tbuckley/cabot-search huggingface dataset:
Maternal age at delivery, lung function and asthma in offspring: a population-based survey
Authors: Francisco Gómez Real, John A. Burgess, Simona Villani, Julia Dratva, Joachim Heinrich, Christer Janson, Debbie Jarvis, Jennifer Koplin, Bénédicte Leynaert, Caroline Lodge, Birger N. Lærum, Melanie C. Matheson, Dan Norbäck, Ernst R. Omenaas, Svein M. Skulstad, Jordi Sunyer, Shyamali C. Dharmage, Cecilie Svanes
Journal: European Respiratory Journal (2018)

There is limited information about potential impact of maternal age on the respiratory health of offspring. We investigated the association of maternal age at delivery with adult offspring's lung function, respiratory symptoms and asthma, and potential differences according to offspring sex. 10 692 adults from 13 countries participating in the European Community Respiratory Health Survey (ECRHS) II responded to standardised interviews and provided lung function measurements and serum for IgE measurements at age 25–55 years. In logistic and linear multilevel mixed models we adjusted for participants’ characteristics (age, education, centre, number of older siblings) and maternal characteristics (smoking in pregnancy, education) while investigating for differential effects by sex. Maternal age was validated in a subsample using data from the Norwegian birth registry. Increasing maternal age was associated with increasing forced expiratory volume in 1 s (2.33 mL per year, 95% CI 0.34–4.32 mL per year), more consistent in females (p trend 0.025) than in males (p trend 0.14). Asthma (OR 0.85, 95% CI 0.79–0.92) and respiratory symptoms (OR 0.87, 95% CI 0.82–0.92) decreased with increasing maternal age (per 5 years) in females, but not in males (p interaction 0.05 and 0.001, respectively). The results were consistent across centres and not explained by confounding factors. Maternal ageing was related to higher adult lung function and less asthma/symptoms in females. Biological characteristics in offspring related to maternal ageing are plausible and need further investigation.
nab-Paclitaxel plus carboplatin or gemcitabine versus gemcitabine plus carboplatin as first-line treatment of patients with triple-negative metastatic breast cancer: results from the tnAcity trial
Authors: D.A. Yardley, R. Coleman, P. Conte, J. Cortes, A. Brufsky, M. Shtivelband, R. Young, C. Bengala, H. Ali, J. Eakel, A. Schneeweiss, L. de la Cruz-Merino, S. Wilks, J. O’Shaughnessy, S. Glück, H. Li, J. Miller, D. Barton, N. Harbeck
Journal: Annals of Oncology (2018)

BackgroundMetastatic triple-negative breast cancer (mTNBC) has a poor prognosis and aggressive clinical course. tnAcity evaluated the efficacy and safety of first-line nab-paclitaxel plus carboplatin (nab-P/C), nab-paclitaxel plus gemcitabine (nab-P/G), and gemcitabine plus carboplatin (G/C) in patients with mTNBC.Patients and methodsPatients with pathologically confirmed mTNBC and no prior chemotherapy for metastatic BC received (1 : 1 : 1) nab-P 125 mg/m2 plus C AUC 2, nab-P 125 mg/m2 plus G 1000 mg/m2, or G 1000 mg/m2 plus C AUC 2, all on days 1, 8 q3w. Phase II primary end point: investigator-assessed progression-free survival (PFS); secondary end points included overall response rate (ORR), overall survival (OS), percentage of patients initiating cycle 6 with doublet therapy, and safety.ResultsIn total, 191 patients were enrolled (nab-P/C, n = 64; nab-P/G, n = 61; G/C, n = 66). PFS was significantly longer with nab-P/C versus nab-P/G [median, 8.3 versus 5.5 months; hazard ratio (HR), 0.59 [95% CI, 0.38–0.92]; P = 0.02] or G/C (median, 8.3 versus 6.0 months; HR, 0.58 [95% CI, 0.37–0.90]; P = 0.02). OS was numerically longer with nab-P/C versus nab-P/G (median, 16.8 versus 12.1 months; HR, 0.73 [95% CI, 0.47–1.13]; P = 0.16) or G/C (median, 16.8 versus 12.6 months; HR, 0.80 [95% CI, 0.52–1.22]; P = 0.29). ORR was 73%, 39%, and 44%, respectively. In the nab-P/C, nab-P/G, and G/C groups, 64%, 56%, and 50% of patients initiated cycle 6 with a doublet. Grade ≥3 adverse events were mainly hematologic.ConclusionsFirst-line nab-P/C was active in mTNBC and resulted in a significantly longer PFS and improved risk/benefit profile versus nab-P/G or G/C.
Almost 1.5m emergency hospital admissions could have been avoided last year
Authors: Ingrid Torjesen
Journal: BMJ (2018)

Almost 1.5 million emergency admissions to hospitals could have been averted last year if the NHS had invested in better preventive care outside hospital, says a report from MPs.1

There were 5.8 million emergency admissions in England during 2016-17, of which 24% might have been avoided if people had had more effective community healthcare and case management to stop them becoming so unwell that they needed emergency hospital care, said House of Commons Public …
Updated survival data and biomarker assessment of the CBCSG006 trial: A randomized phase III trial of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer.
Authors: Jian Zhang, Ying Lin, Xi-Chun Hu, Wentao Yang, Xiangjie Sun, Biyun Wang, Zhonghua Wang, Jianfeng Luo, Leiping Wang, Sheng Zhang, Jun Cao, Zhonghua Tao, Jiong Wu, Zhimin Shao
Journal: Journal of Clinical Oncology (2018)

1093 Background: It was previously reported in CBCSG006 trial that patients with metastatic TNBC were more likely to have higher response rate and longer PFS to cisplatin plus gemcitabine (GP) than to paclitaxel plus gemcitabine (GT) treatment. Here, we reported the updated survival data and the explorations of biomarkers for higher sensitivity to platinum doublet. Methods: 132 Blood and 114 archival tissue samples were collected prospectively. gBRCA1/2 genotyping and germ-line HRD panel status were detected by NGS. Core basal markers and PD-L1 expression were detected immunohistochemistry. Tumor-infiltrating lymphocytes (TILs) evaluation was performed on HE–stained sections. A model of composite measure of progression risk was developed to analyze the absolute survival benefits between two arms in CBCSG006 trial by a nonparametric sliding-window subpopulation treatment effect patter plot (STEPP) methodology. Results: Median PFS was 7.73 months (95% CI 6.46-9.00) for GP arm and 6.07 months (5.32-6.83) for GT arm (p = 0.005). No significant differences in OS were observed. Patients with gBRCA1/2 mutations had numerically higher ORR and prolonged PFS in GP than GT arm. Patients with germ-line HRD panel mutations had significantly higher ORR and longer PFS in GP than GT arm. Core basal subtype, lymphocyte-predominant breast cancer subtype and positive PD-L1 expression were not correlated with ORR or PFS. In STEPP analysis, patients with lower composite measure of progression risks had more absolute PFS benefits than those with high composite measure of progression risks, with absolute difference in 6-month PFS rates ranging from approximately 40% to none. Conclusions: gBRCA1/2 and germ-line HRD mutations are possible markers for platinum-based regimens. A composite risk model was developed to guide patient selection for GP treatment in TNBC. Clinical trial information: NCT01287624.
Telomerase regulation by the long non-coding RNA H19 in human acute promyelocytic leukemia cells
Authors: Joëlle El Hajj, Eric Nguyen, Qingyuan Liu, Claire Bouyer, Eric Adriaenssens, George Hilal, Evelyne Ségal-Bendirdjian
Journal: Molecular Cancer (2018)

Since tumor growth requires reactivation of telomerase (hTERT), this enzyme is a challenging target for drug development. Therefore, it is of great interest to identify telomerase expression and activity regulators. Retinoids are well-known inducers of granulocytic maturation associated with hTERT repression in acute promyelocytic leukemia (APL) blasts. In a maturation-resistant APL cell line, we have previously identified a new pathway of retinoid-induced hTERT transcriptional repression independent of differentiation. Furthermore, we reported the isolation of a cell variant resistant to this repression. Those cell lines could serve as unique tools to identify new telomerase regulators. Using a microarray approach we identified the long non-coding RNA, H19 as a potential candidate playing a role in telomerase regulation. Expression of H19, hTERT, and hTR were examined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Telomerase activity was quantified by quantitative telomeric repeats amplification protocol (qTRAP). In vitro and in vivo assays were performed to investigate H19 function on telomerase expression and activity. We showed both in retinoid-treated cell lines and in APL patient cells an inverse relationship between the expression of H19 and the expression and activity of hTERT. Exploring the mechanistic link between H19 and hTERT regulation, we showed that H19 is able to impede telomerase function by disruption of the hTERT-hTR interaction. This study identifies a new way of telomerase regulation through H19's involvement and thereby reveals a new function for this long non-coding RNA that can be targeted for therapeutic purpose.
Efficacy of olaparib monotherapy in patients (pts) with HER2-negative metastatic breast cancer (MBC) with germline <i>BRCA</i> mutation (g<i>BRCAm</i>) or lesional <i>BRCA</i> mutation (l<i>BRCAm</i>).
Authors: Eleanor Meisner, Rebecca Rollins, Joe Ensor, Amber Moran, Amanda Woodward, Eugene R Ahn, Cynthia Anne Lynch, Dennis L. Citrin, Damien Hansra, Sramila S. Aithal, Mary Ninan, Daniel W. Nixon, Susan Zook, Siraj Mahamed Ali, Maurie Markman, Ricardo H. Alvarez
Journal: Journal of Clinical Oncology (2018)

1074 Background: A recent Phase III study in MBC with gBRCAm, olaparib monotherapy provided a statistical significant and clinically meaningful PFS benefit compared to standard physician of choice treatment. (Robson M, NEJM 2017) Recently, olaparib was FDA approved for MBC with gBRCAm. Methods: IRB-approved analysis of pts underwent to genomic or genetic analysis. Retrospective review charts for pts with MBC who had received ≥2 chemotherapy lines for MBC were tested with genomic or genetic studies. The objective of this analysis was to determine the PFS2/PFS1 ratio. [von Hoff DD, 2014]. lBRCAm were detected in 12 out 19 pts [8 Foundation One, 3 Foundation Act and 1 Guardant 360] where somatic versus germline nature was not determined and gBRCAm 7 out 19 pts. Results: From 03/2014 to 08/2017, 319 pts with advanced cancer were treated with targeted therapy based on molecular abnormality. Overall 19 out 319 (6%) consisted on olaparib for MBC with gBRCAm or lBRCAm. Median age 45.1 years (range, 31-67), 18 out 19 pts were female, 14/19 were Caucasians, median number of previous lines of treatment for MBC was 4 (range, 2-8). Olaparib was dosed at 300 mg po bid until disease progression. A total of 12 out 19 pts (63%) the PFS ratio was ≥ 1.3, with a Wilson score 95% CI of (0.7, 3.). Nine out 12 pts (75%) with lBRCAm had increased PFS ratio. The 6-month PFS was 69.4% [95% CI: (40%, 86.4%)], and the 6-month OS was 88.8% [95% CI: (62.1%, 97.1%)] There was no Grade 3-4 toxicity. Conclusions: Olaparib monotherapy provided a statistically significant increment of PFS in almost 2/3 (63%) of heavily pretreated MBC pts harboring gBRCAm and lBRCAm. Interestingly, 75% of patients with lBRCAm resulted in improvement the PFS with minimal toxicity. Further research is necessary to extend the olaparib approval for lBRCAm in MBC pts.
Family‐based study reveals decreased abundance of sputum Granulicatella in asthmatics
Authors: L. Wang, D. de Ángel Solá, Y. Mao, P. Bielecki, Y. Zhu, Z. Sun, L. Shan, R. A. Flavell, A. Bazzy‐Asaad, A. DeWan
Journal: Allergy (2018)

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Adjuvant radiation therapy in patients with breast cancer and Li-Fraumeni syndrome: Oncologic results and incidence of second neoplasms.
Authors: Guilherme Rocha Melo Gondim, Maria Nirvana Cruz Formiga, Douglas Guedes Castro, Maria Leticia GOBO Silva, Michael .Chen, Ricardo Fogaroli, Henderson Ramos, Tharcisio Machado Coelho, Antonio Cassio Assis Pellizzon, Alexandre Andre B. A. Da Costa
Journal: Journal of Clinical Oncology (2018)

e12589 Background: Li-Fraumeni syndrome (LFS) is an autosomal dominant disease related to an increased risk of various types of cancer, including radio-induced neoplasms, due to the TP53 gene mutation. We describe here the oncological results and the incidence of second neoplasms in LFS patients submitted to adjuvant radiotherapy (RT) for breast cancer (BC). As far as we know, this is the largest worldwide experience ever reported in this clinical setting. Methods: Patients with BC and with indication of genetic testing for LFS were referred to the Oncogenetics Department and, after screening by a Geneticist, the patients were submitted to genetic sequencing to detect the R337H mutation of the TP53 gene. The medical records of the patients diagnosed with this mutation were retrospectively analyzed to identify BC patients with history of previous adjuvant RT to verify the oncologic outcomes and the incidence of second neoplasms in these patients. Results: Nine patients with LFS and BC submitted to previous RT were identified. The median follow-up from the end of RT was 56 months. 5/9 patients developed more than one primary tumor (3 patients with 2 primary tumors and 2 patients with 4 primary tumors), 1 of which was unequivocally radio-induced (Cutaneous Malignant Fibrohistiocytoma in the Lumpectomy scar). Of the 9 patients evaluated, 8 were alive and without evidence of BC. The only death occurred in a patient with 2 primary tumors (Non-Special Breast Carcinoma, pT4N2, and Brenner Tumor of Ovary) after metastases to the Central Nervous System. Local control after adjuvant breast RT was 100%. Conclusions: Adjuvant RT should be used with caution in LFS patients. Second neoplasms occurred in 5 of 9 patients, 1 of which was unequivocally radio-induced. The R337H mutation of the TP53 gene seems to be related to a lower incidence of radio-induced tumors and greater local control in BC patients after adjuvant RT when compared to another series (1). Reference: (1) Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syndrome. Heymann S, et al. Radiat Oncol. 2010 Nov 8; 5:104.
Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030
Authors: Chris Estes, Quentin M. Anstee, Maria Teresa Arias-Loste, Heike Bantel, Stefano Bellentani, Joan Caballeria, Massimo Colombo, Antonio Craxi, Javier Crespo, Christopher P. Day, Yuichiro Eguchi, Andreas Geier, Loreta A. Kondili, Daniela C. Kroy, Jeffrey V. Lazarus, Rohit Loomba, Michael P. Manns, Giulio Marchesini, Atsushi Nakajima, Francesco Negro, Salvatore Petta, Vlad Ratziu, Manuel Romero-Gomez, Arun Sanyal, Jörn M. Schattenberg, Frank Tacke, Junko Tanaka, Christian Trautwein, Lai Wei, Stefan Zeuzem, Homie Razavi
Journal: Journal of Hepatology (2018)

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data.A model was used to estimate NAFLD and NASH disease progression in eight countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections.If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0-30%), between 2016-2030, with the highest growth in China as a result of urbanization and the lowest growth in Japan as a result of a shrinking population. However, at the same time, NASH prevalence will increase 15-56%, while liver mortality and advanced liver disease will more than double as a result of an aging/increasing population.NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden.Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis can lead to advanced liver disease. Both conditions are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase. A mathematical model was built to understand how the disease burden associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis will change over time. Results suggest increasing cases of advanced liver disease and liver-related mortality in the coming years.
Risk, Risk Factors, and Surveillance of Subsequent Malignant Neoplasms in Survivors of Childhood Cancer: A Review
Authors: Lucie M. Turcotte, Joseph P. Neglia, Raoul C. Reulen, Cecile M. Ronckers, Flora E. van Leeuwen, Lindsay M. Morton, David C. Hodgson, Yutaka Yasui, Kevin C. Oeffinger, Tara O. Henderson
Journal: Journal of Clinical Oncology (2018)

Subsequent malignant neoplasms (SMNs) in childhood cancer survivors cause substantial morbidity and mortality. This review summarizes recent literature on SMN epidemiology, risk factors, surveillance, and interventions. Survivors of childhood cancer experience long-term increased SMN risk compared with the general population, with a greater than twofold increased solid tumor risk extending beyond age 40 years. There is a dose-dependent increased risk for solid tumors after radiotherapy, with the highest risks for tumors occurring in or near the treatment field (eg, greater than fivefold increased risk for breast, brain, thyroid, skin, bone, and soft tissue malignancies). Alkylating and anthracycline chemotherapies increase the risk for development of several solid malignancies in addition to acute leukemia/myelodysplasia, and these risks may be modified by other patient characteristics, such as age at exposure and, potentially, inherited genetic susceptibility. Strategies for identifying survivors at risk and initiating long-term surveillance have improved and interventions are underway to improve knowledge about late-treatment effects among survivors and caregivers. Better understanding of treatment-related risk factors and genetic susceptibility holds promise for refining surveillance strategies and, ultimately, upfront cancer therapies.
Analysis of circulating tumor cells (CTCs) in patients across multiple metastatic breast cancer (mBCa) cohorts identifies marked inter- and intra-patient heterogeneity in CTC size, shape, and overall morphology.
Authors: Gordon Vansant, Yipeng Wang, Beverly Hom, Adam Jendrisak, Joseph Schonhoft, Ryon P Graf, Priscilla Ontiveros, Megan Kearney, Mark Andrew Landers, Ryan Dittamore
Journal: Journal of Clinical Oncology (2018)

1084 Background: The choice between hormonal therapies and chemotherapy is a frequent decision in the care of mBCa pts. We previously developed quantitative measures of phenotypic CTC heterogeneity in mCRPC, and found higher heterogeneity was associated with better survival on chemotherapy vs. targeted hormonal therapies, and the reverse was true in low heterogeneity patients (Scher et al. 2017 Cancer Research). We sought to apply our previous heterogeneity quantitation methodologies to a cohort of mBCa patient CTCs to ascertain feasibility in mBCa. Methods: 295 blood samples from mBCa patients were processed for CTC analysis utilizing the Epic Sciences platform. Following enumeration, multi-dimensional phenotypic characterization analysis was performed utilizing protein expression and digital pathology features. Features from each CTC (3994 CTCs from 165 pts, 84 HR+, 19 Her2+, 8 HR+/Her2+, 54 TNBC) were compared by unsupervised clustering, Shannon Index and intra-patient variance analyses to assess the intra-patient heterogeneity among mBCa CTC phenotypes. Results: CTCs were detected in 76.9% (227/295) of mBCa patients (med = 2.4 CTC/mL, Range 0 - 747). Distinct CTC phenotypes were identified and associated with mBCa subtypes. Subset of CTCs from TNBC pts had larger nuclear area and higher CK expression vs. other subtypes. In addition, we observed marked differences in heterogeneity in CTCs across patients, with some patients having relative uniform CTC profiles, and others with high phenotypic diversity. mBCa subtypes had similar intra-patient heterogeneity level. Conclusions: Distinct CTC phenotypes can be visualized reproducibly across patients and associated with specific mBCa subtypes. Our analysis revealed significant heterogeneity between individual CTCs both between and within patients. Identification of patients with high heterogeneity may help to find patients unlikely to respond to targeted therapies. Studies to link heterogeneity to therapeutic efficacy and pt outcome are ongoing.
The transcription factor Grainy head primes epithelial enhancers for spatiotemporal activation by displacing nucleosomes
Authors: Jelle Jacobs, Mardelle Atkins, Kristofer Davie, Hana Imrichova, Lucia Romanelli, Valerie Christiaens, Gert Hulselmans, Delphine Potier, Jasper Wouters, Ibrahim I. Taskiran, Giulia Paciello, Carmen B. González-Blas, Duygu Koldere, Sara Aibar, Georg Halder, Stein Aerts
Journal: Nature Genetics (2018)
Undersampling Genomes has Biased Time and Rate Estimates Throughout the Tree of Life
Authors: Julie Marin, S Blair Hedges
Journal: Molecular Biology and Evolution (2018)

Genomic data drive evolutionary research on the relationships and timescale of life but the genomes of most species remain poorly sampled. Phylogenetic trees can be reconstructed reliably using small data sets and the same has been assumed for the estimation of divergence time with molecular clocks. However, we show here that undersampling of molecular data results in a bias expressed as disproportionately shorter branch lengths and underestimated divergence times in the youngest nodes and branches, termed the small sample artifact. In turn, this leads to increasing speciation and diversification rates towards the present. Any evolutionary analyses derived from these biased branch lengths and speciation rates will be similarly biased. The widely used timetrees of the major species-rich studies of amphibians, birds, mammals, and squamate reptiles are all data-poor and show upswings in diversification rate, suggesting that their results were biased by undersampling. Our results show that greater sampling of genomes is needed for accurate time and rate estimation, which are basic data used in ecological and evolutionary research.
How to make replications mainstream
Authors: Hans IJzerman, Jon Grahe, Mark J. Brandt
Journal: Behavioral and Brain Sciences (2018)

Abstract Zwaan et al. integrated previous articles to promote making replications mainstream. We wholeheartedly agree. We extend their discussion by highlighting several existing initiatives – the Replication Recipe and the Collaborative Education and Research Project (CREP) - which aim to make replications mainstream. We hope this exchange further stimulates making replications mainstream.