tbuckley/cabot-search huggingface dataset:
Maternal pre-pregnancy infection with hepatitis B virus and the risk of preterm birth: a population-based cohort study
Authors: Jue Liu, Shikun Zhang, Min Liu, Qiaomei Wang, Haiping Shen, Yiping Zhang
Journal: The Lancet Global Health (2017)

BackgroundPreterm birth is the leading cause of child death in children younger than 5 years. Large cohort studies in developed countries have shown that maternal hepatitis B virus infection is associated with preterm birth, but there is little reliable evidence from China and other developing countries, where hepatitis B virus prevalence is intermediate or high. Hence, we designed this study to investigate the association between pre-pregnancy hepatitis B virus infection and risk of preterm and early preterm birth.MethodsBetween Jan 1, 2010, and Dec 31, 2012, we did a population-based cohort study using data from 489 965 rural women aged 21–49 years who had singleton livebirths from 220 counties of China who participated in the National Free Preconception Health Examination Project. Participants were divided into three groups according to their pre-pregnancy status of hepatitis B virus infection: women uninfected with hepatitis B virus (control group), women who were HBsAg positive and HBeAg negative (exposure group 1), and women who were both HBsAg and HBeAg positive (exposure group 2). The primary outcome was preterm birth (gestation at less than 37 weeks). We used log-binomial regression to estimate adjusted risk ratios (aRR) of preterm birth for women with pre-pregnancy hepatitis B virus infection, and risk of early preterm birth (gestation less than 34 weeks).Findings489 965 women met inclusion criteria and were included in this study; of these, 20 827 (4·3%) were infected with hepatitis B virus. Compared with women who were not infected with hepatitis B virus, women who were HBsAg positive and HBeAg negative had a 26% higher risk of preterm birth (aRR 1·26, 95% CI 1·18–1·34) and women who were both HBsAg and HBeAg positive had a 20% higher risk of preterm birth (aRR 1·20, 1·08–1·32). Compared with women who were not infected with hepatitis B virus, women who were HBsAg positive and HBeAg negative manifested an 18% higher risk of early preterm birth (gestation less than 34 weeks; aRR 1·18, 1·04–1·34) and women who were both HBsAg and HBeAg positive had a 34% higher risk of early preterm birth (aRR 1·34, 1·10–1·61). Maternal pre-pregnancy hepatitis B virus infection was independently associated with higher risk of preterm birth and early preterm birth. These associations were similar in subgroups of participants as defined by baseline characteristics.InterpretationBesides mother-to-child transmission, the risk of preterm birth in women infected with hepatitis B virus should not be neglected. Comprehensive programmes that focus on early detection of hepatitis B virus infection before pregnancy and provide appropriate medical intervention for women infected with hepatitis B virus before and during pregnancy would be helpful in improving maternal and neonatal outcomes and reducing child mortality.FundingChinese Association of Maternal and Child Health Studies.
Abstract #LB-204: MPI-0479605: A novel small molecule inhibitor of the mitotic kinase TTK with anti-tumor activity in pre-clinical models
Authors: Brandi Williams, Daniel Cimbora, Vijay Baichwal, Damon Papac, Ian McAlexander, J. Willardsen, D. Kumar
Journal: Cancer Research (2009)

Background: TTK is a dual-specificity protein kinase that is essential for the proper attachment of chromosomes to the mitotic spindle and for maintaining the spindle assembly checkpoint. TTK is expressed at high levels during mitosis and is overexpressed in cancer cells. Disruption of TTK function results in mitotic aberrations and apoptosis. In an ongoing drug discovery program, we have developed a potent and selective inhibitor of TTK with favorable ADME/PK properties that inhibits the growth of cancer cells in culture and demonstrates anti-tumor activity in a mouse xenograft model. Materials and Methods: Kinase activity was measured in biochemical assays monitoring the incorporation of 33P into protein substrate. Phosphorylated Smad2 was detected by Western blot or ELISA using phospho-specific antibodies. Inhibition of the spindle assembly checkpoint was determined by image analysis of cells stained with anti-phospho-histone H3 antibody. Viability was determined by measuring cellular ATP levels. Apoptosis was assessed by measuring caspase-3/7 induction. Anti-tumor activity was evaluated in an HCT-116 xenograft in nu/nu mice. Results: MPI-0479605 inhibited TTK kinase activity in vitro with an IC50 = 4 nM. This compound had moderate activity towards JNK (IC50 =110 nM) and FER (IC50 =590 nM) kinases and little or no activity against a panel of 25 other kinases, suggesting good selectivity for TTK. MPI-0479605 induced apoptotic cell death in a dose- and time-dependent manner in HCT116 cells and demonstrated cytotoxicity against a panel of other tumor cell lines. Furthermore, nocodazole-induced activation of the spindle assembly checkpoint and phosphorylation of Smad2 were overcome by MPI-0479605. In mouse pharmacokinetic studies, MPI-0479605 displayed a dose-proportional increase in Cmax following intraperitoneal injection in Swiss Webster mice. Finally, in HCT-116 tumor-bearing mice, daily treatment with 30 mg/kg MPI-0479605 resulted in a 50% tumor growth inhibition, whereas treatment with 150 mg/kg (q4d x 21 days) caused a 75% tumor growth inhibition relative to vehicle-treated animals. The latter effect was comparable to treatment with 5-fluorouracil (100 mg/kg, weekly). Animals dosed with MPI-0479605 had less than a 15% reduction in body weight over the course of the study. Conclusions: The small molecule inhibitor MPI-0479605 potently inhibits TTK kinase activity in vitro and demonstrates marked anti-tumor activity in a xenograft model.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-204.
A prospective multicentre phase III validation study of AZGP1 as a biomarker in localized prostate cancer
Authors: A.Y. Zhang, J.S. Grogan, K.L. Mahon, K. Rasiah, P. Sved, D.R. Eisinger, J. Boulas, A. Vasilaris, S.M. Henshall, P.D. Stricker, J.G. Kench, L.G. Horvath
Journal: Annals of Oncology (2017)
Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117
Authors: Mikkael A. Sekeres, Megan Othus, Alan F. List, Olatoyosi Odenike, Richard M. Stone, Steven D. Gore, Mark R. Litzow, Rena Buckstein, Min Fang, Diane Roulston, Clara D. Bloomfield, Anna Moseley, Aziz Nazha, Yanming Zhang, Mario R. Velasco, Rakesh Gaur, Ehab Atallah, Eyal C. Attar, Elina K. Cook, Alyssa H. Cull, Michael J. Rauh, Frederick R. Appelbaum, Harry P. Erba
Journal: Journal of Clinical Oncology (2017)

Purpose Azacitidine is standard, first-line therapy in higher-risk myelodysplastic syndromes (MDS). Whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates (ORRs) to azacitidine is not known. Patients and Methods North American Intergroup Study S1117 is a phase II/III trial that randomly assigned patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML) 1:1:1 to azacitidine (75 mg/m 2 /day on days 1 to 7 of a 28-day cycle); azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or azacitidine plus vorinostat (300 mg twice daily on days 3 to 9). The primary phase II end point was improved ORR. Results Of 277 patients from 90 centers, 92 received azacitidine, 93 received azacitidine plus lenalidomide, and 92 received azacitidine plus vorinostat. Median age was 70 years (range, 28 to 93 years), 85 patients (31%) were female, and 53 patients (19%) had CMML. Serious adverse events were similar across arms, although combination-arm patients were more likely to undergo nonprotocol-defined dose modifications ( P &lt; .001).With a median follow-up of 23 months (range, 1 to 43 months), the ORR was 38% for patients receiving azacitidine, 49% for azacitidine plus lenalidomide ( P = .14 v azacitidine), and 27% for azacitidine plus vorinostat ( P = .16 v azacitidine). For patients with CMML, ORR was higher for azacitidine plus lenalidomide versus azacitidine (68% v 28%, P = .02) but similar for all arms across cytogenetic subgroups, as was remission duration and overall survival. ORR was higher with mutations in DNMT3A and lower for SRSF2, whereas ORR duration improved with fewer mutations. Lenalidomide dose reduction was associated with worse overall survival (hazard ratio, 1.30; P = .05). Conclusion Patients with higher-risk MDS treated with azacitidine-based combinations had similar ORR to azacitidine monotherapy, although patients with CMML benefitted from azacitidine plus lenalidomide. The efficacy of combination regimens may have been affected by dose modifications.
Contraception advice for women with epilepsy
Authors: Inuka Kishara Gooneratne, Mayurika Wimalaratna, A K Probhodana Ranaweera, Sunil Wimalaratna
Journal: BMJ (2017)

A 22 year old student attends your practice asking for contraception. She has idiopathic generalised epilepsy diagnosed five years ago, which is controlled with lamotrigine. She does not plan to conceive in the near future. Active epilepsy affects around 6.4 per 1000 persons,1 Globally, 50% of women and girls with epilepsy are in the reproductive age range.2 Counsel women about the potential teratogenic effects of anti-epileptic drugs and provide information on contraception to avoid an unplanned pregnancy.3 Consider interactions between anti-epileptic drugs and hormonal contraceptives because using them together can reduce the efficacy of contraception or of seizure control.4 #### What you need to know ### History #### Consider asking about
Presence of metabolic syndrome and low CD4 count are independently associated with liver fibrosis in human immunodeficiency virus-infected patients with non-alcoholic fatty liver
Authors: H. Perazzo, S.W. Cardoso, C. Yanavich, M. Munteanu, M. Morata, P. Simplicio, C. Cardoso, C. Almeida, T. Poynard, V.G. Veloso, B. Grinsztejn
Journal: Journal of Hepatology (2017)
Characterization of hepatitis delta infection in Israel: prevalence and genotypes
Authors: R. Shirazi, D. Ram, A. Rakovsky, Y. Gozlan, E. Bucris, P. Shaked-Mishan, O. Picard, Y. Shemer-Avni, H. Ben-Zvi, O. Halutz, O. Mor, Y. Lurie, R. Safadi, Z. Ben-Ari, O. Mor
Journal: Journal of Hepatology (2017)
Safety of Rituximab Compared with Steroids and Cyclophosphamide for Idiopathic Membranous Nephropathy
Authors: Jan A.J.G. van den Brand, Piero Ruggenenti, Antonietta Chianca, Julia M. Hofstra, Annalisa Perna, Barbara Ruggiero, Jack F.M. Wetzels, Giuseppe Remuzzi
Journal: Journal of the American Society of Nephrology (2017)

Guidelines recommend steroid plus cyclical cyclophosphamide (St-Cp) therapy for patients with idiopathic membranous nephropathy at high risk of progression to ESRD. Rituximab (Rtx) may be a safer alternative. In this retrospective, observational cohort study, we compared time to any adverse event (primary outcome); serious or nonserious events; partial and complete remission of the nephrotic syndrome; and a composite of doubling of serum creatinine, ESRD, or death between 100 Rtx-treated patients and 103 patients who received daily St-Cp We monitored patients with standardized protocols and adjusted for baseline characteristics by Cox regression. Over a median follow-up of 40 months, the Rtx group had significantly fewer adverse events than the St-Cp group (63 versus 173; P<0.001), both serious (11 versus 46; P<0.001) and nonserious (52 versus 127; P<0.001). Cumulative incidence of any first (35.5% versus 69.0%; P<0.001), serious (16.4% versus 30.2%; P=0.002), or nonserious (23.6% versus 60.8%; P<0.001) event was significantly lower with Rtx Adjusted hazard ratios (95% confidence intervals) between Rtx and St-Cp groups were 0.27 (0.16 to 0.44) for any first adverse event, 0.32 (0.15 to 0.68) for serious adverse events, and 0.23 (0.13 to 0.41) for nonserious adverse events. Although the cumulative incidence of partial remission was lower in the Rtx group, rates of complete remission and the composite renal end point did not differ significantly between groups. Because of its superior safety profile, we suggest that Rtx might replace St-Cp as first-line immunosuppressive therapy in patients with idiopathic membranous nephropathy and nephrotic syndrome.
High efficacy is accompanied with substantial gains in patient reported outcomes in cirrhotic patients with chronic hepatitis C treated with sofosbuvir (SOF), velpatasvir with or without voxilaprevir (VOX): data from POLARIS 1, 2, 3 and 4
Authors: Z.M. Younossi, M. Stepanova, I. Jacobson, S. Zeuzem, M. Bourliere, G. Foster, S. Roberts, T. Asselah, A. Thompson, E. Gane, B. Willems, E. Lawitz, S. Gordon, M. Mann, K.R. Reddy, C. Cooper, S. Flamm, K. Kowdley, S. Hunt
Journal: Journal of Hepatology (2017)
Wide QRS Complex Tachycardia
Authors: Gaopin Wang, Renguang Liu, Qinghua Chang
Journal: Circulation (2017)

ECG CHALLENGEA 71-year-old man with a history of previous myocardial infarction was referred to our hospital for recurrent symptoms of palpitation and syncope.During an episode of palpitations, a 12-lead ECG (Figure 1) was obtained in the emergency room.The ECG shows a wide-QRS complex tachycardia at a rate of 167 bpm.The P waves are positive in lead II (↑) before each QRS complex, and the PR interval is 80 milliseconds.The QRS duration is prolonged with apparent slurring of the QRS upstoke, suggesting the possible presence of a delta wave.Are these features consistent with a diagnosis of atrial tachycardia with pre-excitation?However, the possibility of ventricular tachycardia (VT) also should be considered in our patient because of the old myocardial infarction.Therefore, the ECG diagnosis is challenging.What are the diagnosis and best management strategy for this patient?
Rates of Local Retinal Nerve Fiber Layer Thinning before and after Disc Hemorrhage in Glaucoma
Authors: Tadamichi Akagi, Linda M. Zangwill, Luke J. Saunders, Adeleh Yarmohammadi, Patricia Isabel C. Manalastas, Min Hee Suh, Christopher A. Girkin, Jeffrey M. Liebmann, Robert N. Weinreb
Journal: Ophthalmology (2017)
Abstract 159: Cardiac Hypertrophy and Sudden Death in a Mouse Model of STIM1 Overexpression
Authors: Sanjeewa A Goonasekera, Jop van Berlo, Adam R Burr, Robert N Correll, Allen J York, Michelle A Sargent, Xiongwen Chen, Steven R Houser, Jeffery D Molkentin
Journal: Circulation Research (2013)

Background: STIM1, an ER/SR resident Ca 2+ sensing protein regulates Ca 2+ entry following internal Ca 2+ store depletion in a broad range of tissues and cell types. However their putative roles in excitable tissue such as cardiac myocytes is uncertain. Results: Here we generated a mouse model of STIM1 overexpression in cardiac and skeletal muscle. Western blot analysis suggested approximately 4-6 fold STIM1 overexpression in Tg mouse hearts compared to Ntg littermates. Immunocytochemistry carried out in ventricular myocytes revealed that STIM1 and the cardiac ryanodine receptor (RyR2) co-localize. Functionally, the amplitude of Ca 2+ entry following SR Ca 2+ depletion was 2-fold greater in myocytes isolated from STIM1 Tg mice compared to NTg littermates. Echocardiographic analysis in STIM1 Tg mice showed age dependent remodeling of the myocardium with a significant decrease in fractional shortening at 16 weeks of age (14.4.5±3.8 in STIM1 Tg vs. 36.9±1.5 in Ntg). These changes were accompanied by a significant increase in heart weight to tibia length (13.6 +/- 1.4 vs 6.5 +/- 0.24) and increased lung weight to tibia length ratio (11.6+/- 2.1 vs 8.1 +/- 0.38) in STIM1 Tg mice compared to Ntg littermates. Photometry experiments in isolated ventricular myocytes demonstrated significantly increased Ca 2+ transient amplitude with an unexpected decrease in the SR Ca 2+ load associated with STIM1 overexpression. In addition transgenic mice showed increased calcineurin-nuclear factor of activated T cells (NFAT) activation in vivo, increased CaMKII activity, interstitial fibrosis and exaggerated hypertrophy following two weeks of neuroendocrine agonist or pressure overload stimulation. Conclusion: Our observations suggest that STIM1 overexpression by itself can lead to cardiac hypertrophy and contribute to pathological cardiac remodeling and possibly sudden cardiac death. The molecular mechanisms underlying these phenomena are currently under investigation.
Prognostic Implications of Moderate Aortic Stenosis in Patients With Left Ventricular Systolic Dysfunction
Authors: Lennart van Gils, Marie-Annick Clavel, E. Mara Vollema, Rebecca T. Hahn, Ernest Spitzer, Victoria Delgado, Tamim Nazif, Peter P. De Jaegere, Marcel L. Geleijnse, Ori Ben-Yehuda, Jeroen J. Bax, Martin B. Leon, Philippe Pibarot, Nicolas M. Van Mieghem
Journal: Journal of the American College of Cardiology (2017)
Next-Generation Sequencing (NGS) of two independent cohorts identifies eleven circulating miRNAs for diagnosis of NASH and fibrosis
Authors: S. Francque, G. Cordonnier, F. Texier, V. Ratziu, S. Harrison, P. Bedossa, Q. Anstee, A. Roudot, S. Megnien, D. Hum, B. Staels, P. Chaumat, R. Hanf, A. Sanyal
Journal: Journal of Hepatology (2017)
AP1G2b, an isoform of clathrin-coated adaptor protein, localizes in the nucleus and transactivates target gene estrogen receptor α
Authors: Rui-An Wang, Qing-Chang Meng, Rakesh Kumar
Journal: Cancer Research (2006)

944  Adaptins are important components of clathrin-coated vesicles transporting ligand-receptor complexes from the plasma membrane or from the trans-Golgi network to lysosomes. The adaptin family of proteins is composed of four classes of molecules named alpha, beta-, beta prime- and gamma- adaptins. Adaptins, together with small and medium subunits, form a hetero-tetrameric complex called an adaptor, whose role is to promote the formation of clathrin-coated pits and vesicles. One of the proteins encoded by this gene is a gamma-adaptin which is thought to function during trafficking between the trans-Golgi network and the cell surface. There are two alternatively spliced transcript variants of this gene encoding the same protein. By yeast two hybrid assay, we identified that the short transcript isoform of this gene, which we named AP1G2b, as an estrogen receptor-alpha (ER) binding protein. Interestingly, AP1G2b is localized inside the nucleus instead of the cytoplasm. By analyzing the protein sequence, we found that AP1G2b contains three consensus LXXLL nuclear receptor binding motif which are common to both the long and short AP1G2, and a nuclear localization signal which is localized in amino acid region unique to AP1G2b. RT-PCR assay showed that AP1G2b is expressed in a variety of breast cancer cell lines including both ER-positive and ER-negative, but the expression appears to be differentially regulated from the longer form AP1G2a. The binding of AP1G2b and ER was confirmed by both immunoprecipitation and GST-pull down assay, and the binding region was found to be predominantly localized to the E fragment of AF2 domain of ER. Cotransfection assay show that AP1G2b stimulates ERE transactivation and strongly transactivates the Gal4-Luc activity when cotransfected with Gal4-AF2, indicating the interaction between AP1G2b and the AF2 domain is critical for the regulation of ER function. Considering the abundance existence of AP1G2 proteins, these findings points to a potential role of AP1G2b in the regulation of ER function, presumably by affecting the nuclear internalization or modulating the chromatin of target genes in mammalian cells. (Supported by NIH grant CA90970 and CA65746).
Patients suspecting cancer put GP listening skills ahead of shorter wait times
Authors: Jacqui Wise
Journal: BMJ (2017)

Patients with possible cancer symptoms are prepared to wait longer for an appointment with a GP who has good listening skills, a survey published in the British Journal of General Practice has found.1

The study used a discrete choice experiment to better understand the trade-offs that patients are willing to make when arranging an appointment for a possible cancer symptom. Researchers surveyed 601 …
Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia
Authors: Donald A. Berry, Shouhao Zhou, Howard Higley, Lata Mukundan, Shuangshuang Fu, Gregory H. Reaman, Brent L. Wood, Gary J. Kelloff, J. Milburn Jessup, Jerald P. Radich
Journal: JAMA Oncology (2017)

<h3>Importance</h3> Minimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. Assessing the association of MRD status following induction therapy in patients with acute lymphoblastic leukemia (ALL) with relapse and mortality may improve the efficiency of clinical trials and accelerate drug development. <h3>Objective</h3> To quantify the relationships between event-free survival (EFS) and overall survival (OS) with MRD status in pediatric and adult ALL using publications of clinical trials and other databases. <h3>Data Sources</h3> Clinical studies in ALL identified via searches of PubMed, MEDLINE, and clinicaltrials.gov. <h3>Study Selection</h3> Our search and study screening process adhered to the PRISMA Guidelines. Studies that addressed EFS or OS by MRD status in patients with ALL were included; reviews, abstracts, and studies with fewer than 30 patients or insufficient MRD description were excluded. <h3>Data Extraction and Synthesis</h3> Study sample size, patient age, follow-up time, timing of MRD assessment (postinduction or consolidation), MRD detection method, phenotype/genotype (B cell, T cell, Philadelphia chromosome), and EFS and OS. Searches of PubMed and MEDLINE identified 566 articles. A parallel search on clinicaltrials.gov found 67 closed trials and 62 open trials as of 2014. Merging results of 2 independent searches and applying exclusions gave 39 publications in 3 arms of patient populations (adult, pediatric, and mixed). We performed separate meta-analyses for each of these 3 subpopulations. <h3>Results</h3> The 39 publications comprised 13 637 patients: 16 adult studies (2076 patients), 20 pediatric (11 249 patients), and 3 mixed (312 patients). The EFS hazard ratio (HR) for achieving MRD negativity is 0.23 (95% Bayesian credible interval [BCI] 0.18-0.28) for pediatric patients and 0.28 (95% BCI, 0.24-0.33) for adults. The respective HRs in OS are 0.28 (95% BCI, 0.19-0.41) and 0.28 (95% BCI, 0.20-0.39). The effect was similar across all subgroups and covariates. <h3>Conclusions and Relevance</h3> The value of having achieved MRD negativity is substantial in both pediatric and adult patients with ALL. These results are consistent across therapies, methods of and times of MRD assessment, cutoff levels, and disease subtypes. Minimal residual disease status warrants consideration as an early measure of disease response for evaluating new therapies, improving the efficiency of clinical trials, accelerating drug development, and for regulatory approval. A caveat is that an accelerated approval of a particular new drug using an intermediate end point, such as MRD, would require confirmation using traditional efficacy end points.