tbuckley/cabot-search huggingface dataset:
Prostate Cancer Risk and DNA Methylation Signatures in Aging Rats following Developmental BPA Exposure: A Dose–Response Analysis
Authors: Gail S. Prins, Shu-Hua Ye, Lynn Birch, Xiang Zhang, Ana Cheong, Han Lin, Esther Calderon-Gierszal, Jacob Groen, Wen-Yang Hu, Shuk-Mei Ho, Richard B. van Breemen
Journal: Environmental Health Perspectives (2017)

Previous studies have uncovered heightened prostatic susceptibility to hormone-induced neoplasia from early-life exposure to low-dose bisphenol A (BPA). However, significant data gaps remain that are essential to address for biological relevance and necessary risk assessment.A complete BPA dose-response analysis of prostate lesions across multiple prostatic lobes was conducted that included internal BPA dosimetry, progression to adenocarcinoma with aging and mechanistic connections to epigenetically reprogramed genes.Male neonatal Sprague-Dawley rats were briefly exposed to 0.1 to 5,000 μg BPA/kg BW on postnatal days (PND) 1, 3, and 5. Individual prostate lobes plus periurethral prostatic ducts were evaluated at 7 mo or 1 y of age without or with adult testosterone plus estradiol (T+E) to promote carcinogenesis. DNA methylation of five genes was quantified by bisulfite genomic sequencing in d-200 dorsal prostates across BPA doses. Serum free-BPA and BPA-glucuronide were quantitated in sera of individual PND 3 pups collected 1 hr postexposure utilizing ultra-high-pressure tandem mass spectrometry (UHPLC-MS-MS).The lowest BPA dose initiated maximal hormonal carcinogenesis in lateral prostates despite undetectable free BPA 1 hr postexposure. Further, prostatic intraepithelial neoplasia (PIN) progressed to carcinoma in rats given neonatal low-dose BPA with adult T+E but not in rats given adult T+E alone. The dorsal and ventral lobes and periurethral prostatic ducts exhibited a nonmonotonic dose response with peak PIN, proliferation and apoptotic values at 10–100 μg/kg BW. This was paralleled by nonmonotonic and dose-specific DNA hypomethylation of genes that confer carcinogenic risk, with greatest hypomethylation at the lowest BPA doses.Developmental BPA exposures heighten prostate cancer susceptibility in a complex dose- and lobe-specific manner. Importantly, elevated carcinogenic risk is found at doses that yield undetectable serum free BPA. Dose-specific epigenetic modifications of selected genes provide a mechanistic framework that may connect early-life BPA to later-life predisposition to prostate carcinogenesis. https://doi.org/10.1289/EHP1050.
Abstract P187: Casein Kinase 2/Histone Deacetylase 2/Krúppel-like Factor 4 Is a Novel Axis of Development of Cardiac Hypertrophy
Authors: Gwang Hyeon Eom, Young Kuk Cho, Jeong-Hyeon Ko, Sera Shin, Nakwon Choe, Yoojung Kim, Hosouk Joung, Hae Jin Kee, Hyun Kook
Journal: Circulation Research (2011)

Background. Cardiac hypertrophy is characterized by transcriptional reprogramming of fetal gene expression, and histone modifiers are tightly linked to the regulation of those genes. We previously reported that activation of histone deacetylase (HDAC) 2, one of the class I HDACs, mediates hypertrophy. Here we suggest that disinhibiting of kruppel-like factor 4 (Klf4) by casein kinase-2α1 (CK2α1)-dependent phosphorylation of HDAC2 S394 develop the cardiac hypertrophy. Methods and Results. Hypertrophic stimuli phosphorylated Hdac2 S394, which was necessary for its enzymatic activation and thereby for the development of hypertrophic phenotypes. Transgenic mice overexpressing Hdac2-wild type exhibited cardiac hypertrophy, whereas those expressing phosphorylation-resistant Hdac2 S394A did not. Compared with that in age-matched normal human hearts, phosphorylation of Hdac2 S394 was dramatically increased in hypertrophic cardiomyopathy patients. Hypertrophy-induced phosphorylation of Hdac2 S394 and its enzymatic activity were completely blocked either by CK2-blockers or by CK2a1 siRNA. Hypertrophic stimuli led CK2α1 to be activated, and its chemical inhibitors blocked hypertrophy in both phenylephrine-treated cardiomyocytes and in isoproterenol-administered mice. However, by utilizing KLF4-binding element-disrupted Nppa promoter, treatment with either TBB or TBCA failed to reduce the mutant promoter activity. These results emphasized that CK2α1-induced hypertrophic events are dependent on both Hdac2 and KLF4. CK2α1-transgenic mice developed hypertrophy, which was attenuated by administration of trichostatin A, an HDAC inhibitor. Overexpression of CK2α1 caused hypertrophy in cardiomyocytes, whereas its chemical inhibitors as well as Hdac2 S394A blunted it. Hypertrophy in CK2α1-transgenic mice was exaggerated by crossing these mice with Hdac2-transgenic mice. By contrast, however, it was blocked when CK2α1-transgenic mice were crossed with Hdac2 S394A-transgenic mice. Conclusions. We have demonstrated a novel mechanism in the development of cardiac hypertrophy by which CK2 activates HDAC2 via phosphorylating HDAC2 S394 and consequence down-regulation of KLF4.
18-month outcomes of heterologous bilateral hand transplantation in a child: a case report
Authors: Sandra Amaral, Sudha Kilaru Kessler, Todd J Levy, William Gaetz, Christine McAndrew, Benjamin Chang, Sonya Lopez, Emily Braham, Deborah Humpl, Michelle Hsia, Kelly A Ferry, Xiaowei Xu, David Elder, Debra Lefkowitz, Chris Feudtner, Stephanie Thibaudeau, Ines C Lin, Stephen J Kovach, Erin S Schwartz, David Bozentka, Robert Carrigan, David Steinberg, Suhail Kanchwala, Dan A Zlotolow, Scott Kozin, Frances E Jensen, Phillip R Bryant, Abraham Shaked, Matthew H Levine, L Scott Levin
Journal: The Lancet Child & Adolescent Health (2017)
Government allocates £325m to England’s “most advanced” STPs
Authors: Gareth Iacobucci
Journal: BMJ (2017)

The government has allocated the first £325m of capital investment funding to spearhead new models of integrated healthcare in England.

The money will be targeted at 15 areas of the country where emerging sustainability and transformation partnerships (STPs) have been assessed as the “strongest and most advanced” on indicators such as leadership and service performance.

Announcing the plans at the King’s Fund on 19 July the health secretary, Jeremy Hunt, and NHS England’s chief executive, Simon Stevens, said that they had identified the high performing STP areas by using a new ratings system designed to establish benchmarks for the 44 geographical areas.

The NHS Confederation welcomed the funding but said it was important that any ranking system did not “stigmatise” STPs that were still at an early stage in their development.

The BMA said that the money …
Poor Reliability and Poor Adherence to Self-Monitoring of Blood Glucose Are Common in Women With Gestational Diabetes Mellitus and May Be Associated With Poor Pregnancy Outcomes
Authors: Emmanuel Cosson, Baz Baz, Françoise Gary, Isabelle Pharisien, Minh Tuan Nguyen, Dorian Sandre-Banon, Yahya Jaber, Camille Cussac-Pillegand, Isabela Banu, Lionel Carbillon, Paul Valensi
Journal: Diabetes Care (2017)

OBJECTIVE To evaluate the compliance with self-monitoring of blood glucose (SMBG) and the reliability of diabetes logbooks in women with gestational diabetes mellitus (GDM), as well as the associated determinants and outcomes. RESEARCH DESIGN AND METHODS We prospectively selected French-speaking women with newly diagnosed GDM who had been referred to our diabetes management program and understood SMBG principles. At the next follow-up visit, we collected SMBG results from glucose meters and logbooks. We analyzed pregnancy outcomes. RESULTS Data were analyzed over 13 ± 3 days in 91 women. Only 61.5% had performed ≥80% of the required tests. Poor compliance was associated with a family history of diabetes, social deprivation, and non-European origin. The average time between pre- and postprandial tests was 141 ± 20 min, with 46.5% of women performing ≥80% of postprandial measurements 100–140 min after meals. Inadequate timing was associated with ethnicity and higher HbA1c at baseline. A total of 23.1% of women had &amp;lt;90% matched values in diary and meter memory, and a poor concordance was associated with a family history of diabetes. Poor adherence was associated with more preeclampsia (12.2 vs. 1.9%, P = 0.049), and inadequate postprandial test timing with a higher HbA1c at delivery (5.3 ± 0.4 vs. 5.0 ± 0.3% [34 ± 2 vs. 31 ± 2 mmol/mol], P &amp;lt; 0.01), despite more frequent insulin therapy. CONCLUSIONS Although women with GDM are considered to be highly motivated, SMBG adherence and reliability are of concern and may be associated with poor gestational prognosis, suggesting that caregivers should systematically check the glucose meter memory to improve GDM management.
Thirsting to understand the temporal dynamics of physical activity and alcohol use
Authors: David E Conroy, Aaron L Pincus, Nilam Ram, Mustafa al’Absi
Journal: British Journal of Sports Medicine (2017)

The British Journal of Sports Medicine recently published two important papers on the health implications of physical activity and alcohol use.1 2 Relations between these behaviours surprise many because they typically exhibit a positive association.3 4 Health behaviours generally cluster into ‘healthy’ or ‘unhealthy’ bundles, so clinicians need to be aware of this mixed clustering before integrating physical activity with treatment for alcohol use disorders.5 These findings also raise questions about the interplay of these health behaviours and invite research that will characterise physical activity, alcohol use and the dynamics of these behaviours in greater detail. To characterise these behaviours, one must first consider some basic features of the behaviours.

First, physical activity is a complex behaviour and little is known about the specific features of physical activity exposure that drive the association with alcohol consumption or the extent to which this association is linear or curvilinear. The global individual difference variable used in mortality analysis by Perreault et …
Cost of achieving WHO sustainable development goals by 2030 is $58 a head
Authors: Ingrid Torjesen
Journal: BMJ (2017)

Achieving the health targets under the sustainable development goals (SDGs) in low and middle income countries by 2030 would cost $58 (£44.50; €50) per head of population, the World Health Organization has estimated in an analysis published in the Lancet Global Health .1

This investment could help prevent 97 million premature deaths worldwide and add as much as 8.4 years of life expectancy in some countries, WHO said.

WHO looked at the costs and benefits of progressively expanding health services to achieve the health targets under the 17 SDGs adopted in September 2015 for delivery by 2030. The targets in the analysis include SDG 3 (health and wellbeing), …
The challenges of repeat biopsies at acquired resistance to EGFR TKIs.
Authors: Meghan Campo, Zofia Piotrowska, Alona Muzikansky, Coleen Rizzo, Justin F. Gainor, Alice Tsang Shaw, Jeffrey A. Engelman, Lecia V. Sequist
Journal: Journal of Clinical Oncology (2016)

e20571 Background: 1st-line EGFR TKIs are active in EGFR mutants though acquired resistance (AR) arises within 1-2y. Describing AR mechanisms like T790M has been crucial in developing effective 2nd-line therapies, but biopsies are not always performed. We sought to examine the frequency of obtaining repeat biopsies within a research-oriented clinic. Methods: We retrospectively reviewed 792 MGH pts with EGFR-mutant cancer to determine factors associated with rebiopsy at AR; we identified 125 with advanced disease and progression (PD) after treatment with their first EGFR TKI between 2008-2015. We excluded exon 20 insertions and pts who didn’t have longitudinal care at MGH since diagnosis (to minimize referral bias). Univariate logistic regression models were fit for gender, age, comorbidities, time on initial TKI, site and calendar year of PD. Results: Among 125 pts, the average age was 63 (range 29-90) and median time on initial TKI 10.9 mo (range 0.1–53). At AR, PD occurred in the CNS alone in 30 (24%), systemically without CNS PD in 89 (71%) and in both sites in 6 (5%). 73 (58%; 95% CI 49-67%) pts underwent rebiopsy with 57 (46%) ultimately having tissue sufficient for molecular analysis. The only variable significantly associated with a lower likelihood of biopsy was PD in the CNS alone (OR 0.37; 95% CI 0.16–0.86, p = 0.02). Removing such pts, we performed AR biopsies in 61 of 95 pts (64%; 95% CI 54%-74%). Conclusions: In practice it is not possible to biopsy all EGFR mutant pts at AR; even at a center with a research focus on AR biopsies, only 58% of EGFR+ pts underwent a biopsy at PD (64% excluding those with CNS-only PD, which was the only significant predictor of rebiopsy). Objective variables (age, gender, etc) did not predict for rebiopsy in this study however there may be less tangible factors related to pts, their disease, and/or physicians that pose challenges and were not documented. While every effort should be made to elucidate AR mechanisms by tissue biopsy at PD, our cohort underscores the potential utility of developing complimentary non-invasive strategies for tumor genotyping which may help capture the > 30% of cases missed.
Artificial Selection Response due to Polygenic Adaptation from a Multilocus, Multiallelic Genetic Architecture
Authors: Yanjun Zan, Zheya Sheng, Mette Lillie, Lars Rönnegård, Christa F. Honaker, Paul B. Siegel, Örjan Carlborg
Journal: Molecular Biology and Evolution (2017)

The ability of a population to adapt to changes in their living conditions, whether in nature or captivity, often depends on polymorphisms in multiple genes across the genome. In-depth studies of such polygenic adaptations are difficult in natural populations, but can be approached using the resources provided by artificial selection experiments. Here, we dissect the genetic mechanisms involved in long-term selection responses of the Virginia chicken lines, populations that after 40 generations of divergent selection for 56-day body weight display a 9-fold difference in the selected trait. In the F15 generation of an intercross between the divergent lines, 20 loci explained >60% of the additive genetic variance for the selected trait. We focused particularly on fine-mapping seven major QTL that replicated in this population and found that only two fine-mapped to single, bi-allelic loci; the other five contained linked loci, multiple alleles or were epistatic. This detailed dissection of the polygenic adaptations in the Virginia lines provides a deeper understanding of the range of different genome-wide mechanisms that have been involved in these long-term selection responses. The results illustrate that the genetic architecture of a highly polygenic trait can involve a broad range of genetic mechanisms, and that this can be the case even in a small population bred from founders with limited genetic diversity.
Targeting Epigenetic Process for Therapeutic Control of Wnt/beta-catenin Signaling in Colorectal Cancer
Authors: Qiang Yu
Journal: Clinical Cancer Research (2007)

PL07-03  Targeting Epigenetic Process for Thearpeutic Control of Wnt/beta-catenin Signaling in Colorectal Cancer  Transcriptional inactivation of tumor suppressors via aberrant epigenetic events plays an important role in cancer development. Cancer epigenetic therapy aims at reversing the epigenetic process to restore the expression of silenced tumor suppressors. Given the complexity and coordination of multiple gene inactivation mechanisms, a drug combination approach that more effectively modulate epigenetic processes needs to be developed. We have developed a novel pharmacological approach that effectively reverses histone modifications in cancer cells by coordinately modulating both histone methylation and deacetylation. This pharmacological combination approach induces strong apoptosis induction through robust reactivation of many silenced tumor suppressors. In particular, we have identified a novel epigenetic regulator of Wnt/beta-catenin signaling that is silenced in colon cancer. Reactivation by gene by our combination treatment leads to strong inhibition of Wnt/β-catenin signaling and massive apoptosis in colorectal cancer cells. Our study points to a novel strategy for cancer epigenetic drug treatment and in particular for therapeutic control of the aberrant Wnt signaling pathway in colorectal cancer.
Elucidation of the molecular and clinical impact of microsatellite instability in Brazilian colorectal cancer patients at Barretos Cancer Hospital.
Authors: Gustavo Noriz Berardinelli, Ronilson Oliveira Duraes, Marco Antonio de Oliveira, Cristovam Scapulatempo, Denise Peixoto-Guimarães, Rui Pereira, Rui Manuel Reis
Journal: Journal of Clinical Oncology (2017)

e23185 Background: Colorectal cancer (CRC) has a high incidence and mortality in the world and in Brazil. The microsatellite instability (MSI) pathway is associated with a distinct mutational profile, which affects MSI target genes contributing to a different clinical impact. Reports have suggested that CRC aspects may be influenced by patients’ ancestry. This study aims to elucidate the molecular and clinical impact of MSI, and to determine Brazilian patients’ genetic ancestry. Methods: We enrolled 1013 patients. MSI was evaluated by molecular analysis, and MSI-H cases were further analyzed for alterations in 24 MSI-target genes, BRAF V600E, and MLH1 methylation. Genetic ancestry was evaluated by an AIMs panel. Results: MSI-H was observed in 10.5% of the cases. MSI-H cases were significantly associated with: right colon localization, staging II, absence of metastasis, mucinous histological type, III/undifferentiated histological grade, presence of synchronic tumor, no disease recurrence, and complete cure response. The most altered MSI target genes was HSP110, followed by ATM and EGFR. The frequency of BRAF V600E mutation was 26.4% and of MLH1 methylation was 72.3% in MSI-H cases. No significant overall survival (OS) differences were observed among the MSI statuses, neither when stratified by 5-FU treatments, nor by HSP110 mutational status. The average ancestry proportion was 74% of European, 12% of African, 7% of Native Americans, and 7% of East Asian. We observed that African ancestry is associated with increased chance of being MSI-H, and that in MSI-H cases, the lower the Asian ancestral component the greater the probability of patient survival. Conclusions: The MSI frequency of 10% identified in Brazilian CRC is in agreement with literature. MSI-H status was found correlated with clinic-pathological features associated with less aggressive tumors, although we did not find significant differences in patient’s OS. The European ancestral component was the most representative one, confirming population genetic studies. In conclusion, this study constituted the deepest and most extensive analyses of the MSI impact in the CRC Brazilian patients.
Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial
Authors: Martin Alberer, Ulrike Gnad-Vogt, Henoch Sangjoon Hong, Keyvan Tadjalli Mehr, Linus Backert, Greg Finak, Raphael Gottardo, Mihai Alexandru Bica, Aurelio Garofano, Sven Dominik Koch, Mariola Fotin-Mleczek, Ingmar Hoerr, Ralf Clemens, Frank von Sonnenburg
Journal: The Lancet (2017)
Is It Time to Change the Type 2 Diabetes Treatment Paradigm? No! Metformin Should Remain the Foundation Therapy for Type 2 Diabetes
Authors: Silvio E. Inzucchi
Journal: Diabetes Care (2017)

Most treatment guidelines, including those from the American Diabetes Association/European Association for the Study of Diabetes and the International Diabetes Federation, suggest metformin be used as the first-line therapy after diet and exercise. This recommendation is based on the considerable body of evidence that has accumulated over the last 30 years, but it is also supported on clinical grounds based on metformin’s affordability and tolerability. As such, metformin is the most commonly used oral antihyperglycemic agent in the U.S. However, based on the release of newer agents over the recent past, some have suggested that the modern approach to disease management should be based upon identification of its etiology and correcting the underlying biological disturbances. That is, we should use interventions that normalize or at least ameliorate the recognized derangements in physiology that drive the clinical manifestation of disease, in this circumstance, hyperglycemia. Thus, it is argued that therapeutic interventions that target glycemia but do not correct the underlying pathogenic disturbances are unlikely to result in a sustained benefit on the disease process. In our field, there is an evolving debate regarding the suggested first step in diabetes management and a call for a new paradigm. Given the current controversy, we provide a Point-Counterpoint debate on this issue. In the point narrative that precedes the counterpoint narrative below, Drs. Abdul-Ghani and DeFronzo provide their argument that a treatment approach for type 2 diabetes based upon correcting the underlying pathophysiological abnormalities responsible for the development of hyperglycemia provides the best therapeutic strategy. Such an approach requires a change in the recommendation for first-line therapy from metformin to a GLP-1 receptor agonist. In the counterpoint narrative below, Dr. Inzucchi argues that based on the medical community’s extensive experience and the drug’s demonstrated efficacy, safety, low cost, and cardiovascular benefits, metformin should remain the “foundation therapy” for all patients with type 2 diabetes, barring contraindications. —William T. Cefalu Chief Scientific, Medical &amp; Mission Officer, American Diabetes Association
Association of the number of dissected lymph node (LN) with the survivals of locally advanced esophageal squamous cell carcinoma (ESCC) patients received preoperative chemoradiotherapy (CRT) followed by surgery.
Authors: Jhe-Cyuan Guo, Chia-Chi Lin, Ta-Chen Huang, Hung-Yang Kuo, Chin-Hao Chang, Jang-Ming Lee, Jason C. Cheng, Kun-Huei Yeh, Chih-Hung Hsu
Journal: Journal of Clinical Oncology (2016)

e15543 Background: Extensive lymphadenectomy has been suggested to associate with an improved prognosis in esophageal cancer patients receiving surgery alone. However, whether the extended LN dissection is associated with better outcomes in patients with locally advanced ESCC treated with preoperative CRT followed by surgery remains controversial. Methods: We reviewed a total of 194 patients who had been enrolled in 3 phase II clinical trials of preoperative CRT for locally advanced ESCC (clinical T3N0-1M0, T1-3N1M0, or M1a according to AJCC 6th edition) conducted between 2000 and 2012. All patients received preoperative CRT consisting of twice weekly paclitaxel/cisplatin-based regimens and radiotherapy 40Gy given in 20 fractions and esophagectomy (Lin CC et al. Ann Oncol 2007;18:93-98). The number of dissected LNs, along with other clinicopathologic factors of potential prognostic significance, were analyzed for their impacts on patients' progression-free survival (PFS) and overall survival (OS) by Cox regression. Results: One hundred and thirty-one men and 8 women, who had received planned esophagectomy, were included for this analysis. Their median PFS and OS were 24.4 months and 31.8 months, respectively. The median number of dissected LNs was 19 (range 2-96). The mean numbers of positive LNs among the four quartile groups of total dissected LNs (1-12, 13-19, 20-27 and 28-96) were not significantly different (Table 1). In univariate and multivariate analyses, the number of total dissected LN, no matter analyzed as dichotomies divided by the median number, as quartiles, or as a continuous variable, was not associated with patients’ PFS or OS. Conclusions: The number of dissected LN was not associated with the outcome of locally advanced ESCC patients received preoperative paclitaxel/cisplatin-based CRT followed by esophagectomy. (The work was supported by the Grant of MOST 104-2314-B-002-111) Total dissected LNs (quartile) Mean positive LNs PFS (months) OS (months) 1-12 0.42 13.3 19.8 13-19 0.60 30.7 51.8 20-27 0.47 26.8 36.6 28-96 0.94 17.4 23.9 P-value 0.348 0.283 0.104