tbuckley/cabot-search huggingface dataset:
Linking Bisphenol S to Adverse Outcome Pathways Using a Combined Text Mining and Systems Biology Approach
Authors: Jean-Charles Carvaillo, Robert Barouki, Xavier Coumoul, Karine Audouze
Journal: Environmental Health Perspectives (2019)

Background: Available toxicity data can be optimally interpreted if they are integrated using computational approaches such as systems biology modeling. Such approaches are particularly warranted in cases where regulatory decisions have to be made rapidly. Objectives: The study aims at developing and applying a new integrative computational strategy to identify associations between bisphenol S (BPS), a substitute for bisphenol A (BPA), and components of adverse outcome pathways (AOPs). Methods: The proposed approach combines a text mining (TM) procedure and integrative systems biology to comprehensively analyze the scientific literature to enrich AOPs related to environmental stressors. First, to identify relevant associations between BPS and different AOP components, a list of abstracts was screened using the developed text-mining tool AOP-helpFinder, which calculates scores based on the graph theory to prioritize the findings. Then, to fill gaps between BPS, biological events, and adverse outcomes (AOs), a systems biology approach was used to integrate information from the AOP-Wiki and ToxCast databases, followed by manual curation of the relevant publications. Results: Links between BPS and 48 AOP key events (KEs) were identified and scored via 31 references. The main outcomes were related to reproductive health, endocrine disruption, impairments of metabolism, and obesity. We then explicitly analyzed co-mention of the terms BPS and obesity by data integration and manual curation of the full text of the publications. Several molecular and cellular pathways were identified, which allowed the proposal of a biological explanation for the association between BPS and obesity. Conclusions: By analyzing dispersed information from the literature and databases, our novel approach can identify links between stressors and AOP KEs. The findings associating BPS and obesity illustrate the use of computational tools in predictive toxicology and highlight the relevance of the approach to decision makers assessing substituents to toxic chemicals. https://doi.org/10.1289/EHP4200
An integrin-based nanoparticle that targets activated hepatic stellate cells and alleviates liver fibrosis
Authors: Yanping Li, Shiyun Pu, Qinhui Liu, Rui Li, Jinhang Zhang, Tong Wu, Lei Chen, Hong Li, Xuping Yang, Min Zou, Jia Xiao, Wen Xie, Jinhan He
Journal: Journal of Controlled Release (2019)

Activation of hepatic stellate cells (HSCs) contributes to the development of liver fibrosis. Because of a relatively small population of HSCs in the liver and the lack of specific membrane targeting proteins, HSC-targeted therapy remains a major clinical challenge. Here we first showed that a hallmark of activated HSC (aHSC) is their increased expression of integrin αvβ3. Thus we established sterically stable liposomes that contain the cyclic peptides (cRGDyK) with a high affinity to αvβ3 to achieve aHSC-specific delivery. Our results showed that the cRGDyK-guided liposomes were preferentially internalized by activated HSCs in vitro and in vivo, and the internalization was abolished by excess free cRGDyK or knockdown of αvβ3. In contrast, quiescent HSCs, hepatocytes, Kupffer cells, sinusoidal endothelial cells, or biliary cells showed minimal uptake of the cRGDyK-guided liposomes. When loaded with the hedgehog inhibitor vismodegib, the cRGDyK-guided liposomes inhibited hedgehog pathway signaling specifically in activated HSCs. Moreover, treatment of mice with vismodegib-loaded cRGDyK-liposomes markedly inhibited the fibrogenic phenotype in bile duct ligation- or thioacetamide-treated mice. We conclude that the cRGDyK-guided liposomes can specifically target the activated HSCs, but not quiescent HSCs. This nanoparticle system showed great promise to deliver therapeutic agents to aHSC to treat liver fibrosis.
Clinical outcomes of patients with both breast and lung cancer diagnoses.
Authors: Eric Nguyen, Garth Andrew Nicholas, Xinni Song
Journal: Journal of Clinical Oncology (2015)

e12048 Background: Breast and lung cancer are two of the most commonly diagnosed cancers in North America. While patients are living longer with advances in treatment and supportive care, some patients are being diagnosed with a second malignancy. In this retrospective cohort study, the primary objectives were to assess the risk of an ipsilateral lung cancer (LC) in breast cancer (BC) patients who received prior radiation therapy and to determine the predominant tumor subtypes and survival outcomes of patients in this clinical situation. Methods: We conducted a single institution (the Ottawa Hospital Cancer Centre) retrospective review of patients with the diagnoses of BC and subsequently LC treated between 1995 to 2013. Data included patient demographics, lifestyle factors, tumor location and subtype, treatment modalities, and survival outcomes. Results: 217 patients were identified and with a median follow-up of 82 months. There were no significant correlation between the laterality of the lung cancer location and the side that received radiation treatment based on Fisher’s exact test. Conclusions: Our data reveals no association between side of radiation treatment and subsequent lung cancer development. This is reassuring for both patients and clinicians. Additional studies with matched patient cohorts are required to further assess treatment and lifestyle factors that may contribute towards the development of second malignancies. Cancer Diagnosis Ipsilateral LC Contralateral LC Number 111 106 Median age at BC diagnosis 64.5 66.2 Median age at LC diagnosis 70.1 71.5 LC stage (%) Stage I – 33 Stage II – 11 Stage III – 23 Stage IV – 33 Stage I – 32 Stage II – 15 Stage III – 15 Stage IV – 38 Median disease-free survival from LC diagnosis 38 months 30 months Smoking history n (%) 97 (87) 100 (94) LC Tumor subtypes (%) Adenocarcinoma (42) NSCLC NOS (25) Squamous cell carcinoma (16) Small cell carcinoma (13) Large cell carcinoma (2) Carcinoid (2) Adenocarcinoma (36) NSCLC NOS (25) Small cell carcinoma (16) Squamous cell carcinoma (15) Large cell l carcinoma (7) Carcinoid (1) Breast Radiation (%) 60 62 BC treatment modalities (%) Surgery: 94 Hormonal Therapy: 64 Chemotherapy: 26 Surgery: 95 Hormonal Therapy: 63 Chemotherapy: 29 Cancer-related mortality (%) 49 42
Functional decline during first-line chemotherapy in elderly patients can be predicted by abnormal G8 score and performance status.
Authors: Camille Chakiba, Carine A. Bellera, Marianne Fonck, Jean-Frédéric Blanc, Joel Ceccaldi, Yves Imbert, Laurent Cany, Jérôme Dauba, Hugo Caillou, Simone Mathoulin-Pélissier, Muriel Rainfray, Pierre Soubeyran
Journal: Journal of Clinical Oncology (2015)

9538 Background: Predicting major adverse events such as functional decline during chemotherapy is an important issue in geriatric oncology. Recent studies have shown that different parts of comprehensive geriatric assessment (CGA) (Geriatric Depression Scale and Instrumental Activities of Daily Living) were predictive of functional decline. However CGA is time-consuming and has to be performed by trained geriatricians who are not in sufficient number to face the increasing demand of elderly cancer patients. Thus screening tools, such as G8-score validated on 1435 patients, have been developed to identify patients who may benefit from CGA. In addition to its value as a screening tool, the value of the G8 as a predictive tool of survival has been suggested and we here investigate whether it can be used to predict functional decline during chemotherapy. Methods: We tested on a cohort of 364 patients over 70 year-old treated with first-line chemotherapy the value of clinical (G8, age, sex, performance status –PS-, disease localization, extension) and biological factors (platelets, creatinine clearance, albumin, CRP, neutrophils) in predicting early functional decline, defined as a decrease of 0.5 points on the Activities of Daily Living (ADL) scale between the beginning of chemotherapy and the second cycle. We performed a multivariate analysis using logistic regression model. Results: Of the 364 patients, 312 were assessable for functional status and 68 experienced functional decline. On univariate analysis, PS 2 to 4, low platelets, metastatic disease and abnormal G8 ( ≤ 14) score were associated with functional decline. On multivariate analysis, abnormal G8 score (OR, 3.56; 95% CI 1.22; 10.34; p = 0.02) and PS 2 to 4 (OR, 2.0; 95% CI 1.1; 3.6; p = 0.04) were significantly associated with increased likelihood of early functional decline. Conclusions: G8 has been developed as a screening tool to predict abnormal geriatric assessment. We have shown here that it could also be used together with performance status to select elderly patients more likely to develop functional decline during chemotherapy. These data reinforce the routine use of G8 in all elderly patients treated for cancer.
Quality of life assessment in retinoblastoma: A cross-sectional study of 122 survivors.
Authors: Atul Batra, Mamta Kumari, Reeja Paul, Deepa Dhawan, Sameer Bakhshi
Journal: Journal of Clinical Oncology (2015)

10068 Background: Retinoblastoma (Rb) is the most common intraocular tumor in childhood. With current modalities, cure rates are high and hence number of survivors is increasing. However, data on quality of life (QOL) in this population are minimal. Methods: We analyzed QOL in 122 retinoblastoma survivors using the PedsQL 4.0 generic core scale in local language, which has been validated in Indian population. The self-reported questionnaire was filled by children of more than 5 years of age who had completed treatment for more than 12 months. The questionnaire consists of 23 questions on physical, social, emotional and school domains on a scale from 0 to 4. This was converted to a scale from 0 to 100, where higher values represented better QOL. The QOL was compared with 50 siblings using student’s t-test. Factors predicting the QOL were assessed. Results: The median age of Rb survivors was 98 (range, 60-247) months and 68% were males. Seventy-nine percent were International Retinoblastoma Staging System (IRSS) stage1 and 25% had bilateral disease. Fourteen percent had extraocular involvement and 22% received radiotherapy. The overall QOL was significantly poorer in Rb survivors as compared to controls (Table). The emotional health domains of QOL (fear, anger and sleeping) were significantly lower in Rb survivors. Difficulties in maintaining friendships and competing were reported in the social health domain. In school health domain, there was significantly higher absenteeism due to sickness and hospital visits among Rb survivors. However, the physical health domain including household work, exercise and self-care was similar in both the groups. Age, sex, IRSS stage and previous radiotherapy did not affect the QOL. Conclusions: QOL is often a neglected aspect in survivors of pediatric solid tumors. We found a significantly poorer QOL in Rb survivors. However, no predicting factors for poor QOL were found in this group. Although a high survival rate has been achieved in early stage Rb, efforts need to be made to improve QOL. Domain Rb Survivors (N = 122) Controls (N = 50) P value Physical 79.1 ± 9.1 81.4 ± 10.1 0.14 Social 71.8 ± 13.1 83.9 ± 10.5 < 0.001 Emotional 78.2 ± 9.8 82.5 ± 12.5 0.02 School 79.9 ± 12.3 91.9 ± 4.7 < 0.001 Overall 77.3 ± 8.6 84.9 ± 5.9 < 0.001
Woman is jailed after exaggerating injuries from vaginal mesh operation
Authors: Clare Dyer
Journal: BMJ (2019)

A woman who tried to defraud the NHS of £2.3m (€2.7m; $3m) by making an exaggerated clinical negligence claim over an unnecessary vaginal mesh operation in 2010 has been given a five month jail sentence.

Lesley Elder, 50, claimed she was in constant pain and could no longer work, walk unaided, or go on holiday, but was caught out by a Facebook photo of her in 2012 at her daughter’s hen party in Ibiza.

Investigators acting on behalf of the NHS put Elder under surveillance in …
SAT-169-Prevalence of resistance associated substitutions and phylogeographic analysis of HCV infection in Russia
Authors: Vasily Isakov, Charlotte Hedskog, Joel Wertheim, Anuj Gaggar, Hongmei Mo, Natalia Geivandova, Morozov Viacheslav, Elena Bessonova, Natalya Gankina, Evguenia S Svarovskaia, Konstantin Zhdanov
Journal: Journal of Hepatology (2019)
Reply
Authors: Xin Chen, Satdarshan P. Monga, Diego F. Calvisi
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. We thank Drs. Gilgenkrantz and Perret for their insightful comments on the article by Qiao et al.1 In agreement with their comments, we believe that all conclusions in our study are based on the experimental system used, including human tumor samples, cell lines, and mouse models. In our study,1 we generated a mouse hepatocellular carcinoma (HCC) model by deleting single‐guide axis inhibition protein 1 (sgAxin1) and simultaneously expressing c‐Met (c‐Met/sgAxin1). Using the "23 β‐catenin gene signature" defined by Abitbol et al.,2 we found that c‐Met/sgAxin1 HCCs did not show activation of this signature based on global gene expression analysis, although activation of the Wnt pathway was evident. We concluded that the "23 β‐catenin gene signature" may represent a distinct, and likely higher extent of, Wnt/β‐catenin pathway activation and may be inadequate to detect low levels of Wnt/β‐catenin activation observed in the c‐Met/sgAxin1 HCC. Another important conclusion by Abitbol et al.,2 based on the gene expression of human HCCs with AXIN1 mutations, was activation of Notch signaling in these cases. Once again, we detected activation of the Notch cascade in c‐Met/sgAxin1 mouse HCC samples. Overall, the c‐Met/sgAxin1 mouse HCCs possess a similar gene expression signature to that described by Abitbol et al. Subsequently, we performed functional analyses of β‐catenin and Notch cascades in c‐Met/sgAxin1 HCC using conditional knockout mice. The data clearly demonstrated that an intact Wnt/β‐catenin cascade was required, whereas the Notch pathway was dispensable for c‐Met/sgAxin1‐driven hepatocarcinogenesis. The key role of the Wnt/β‐catenin cascade in AXIN1 mutant HCC was further validated using several human HCC cell lines. Altogether, our data suggested that gene expression data provide useful information on the pathways involved in tumorigenesis. However, additional genetic and/or biochemical analyses are imperative to elucidate the functional contribution of pathways in tumor development and progression. We agree that our data should only be interpreted in the context of the c‐Met/sgAxin1 mouse HCC model along with the human HCC cell lines employed in the study. Human HCC is highly heterogeneous, and c‐Met/sgAxin1 HCC likely represents around 40%‐60% of AXIN1‐mutated HCC. Based on The Cancer Genome Atlas analysis, AXIN1 mutants could co‐occur with other genetic events, including tumor protein P53, TSC complex subunit 2, and AT‐rich interaction domain 1A mutations. Therefore, it is important to establish additional mouse HCC models harboring Axin1 mutations or deletions in combination with the alterations in the aforementioned genes for a more universal conclusion on the roles of the Wnt/β‐catenin pathway in various classes of HCC including those exhibiting Axin1 loss of function, using genetic approaches as described in our study.
FRI-057-A review of primary biliary cholangitis practice in Wales: Time for specialist care
Authors: Hasan Haboubi, Lavanya Shenbagaraj, Asma Abdul-Sattar, Philip Harborne, Andrew Philips, Gautham Appanna, Dr. Imran Yahya, Janardhan Navaratnam, Dr. Kate Edwards, Laith Alrubaiy, Dr. Rachel Newbould, Dr. Rebecca Vincent, Dr. Seetharam Mannem, Dr. Syed Anjum Gardezi, Dr. Usama Aslam, Dr. Victoria Jennings, David Samuel, Tom Pembroke, Chin Lye Ch’ng, Dr. Brijesh Srivastava, Dr. Fidan Yousuf, Andrew Yeoman
Journal: Journal of Hepatology (2019)
THU-121-Real world outcomes from NS5a treatment failures undergoing therapy with sofosbuvir/velpatasvir/voxilaprevir and sofosbuvir/ glecaprevir/pibrentasvir
Authors: Alison Boyle, Fiona Marra, Raymod Fox, Rory Gunson, Amanda Bradley, Emma Thomson, Erica Peters, Stephen Barclay
Journal: Journal of Hepatology (2019)
Abstract P6-13-06: Estrogen-based hormone replacement [HRT] therapy is substantially more effective than tamoxifen in reducing breast cancer mortality and breast cancer case fatality ratio: Emergence of a new paradigm
Authors: J Ragaz, S Shakeraneh, H Qian, KS Wilson, H Wong, JJ Spinelli
Journal: Cancer Research (2019)

Abstract OBJECTIVE: To compare, in the setting of breast cancer (BrCa) prevention, the impact of estrogen-based hormone replacement therapy (E-HRT) vs. tamoxifen (TAM) on breast cancer mortality (BrCa-M) and breast cancer case fatality ratio (BrCa-CFR), by analyzing data from the Women's Health Initiative Trial 2 (WHI HRT Trial 2, E-HRT vs. placebo [P])1 and the International Breast Cancer Intervention Study 1 (IBIS-1), TAM vs. P.2 METHODS: Hazard ratios (HR) and confidence intervals (CI) for BrCa incidence and mortality were extracted from the original WHI HRT Trial 2 and IBIS-1 trials.1,2 BrCa-CFRs were estimated by dividing the mortality HR by the incidence HR. Subsequently, to compare E-HRT vs. TAM outcomes, the ratios of HRs (HR1/HR2) between the two trials were estimated separately for BrCa-M and BrCa-CFR. The 95% CI was derived through logarithmic transformation of the 95% CI originally reported. RESULTS: Mortality and Case Fatality Outcomes: Impact of E-HRT versus TAM, expressed as ratio of HRs E-HRT vs. Placebo, HR1TAM vs. Placebo, HR2HR1/HR2pMortality0.55 (0.33-0.92)1.19 (0.68-2.10)0.46 (0.22-0.99)0.046Case Fatality0.70 (0.40-1.20)1.68 (0.93-3.01)0.42 (0.18-0.94)0.040 CONCLUSIONS: While acknowledging between-trial comparisons including eligibility differences, E-HRT yields significant reductions in BrCa mortality and case fatality as compared with TAM (54% and 58% respectively). These unexpected breast cancer mortality reductions represent major public health gains, additional to the already known superiority of E-HRT over TAM in terms of skeletal fracture rates and Alzheimer's dementia mortality reduction, and, in women entering menopause, also of cardiac and all-cause mortality reductions. REFERENCES: 1. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. JAMA 2017;318:927-38. 2. Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. The Lancet Oncology 2015;16:67-75. Citation Format: Ragaz J, Shakeraneh S, Qian H, Wilson KS, Wong H, Spinelli JJ. Estrogen-based hormone replacement [HRT] therapy is substantially more effective than tamoxifen in reducing breast cancer mortality and breast cancer case fatality ratio: Emergence of a new paradigm [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 P6-13-06.
THU-389-Assessment of hepatitis C screening strategies in different community settings in a Canadian metropolitan area
Authors: Camelia Capraru, Bettina Hansen, Aaron Vanderhoff, Steven Friedman, Kathy Bates, Tony Mazzulli, Danielle Porplycia, Bentley McCormack, Joshua Juan, Hsiao-Ming Jung, Hemant A Shah, Jordan Feld, Harry Janssen
Journal: Journal of Hepatology (2019)
Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab
Authors: Amy K. Erbe, Wei Wang, Lakeesha Carmichael, Anna Hoefges, Bartosz Grzywacz, Patrick K. Reville, Erik A. Ranheim, Jacquelyn A. Hank, KyungMann Kim, Songwon Seo, Eneida A. Mendonca, Yiqiang Song, Vaishalee P. Kenkre, Fangxin Hong, Randy D. Gascoyne, Elisabeth Paietta, Sandra J. Horning, Jeffrey S. Miller, Brad Kahl, Paul M. Sondel
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> The ECOG-ACRIN Cancer Research Group evaluated rituximab treatment schedules for patients with newly-diagnosed low-tumor-burden follicular-lymphoma (FL). All patients received 4-weekly rituximab treatments as induction therapy. Clinically-responding patients were randomized to receive rituximab every 13 weeks ("maintenance") vs. no additional rituximab until progression ("non-maintenance"). Based on "time-to-rituximab-failure (TTRF)", the study-committee reported there was no overall-benefit for maintenance rituximab in this setting. Tumor-reactive mAbs, like rituximab, trigger natural killer (NK) cells. NK-cell responses are regulated, in part, by interactions between killer immunoglobulin-like receptors (KIRs) on NK cells and their interactions with KIR-ligands. In a separate study of children with neuroblastoma treated with a different mAb, we found certain KIR/KIR-ligand genotypes associated with improved outcome. Here, we assessed whether a subset of FL patients show improved outcome from the maintenance rituximab based on these same KIR/KIR-ligand genotypes. <h3>Methods</h3> Genotypes for KIR/KIR-ligand were determined and assessed for associations with outcome [duration of response, TTRF and % tumor shrinkage] as a post-hoc analysis of this phase III trial. Our primary objective was to assess specific KIR/KIR-ligand genotype associations, followed by separate prespecified KIR/KIR-ligand genotype associations in follow-up analyses. Statistical analyses for association of genotype with clinical outcome included: Log-rank tests and Cox proportional hazards regression models to assess duration of response and TTRF; analysis of variance (ANOVA) was used for assessment of % tumor shrinkage. <h3>Results</h3> We found that patients inheriting KIR2DL2 and its ligand (HLA-C1) along with KIR3DL1 and its ligand (HLA-Bw4) had improved outcome over patients without this genotype. In addition, patients with KIR2DL2 and HLA-C1 along with KIR3DL1 and HLA-Bw4 also showed improved duration of response and tumor shrinkage if they received maintenance, while patients without this genotype showed no such improvement when receiving maintenance. <h3>Conclusions</h3> The data presented here indicate that a subset of FL patients, identified by certain KIRs/KIR-ligands, have improved outcome and may benefit from additional rituximab treatment. Taken together, this suggests that the efficacy of tumor-reactive mAb treatment for some patients is influenced by KIRs on NK cells. However, prior to considering these genotypes in a clinically-actionable manner, these findings need independent validation in other studies.
SAT-194-The utility of monomeric HBV genomes for interrogating the HBV cccDNA minichromosome, using in vitro and in vivo models of HBV replication
Authors: Thao Huynh, Michelle Clark, Liana Mackiewicz, Vitini Sozzi, Hugh Mason, Marc Pellegrini, Greg Ebert, Hans J Netter, Peter Revill
Journal: Journal of Hepatology (2019)
Cyclooxygenase inhibition in mice heightens adaptive‐ and innate‐type responses against inhaled protease allergen and <scp>IL</scp>‐33
Authors: Natsuko Maruyama, Toshiro Takai, Seiji Kamijo, Punyada Suchiva, Mai Ohba, Tomohito Takeshige, Mayu Suzuki, Mutsuko Hara, Kei Matsuno, Sonoko Harada, Norihiro Harada, Susumu Nakae, Katsuko Sudo, Toshiaki Okuno, Takehiko Yokomizo, Hideoki Ogawa, Ko Okumura, Shigaku Ikeda
Journal: Allergy (2019)

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SAT-183-High resolution insight into hepatitis B virus infection and immunity in Africa to inform on intervention strategies
Authors: Anna Mcnaughton, José Lourenço, Phillip Armand Bester, Jolynne Mokaya, Sheila F Lumley, Donall Forde, Tongai G Maponga, Kenneth R Katumba, Dominique Goedhals, Sunetra Gupta, Janet Seeley, Robert Newton, Ponsiano Ocama, Philippa C Matthews
Journal: Journal of Hepatology (2019)