tbuckley/cabot-search huggingface dataset:
Combined Genetic Assessment of Transforming Growth Factor-β Signaling Pathway Variants May Predict Breast Cancer Risk
Authors: Virginia G. Kaklamani, Lisa Baddi, Junjian Liu, Diana Rosman, Sharbani Phukan, Ciarán Bradley, Chris Hegarty, Bree McDaniel, Alfred Rademaker, Carole Oddoux, Harry Ostrer, Loren S. Michel, Helen Huang, Yu Chen, Habibul Ahsan, Kenneth Offit, Boris Pasche
Journal: Cancer Research (2005)

Abstract There is growing evidence that common variants of the transforming growth factor-β (TGF-β) signaling pathway may modify breast cancer risk. In vitro studies have shown that some variants increase TGF-β signaling, whereas others have an opposite effect. We tested the hypothesis that a combined genetic assessment of two well-characterized variants may predict breast cancer risk. Consecutive patients (n = 660) with breast cancer from the Memorial Sloan-Kettering Cancer Center (New York, NY) and healthy females (n = 880) from New York City were genotyped for the hypomorphic TGFBR1*6A allele and for the TGFB1 T29C variant that results in increased TGF-β circulating levels. Cases and controls were of similar ethnicity and geographic location. Thirty percent of cases were identified as high or low TGF-β signalers based on TGFB1 and TGFBR1 genotypes. There was a significantly higher proportion of high signalers (TGFBR1/TGFBR1 and TGFB1*CC) among controls (21.6%) than cases (15.7%; P = 0.003). The odds ratio [OR; 95% confidence interval (95% CI)] for individuals with the lowest expected TGF-β signaling level (TGFB1*TT or TGFB1*TC and TGFBR1*6A) was 1.69 (1.08-2.66) when compared with individuals with the highest expected TGF-signaling levels. Breast cancer risk incurred by low signalers was most pronounced among women after age 50 years (OR, 2.05; 95% CI, 1.01-4.16). TGFBR1*6A was associated with a significantly increased risk for breast cancer (OR, 1.46; 95% CI, 1.04-2.06), but the TGFB1*CC genotype was not associated with any appreciable risk (OR, 0.89; 95% CI, 0.63-1.21). TGFBR1*6A effect was most pronounced among women diagnosed after age 50 years (OR, 2.20; 95% CI, 1.25-3.87). This is the first study assessing the TGF-β signaling pathway through two common and functionally relevant TGFBR1 and TGFB1 variants. This approach may predict breast cancer risk in a large subset of the population.
Latent tuberculosis infection (LTBI) treatment completion and complication in Leeds, UK
Authors: Rizwan Ahmed, Mohammad Arif, Daniel Hopper, Catherine Mullarkey, Sandy Moffitt, John Watson
Journal: European Respiratory Journal (2011)

Background: Successful LTBI treatment (Rx) is essential in controlling TB in low incidence countries. Reported LTBI Rx completion rate in USA, Canada and UK is around 50% [1.2]. In Leeds we run an active screening programme for both new entrant and contact screening with a great emphasis on patient education and close follow-up.

Methods: We conducted a retrospective review of all the LTBI patients (excluding those starting Rx pre anti-TNF) who were offered and accepted Rx in 2009 in Leeds. We looked at the completion rate, side effects (SE) of the Rx and reasons for not completing Rx.

Results: 184 LTBI patients were offered and accepted Rx. 89% (163/184) of the patients successfully completed the Rx.

View this table:

Table 1





Of those not completing the Rx 38% (8/21) had moved out of Leeds and another 38% (8/21) failed to follow up without known reason, only 3 patients stopped Rx due to SE.

Conclusion: Good compliance is achievable with patient education and close follow-up. Treatment side effects of LTBI are usually mild and self resolving.

References: 

*   1. Horsburgh C.R. Jr et al. Latent TB infection treatment acceptance and completion in the United States and Canada. Chest 2010;137(2):401-9.

*   2. Rennie T.W. et al. Patient choice promotes adherence in preventive treatment for latent tuberculosis. Eur Respir J 2007;30:728-735.
Results of Scottish study may be due to confounding with age
Authors: G. Raab
Journal: BMJ (1996)

students and not therefore classed.This is an exceptionally skewed population and not appropriate as a basis for drawing general conclusions.The authors' selective quotation from the world literature is unfortunate.They could have quoted papers from countries where there has been no decline in semen quality.Their reference to Carlsen et als paper is also selective.2Most serious reanalyses of the data in that paper suggest that no decline has occurred in the past 30 years.What is in dispute is why figures in the 20 years before that seem to have been higher.The factors that influence sperm quality are numerous, and the variability of specimens is considerable.Unless authors base their results on large studies and control for the many confounding variables then their contribution to our understanding of the problem is likely to be modest at best and in some cases misleading.
Anti-Tumour Efficacy Study Of The Bruton’s Tyrosine Kinase (Btk) Inhibitor, ONO-4059, In Combination With The Glycoengineered Type II Anti-CD20 Monoclonal Antibody, Obinutuzumab (GA101) Demonstrates Superior In Vivo Efficacy Compared To ONO-4059 In Combination With Rituximab
Authors: Toshio Yoshizawa, Tomoko Yasuhiro, Joseph TP Birkett, Christian Klein, Kazuhito Kawabata
Journal: Blood (2013)
Important research questions in allergy and related diseases: nonallergic rhinitis: a GA<sup>2</sup>LEN paper
Authors: J. Bousquet, W. Fokkens, P. Burney, S. R. Durham, C. Bachert, C. A. Akdis, G. W. Canonica, S.‐E. Dahlen, T. Zuberbier, T. Bieber, S. Bonini, P. J. Bousquet, J. L. Brozek, L.‐O. Cardell, R. Crameri, A. Custovic, P. Demoly, R. G. Van Wijk, M. Gjomarkaj, C. Holland, P. Howarth, M. Humbert, S. L. Johnston, F. Kauffmann, M. L. Kowalski, B. Lambrecht, S. Lehmann, B. Leynaert, K. Lodrup‐Carlsen, J. Mullol, B. Niggemann, E. Nizankowska‐Mogilnicka, N. Papadopoulos, G. Passalacqua, H. J. Schünemann, H.‐U. Simon, A. Todo‐Bom, E. Toskala, R. Valenta, M. Wickman, J. P. Zock
Journal: Allergy (2008)

Nonallergic rhinitis (NAR) can be defined as a chronic nasal inflammation which is not caused by systemic IgE-dependent mechanisms. It is common and probably affects far more than 200 million people worldwide. Both children and adults are affected. However, its exact prevalence is unknown and its phenotypes need to be evaluated using appropriate methods to better understand its pathophysiology, diagnosis and management. It is important to differentiate between infectious rhinitis, allergic/NAR and chronic rhinosinusitis, as management differs for each of these cases. Characterization of the phenotype, mechanisms and management of NAR represents one of the major unmet needs in allergic and nonallergic diseases. Studies on children and adults are required in order to appreciate the prevalence, phenotype, severity and co-morbidities of NAR. These studies should compare allergic and NAR and consider different age group populations including elderly subjects. Mechanistic studies should be carried out to better understand the disease(s) and risk factors and to guide towards an improved diagnosis and therapy. These studies need to take the heterogeneity of NAR into account. It is likely that neuronal mechanisms, T cells, innate immunity and possibly auto-immune responses all play a role in NAR and may also contribute to the symptoms of allergic rhinitis.
The CXCR4 Antagonist BL-8040 Efficiently Induces Apoptosis and Inhibits The Survival Of AML Cells
Authors: Sigal Tavor, Ido Weiss, Katia Beider, Hanna Wald, Orly Eizenberg, Yaron Pereg, Leah Klapper, Arnon Nagler, Amnon Peled, Michal Abraham
Journal: Blood (2013)
Abstract 953: Ca <sup>2+</sup> -permeable TRP Channels In Human Cardiac Fibroblasts
Authors: Jianyang Du, David Silverman, Bruce Liang, Lixia Yue
Journal: Circulation (2007)

In our laboratory, recent single cell electrophysiologic studies have demonstrated the absence of voltage-gated Ca 2+ channels in human cardiac fibroblasts. The more positive membrane potential found in these cells suggests that Ca 2+ entry occurs through a different mechanism. We hypothesized that non-voltage-gated Ca 2+ -permeable TRP channels are responsible for Ca 2+ entry in human cardiac fibroblasts. With informed consent, right atrial biopsies were obtained from patients undergoing cardiac surgery (n=4:.3M, 1F; mean age 65±8 yrs, EF 63±5%, LVEDP 24±4 mm Hg). Fibroblasts were dissociated and cultured for 7 to 10 days. We found that TRPC1, TRPC4, TRPC6, TRPV4, TRPV5, TRPV6, TRPM4 and TRPM7 were detectable at message levels by RT-PCR. Functional expression of these channels was evaluated by patch-clamp technique. An outward rectifying current with typical I–V relation of TRPM7 was readily recorded in the fibroblasts. The averaged current density was 14.5±0.8 pA/pF (mean±SEM, n=60 from four patients). These currents exhibit similar properties to those of heterologues expressed TRPM7, including permeation to Ca 2+ and Mg 2+ , single channel conductance, and inhibition by 2-APB. Moreover, the TRPM7-like current in human fibroblasts was activated by acidic pH conditions, suggesting that this channel function may be enhanced under ischemic conditions. To study whether this TRPM7-like current promotes fibroblast proliferation, we designed siRNA specifically targeting human TRPM7. Fibroblasts treated with TRPM7 siRNA for five days showed a 76.3% decrease in current density, indicating that transcription of trpm7 produces the message for the Ca 2+ -pemeable channel in human cardiac fibroblasts. Consistent with the decreased current amplitude, Ca 2+ influx in siRNA treated fibroblasts was significantly smaller than those of control fibroblasts, further suggesting that TRPM7-like current contributes to calcium signaling in these cells. Taken together, our results indicate that TRPM7 provides the molecular basis of the Ca 2+ -permeable cation channel in human cardiac fibroblast, and that TRPM7 may play a crucial role in the fibrogenesis cascade in human heart.
Manic-depressive illness and good prognosis schizophrenia
Authors: M A Taylor, R Abrams
Journal: American Journal of Psychiatry (1975)

The authors examined 88 patients with an admission diagnosis of schizophrenia for the presence of good and poor clinical prognostic signs and related their findings to the clinical presentation, response to somatic treatments, and prevalence of illness in first-degree relatives. The results augment the growing evidence that good and poor prognosis schizophrenia are different illnesses and that good prognosis schizophrenia is frequently indistinguishable from manic-depressive illness.
Interleukin-9 expression in human malignant lymphomas: unique association with Hodgkin's disease and large cell anaplastic lymphoma
Authors: H Merz, FA Houssiau, K Orscheschek, JC Renauld, A Fliedner, M Herin, H Noel, M Kadin, HK Mueller-Hermelink, J Van Snick
Journal: Blood (1991)
The clinical meaning of refractory depression: a review for the clinician
Authors: R Guscott, P Grof
Journal: American Journal of Psychiatry (1991)

The authors' goal is to address the complex issue of treatment-refractory depression from a clinical perspective.They review the literature on the major clinical and methodological issues involved in the treatment and study of treatment-refractory depression as well as primary and tertiary care surveys of patients whose depression has not responded to treatment.There are methodological problems in defining treatment-refractory depression and in the tertiary care surveys of treatment-refractory depression. The authors define treatment-refractory depression as primarily involving diagnostic-treatment variables rather than patient variables. They articulate these variable as a series of questions the clinician may consider when confronted with patients who are considered refractory: 1) Is the diagnosis correct? 2) Has the patient received adequate treatment? 3) Was a rational stepped-care approach used? 4) How was outcome measured? 5) Is there a coexisting medical or psychiatric disorder that interferes with response to treatment? and 6) Are there factors in the clinical setting that are interfering with treatment?The problem of treatment-refractory depression has to do primarily with the diagnostic-treatment process than with patient variables. This has a number of implications in the areas of training, education, research, and public health. The evidence indicates that improvements in the recognition and treatment of depression are needed.
Abstract 3384: p66shc Deletion Rescues EPC Deficit Induced by High Glucose
Authors: Valeria Di Stefano, Chiara Cencioni, Maurizio C Capogrossi, Fabio Martelli
Journal: Circulation (2008)

Reduced Endothelial Progenitor Cell (EPC) number and function are relevant components of the angiogenesis impairment observed in diabetic patients. A close relationship exists between hyperglycemia...
Abstract 9973: Mitral Regurgitation with Mechanical Dyssynchrony as a Substrate Associated with Long-Term Survival After Cardiac Resynchronization Therapy
Authors: Tetsuari Onishi, Toshinari Onishi, Olusegun A Oyenuga, Stephanie C Haberman, Samir Saba, John Gorcsan
Journal: Circulation (2011)

Background: Mechanisms for mitral regurgitation (MR) in patients with left ventricular (LV) dysfunction are complex. Cardiac resynchronization therapy (CRT) may improve MR. However, effects are variable and the influence of mechanical dyssynchrony on MR and its association with long-term outcome is unclear. Methods: We prospectively studied 138 consecutive CRT patients with NYHA class III/IV heart failure, QRS width ≥120ms, and ejection fraction (EF) ≤35%. Quantitative echocardiography was performed before CRT and 1.5±2 months after CRT. Baseline dyssynchrony was assessed as interventricular mechanical delay (IVMD) &gt; 40ms, tissue Doppler opposing wall delay (OWD) &gt; 65ms, Yu Index &gt; 32ms, and speckle tracking radial strain delay &gt;130ms. MR was quantified by vena contracta width and jet area, and severity expressed as a grade from 1 to 4. Long-term outcome events were pre-specified as death, transplant or left ventricular assist device over 4 years. Results: Of 138 CRT patients aged 66±12 yrs with EF 24±7%, 74 patients (54%) had no significant baseline MR (≤grade 1+), and 64 patients (46%) had significant baseline MR: n=35 grade 2+, n=20 grade 3+, and n=9 grade 4+. At baseline, There are significant differences in EF (p&lt;0.01) and MR severity (&lt;0.0001) between patients with and without significant MR. Dyssynchrony at baseline by all indices were statistically associated with MR reduction (all p&lt;0.03). Among patients with significant MR at baseline, speckle-tracking radial dyssynchrony was significantly associated with long-term event free survival. Conclusion: The co-existence of baseline dyssynchrony by radial strain in patients with significant MR was associated with a more favorable long term survival after CRT. Patients with significant MR who lacked dyssynchrony had the least favorable outcome. These observations have mechanistic and clinical implications.
An oyster-associated hepatitis A outbreak in France in 2007
Authors: Y Guillois-Bécel, E Couturier, J C Le Saux, A M Roque-Afonso, F S Le Guyader, A Le Goas, J Pernès, S Le Bechec, A Briand, C Robert, E Dussaix, M Pommepuy, V Vaillant
Journal: Eurosurveillance (2009)

Following the notification of nine hepatitis A cases clustered in the Cotes d Armor district in northwestern France, epidemiological, environmental and microbiological investigations were set up in order to identify the source and vehicle of contamination and implement control measures. In total, 111 cases were identified in the outbreak, all of whom lived or had stayed as tourists in the Cotes d Armor district. Of the cases, 87% had eaten raw shellfish, and 81% specifically oysters. Traceback investigations carried out on raw shellfish consumed by the cases showed that the raw shellfish originated from a single shellfish farm. The shellfish were probably contaminated either in the submersible tanks or in a depuration land-based tank where they were stored. The source of contamination was not identified but shellfish could have been tainted by sewage overflows or by wastewater releases from a polluted storm sewer close to the shellfish farm or from on-site sanitation facilities. To prevent future hepatitis A outbreaks due to shellfish consumption from this area, hazards specific to each farm should be analysed. Timely information on sewage overflows should also be part of communities efforts regarding sewage collection and treatment.
Abstract 3356: Does Severe Obesity Cause Progressive Impairment of Left Ventricular Systolic Function?
Authors: Theophilus Owan, Kimberly Morley, Travis G Ault, Ronny Jiji, Nathaniel Hall, Kevin Preece, Zachary Williams, Ted Adams, Steve Hunt, Sheldon Litwin
Journal: Circulation (2007)

Background: Obesity is associated with an increased risk of developing heart failure. Based on cross sectional studies, it has been hypothesized that the duration of obesity is the key factor leading to impaired cardiac function. However, longitudinal data to confirm this hypothesis are not available. Methods: We prospectively studied 62 severely obese patients at baseline, 2 and 5 years after randomization to nonsurgical therapy (NonSurg, n = 25) or Rouxen-Y gastric bypass surgery (GBS, n = 37). Echocardiography was used to measure left ventricular (LV) size and ejection fraction (EF). Results: At enrollment, the mean BMI was 46±9 and the mean age was 47±11 years (range 25– 66). GBS subjects lost 96± 26 vs. 6±18 lbs at 2 years and 78±42 vs. 17±42 lbs at 5 years compared to NonSurg (p&lt;0.0001 for both). At baseline LVEF was not different between GBS and nonsurg (67±9 vs. 64±8%) and it did not change at 2 years (64±9 vs. 63±9%) or 5 years (63±9 vs. 63±10%). LV diastolic dimension did not change over time in control (4.3±1.0 vs. 4.2±0.6 vs. 4.5±0.3) or GBS patients (4.4±0.6 vs. 4.3±0.7 vs. 4.4±0.4). Stratifying the entire group by quartiles of age or duration of obesity (quartile 1 avg duration = 16 years, quartile 4 average duration = 56 years), we found no evidence of time-dependent changes in LV size or function. Conclusion: In this, prospective study of severely obese patients we found no evidence of progressive changes in LV size or EF over a period of 5 years. Moreover, we find no relationship between age or duration of obesity and LV size or LVEF. These data argue strongly that other factors such as the development of coronary disease are the most likely causes of heart failure in obese patients.
Molecular Heterogeneity of Somatostatin Analogue BIM-23014C Receptors in Human Breast Carcinoma Cells Using the Chemical Cross-Linking Assay
Authors: Grégoire Prévost, Monique Lanson, François Thomas, Nathalie Veber, Walter Gonzalez, René Beaupain, Anna Starzec, Arthur Bogden
Journal: Cancer Research (1992)

Abstract  Distinct proteins complexed with somatostatin and the somatostatin analogue BIM-23014C were revealed in human breast cancer cells using the cross-linking assay. One BIM-23014C-specific complex ( M  r  57,000) was observed in MCF-7 (monolayer, nodule, and tumor) and T47D. Growth inhibition of MCF-7 tumor xenografts by BIM-23014C was dose related in the 6-day subrenal capsule assay. Three complexes ( M  r  27,000, 42,000, and 57,000) were detected in MDA-MB-231, and no complex was visible in HBL-100. No correlation was found between receptors for BIM-23014C and epidermal growth factor in these lines. Twenty-seven of 30 human breast tumors (90%) had at least one BIM-23014C receptor. Sixteen had three complexes ( M  r , 27,000, 42,000, and 57,000). Six had the two complexes ( M  r  27,000 and 57,000), two had  M  r  42,000 and 57,000 complexes, two had just the  M  r  27,000 complex, and one had just the  M  r  42,000 complex. The presence of the three BIM-23014C receptors was positively correlated ( P   versus  four of 14 (estrogen receptor positive, progesterone receptor positive)]. Another positive correlation was established between the absence of progesterone receptors and the presence of these three complexes [12 of 16 (progesterone receptor negative)  versus  four of 14 (progesterone receptor positive)]. This high percentage of BIM-23014C receptor-positive biopsies and its inhibitory activity would support its clinical potential for the treatment of breast cancer.
Mechanism of Spermidine Cytotoxicity at 37°C and 43°C in Chinese Hamster Ovary Cells
Authors: Kurt J. Henle, Alfred J. Moss, William A. Nagle
Journal: Cancer Research (1986)

Spermidine (SPD) cytotoxicity is mediated largely through SPD oxidation by serum amine oxidases at both 37 degrees C and 43 degrees C. Alkaline sucrose gradient data suggest random induction of DNA strand breaks. A dose response with time at 37 degrees C or 43 degrees C (constant SPD) or with SPD concentration (constant time at 43 degrees C) was observed in terms of both DNA strand breaks and cell survival. The generation of peroxide was demonstrated in the absence of cells by the addition of SPD to medium containing 10% fetal bovine serum. Toxicity of SPD was reduced in saline, with catalase-thiourea and aminoguanidine, and enhanced by prior depletion of glutathione. Thermotolerance induced 16 h previously did not protect against SPD toxicity, suggesting that the reactive species from spermidine oxidation and heat damage do not produce related subcellular lesions.
Abstract 18432: Global Transcriptional Profiling of Monocytes and Macrophages and Association with Coronary Artery Disease Risk Factors in a Large Multi-Center Collaborative Study: The Cardiogenics Transcriptomic Study
Authors: Seraya Maouche, Christian Hengstenberg, Nilesh J Samani, Willem H Ouwehand, Francois Cambien, Alison H Goodall, Heribert Schunkert
Journal: Circulation (2011)

Objective: Global transcriptional profile of cells involved in the pathogenesis of coronary artery disease (CAD) is poorly characterized. We thus aimed to identify biological processes and transcription factors (TFs) accompanying the transition of monocytes to macrophages as well as expression patterns associated to CAD risk factors. Methods: Within Cardiogenics Consortium, we recruited 459 CAD patients and 458 healthy subjects. Most CAD patients had a validated MI within the previous 3-36 months and were aged between 40 and 65 years. Healthy subjects were all blood donors (42% male), without history of CAD. 1,533 RNA samples (849 monocytes and 684 macrophages) from the 917 subjects were analyzed on the Illumina Ref-8 v3.0 arrays. Results: Monocyte to macrophages differentiation process involves massive changes in gene expression with 4.181 genes being significantly (P&lt;10-3) modulated. Overall, this process is characterized by repression of large numbers of genes involved in the immune response and over-expression of genes of the lipid metabolism. Specifically, multiple genes expressed only in macrophages are involved in cholesterol metabolism such as APOE, PLAU, A2M, and SPP1. We found 155 TFs being significantly modulated between monocytes and macrophages. Among which 84.5% were down-regulated in macrophages. We found 28 and 14 genes being associated with gender in monocyte and macrophages, respectively. In monocytes, the expression of 21 genes was associated with BMI, including genes involved in cholesterol, steroid and lipid metabolic processes such as ABCG1, YWHAH, SARD5A1, and SORT1, and genes involved in obesity such as ADRB2 and GPX3. Only two genes, NEFH and AGPAT4 were found to be associated with age in monocytes. Conclusions: We provide the first comprehensive large-scale analyses of monocyte and macrophage transcriptomes. The finding that multiple genes of the lipid system were over-expressed in macrophages is not only concordant with the fact that these cells are essential modulators of lipid metabolism but shows that macrophages express lipid handling genes even in the absence of exposure to exogenous lipids. Our results might be used to interpret GWAS finding and shed light on the role of monocyte and macrophage cells in CAD.