), and higher mortality (in hospital6 and long term).37 Prompt identification of AKI and early management initiated in primary care is central to improving outcomes.

AKI in the community is most commonly due to infections such as influenza or gastroenteritis, with associated fluid depletion.8 …
Abstract 4805: Cannabinoid WIN 55,212-2 induces endoplasmic reticulum stress in prostate cancer cells through CB1and CB2receptors
Authors: Domenica Roberto, Laurence H. Klotz, Vasundara Venkateswaran
Journal: Cancer Research (2019)

Abstract Cannabinoids have demonstrated anticarcinogenic properties in a variety of malignancies, including prostate cancer. WIN 55,212-2 (WIN) is a highly potent synthetic cannabinoid that binds to cannabinoid receptors (CB1 and CB2). We have previously demonstrated that WIN significantly reduces prostate cancer cell proliferation, migration, invasion, induces apoptosis, and arrests cells in the G0/G1 phase through a cannabinoid receptor 2 dependent manner. We also determined that these effects were mediated though a pathway involving cell cycle regulators p27, Cdk4, and pRb. The current study aims to examine the role of endoplasmic reticulum (ER) stress in apoptosis and investigates whether this effect is modulated by WIN and the cannabinoid receptors. In this study, we evaluated the effect of WIN and CB receptors on ER stress induced apoptosis in established prostate cancer cells (DU145, PC3). Cells were treated with WIN, cannabinoid receptor 1 antagonist (AM251), and cannabinoid receptor 2 antagonist (AM630). Cell proliferation was determined using MTS assays. Quantitative PCR was used to examine changes in expression of ER stress related genes, including CHOP, TRIB3, and ATF4. Western blotting will be completed to determine changes in the expression of apoptotic markers after treatment with WIN and cannabinoid antagonists. Further studies are ongoing looking at the use of the ER stress inhibitor, Salubrinal, to determine whether ER stress is vital for WIN-induced apoptosis. Our results reveal that treatment with 20μM WIN resulted in a significant reduction in the proliferation of DU145 and PC3 cells after 24 h compared to control (p&amp;lt;0.05). In contrast, treatment with 5μM of either AM251 or AM630 did not result in any significant changes in cell proliferation. Quantitative PCR studies revealed significant upregulation of ER stress genes CHOP, TRIB3 and ATF4 in WIN treated cells (p&amp;lt;0.05). Expression of ER stress genes were significantly downregulated after blocking CB1 and CB2 receptors (p&amp;lt;0.05). Interim results suggest that WIN has significant antitumoral activity and modulates ER stress-induced apoptosis in prostate cancer cells, thus, may offer a novel therapeutic strategy in the treatment of prostate cancer. Citation Format: Domenica Roberto, Laurence H. Klotz, Vasundara Venkateswaran. Cannabinoid WIN 55,212-2 induces endoplasmic reticulum stress in prostate cancer cells through CB1and CB2receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4805.
Editor's Note: The Efficacy of the Novel Dual PI3-Kinase/mTOR Inhibitor NVP-BEZ235 Compared with Rapamycin in Renal Cell Carcinoma
Authors: Daniel C. Cho, Matthew B. Cohen, David J. Panka, Michael Collins, Musie Ghebremichael, Michael B. Atkins, Sabina Signoretti, James W. Mier
Journal: Clinical Cancer Research (2019)

The editors are publishing this note to alert readers to a concern about this article (1): Western blot similarities exist in Fig. 4A (C-Myc and Vinculin). The original gels are not available for review.
Abstract 3859: Targeting CDK9 and MCL-1 by a New CDK9/p-TEFB Inhibitor with and without 5-fluorouracil in esophageal adenocarcinoma
Authors: zhimin Tong, Alicia Mejia, Omkara Veeranki, Anuj Verma, Arlene Correa, Viren Patel, Rashmi Dokey, Luisa Solis, Barbara Mino, Riham Kathkuda, Jaime Canales, Steven Lin, Sunil Krishnan, Scott Kopetz, Mariela Blum, Jaffer Ajani, Wayne Hofstetter, Dipen M Maru
Journal: Cancer Research (2019)

Abstract Background: CDK9 inhibitors are anti-tumorigenic against several solid tumors including esophageal adenocarcinoma (EAC). However, efficacy of CDK9 inhibitor as adjuvant to chemotherapy and target proteins shared between these two drugs are not known. Methods: Efficacy of a new CDK9 inhibitor, BAY1143572 with and without 5-fluorouracil (5-FU) on tumor growth was tested in vitro and xenograft models of EAC. We tested effects of these agents on MCL-1 in vitro. We also analyzed a possible role of MCL-1 as a predictor of survival in patients with EAC. Results: BAY1143572 had a dose-dependent anti-proliferative and pro-apoptotic effects in vitro. BAY1143572 and 5-FU had strong synergy in vitro. Median tumor volume of FLO1 or ESO26 xenografts in cohort treated with combination of two drugs was 82% or 55% smaller than the cohort treated with 5-FU alone, and 46 % or 33% smaller than the cohort treated with BAY114352 alone (p&amp;lt;0.05). BAY1143572 transcriptionally downregulated MCL-1 by inhibiting HIF-1α binding to the MCL-1 promoter. 5-FU enhanced BAY1143572 induced MCL-1 downregulation in vitro. Stable overexpression of MCL-1 reduced apoptosis by BAY1143572 and 5-FU. Higher tumor cell MCL-1 expression correlated with shorter overall survival in patients with EAC treated with chemoradiation and surgery. Conclusion: CDK9 inhibitor and 5-FU are synergistic and MCL-1 is a target of CDK9 inhibitor in EAC. Citation Format: zhimin Tong, Alicia Mejia, Omkara Veeranki, Anuj Verma, Arlene Correa, Viren Patel, Rashmi Dokey, Luisa Solis, Barbara Mino, Riham Kathkuda, Jaime Canales, Steven Lin, Sunil Krishnan, Scott Kopetz, Mariela Blum, Jaffer Ajani, Wayne Hofstetter, Dipen M Maru. Targeting CDK9 and MCL-1 by a New CDK9/p-TEFB Inhibitor with and without 5-fluorouracil in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3859.
Quality of life in patients treated with aflibercept and FOLFIRI for metastatic colorectal cancer: interim analysis with focus on therapy lines of the non-interventional study QoLiTrap (AIO-LQ-0113)
Authors: R. Hofheinz, F. Scholten, H. Derigs, J. Thaler, R. von Moos
Journal: Annals of Oncology (2019)
Abstract 19004: Sexual Dimorphic Characteristics in a Mouse Model of Atrial Fibrillation
Authors: Uma Avula, Charlotte Buck, Meghana Noonavath, Hasan Garan, Steven Marx, Elaine Wan
Journal: Circulation (2017)

Introduction: The incidence of atrial fibrillation (AF) is higher in men than in women. There is currently a lack of an animal model to study the gender-specific pathophysiology of spontaneous and ...
Abstract LB-212: FCRF: An efficient algorithm for detecting circular fusion transcript from RNA-Seq data
Authors: Han Yu, Xuanping Zhang, Yanfang Guan, Yongsheng Chen, Xiao Xiao, Jiayin Wang
Journal: Cancer Research (2019)

Abstract Fusion circular RNAs (f-circRNAs) are circular RNAs derived from rearranged genome translocations. Their formation is caused by back-splicing happening to the genome regions of aberrant chromosomal translocation. Their cancer-promoting roles have been implicated in recent studies. One of them adopted both in vivo and in vitro models to demonstrate the oncogenic roles of f-circRNAs including promoting cellular transformation, cell viability and resistance to treatment. Therefore, it is suggested that accurate identification of f-circRNA will contribute to cancer diagnosis and therapy. But until now there is only one tool called Acfs (accurate circRNA finder suite) ever mentioned detecting f-circRNAs whose primary job is to detect normal circRNAs and only 10 f-circRNAs have been tested for verification without considering realistic sequencing problems. Here, we proposed the first algorithm, FCRF (Fusion CircRNA Finder), to identify f-circRNAs from RNA-Seq data. The SAM file aligned by BWA was used as input, and paired fusion junction site locations would be output. After pre-processing and correcting the original data in consideration of the sequencing fault tolerance, we divided the candidates into balance set and unbalance set according to the relative aligned length. For balance set, we extracted reads from non-homologous chromosomes owing to the fusion events and further detected the paired clipping signals specific to fusion junctions. On the other hand, for unbalance set, we could not use the paired signal because BWA only reported one alignment for them. So we handled them with local similar sequence considering that each junction read has similar sequences with the other read spanning the same junction. Finally we searched all the candidate fusion junctions in accord with the threshold window size and cyclization characteristics, and then recorded two special junction site locations for each fusion-circRNA. We conducted a series of simulation experiments to evaluate our algorithm. The proposed algorithm FCRF achieved 95% on precision and 85% on sensitivity where Acfs output nothing from our improved dataset. Note: This abstract was not presented at the meeting. Citation Format: Han Yu, Xuanping Zhang, Yanfang Guan, Yongsheng Chen, Xiao Xiao, Jiayin Wang. FCRF: An efficient algorithm for detecting circular fusion transcript from RNA-Seq data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-212.