tbuckley/cabot-search huggingface dataset:
Pervasive Rightward Asymmetry Shifts of Functional Networks in Autism Spectrum Disorder
Authors: Ryan C. Cardinale, Patricia Shih, Inna Fishman, Leanne M. Ford, Ralph-Axel Müller
Journal: JAMA Psychiatry (2013)

Autism spectrum disorder (ASD) is a brain-based pervasive developmental disorder, which-by growing consensus-is associated with abnormal organization of functional networks. Several previous studies of ASD have indicated atypical hemispheric asymmetries for language. To examine the asymmetry of functional networks using a data-driven approach for a comprehensive investigation of hemispheric asymmetry in ASD. This cross-sectional study involved 24 children with ASD and 26 matched typically developing children at San Diego State University and the University of California, San Diego. Data from 10 children had to be excluded for excessive motion, resulting in final samples of 20 participants per group. Asymmetry indices of functional networks identified from independent component analysis of resting-state functional magnetic resonance imaging data. Temporal concatenation independent component analysis, performed separately in each group, showed significant group differences in asymmetry indices for 10 out of 17 functional networks. Without exception, these networks (visual, auditory, motor, executive, language, and attentional) showed atypical rightward asymmetry shifts in the ASD group. Atypical rightward asymmetry may be a pervasive feature of functional brain organization in ASD, affecting sensorimotor, as well as higher cognitive, domains.
Regulation of Minichromosome Maintenance Gene Family by MicroRNA-1296 and Genistein in Prostate Cancer
Authors: Shahana Majid, Altaf A. Dar, Sharanjot Saini, Yi Chen, Varahram Shahryari, Jan Liu, Mohd Saif Zaman, Hiroshi Hirata, Soichiro Yamamura, Koji Ueno, Yuichiro Tanaka, Rajvir Dahiya
Journal: Cancer Research (2010)

The minichromosome maintenance (MCM) gene family is essential for DNA replication and is frequently upregulated in various cancers. Here, we examined the role of MCM2 in prostate cancer and the effect of microRNA-1296 (miR-1296), genistein, and trichostatin A (TSA) on the MCM complex. Profiling results showed that expression of MCM genes was higher in tumor samples. Genistein and TSA significantly downregulated the expression of all MCM genes. Genistein, TSA, and small interfering RNA duplexes caused a significant decrease in the S phase of the cell cycle. There was also downregulation of CDT1, CDC7, and CDK2 genes, which govern loading of the MCM complex on chromatin. We also found that miR-1296 was significantly downregulated in prostate cancer samples. In PC3 cells, inhibition of miR-1296 upregulated both MCM2 mRNA and protein, whereas overexpression caused a significant decrease in MCM2 mRNA, protein, and the S phase of the cell cycle. MCM genes are excellent anticancer drug targets because they are essential DNA replication factors that are highly expressed in cancer cells. This is the first report showing anti-MCM effect by miR-1296, genistein, and TSA. TSA is undergoing clinical trials as a prostate cancer treatment but has high toxicity. Genistein, a natural, nontoxic dietary isoflavone, may be an advantageous therapeutic agent for treating prostate cancer. The use of RNA interference is currently being implemented as a gene-specific approach for molecular medicine. The specific downregulation of oncogenes by miR may contribute to novel therapeutic approaches in the treatment of prostate cancer.
Capillarization and venularization of hepatic sinusoids in porcine serum-induced rat liver fibrosis: A mechanism to maintain liver blood flow
Authors: Ekapot Bhunchet, Kaori Fujieda
Journal: Hepatology (1993)

The processes of capillarization and venularization of sinusoids after porcine serum-induced rat liver fibrosis were studied by light and electron microscopy. Accompanying the development of fibrosis in the walls of central veins, most of the sinusoidal outlets collapsed, resulting in the formation of hepatic limiting plates around central veins. A few remaining sinusoids underwent capillarization (the development of a basal lamina and the defenestration of the sinusoidal endothelial cell), followed by venularization (the transformation into venules of sinusoids, characterized by the enlargement of the diameters with the lumina being lined with several endothelial cells, which lose fenestrae and develop a basal lamina). These newly formed venules served to maintain blood flow from sinusoids into central veins and thus have been designated the “outlet venules.” Diameters of these venules could reach about 25 μm. They were classified into two types: (a) the septal outlet venules, which developed inside the septa; and (b) the angular outlet venules, which drained blood directly from the parenchyma into the fibrotic central veins at the angles between two septa. Associated with venularization, perisinusoidal stellate cells (fat-storing cells or Ito cells) differentiated to myofibroblasts. (HEPATOLOGY 1993;18:1450-1458.)
Neighbor-Joining Revealed
Authors: O. Gascuel
Journal: Molecular Biology and Evolution (2006)

It is nearly 20 years since the landmark paper (Saitou and Nei 1987) in Molecular Biology and Evolution introducing Neighbor-Joining (NJ). The method has become the most widely used method for building phylogenetic trees from distances, and the original paper has been cited about 13,000 times (Science Citation Index). Yet the question “what does the NJ method seek to do?” has until recently proved somewhat elusive, leading to some imprecise claims and misunderstanding. However, a rigorous answer to this question has recently been provided by further mathematical investigation, and the purpose of this note is to highlight these results and their significance for interpreting NJ. The origins of this story lie in a paper by Pauplin (2000) though its continuation has unfolded in more mathematically inclined literature. Our aim here is to make these findings more widely accessible.
Designing hypoallergenic derivatives for allergy treatment by means of in silico mutation and screening
Authors: Theresa Thalhamer, Heidi Dobias, Tatjana Stepanoska, Martina Pröll, Hanno Stutz, Oliver Dissertori, Peter Lackner, Fatima Ferreira, Michael Wallner, Josef Thalhamer, Arnulf Hartl
Journal: Journal of Allergy and Clinical Immunology (2010)
The ACPA recognition profile and subgrouping of ACPA-positive RA patients
Authors: Annemiek Willemze, Stefan Böhringer, Rachel Knevel, EW Nivine Levarht, Gerrie Stoeken-Rijsbergen, Jeanine J Houwing-Duistermaat, Annette HM van der Helm-van Mil, Tom WJ Huizinga, René EM Toes, Leendert A Trouw
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> Anticitrullinated protein antibodies (ACPA) are the most predictive factor for the development of rheumatoid arthritis (RA). Epitope spreading towards more citrullinated epitopes occurs before the onset of RA. Here, the authors investigated whether specific epitope recognition allows the identification of specific RA subgroups and whether it is associated with clinical features of RA. <h3>Methods</h3> The reactivity of 661 patients with RA from the Leiden Early Arthritis Clinic against several citrullinated antigens was determined by ELISA. Cluster analyses were performed to identify subgroups of patients on the basis of their ACPA recognition profile. The association of the specific reactivities with clinical characteristics was studied. <h3>Results</h3> ACPA-positive patients displayed a heterogeneous ACPA recognition profile. After performing cluster analyses, no apparent clustering of patients was found, and on the basis of the reactivities analysed, 64 different subgroups could already be identified. The extent of epitope recognition was associated with anticyclic citrullinated peptide-2 levels. The recognition of specific citrullinated epitopes was not associated with baseline characteristics. Likewise, patients with an extended fine specificity repertoire did not display differences in baseline characteristics or joint damage after 7 years of follow-up using cyclic citrullinated peptide-2 levels as a proxy, compared to ACPA-positive patients recognising fewer peptides. <h3>Conclusion</h3> These data show that the ACPA response is highly diverse with respect to recognition of specific citrullinated epitopes. Furthermore, the authors9 data indicate that clinical correlates in established ACPA-positive RA are independent from the specific (group of) citrullinated peptides recognised.
Loss of Heterozygosity in Benign Breast Epithelium in Relation to Breast Cancer Risk
Authors: D. M. Euhus, L. Cler, N. Shivapurkar, S. Milchgrub, G. N. Peters, A. M. Leitch, S. Heda, A. F. Gazdar
Journal: JNCI Journal of the National Cancer Institute (2002)

The multistage model of breast carcinogenesis suggests that errors in DNA replication and repair generate diversity in the breast epithelium (the mutator phenotype), resulting in selection and expansion of premalignant clones with an acquired survival advantage. We measured loss of heterozygosity (LOH) in breast epithelial cells obtained by random fine-needle aspiration (FNA) biopsy from 30 asymptomatic women whose risk of breast cancer had been defined by the Gail model. Polymorphic microsatellite markers were selected on the basis of their relevance to breast cancer. Breast epithelium of 11 (37%) of 30 women had normal cytology, and that of 19 (63%) had proliferative cytology (eight with atypia and 11 without atypia). LOH was detected in two women with normal cytology and in 14 women (seven with atypia and seven without atypia) with proliferative cytology (P =.007). The frequency of LOH was associated with the cytological diagnosis, as well. The mean proportion (range) of informative markers demonstrating LOH was 0.02 (0-0.20) for the 11 women with normal cytology, as compared with 0.15 (0-0.50) for the 19 women with proliferative cytology (P =.02). Mean lifetime risk for developing breast cancer, as calculated by the Gail model, was 16.7% for women with no LOH compared with 22.9% for women with any LOH (P =.05). These observations support a multistage model of breast carcinogenesis where the initiating events are those that result in genomic instability. Accurate individualized breast cancer risk assessment may be possible based on molecular analysis of breast epithelial cells obtained by random FNA.
Nitrate Tolerance in Hypertension
Authors: Harm J. Knot
Journal: Circulation Research (2003)

itrate tolerance to a vascular physiologist is the intriguing insensitivity or loss of responsiveness to drugs whose actions mimic the powerful endogenous vasodilator and platelet inhibitor nitric oxide (NO).To the clinician, it is a serious limitation in the use of an otherwise highly promising and widely used therapeutic class of drugs collectively referred to as nitrates.Nitroglycerin (NTG) and organic nitrates are used in the therapy of ischemic heart disease and heart failure.Clinical trials such as the ISIS-4 trial showed a 20% reduction in 24-hour postinfarct mortality with the use of an oral nitrate such as isosorbide mononitrate (ISMN).Sublingual NTG is the drug of choice for chest pain and acute angina attacks, and intravenous NTG is the drug of choice in acute coronary syndromes.Oral long-acting nitrates are effective in the treatment of chronic stable angina.
Synthesis and degradation of myocardial protein during the development and regression of thyroxine-induced cardiac hypertrophy in rats.
Authors: C F Sanford, E E Griffin, K Wildenthal
Journal: Circulation Research (1978)

Cardiac hypertrophy was induced in rats by daily injections of L-thyroxine (1.0 mg/kg). Regression from hypertrophy was studied 4 days after discontinuing thyroxine. Isolated, Langendorff-perfused hearts were perfused with Krebs-Henseleit buffer, glucose, insulin, and amino acids. To measure protein synthesis, left ventricular tissue was assayed for incorporation of tritiated phenylalanine into protein. Indices of rates of protein degradation were obtained by measuring the release of cold phenylalanine after blocking protein synthesis with cycloheximide. After 3 days of thyroxine (when cardiac growth was maximally increased), the rate of protein synthesis increased by 22% (P less than 0.001). After 1 week, synthesis was 8% greater than control (P less than 0.05), and by 2 weeks (when hypertrophy was stable and the rate of cardiac growth was similar to controls), synthesis had returned to control levels. In hearts regressing from hypertrophy, synthesis was reduced to 68% of control (P less than 0.001). The rate of protein degradation was decreased by 12% (P less than 0.05) after 3 days of thyroxine, but was not different from control at 1 or 2 weeks. During regression, degradation was 12% below control (P less than 0.05). Changes in the release of several amino acids that are synthesized or metabolized in heart (e.g., alanine, glycine, serine) were different from changes in phenylalanine release. In conclusion thyroxine-induced cardiac hypertrophy and regression are accompanied by changes in protein synthesis and degradation, and amino acid metabolism. The predominant change in hypertrophy is increased protein synthesis with a minor contribution from reduced degradation. Regression of hypertrophy is accompanied by decreased synthesis, not increased degradation.
A Human Stem Cell Model of Early Alzheimer’s Disease Pathology in Down Syndrome
Authors: Yichen Shi, Peter Kirwan, James Smith, Glenn MacLean, Stuart H. Orkin, Frederick J. Livesey
Journal: Science Translational Medicine (2012)

Human cellular models of Alzheimer's disease (AD) pathogenesis would enable the investigation of candidate pathogenic mechanisms in AD and the testing and developing of new therapeutic strategies. We report the development of AD pathologies in cortical neurons generated from human induced pluripotent stem (iPS) cells derived from patients with Down syndrome. Adults with Down syndrome (caused by trisomy of chromosome 21) develop early-onset AD, probably due to increased expression of a gene on chromosome 21 that encodes the amyloid precursor protein (APP). We found that cortical neurons generated from iPS cells and embryonic stem cells from Down syndrome patients developed AD pathologies over months in culture, rather than years in vivo. These cortical neurons processed the transmembrane APP protein, resulting in secretion of the pathogenic peptide fragment amyloid-β42 (Aβ42), which formed insoluble intracellular and extracellular amyloid aggregates. Production of Aβ peptides was blocked by a γ-secretase inhibitor. Finally, hyperphosphorylated tau protein, a pathological hallmark of AD, was found to be localized to cell bodies and dendrites in iPS cell-derived cortical neurons from Down syndrome patients, recapitulating later stages of the AD pathogenic process.
A Common Mutation in the Defensin <i>DEFB126</i> Causes Impaired Sperm Function and Subfertility
Authors: Theodore L. Tollner, Scott A. Venners, Edward J. Hollox, Ashley I. Yudin, Xue Liu, Genfu Tang, Houxun Xing, Robert J. Kays, Tsang Lau, James W. Overstreet, Xiping Xu, Charles L. Bevins, Gary N. Cherr
Journal: Science Translational Medicine (2011)

A frequent frameshift mutation in defensin DEFB126 , a protein that adheres to the surface of human sperm, weakens its ability to penetrate cervical mucus-like gels and causes low fertility.
Impact of morning symptoms experienced by COPD patients on exacerbation risk, rescue inhaler usage and normal daily activities
Authors: Mark Small, Sarah Broomfield, Ryan Pollard, Steve Fermer
Journal: European Respiratory Journal (2012)

Background 

Patients consider the impact of COPD on morning activities to be substantial. Evidence of the association of morning symptoms and the impact on the entire day with poor breathing control contributes to the understanding of their importance for managing COPD patients.

Objectives 

To quantify the impact of morning symptoms experienced by patients receiving inhaled corticosteroid plus long-acting β2-agonist (ICS/LABA) by association with exacerbation frequency, rescue usage and impact on daily activities.

Methods 

Data were drawn from a real world study of consulting COPD patients in the USA and Europe in 2011. Results were tested for significance (p<0.05) using Mann-Whitney and negative binomial regressions. Confounders included age, gender, BMI, comorbidities, severity, smoking status and adherence.

Results 

Of the 3790 patients in the study, 593 were receiving ICS/LABA-only (+/- rescue). Of the 177 patients reported to experience morning symptoms, cough (65.5%) and excess sputum (53.1%) were the most common. Compared with patients without morning symptoms, these patients were associated with higher mean exacerbation frequency in the last 12 months (1.04 vs 0.63 p<0.001), rescue usage per day (0.58 vs 0.46 p=0.025) and daytime impact on a 7-point Likert scale where 7 represents a constant impact (3.61 vs 3.00 p<0.001).

Conclusion 

Morning symptoms were associated with significantly more impaired breathing control for patients treated with ICS/LABA-only therapy. The association implies morning symptoms are an important indicator when assessing the impact of COPD and their presence suggests that further therapeutic intervention may be necessary.
Biomarkers Predict <i>p53</i> Gene Therapy Efficacy in Recurrent Squamous Cell Carcinoma of the Head and Neck
Authors: John Nemunaitis, Gary Clayman, Sanjiv S. Agarwala, William Hrushesky, James R. Wells, Charles Moore, John Hamm, George Yoo, Jose Baselga, Barbara A. Murphy, Kerstin A. Menander, Laura L. Licato, Sunil Chada, Robert D. Gibbons, Magali Olivier, Pierre Hainaut, Jack A. Roth, Robert E. Sobol, W. Jarrard Goodwin
Journal: Clinical Cancer Research (2009)

PURPOSE: Most recurrent squamous cell carcinomas of the head and neck have a dysfunctional p53 tumor suppressor pathway contributing to treatment resistance. We hypothesized that tumor p53 biomarkers may predict the efficacy of normal p53 delivered by gene therapy in these patients. EXPERIMENTAL DESIGN: Tumor p53 biomarkers were evaluated in 116 patients, including 29 treated with methotrexate in a phase III randomized controlled trial. Profiles favorable for p53 gene therapy efficacy were hypothesized to have either normal p53 gene sequences or low-level p53 protein expression, whereas unfavorable p53 inhibitor profiles were predicted to have high-level expression of mutated p53 that can inhibit normal p53 protein function. RESULTS: A statistically significant increase in tumor responses was observed for patients with favorable p53 efficacy profiles compared with those with unfavorable p53 inhibitor profiles [phase I/II trials: favorable (34 of 46, 74%) versus unfavorable (1 of 5, 20%), P = 0.0290; phase III trial: favorable (17 of 24, 71%) versus unfavorable (2 of 11, 18%), P = 0.0088]. In the phase III trial, there was statistically significant increased time to progression (TTP) and survival following p53 gene therapy in patients with favorable p53 profiles compared with unfavorable p53 inhibitor profiles (median TTP, 2.7 months versus 1.4 months, P = 0.0121; median survival, 7.2 months versus 2.7 months, P < 0.0001). In contrast, the biomarker profiles predictive of p53 gene therapy efficacy did not predict methotrexate response, TTP, or survival outcomes. CONCLUSIONS: These results indicate that tumor p53 biomarker profiles may predict p53 gene therapy efficacy in recurrent squamous cell carcinoma of the head and neck. (Clin Cancer Res 2009;15(24):7719-25).
A recurrent fusion gene in high-grade endometrial stromal sarcoma: a new tool for diagnosis and therapy?
Authors: Thomas Ried, Timo Gaiser
Journal: Genome Medicine (2012)

High-grade endometrial stromal sarcomas (ESSs) are an aggressive group of endometrial stromal tumors. A recent study described a recurrent chromosomal translocation (t(10;17)) occurring in ESS, which joins the gene 14-3-3ε with either FAM22A or FAM22B. Expression of the resulting fusion gene leads to malignant transformation, and silencing of its expression reverses the malignant phenotype. Because the fusion can be readily detected in diagnostic samples using fluorescent in situ hybridization, this chromosomal aberration could be used to differentiate high-grade ESS from the low-grade, less aggressive form. Discovery of the new oncoprotein could also provide entry points for targeted therapies.
My surprise at fallout over dispatches from Israel
Authors: A M. Clarfield
Journal: BMJ (2009)

Despite the fact that I like to write, I have never before thought of publishing a blog anywhere. Although my generation’s aversion to electrons and a preference for paper may be partly responsible, I had always considered such postings to be a vaguely narcissistic act. After all, who would actually want to read my thoughts on the latest movie I had seen or learn about a fight I had had with my boss? That being said, when the BMJ asked me to write about my experiences in the recent war in southern Israel and Gaza, it all came pouring out.

Although in the end I was able to post a mere fraction of what I actually put to pen, I wrote about the heavy responsibility I had felt in trying to look after my frail elderly patients in a hospital that Hamas had targeted with sophisticated Grad missiles. I wrote about watching friends and colleagues being called up to serve in the army and how we coped, psychologically and clinically, with this sudden absence. I wrote about Matan, my son’s friend and our friends’ son, whose task it was in the army to neutralise explosives in an endless number of homes (yes, civilian homes) that Hamas had boobytrapped in the hope that they would kill our soldiers—and hang the possibility that innocent Palestinian civilians might be hurt. I wrote about the careful instructions that he and his mates had received throughout training and during combat to minimise civilian casualties. Owing to the fog of war, they could not always succeed, but I have personal knowledge of the type of instructions received.

Although I wrote about many things on my pad of paper, in the blog postings I only …
The placebo effect
Authors: P. Sedgwick
Journal: BMJ (2011)

Varenicline is used as a smoking cessation aid. Its efficacy and safety were assessed by a double blind, placebo controlled, randomised controlled trial. In total, 213 participants were randomised to varenicline and 218 to placebo. Treatment was for 12 weeks, and participants were followed up for 14 weeks after treatment.1

The primary end point was continuous abstinence from smoking for the final four weeks of treatment (weeks 9 to 12). The observed treatment effect—the rate of continuous abstinence—was 59% in the varenicline group and 39% in the placebo group. The difference between the varenicline and placebo treatment groups in continued absence between weeks 9 and 12 was significant (relative risk 1.6 (95% …