tbuckley/cabot-search huggingface dataset:
DNA Ploidy Cytometry Testing for Cervical Cancer Screening in China (DNACIC Trial): a Prospective Randomized, Controlled Trial
Authors: Hua Tong, Rong Shen, ZhuMing Wang, YanJing Kan, YiQuan Wang, FengShan Li, FuZhou Wang, Jie Yang, XiRong Guo
Journal: Clinical Cancer Research (2009)

Abstract Purpose: This randomized, controlled trial was designed to determine whether the DNA cytometry testing is superior to the conventional cytologic testing for mass cervical cancer screening. Experimental Design: After approval by the institutional ethics review boards from three separate screening centers, a total of 23,993 Chinese women ages 20 to 65 years were randomly assigned into one of the two groups: a DNA cytometry testing group (11,999 women) and a cytologic testing group (11,994 women). Each woman underwent the other testing after first attending the assigned screening test. Women with positive results after assigned testing additionally underwent colposcopy and human papillomaviruses detections, and those with cervical precancerous or cancerous lesions received appropriate treatment. Sensitivity and specificity estimates were adjusted for verification bias. Analyses were by intention to treat and per protocol ways. Results: In the cytometric DNA testing group, cervical cancer was diagnosed in 40 subjects, compared with 24 subjects in the cytologic testing group [hazard ratio for the detection of advanced cancer in the DNA cytometry testing group, 0.42; 95% confidence interval (CI), 0.27-0.60]. The sensitivity of the DNA cytometry testing for cervical cancer was 91.7% (95% CI, 64.3-95.8), whereas the sensitivity of cytologic testing was 44.5% (95% CI, 25.2-61.3; P = 0.008). The specificity was 54.1% (95% CI, 31.6-69.0) for DNA cytometry testing and 70.6% (95% CI, 46.8-82.5; P = 0.003) for cytologic testing. The sensitivity of both tests used together was 100%, and the specificity was 91.8%. A total of 187 subjects reported mild to severe adverse events after treatment with positive results in 319 women. Conclusions: Our results highlight the benefit of the DNA cytometry testing strategy in mass cervical cancer screening with greater sensitivity and positive predicted value than the conventional cytologic testing in developing settings. (Clin Cancer Res 2009;15(20):6438–45)
Anti-Ro52 monoclonal antibodies specific for amino acid 200–239, but not other Ro52 epitopes, induce congenital heart block in a rat model
Authors: Aurélie Ambrosi, Vijole Dzikaite, Jeongsook Park, Linn Strandberg, Vijay K Kuchroo, Eric Herlenius, Marie Wahren-Herlenius
Journal: Annals of the Rheumatic Diseases (2011)

Background Congenital heart block (CHB) may develop in fetuses of women with anti-Ro/La autoantibodies following placental transfer of maternal autoantibodies and disruption of the fetal atrioventricular (AV) conduction system. Animal models of CHB currently rely on immunisation or transfer of anti-Ro/La antibodies purified from mothers of children with CHB, which does not allow precise identification of the disease-inducing antibody specificity. Objective To determine the ability of different anti-Ro52 monoclonal antibodies to induce cardiac electrophysiological abnormalities in vivo and affect the calcium homoeostasis of cardiomyocytes in vitro. Methods Monoclonal antibodies recognising different domains of Ro52 were generated and injected into pregnant rats, and ECG was recorded on newborn pups. Cultures of rat neonatal cardiomyocytes were established to assess the effect of the different anti-Ro52 monoclonal antibodies on calcium homoeostasis. Results First-degree AV block and bradycardia developed after maternal transfer of antibodies specific for amino acids 200–239 of Ro52 (p200), while pups exposed to antibodies targeting N- or C-terminal epitopes of Ro52 did not show any electrocardiogram abnormalities. Addition of an anti-p200 antibody to cultured cardiomyocytes induced calcium dyshomoeostasis in a time- and dose-dependent manner, while addition of other Ro52 antibodies had no effect. Conclusion These data for the first time show unambiguously that antibodies specific for amino acids 200–239 of Ro52 can induce cardiac conduction defects in the absence of other autoantibodies, and may therefore be the main initiators of cardiac pathology in the pool of anti-Ro52 antibodies in mothers of children with CHB.
The behaviour of Bcl-2, Bax and Bcl-x in Darier's disease
Authors: M.R. Bongiorno, M. Arico
Journal: British Journal of Dermatology (2002)

Summary Background Darier's disease (DD) is a rare autosomal dominant disorder of keratinization caused by a mutation of the ATP2A2 gene. There is little information on the behaviour of Bcl-2, Bax and Bcl-x in DD. Objectives To investigate the dynamic control and the behaviour of Bax, Bcl-2 and Bcl-x in DD. We asked whether members of the Bcl-2 family might manifest their effects through modulation of intracellular calcium signalling or whether the gene that encodes the sarco/endoplasmic reticulum Ca2+ ATPase isoform 2 (SERCA2) modulates the Bcl-2 family in the regulation of apoptosis in DD. Methods Immunohistochemical methods were used. Results There was no immunoreactivity for Bcl-2 and Bcl-x in epidermal keratinocytes in lesional epidermis. Staining for Bax was evident in the cells of the perilesional uninvolved skin, but decreased in the epidermal cells of lesional involved skin. Conclusions The decrease or absence of Bcl-2 and Bcl-x and the imbalance of Bax in the epithelial cells of affected DD skin is likely to be an important control point determined by the genetic mutation of SERCA2, which modifies the programme of the antiapoptotic proteins. The consequent imbalance of the factors controlling apoptosis in keratinocytes underlines another apoptotic pathway responsible for the dyskeratotic cells in DD.
Neuromedin U and Its Receptors: Structure, Function, and Physiological Roles
Authors: Paul J. Brighton, Philip G. Szekeres, Gary B. Willars
Journal: Pharmacological Reviews (2004)

Neuromedin U (NmU) is a structurally highly conserved neuropeptide. It is ubiquitously distributed, with highest levels found in the gastrointestinal tract and pituitary. Originally isolated from porcine spinal cord, it has since been isolated and sequenced from several species. Amino acid alignment of NmU from different species reveals a high level of conservation, and particular features within its structure are important for bioactivity. Specifically, the C terminus, including a terminal asparagine-linked amidation, is essential for activity. The conservation of NmU across a wide range of species indicates a strong evolutionary pressure to conserve this peptide and points to its physiological significance. Despite this, the precise physiological and indeed pathophysiological roles of NmU have remained elusive. NmU was first isolated based on its ability to contract rat uterine smooth-muscle (hence the suffix "U") and has since been implicated inthe regulation of smooth-muscle contraction, blood pressure and local blood flow, ion transport in the gut, stress responses, cancer, gastric acid secretion, pronociception, and feeding behavior. Two G-protein-coupled receptors for NmU have recently been cloned. These receptors are widespread throughout the body but have differential distributions suggesting diverse but specific roles for the receptor subtypes. Here we detail the isolation and characterization of NmU, describe the discovery, cloning, distribution, and structure of its two receptors, and outline its possible roles in both physiology and pathophysiology. Ultimately the development of receptor-specific ligands and the generation of animals in which the receptors have been selectively knocked out will hopefully reveal the true extent of the biological roles of NmU and suggest novel therapeutic indications for selective activation or blockade of either of its receptors.
Irinotecan Pharmacogenetics: Influence of Pharmacodynamic Genes
Authors: Janelle M. Hoskins, Eugenio Marcuello, Albert Altes, Sharon Marsh, Taylor Maxwell, Derek J. Van Booven, Laia Paré, Robert Culverhouse, Howard L. McLeod, Montserrat Baiget
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Irinotecan is an important drug for the treatment of solid tumors. Although genes involved in irinotecan pharmacokinetics have been shown to influence toxicity, there are no data on pharmacodynamic genes. CDC45L, NFKB1, PARP1, TDP1, and XRCC1 have been shown to influence the cytotoxic action of camptothecins, including irinotecan. Polymorphisms in the drug target of camptothecins, topoisomerase I (TOP1), and downstream effectors may influence patient outcomes to irinotecan therapy. We undertook a retrospective candidate gene haplotype association study to investigate this hypothesis. Experimental Design: Haplotype compositions of six candidate genes were constructed in European (n = 93), East Asian (n = 94), and West African (n = 95) populations. Haplotype-tagging single nucleotide polymorphisms (htSNP) were selected based on genealogic relationships between haplotypes. DNA samples from 107 European, advanced colorectal cancer patients treated with irinotecan-based regimens were genotyped for htSNPs as well as three coding region SNPs. Associations between genetic variants and toxicity (grade 3/4 diarrhea and neutropenia) or efficacy (objective response) were assessed. Results: TOP1 and TDP1 htSNPs were related to grade 3/4 neutropenia (P = 0.04) and response (P = 0.04), respectively. Patients homozygous for an XRCC1 haplotype (GGCC-G) were more likely to show an objective response to therapy than other patients (83% versus 30%; P = 0.02). This effect was also seen in a multivariate analysis (odds ratio, 11.9; P = 0.04). No genetic variants were associated with diarrhea. Conclusions: This is the first comprehensive pharmacogenetic investigation of irinotecan pharmacodynamic factors, and our findings suggest that genetic variation in the pharmacodynamic genes may influence the efficacy of irinotecan-containing therapies in advanced colorectal cancer patients.
Remodeling of the Mononuclear Phagocyte Network Underlies Chronic Inflammation and Disease Progression in Heart Failure
Authors: Mohamed Ameen Ismahil, Tariq Hamid, Shyam S. Bansal, Bindiya Patel, Justin R. Kingery, Sumanth D. Prabhu
Journal: Circulation Research (2013)

Rationale: The role of mononuclear phagocytes in chronic heart failure (HF) is unknown. Objective: Our aim was to delineate monocyte, macrophage, and dendritic cell trafficking in HF and define the contribution of the spleen to cardiac remodeling. Methods and Results: We evaluated C57Bl/6 mice with chronic HF 8 weeks after coronary ligation. As compared with sham-operated controls, HF mice exhibited: (1) increased proinflammatory CD11b + F4/80 + CD206 − macrophages and CD11b + F4/80 + Gr-1 hi monocytes in the heart and peripheral blood, respectively, and reduced CD11b + F4/80 + Gr-1 hi monocytes in the spleen; (2) significantly increased CD11c + B220 − classical dendritic cells and CD11c +/low B220 + plasmacytoid dendritic cells in both the heart and spleen, and increased classic dendritic cells and plasmacytoid dendritic cells in peripheral blood and bone marrow, respectively; (3) increased CD4 + helper and CD8 + cytotoxic T-cells in the spleen; and (4) profound splenic remodeling with abundant white pulp follicles, markedly increased size of the marginal zone and germinal centers, and increased expression of alarmins. Splenectomy in mice with established HF reversed pathological cardiac remodeling and inflammation. Splenocytes adoptively transferred from mice with HF, but not from sham-operated mice, homed to the heart and induced long-term left ventricular dilatation, dysfunction, and fibrosis in naive recipients. Recipient mice also exhibited monocyte activation and splenic remodeling similar to HF mice. Conclusions: Activation of mononuclear phagocytes is central to the progression of cardiac remodeling in HF, and heightened antigen processing in the spleen plays a critical role in this process. Splenocytes (presumably splenic monocytes and dendritic cells) promote immune-mediated injurious responses in the failing heart and retain this memory on adoptive transfer.
HYPOCHONDRIACAL COMPLAINTS WITH SPECIAL REFERENCE TO PERSONALITY AND ENVIRONMENT
Authors: SOLOMON KATZENELBOGEN
Journal: American Journal of Psychiatry (1942)

1. The issue of hypochondriasis has been confused through its identification, on one hand, with somatic delusions in psychoses and, on the other, with any and all somatic disorders of functional origin. This study supports the thesis that there exists a clinical nosological entity, called hypochondriasis, as here defined. 2. Hypochondriacal patients, with very few exceptions, have numerous complaints. These involve organs, systems of organs, the whole or parts of the body not referable to any special organs. In contrast to their usual diffuseness, the complaints in a few of our patients are circumscribed warranting the term monosymptomatic hypochondriasis. 3. The only common and very outstanding characteristic of hypochondriacal individuals is their unusual, peculiar hypochondriacal attitude towards health and sickness. The consistency of such an attitude and its persistence more or less overtly throughout life leads one to speak of constitutional hypochondriasis. However, aside from the hypochondriacal attitude, both male and female patients with hypochondriacal reactions do not, all of them, otherwise show distinctly characteristic personality traits. They rather present a rich collection of varied human specimens. 4. It is granted that in the hypochondriacal reactions of our patients, their special personality make-up played the all-prevalent part. Yet, from our material it is also clear that environmental influences, including iatrogenic factors of long and short duration, equally contributed their share.
Abstract 4124: Chronic estrogen and NNK stimulate small airway epithelial cells via modulation of nicotinic acetylcholine receptors
Authors: Hussein AN Al-Wadei, Mohammed H. Al-Wadei, Howard K. Plummer, Hildegard M. Schuller
Journal: Cancer Research (2010)

Abstract Small airway epithelial cell-derived adenocarcinoma is the most common human lung cancer and is particularly prevalent in women. We have previously reported that the proliferation of immortalized human small airway epithelial cells HPL1D is stimulated by a single dose of the tobacco carcinogen NNK via cAMP signaling activated by binding of NNK to the beta-1-adrenergic receptor (β1-AR) and that estrogen enhances this response. In the current study we show that γ-aminobutyric acid (GABA) blocks this cooperative signaling of NNK and estrogen in HPL1D cells by inhibiting the activation of adenylyl cyclase. In addition, HPL1D cells produced the stress neurotransmitters noradrenaline and adrenaline in response to binding of a single dose of NNK to the α7 nicotinic acetylcholine receptor (α7nAChR). Since both stress neurotransmitters are beta-adrenergic agonists, this response further enhanced cAMP-dependent stimulatory signaling. On the other hand, GABA production by these cells was reduced by a single dose of NNK via desensitization of the α4β2 nAChR. Exposure to NNK, estrogen or the combination of both agents for 7 days upregulated and sensitized the α7nAChR, resulting in an enhanced noradrenergic response to agonist. At the same time, chronic NNK and estrogen suppressed the production of GABA by desensitizing its regulatory α4β2nAChR. The resulting predominance of stimulatory cAMP signaling over inhibitory GABA signaling may contribute to the development and progression of small airway-derived adenocarcinoma in women who smoke and offer a novel target for the marker-guided prevention of this cancer. Supported by a grant from the National Lung Cancer Partnership and LUNGevity Foundation. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4124.
Foundation trust status makes little difference to performance, finds study
Authors: A. O'Dowd
Journal: BMJ (2011)

Giving “foundation” status to a hospital trust doesn’t improve its clinical or financial performance, concludes a new study by health experts.

An analysis of trusts’ performance by York University showed that giving hospitals in England the greater independence promised with foundation trust status did not automatically lead to enhanced productivity and performance, as expected.

A team of researchers from the university’s Centre for Health Economics discovered that differences between trusts were of long standing and existed before foundation trusts were introduced in 2004, with the expectation that they would achieve high productivity, greater innovation, and better care.

The centre’s team …
Inhibitory G Protein Overexpression Provides Physiologically Relevant Heart Rate Control in Persistent Atrial Fibrillation
Authors: Alexander Bauer, Amy D. McDonald, Khurram Nasir, Leah Peller, Jeffrey J. Rade, Julie M. Miller, Alan W. Heldman, J. Kevin Donahue
Journal: Circulation (2004)

The need for new treatment strategies for cardiac arrhythmias has motivated our continuing development of gene therapeutic options. Previously, we reported a decreased heart rate in an acute model of atrial fibrillation after atrioventricular nodal gene transfer. Here, we expand those observations to persistent atrial fibrillation and severe heart failure.After 3 weeks of atrial fibrillation, domestic swine received atrioventricular nodal gene transfer with adenoviruses encoding beta-galactosidase (beta-gal), wild-type Galpha(i2) (wtGi), or constitutively active mutant (cGi). Heart rates in awake, alert animals were not altered by beta-gal or wtGi. cGi caused a sustained 15% to 25% decrease in heart rate. The wtGi effect became evident with sedation. A tachycardia-induced cardiomyopathy was present before gene transfer. In the beta-gal group, cardiomyopathy worsened over time. In the wtGi group, the condition improved slightly, and in the cGi group, ejection fraction was near normal at the end of the study. TUNEL staining results corroborated this finding.cGi overexpression in the porcine atrioventricular node causes physiologically relevant heart rate control in persistent atrial fibrillation. These data advance the development of gene therapy as a potential treatment for common cardiac arrhythmias.
Tuberculosis and airflow obstruction: evidence from the PLATINO study in Latin America
Authors: A. M. B. Menezes, P. C. Hallal, R. Perez-Padilla, J. R. B. Jardim, A. Muiño, M. V. Lopez, G. Valdivia, M. Montes de Oca, C. Talamo, J. Pertuze, C. G. Victora
Journal: European Respiratory Journal (2007)

The aim of the present study was to evaluate the association between history of tuberculosis and airflow obstruction. A population-based, multicentre study was carried out and included 5,571 subjects aged ≥40 yrs living in one of five Latin American metropolitan areas: Sao Paulo (Brazil); Montevideo (Uruguay); Mexico City (Mexico); Santiago (Chile); and Caracas (Venezuela). Subjects performed pre- and post-bronchodilator spirometry and were asked whether they had ever been diagnosed with tuberculosis by a physician. The overall prevalence of airflow obstruction (forced expiratory volume in one second/forced vital capacity post-bronchodilator &lt;0.7) was 30.7% among those with a history of tuberculosis, compared with 13.9% among those without a history. Males with a medical history of tuberculosis were 4.1 times more likely to present airflow obstruction than those without such a diagnosis. This remained unchanged after adjustment for confounding by age, sex, schooling, ethnicity, smoking, exposure to dust and smoke, respiratory morbidity in childhood and current morbidity. Among females, the unadjusted and adjusted odds ratios were 2.3 and 1.7, respectively. In conclusion, history of tuberculosis is associated with airflow obstruction in Latin American middle-aged and older adults.
Rotator cuff tendinopathy: a model for the continuum of pathology and related management
Authors: Jeremy S Lewis
Journal: British Journal of Sports Medicine (2009)

Background Pathology of the soft tissues of the shoulder including the musculotendinous rotator cuff and subacromial bursa are extremely common and are a principal cause of pain and suffering. Competing theories have been proposed to explain the pathoaetiology of rotator cuff pathology at specific stages and presentations of the condition. This review proposes a model to describe the continuum of the rotator cuff pathology from asymptomatic tendon through full thickness rotator cuff tears. Conclusions The pathoaetiology of rotator cuff failure is multifactorial and results from a combination of intrinsic, extrinsic and environmental factors. Recently a new and generic model detailing the continuum of tendon pathology has been proposed. This model is relevant for the rotator cuff and provides a framework to stage the continuity of rotator cuff pathology. Furthermore, it provides a structure to identify the substantial deficiencies in our knowledge base and areas where research would improve our understanding of the pathological and repair process, together with assessment and management. The strength of this model adapted for the rotator cuff tendons and subacromial bursa will be tested in its ability to incorporate and adapt to emerging research.
Nicotinic Acetylcholine Receptor Signalling: Roles in Alzheimer's Disease and Amyloid Neuroprotection
Authors: Steven D. Buckingham, Andrew K. Jones, Laurence A. Brown, David B. Sattelle
Journal: Pharmacological Reviews (2009)

Alzheimer's disease (AD), the major contributor to dementia in the elderly, involves accumulation in the brain of extracellular plaques containing the beta-amyloid protein (Abeta) and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is also characterized by a loss of neurons, particularly those expressing nicotinic acetylcholine receptors (nAChRs), thereby leading to a reduction in nAChR numbers. The Abeta(1-42) protein, which is toxic to neurons, is critical to the onset and progression of AD. The discovery of new drug therapies for AD is likely to be accelerated by an improved understanding of the mechanisms whereby Abeta causes neuronal death. We examine the evidence for a role in Abeta(1-42) toxicity of nAChRs; paradoxically, nAChRs can also protect neurons when activated by nicotinic ligands. Abeta peptides and nicotine differentially activate several intracellular signaling pathways, including the phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog pathway, the extracellular signal-regulated kinase/mitogen-activated protein kinase, and JAK-2/STAT-3 pathways. These pathways control cell death or survival and the secretion of Abeta peptides. We propose that understanding the differential activation of these pathways by nicotine and/or Abeta(1-42) may offer the prospect of new routes to therapy for AD.