tbuckley/cabot-search huggingface dataset:
Abstract 347: Identification and Characterization of a miRNA Cohort Initiated Transitional Program That Controls Cell Cycle Arrest of the Perinatal Heart
Authors: Patrick G Burgon, Jonathan J Weldrick
Journal: Circulation Research (2015)

During fetal and early perinatal development the myocardium undergoes a period of hyperplastic growth, which results in an exponential increase in the number of cardiomyocytes (CM) that will constitute the adult heart. Soon after birth, CMs proceed through a final round of cell division in the absence cytokinesis that results in binucleation of &gt;95% of adult CMs. Fetal heart genes are re-activated with the onset of pathological hypertrophic or dilated cardiomyopathies, yet there is no evidence of CM re-entry into the cell cycle. Despite the importance of this phenomenon, little is known about the molecular basis for the transition from hyperplastic to hypertrophic-based myocardial growth. Hypothesis: A perinatal heart gene program is necessary for the normal transition from a fetal heart gene program to an adult heart gene program. To identify the molecular mechanisms and pathways involved in CM differentiation during the perinatal transition, RNA was isolated from E18, and 1, 3, 5, 7, 10 and 35d old mouse hearts. CM gene expression and micro-RNA profiles (n=3 arrays/time point) were determined by oligonucleotide array analysis. The raw array data was normalized by Robust Multi-array analysis. Empirical Bayes estimation of gene-specific variances was performed between each of the time points in order to identify genes that are transiently and significantly changed at days 3 and 5 as compare to E18 and 10d post-birth. The analysis identified 2,799 genes (E18 v 5d) and 3,347 genes (5d v 10d) that were then clustered to determine significant pathway enrichment (p&lt;0.05) with Ingenuity Pathway Analysis. Our analysis confirmed previous observations of a down regulation of glucose oxidative metabolism (p=0.02) with an up-regulation of fatty acid metabolism (p=0.0001) between E18 and 5d post-birth. Also, 63 cell cycle genes are collectively down regulated (p=4.3x10-4) between 5d and 10d post-birth. We identified 131 genes that are transiently up regulated at 5d compared to E18 and 10d and this transition was proceeded by a specific cohort of miRNAs. The data generated from this study provide new insight into the molecular mechanisms by which CMs regulate and permanently exit from the cell cycle.
Body weight response with anamorelin in advanced non-small cell lung cancer (NSCLC) patients with anorexia/cachexia: Pooled analysis of two phase III trials.
Authors: David Christopher Currow, Jennifer S. Temel, Amy Pickar Abernethy, John Friend, Ruben Giorgino
Journal: Journal of Clinical Oncology (2017)

10097 Background: Anorexia/cachexia commonly occurs in patients with advanced NSCLC and is associated with increased morbidity and mortality. In two randomized, double-blind, placebo-controlled phase 3 trials in NSCLC patients with cachexia, the ghrelin receptor agonist anamorelin was well tolerated and significantly increased body weight, lean and fat mass, and anorexia/cachexia symptom burden over 12 weeks compared to placebo (Temel J. Lancet Oncol. 2016). Since an involuntary weight loss of ≥ 5% is an established diagnostic criterion for cancer anorexia/cachexia, an analysis was conducted to assess the proportion of patients with ≥ 5% increase in body weight. Methods: NSCLC patients [ROMANA 1 (NCT01387269; N = 484) and ROMANA 2 (NCT01387282; N = 495)] with stage III/IV disease and cachexia (BMI &lt; 20 kg/m 2 or ≥ 5% weight loss during prior 6 months) were randomized 2:1 to receive 100 mg once daily oral anamorelin or placebo up to 12 weeks. A pooled analysis was conducted post-hoc in the modified intent-to-treat population (N = 829) to measure the proportion of patients with ≥ 5% increase in body weight at the end of study (or last observation carried forward since week 6 or 9). Results: The percentage of patients with ≥ 5% increase in body weight at the end of study was significantly higher in the anamorelin arm (N = 188/552, 34.1%) compared to placebo (N = 37/277; 13.4%). Among patients with BMI &lt; 20kg/m 2 at baseline (N = 182), 47.3% (N = 53/112) of anamorelin patients had a weight increase of ≥ 5% compared to 17.4% (N = 12/69) in the placebo arm. In both cases the nominal p-value was lower than 0.0001. Conclusions: Data from two published large pivotal studies in advanced NSCLC patients with anorexia/cachexia suggest that anamorelin treatment effect size on body weight is clinically relevant, as shown by the higher response rate achieved when the stringent cut-off of ≥ 5% weight gain was applied. The proportion of patients with BMI &lt; 20kg/m 2 that benefited from anamorelin treatment was greater than the proportion of patients who benefited in the entire study sample, suggesting that patients with more advanced cachexia may still benefit from anamorelin treatment. Clinical trial information: ROMANA 1: NCT01387269; ROMANA 2: NCT01387282.
RGS12 Is a Novel Tumor-Suppressor Gene in African American Prostate Cancer That Represses AKT and MNX1 Expression
Authors: Yongquan Wang, Jianghua Wang, Li Zhang, Omer Faruk Karatas, Longjiang Shao, Yiqun Zhang, Patricia Castro, Chad J. Creighton, Michael Ittmann
Journal: Cancer Research (2017)

Abstract African American (AA) men exhibit a relatively high incidence and mortality due to prostate cancer even after adjustment for socioeconomic factors, but the biological basis for this disparity is unclear. Here, we identify a novel region on chromosome 4p16.3 that is lost selectively in AA prostate cancer. The negative regulator of G-protein signaling RGS12 was defined as the target of 4p16.3 deletions, although it has not been implicated previously as a tumor-suppressor gene. RGS12 transcript levels were relatively reduced in AA prostate cancer, and prostate cancer cell lines showed decreased RGS12 expression relative to benign prostate epithelial cells. Notably, RGS12 exhibited potent tumor-suppressor activity in prostate cancer and prostate epithelial cell lines in vitro and in vivo. We found that RGS12 expression correlated negatively with the oncogene MNX1 and regulated its expression in vitro and in vivo. Further, MNX1 was regulated by AKT activity, and RGS12 expression decreased total and activated AKT levels. Our findings identify RGS12 as a candidate tumor-suppressor gene in AA prostate cancer, which acts by decreasing expression of AKT and MNX1, establishing a novel oncogenic axis in this disparate disease setting. Cancer Res; 77(16); 4247–57. ©2017 AACR.
Epithelial proteome profiling suggests the essential role of interferon-inducible proteins in patients with allergic rhinitis
Authors: Joseph Ndika, Liisa Airaksinen, Hille Suojalehto, Piia Karisola, Nanna Fyhrquist, Anne Puustinen, Harri Alenius
Journal: Journal of Allergy and Clinical Immunology (2017)

Seasonal allergic rhinitis (SAR) caused by intermittent exposure to seasonal pollen causes itching, nasal congestion, and repeated sneezing, with profound effects on quality of life, work productivity, and school performance. Although both the genotype and environmental factors can contribute to the immunologic basis of allergic reactions, the molecular underpinnings associated with the pathogenesis of allergic rhinitis are not entirely clear.To address these questions, nasal epithelial brushings were collected from 29 patients with SAR and 31 control subjects during and after the pollen season. We then implemented an orbitrap-based, bottom-up, label-free quantitative proteomics approach, followed by multivariate analyses to identify differentially abundant (DA) proteins among the 4 sample groups.We identified a total of 133 DA proteins for which the most significantly overrepresented functional category was found to be interferon 1 signaling. Two proteins, cystatin 1 and myeloblastin, the former of which protects against protease activity of allergens and the latter with a role in epithelial barrier function, were DA in patients with SAR and control subjects, irrespective of season. Moreover, interferon-inducible protein with tetratricopeptide repeats 1, cystatin 1, and interferon-inducible protein with tetratricopeptide repeats 3 were found to be differentially regulated between patients with SAR and control subjects, with inverse abundance dynamics during the transition from fall to spring.We identified type 1 interferon-regulated proteins as biomarkers in patients with SAR, potentially playing an important role in its pathogenesis. Moreover, when compared with patients with SAR, healthy subjects exhibit an antagonistic proteomic response across seasons, which might prove to be a therapeutic target for disease prevention.
Time to Delivery of an Automated External Defibrillator Using a Drone for Simulated Out-of-Hospital Cardiac Arrests vs Emergency Medical Services
Authors: Andreas Claesson, Anders Bäckman, Mattias Ringh, Leif Svensson, Per Nordberg, Therese Djärv, Jacob Hollenberg
Journal: JAMA (2017)

This study compares the time to delivery of an automated external defibrillator using fully autonomous drones for simulated out-of-hospital cardiac arrests vs emergency medical services real-time responses.
Diagnosis of hereditary non-polyposis colorectal cancer (HNPCC)
Authors: J R Jass
Journal: Gut (2004)

The paper addressing the role of monogenic inheritance in the aetiology of colorectal cancer highlights the importance of achieving a meaningful working diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) ( Gut 2004; 53 :115–22). The diagnosis of HNPCC may be achieved in two ways:



1.  by equating the Amsterdam criteria with a clinical diagnosis,

2.  by compiling a comprehensive set of clinical, pathological, and molecular features that would together support the diagnosis of a specific condition caused by a germline mutation in a DNA mismatch repair gene such as hMLH1 or hMSH2.



It is clear that there is potential for considerable confusion if the label HNPCC is used in these very different ways.

The original Amsterdam criteria were not developed to serve as the diagnostic criteria for HNPCC but merely to introduce a uniform approach to the selection of families for collaborative studies.1 It was originally considered that the criteria would be relatively specific rather than sensitive. However, colorectal cancer is a common disease, and the finding of three close relatives affected by bowel cancer within a single large family would not necessarily …
Childhood and Adolescent Obesity as a Winnable Battle
Authors: William H. Dietz
Journal: JAMA (2017)

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What's in a name? Atopic dermatitis or atopic eczema, but not eczema alone
Authors: J. I. Silverberg, J. P. Thyssen, A. S. Paller, A. M. Drucker, A. Wollenberg, K. H. Lee, K. Kabashima, G. Todd, P. Schmid‐Grendelmeier, T. Bieber
Journal: Allergy (2017)

The ideal nomenclature of atopic dermatitis (AD) / atopic eczema (AE) has long been contested. However, it is becoming increasingly clear that the disparate nomenclature of this disease may have important deleterious ramifications for clinical care and research. An electronic questionnaire regarding the preferred nomenclature for AD was sent to councilors of the International Eczema Council (IEC) (n=77), an international group of clinicians and researchers with expertise in AD/AE. The survey consisted of 2 questions for consensus regarding the preference for an atopic prefix, and preference for the term AD or AE, and an exploratory question about the acceptability of the terms AD, AE or eczema. Consensus was defined a priori as at least 90% agreement for each question with a response rate of at least 90%. Seventy-one of 77 (92.2%) IEC councilors and associates responded to the survey, with all respondents completing the entire survey. Consensus was reached for question 1, with 69 of 71 respondents (97.2%) preferring the atopic prefix. However, consensus was not reached for question 2, with 40 respondents (58.0%) preferring the term AD and 30 (43,5%) preferring AE. Sixty-three respondents (88.7%) and 55 (77.5%) felt that the terms AD and AE were acceptable, whereas only 11 (15.5%) felt that eczema was acceptable. The IEC noted that the term eczema is imprecise, and its use is confusing. The consensus of the IEC was to recommend use of the prefix "atopic" (i.e., AD or AE) in all publications, presentations and discussions about the disorder.
The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B
Authors: George V. Papatheodoridis, Ramazan Idilman, George N. Dalekos, Maria Buti, Heng Chi, Florian van Boemmel, Jose Luis Calleja, Vana Sypsa, John Goulis, Spilios Manolakopoulos, Alessandro Loglio, Spyros Siakavellas, Onur Keskın, Nikolaos Gatselis, Bettina E. Hansen, Maria Lehretz, Juan de la Revilla, Savvoula Savvidou, Anastasia Kourikou, Ioannis Vlachogiannakos, Kostantinos Galanis, Cihan Yurdaydin, Thomas Berg, Massimo Colombo, Rafael Esteban, Harry L.A. Janssen, Pietro Lampertico
Journal: Hepatology (2017)

Whether there is a change of hepatocellular carcinoma (HCC) incidence in chronic hepatitis B patients under long‐term therapy with potent nucleos(t)ide analogues is currently unclear. We therefore assessed the HCC incidence beyond year 5 of entecavir/tenofovir (ETV/TDF) therapy and tried to determine possible factors associated with late HCC occurrence. This European, 10‐center, cohort study included 1,951 adult Caucasian chronic hepatitis B patients without HCC at baseline who received ETV/TDF for ≥1 year. Of them, 1,205 (62%) patients without HCC within the first 5 years of therapy have been followed for 5‐10 (median, 6.8) years. HCCs have been diagnosed in 101/1,951 (5.2%) patients within the first 5 years and 17/1,205 (1.4%) patients within 5‐10 years. The yearly HCC incidence rate was 1.22% within and 0.73% after the first 5 years ( P = 0.050). The yearly HCC incidence rate did not differ within and after the first 5 years in patients without cirrhosis (0.49% versus 0.47%, P = 0.931), but it significantly declined in patients with cirrhosis (3.22% versus 1.57%, P = 0.039). All HCCs beyond year 5 developed in patients older than 50 years at ETV/TDF onset. Older age, lower platelets at baseline and year 5, and liver stiffness ≥12 kPa at year 5 were independently associated with more frequent HCC development beyond year 5 in multivariable analysis. No patient with low Platelets, Age, Gender‐Hepatitis B score at baseline or year 5 developed HCC. Conclusion : The HCC risk decreases beyond year 5 of ETV/TDF therapy in Caucasian chronic hepatitis B patients, particularly in those with compensated cirrhosis; older age (especially ≥50 years), lower platelets, and liver stiffness ≥12 kPa at year 5 represent the main risk factors for late HCC development. (H epatology 2017;66:1444–1453).
Physicochemical, functional, and pharmacologic comparability between the proposed biosimilar rituximab GP2013 and originator rituximab as the foundation for biosimilarity.
Authors: Antonio da Silva, Ulrich Kronthaler, Ines Meyer, Cornelius Fritsch, Timo Schneiderer, Thomas Stangler, Jan Marinus Visser
Journal: Journal of Clinical Oncology (2013)

3075 Background: Development of a biosimilar involves extensive characterization of the originator product and a target-directed iterative development process ensuring comparability to the originator with similar clinical efficacy, safety and quality. Here we report the physicochemical, functional and pre-clinical pharmacological characterization of a proposed rituximab biosimilar (GP2013). Methods: A variety of physicochemical methods were used to analyze primary and higher order structure, post-translational modifications and size heterogeneity. Functional characterization included a series of bioassays (in vitro target binding, ADCC, CDC and apoptosis) and SPR-based Fc receptor binding assays. Comparative PK and PD were assessed in cynomolgus monkeys, the pharmacologically most relevant species. Results: GP2013 has the same primary amino acid sequence and higher order structure as the originator rituximab and both were comparable with regard to charge variants, specific amino acid modifications, glycan pattern and size heterogeneity (low- and high-molecular weight variants &amp; particles). Functionally GP2013 could not be distinguished from originator rituximab preclinically. In primates, PK analysis confirmed bioequivalence between GP2013 and originator rituximab with nearly identical AUC values and 90% CIs entirely within the standard acceptance range of 0.8-1.25. Bioequivalence of PD response was also shown, with 95% CIs of areas under the effect-time curves (AUEC) ratios for relative change from baseline in B-cell populations within the 0.8-1.25 acceptance range. Conclusions: Using a broad panel of analytical methods it was shown that GP2013 is highly similar to originator rituximab at the physicochemical level. In addition, the preclinical comparability exercise confirmed that GP2013 and originator rituximab are pharmacologically similar with regard to FcR and CD20 binding, ADCC, CDC and apoptosis potency, PK exposure and B-cell depletion. As such, we anticipate that the ongoing clinical trials will help provide confirmatory evidence of similar efficacy and safety to the originator product.
Dibenzazepine-Loaded Nanoparticles Induce Local Browning of White Adipose Tissue to Counteract Obesity
Authors: Chunhui Jiang, Mario Alberto Cano-Vega, Feng Yue, Liangju Kuang, Naagarajan Narayanan, Gozde Uzunalli, Madeline P. Merkel, Shihuan Kuang, Meng Deng
Journal: Molecular Therapy (2017)

Inhibition of Notch signaling via systemic drug administration triggers conversion of white adipocytes into beige adipocytes (browning) and reduces adiposity. However, translation of this discovery into clinical practice is challenged by potential off-target side effects and lack of control over the location and temporal extent of beige adipocyte biogenesis. Here, we demonstrate an alternative approach to stimulate browning using nanoparticles (NPs) composed of FDA-approved poly(lactide-co-glycolide) that enable sustained local release of a Notch inhibitor (dibenzazepine, DBZ). These DBZ-loaded NPs support rapid cellular internalization and inhibit Notch signaling in adipocytes. Importantly, focal injection of these NPs into the inguinal white adipose tissue depots of diet-induced obese mice results in localized NP retention and browning of adipocytes, consequently improving the glucose homeostasis and attenuating body-weight gain of the treated mice. These findings offer new avenues to develop a potential therapeutic strategy for clinical treatment of obesity and its associated metabolic syndrome.
Modifiable Risk Factors for Incident Heart Failure in Atrial Fibrillation
Authors: Neal A. Chatterjee, Claudia U. Chae, Eunjung Kim, M. Vinayaga Moorthy, David Conen, Roopinder K. Sandhu, Nancy R. Cook, I-Min Lee, Christine M. Albert
Journal: JACC Heart Failure (2017)

This study sought to identify modifiable risk factors and estimate the impact of risk factor modification on heart failure (HF) risk in women with new-onset atrial fibrillation (AF). Incident HF is the most common nonfatal event in patients with AF, although strategies for HF prevention are lacking. We assessed 34,736 participants in the Women's Health Study who were free of prevalent cardiovascular disease at baseline. Cox models with time-varying assessment of risk factors after AF diagnosis were used to identify significant modifiable risk factors for incident HF. Over a median follow-up of 20.6 years, 1,495 women developed AF without prevalent HF. In multivariable models, new-onset AF was associated with an increased risk of HF (hazard ratio [HR]: 9.03; 95% confidence interval [CI]: 7.52 to 10.85). Once women with AF developed HF, all-cause (HR: 1.83; 95% CI: 1.37 to 2.45) and cardiovascular mortality (HR: 2.87; 95% CI: 1.70 to 4.85) increased. In time-updated, multivariable models accounting for changes in risk factors after AF diagnosis, systolic blood pressure >120 mm Hg, body mass index ≥30 kg/m2, current tobacco use, and diabetes mellitus were each associated with incident HF. The combination of these 4 modifiable risk factors accounted for an estimated 62% (95% CI: 23% to 83%) of the population-attributable risk of HF. Compared with women with 3 or 4 risk factors, those who maintained or achieved optimal risk factor control had a progressive decreased risk of HF (HR for 2 risk factors: 0.60; 95% CI: 0.37 to 0.95; 1 risk factor: 0.40; 95% CI: 0.25 to 0.63; and 0 risk factors: 0.14; 95% CI: 0.07 to 0.29). In women with new-onset AF, modifiable risk factors including obesity, hypertension, smoking, and diabetes accounted for the majority of the population risk of HF. Optimal levels of modifiable risk factors were associated with decreased HF risk. Prospective assessment of risk factor modification at the time of AF diagnosis may warrant future investigation.
Apremilast treatment of atopic dermatitis and other chronic eczematous dermatoses
Authors: Michael Abrouk, Benjamin Farahnik, Tian Hao Zhu, Mio Nakamura, Rasnik Singh, Kristina Lee, Sara-Marian Lucking, Jessin Blossom, Wilson Liao, John Koo, Tina Bhutani, Kanade Shinkai, Tien Nguyen
Journal: Journal of the American Academy of Dermatology (2017)