tbuckley/cabot-search huggingface dataset:
Interleukin 4 Gene–defective Mice Reconstituted with Wild-type Bone Marrow Fail to Produce Normal Immunoglobulin E Levels
Authors: Claudia Lange, Thomas Schüler, Thomas Blankenstein
Journal: The Journal of Experimental Medicine (1998)

The ability to reconstitute interleukin (IL)-4−/− mice with bone marrow of IL-4+/+ mice was investigated. The absence of the IL-4−/− gene in donor or recipient cells did not impair the reconstitution. All immunoglobulin (Ig) subsets occurred at normal serum levels except for IgE and to some extent IgG1. IgE production did not recover in the reconstituted mice over prolonged time. However, these mice were competent for IgE production, because a single intrasplenic injection of IL-4 restored IgE levels, which then remained constant. Wild-type mice reconstituted with wild-type bone marrow constantly had IgE serum levels comparable to untreated animals. In wild-type mice reconstituted with IL-4−/− bone marrow, IgE levels dropped gradually and disappeared by week 12. We make three unrelated but nonetheless important conclusions: (a) (immunoregulation) the tightly regulated IL-4 gene should be expressed constantly in low amounts (and with apparent absence of antigen stimulation) to keep the normal threshold of IgE; (b) (ontogeny of the immune system) an early unidentified source of IL-4 must be postulated which is lost in adult mice; and (c) (bone marrow transfer/gene therapy) under certain circumstances, the genotype of the recipient influences the reconstitution.
Long‐term survival in young and middle‐aged <scp>H</scp>odgkin lymphoma patients in <scp>S</scp>weden 1992–2009—trends in cure proportions by clinical characteristics
Authors: Ingrid Glimelius, Sara Ekberg, Mats Jerkeman, Ellen T. Chang, Magnus Björkholm, Therese M.L. Andersson, Karin E. Smedby, Sandra Eloranta
Journal: American Journal of Hematology (2015)

Trends in Hodgkin lymphoma (HL) survival among patients treated outside of clinical trials provide real-world benchmark estimates of prognosis and help identify patient subgroups for targeted trials. In a Swedish population-based cohort of 1947 HL patients diagnosed in 1992-2009 at ages 18-59 years, we estimated relative survival (RS), cure proportions (CP), and median survival times using flexible parametric cure models. Overall, the CP was 89% (95% CI: 0.87-0.91) and median survival of the uncured was 4.6 years (95% CI: 3.0-6.3). For patients aged 18-50 years diagnosed after the year 2000, CP was high and stable, whereas for patients of 50-59 years, cure was not reached. The survival of relapse-free patients was similar to that of the general population (RS5-year : 0.99; 95% CI: 0.98-0.99, RS15-year : 0.95; 95% CI: 0.92-0.97). The excess mortality of relapsing patients was 19 times (95% CI: 12-31) that of relapse-free patients. Despite modern treatments, patients with adverse prognostic factors (e.g., advanced stage) still had markedly worse outcomes [CP stage: IIIB 0.82 (95% CI: 0.73-0.89); CP stage: IVB 0.72, (95% CI: 0.60-0.81)] and patients with international prognostic score (IPS) ≥3 had 2.7 times higher excess mortality (95% CI: 1.0-7.0, p = 0.04) than patients with IPS <3. High-risk patients selected for 6-8 courses of BEACOPP (bleomycin, etoposide, doxorubicin, cyclofosphamide, vincristine, procarbazine, prednisone)-chemotherapy had a 15-year relative survival of 87%, (95% CI: 0.80-0.92), whereas the corresponding estimate for patients selected for 6-8 courses of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) was 93% (95% CI: 0.88-0.97). These population-based results indicate limited fatal side-effects in the 15-year perspective with contemporary treatments, while the unmet need of effective relapse treatment remains of concern. BEACOPP-chemotherapy was still not sufficient in high-risk HL patients.
The efficacy of convex probe endobronchial ultrasound for sampling of parenchymal lung lesions
Authors: Nadim Akasheh, Judith Lyons, Amir Rani, Finbarr O'Connell
Journal: European Respiratory Journal (2014)

CT guided biopsy is the gold standard for assessment of pulmonary masses if transbronchial biopsy under fluoroscopy is not feasible due to parabronchial lesion location. Both of these modalities are associated with complications including bleeding and pneumothorax leading to significant morbidity. Convex probe endobronchial ultrasound (CP-EBUS) is an established technique for assessment of mediastinal lymph nodes in the staging of lung cancer. In this study we sought to examine the efficacy of CP-EBUS as a standalone technique in the assessment of central parenchymal pulmonary lesions.  We reviewed 3739 bronchoscopy reports from 2009 to 2013 at our centre. Total number of EBUS procedures performed, the number of these targeting primary lesions, lesion size and location radiologically were noted. Histopathological results were reviewed to establish diagnostic yield and crossover confirmation in some cases.  41 CP-EBUS guided procedures targeting parenchymal lung masses were performed over the period. The histological diagnosis was achieved in 35 out of 41 cases. Histology results included small and non small cell subtypes as well as neuroendocrine and carcinoid tumours. EBUS FNA was also effective in immuohistochemical and genotypic analysis of diagnosed lesions. All lesions were proximal with a mean distance of 4.6cm from the carina and 75% were larger than 2 cm in size. No lobar predominance was noted.  These results suggest that EBUS is effective and represents an alternative to CTBX for assessment of selected proximal pulmonary lesions.
Imidazoline binding sites and their ligands: An overview of the different chemical structures
Authors: Christophe Dardonville, Isabel Rozas
Journal: Medicinal Research Reviews (2004)

Abstract Since Bousquet et al. discovered the imidazoline binding sites (IBS) two decades ago, when they realized that the antihypertensive drug clonidine interacts not only with the α 2 ‐adrenenoceptors (α 2 ‐AR) but also with a distinct imidazoline preferring binding site, these receptors have been paid a great deal of attention. At least two subtypes, I 1 and I 2 , have been characterised based on their binding affinity for different radioligands, but their structures still remain unknown. The pharmacological profile of these IBSs has been the objective of several and very thorough reviews. However, a medicinal chemistry overview of the different IBS ligands prepared to date has never been attempted. In this study, we attempt to compile all the different chemical structures reported to date as IBS ligands and classify them in function of their chemical structure and binding affinity for the different IBS subtypes. Thus, we comment on the different endogenous IBS ligands known as well as the drugs described to interact with the I 1 ‐IBS which have found application as antihypertensive drugs. Then, we review those compounds described in the literature to interact with the I 2 ‐IBS, classifying them by their chemical families (imidazolines, guanidines, 2‐aminoimidazolines, β‐carbolines). Finally, some conclusions are drawn. © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 5, 639–661, 2004
Anti-TNF therapy in women with rheumatoid arthritis with a history of carcinoma in situ of the cervix: Table 1
Authors: Louise Kate Mercer, Audrey Sze Lin Low, James B Galloway, Kath D Watson, Mark Lunt, Deborah P M Symmons, Kimme L Hyrich
Journal: Annals of the Rheumatic Diseases (2012)

While many studies have investigated the risk of cancer following exposure to tumour necrosis factor (TNF) inhibitors,1–3 data are scarce with respect to people with cancer prior to treatment.2 ,4 To our knowledge, no studies have looked at cancer risk following exposure to anti-TNF in patients with a history of premalignant conditions, such as cervical dysplasia and Barrett's oesophagus. Guidelines from the British Society for Rheumatology (BSR) advise caution when using anti-TNF in subjects with premalignant conditions.5 Given the uncertainties regarding the use of anti-TNF in people with premalignant conditions, we investigated the outcome of women with rheumatoid arthritis (RA) with a previous history of carcinoma in situ (CIS) of the cervix registered with the BSR Biologics Register.6 

The BSR Biologics Register, established in 2001, is following two cohorts of patients: one cohort of patients with RA …
Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice
Authors: Q.-j. Zhang, Z. Wang, H.-z. Chen, S. Zhou, W. Zheng, G. Liu, Y.-s. Wei, H. Cai, D.-p. Liu, C.-c. Liang
Journal: Cardiovascular Research (2008)

Hazardous environmental and genetic factors can damage endothelial cells to induce atherosclerotic vascular disease. Recent studies suggest that class III deacetylase SIRT1 may promote cell survival via novel antioxidative mechanisms. The current study tested the hypothesis that SIRT1, specifically overexpressed in the endothelium, is atheroprotective.Human umbilical vein endothelial cells (HUVECs) were used to study the effects of oxidized low-density lipoprotein (LDL) on SIRT1 expression. Endothelial cell-specific SIRT1 transgenic (SIRT1-Tg) mice were used to study the effects of SIRT1 on aortic vascular tone. SIRT1-Tg mice were crossed with apolipoprotein E null (apoE(-/-)) mice to obtain SIRT1-Tg/apoE(-/-) mice for the analysis of atherogenesis in the presence of endothelial overexpression of SIRT1. SIRT1 expression in HUVECs was increased by the treatment with oxidative LDL. Adenoviral-mediated overexpression of SIRT1 was protective of apoptosis of HUVECs. Calorie restriction increased, whereas high-fat diet decreased, the SIRT1 expression in mouse aortas. In SIRT1-Tg mice, high fat-induced impairment in endothelium-dependent vasorelaxation was improved compared with that of wild-type littermates. This was accompanied by an upregualtion of aortic endothelial nitric oxide synthase expression in the SIRT1-Tg mice. The SIRT1-Tg/apoE(-/-) mice had less atherosclerotic lesions compared with apoE(-/-) controls, without affecting blood lipids and glucose levels.These results suggest that endothelium-specific SIRT1 overexpression likely suppresses atherogenesis via improving endothelial cell survival and function.
Ethnic and Sex Differences in Suicide Rates Relative to Major Depression in the United States
Authors: M A Oquendo, S P Ellis, S Greenwald, K M Malone, M M Weissman, J J Mann
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: Suicide rates differ between ethnic groups in the United States. Since suicide is commonly associated with a mood disorder, the authors compared suicide rates relative to depression rates in five ethnic groups in the United States. METHOD: Rates of major depression were generated from the Epidemiologic Catchment Area study and the Hispanic Health and Nutrition Epidemiologic Survey. Sociodemographic effects were determined by examining depression rates for respondents who were separated or divorced, earning low incomes, or not working for pay. The survey data were analyzed with age and sex standardization to generate 1-year prevalence rates of major depression. The depression rates of the different ethnic groups were compared and were examined in relation to suicide rates. RESULTS: The 1-year prevalence rates of major depression were 3.6% for whites, 3.5% for blacks, 2.8% for Mexican Americans, 2.5% for Cuban Americans, and 6.9% for Puerto Ricans. Compared to the rate for whites, the rate of depression was significantly higher in Puerto Ricans and significantly lower in Mexican Americans. Relative to the depression rates, the annual suicide rates were higher for males than for females. Mexican American and Puerto Rican males had lower relative suicide rates than white males. CONCLUSIONS: Identifying reasons for differences in suicide rates relative to depression among ethnic groups and between males and females may suggest interventions to reduce suicide rates. Some possibilities are that depression differs in form or severity or that unidentified factors protect against suicide in different subgroups.
Molecular interplay between Δ5/Δ6 desaturases and long-chain fatty acids in the pathogenesis of non-alcoholic steatohepatitis
Authors: Cristina López-Vicario, Ana González-Périz, Bibiana Rius, Eva Morán-Salvador, Verónica García-Alonso, Juan José Lozano, Ramón Bataller, Montserrat Cofán, Jing X Kang, Vicente Arroyo, Joan Clària, Esther Titos
Journal: Gut (2013)

<h3>Objective</h3> The mechanisms underlying non-alcoholic steatohepatitis (NASH) are not completely elucidated. In the current study we integrated gene expression profiling of liver biopsies from NASH patients with translational studies in mouse models of steatohepatitis and pharmacological interventions in isolated hepatocytes to identify new molecular targets in NASH. <h3>Design and results</h3> Using oligonucleotide microarray analysis we identified a significant enrichment of genes involved in the multi-step catalysis of long-chain polyunsaturated fatty acids, namely, Δ-5 desaturase (Δ5D) and Δ6D in NASH. Increased expression of Δ5D and Δ6D at both mRNA and protein level were confirmed in livers from mice with high-fat diet-induced obesity and NASH. Gas chromatography analysis revealed impaired desaturation fluxes toward the ω-6 and ω-3 pathways resulting in increased ω-6 to ω-3 ratio and reduced ω-3 index in human and mouse fatty livers. Restoration of hepatic ω-3 content in transgenic <i>fat-1</i> mice expressing an ω-3 desaturase, which allows the endogenous conversion of ω-6 into ω-3 fatty acids, produced a significant reduction in hepatic insulin resistance, steatosis, macrophage infiltration, necroinflammation and lipid peroxidation, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were mostly reproduced by feeding obese mice with an exogenous ω-3-enriched diet. A combined Δ5D/Δ6D inhibitor, CP-24879, significantly reduced intracellular lipid accumulation and inflammatory injury in hepatocytes. Interestingly, CP-24879 exhibited superior antisteatotic and anti-inflammatory actions in <i>fat-1</i> and ω-3-treated hepatocytes. <h3>Conclusions</h3> These findings indicate that impaired hepatic fatty acid desaturation and unbalanced ω-6 to ω-3 ratio play a role in the pathogenesis of NASH.
Rap1 Stabilizes β-Catenin and Enhances β-Catenin–Dependent Transcription and Invasion in Squamous Cell Carcinoma of the Head and Neck
Authors: Mitsuo Goto, Raj S. Mitra, Min Liu, Julia Lee, Bradley S. Henson, Thomas Carey, Carol Bradford, Mark Prince, Cun-Yu Wang, Eric R. Fearon, Nisha J. D'Silva
Journal: Clinical Cancer Research (2009)

In head and neck squamous cell carcinoma (HNSCC) cells, Rap1 shuttles between the nucleus and cytoplasm. Prior findings suggested that Rap1 may modulate the beta-catenin-independent Wnt pathway in some settings, but the role of Rap1 in beta-catenin-dependent Wnt signaling remains undefined.We observed that beta-catenin bound to active Rap1 in vitro and Rap1 activated beta-catenin/T-cell factor (TCF)-dependent transcription. Immunofluorescence studies showed that ectopic expression of Rap1 increased nuclear translocation of beta-catenin. Overexpression of active Rap1 facilitated an increase in beta-catenin-mediated transcription that was abrogated by dominant-negative TCF4. Conversely, small interfering RNA-mediated inhibition of endogenous Rap1 expression inhibited beta-catenin/TCF-mediated transcription as well as invasion of HNSCC. Furthermore, inhibition of Rap1 expression downregulated the expression of matrix metalloproteinase 7, a transcriptional target of beta-catenin/TCF. In HNSCC cells stably transfected with beta-catenin or treated with lithium chloride or Wnt3A to stabilize endogenous beta-catenin, inhibition of Rap1 expression led to decreases in the free pool of beta-catenin. Immunohistochemical studies of tissue from HNSCC patients revealed that increased beta-catenin intensity correlated with higher tumor stage. Furthermore, the prognostic effect of active Rap1 on tumor N stage was found to depend on cytosolic beta-catenin expression (P < 0.013). When beta-catenin is high, higher Rap1GTP intensity is associated with more advanced N stage.The findings suggest that Rap1 enhances beta-catenin stability and nuclear localization. In addition to indicating that Rap1 has a significant role in regulating beta-catenin and beta-catenin-dependent progression to more advanced N-stage lesions, these data highlight Rap1 as a potential therapeutic target in HNSCC.
Deficiency of X-Linked Inverted Duplicates with Male-Biased Expression and the Underlying Evolutionary Mechanisms in the Drosophila Genome
Authors: Zhen-Xia Chen, Yong E. Zhang, Maria Vibranovski, Jingchu Luo, Ge Gao, Manyuan Long
Journal: Molecular Biology and Evolution (2011)

Inverted duplicates (IDs) are pervasive in genomes and have been reported to play functional roles in various biological processes. However, the general underlying evolutionary forces that maintain IDs in genomes remain largely elusive. Through a systematic screening of the Drosophila melanogaster genome, 20,223 IDs were detected in nonrepetitive intergenic regions, far more than expectation under the neutrality model. 3,846 of these IDs were identified to have stable hairpin structure (i.e., the structural IDs). Based on whole-genome transcriptome profiling data, we found 628 unannotated expressed structural IDs, which had significantly different genomic distributions and structural properties from the unexpressed IDs. Among the expressed structural IDs, 130 exhibited higher expression in males than in females (i.e., male-biased expression). Compared with sex-unbiased ones, these male-biased IDs were significantly underrepresented on the X chromosome, similar to previously reported pattern of male-biased protein-coding genes. These analyses suggest that a selection-driven process, rather than a purely neutral mutation-driven mechanism, contributes to the maintenance of IDs in the Drosophila genome.
Insulin Assay Standardization: Leading to Measures of Insulin Sensitivity and Secretion for Practical Clinical Care
Authors: Lutz Heinemann
Journal: Diabetes Care (2010)

In their recent commentary, Staten et al. (1) describe their very valuable attempt to standardize insulin assays. Their aim is to allow quantitative comparison of the results obtained in one lab with those measured by a different assay in another lab. I'd like to highlight an issue when it comes to reporting the results. The insulin concentration must be stated in SI units nowadays, i.e., in pmol/l instead of μU/ml. The latter unit refers to the biologic action of this hormone (i.e., its blood glucose–lowering activity) and the former to the number of insulin molecules in a given volume. A fixed conversion factor is used to convert the microunits …
Spotlight on microvascular permeability
Authors: F.-R. E. Curry, T. Noll
Journal: Cardiovascular Research (2010)

This editorial refers to a collection of fourteen review articles invited for this special issue on microvascular permeability, guest edited by Fitz-Roy Curry and Thomas Noll. 

The normal endothelium forms a stable anti-inflammatory, anti-thrombotic, and anti-adhesive interface between circulating blood components and cells within all tissues of the body. The endothelium and its associated structures, e.g. glycocalyx, basement membrane, and pericytes, form the primary barrier to water and plasma protein exchange. This barrier is sufficient to maintain the plasma volume and venous return, and prevent tissue oedema while it enables transvascular exchange to meet metabolic and homeostatic demands of the tissues. Under normal physiological conditions, an increase in the amount of nutrient exchange is most probably the result of vasodilation to increase the surface area and the driving forces for water (microvessel pressure) and solute exchange (concentration differences) without a significant increase in permeability.1,2 The view of the endothelium as a stable barrier allowing selective exchange of water, nutrients, and plasma proteins stands in contrast to the other well-recognized role of the endothelial barrier as a major player in inflammatory processes in which the components of the normal barrier, including the surface glycocalyx and the junctions between adjacent endothelial cells, are acutely or permanently modified as part of immune responses and, at the same time, compromise barrier function. In this case, vasodilation caused by inflammatory mediators or clinical interventions only exacerbates the dysfunctional state. Thus, microvascular exchange is modulated not only by changes in the conductance of the endothelial barrier (measured as a real change in microvascular permeability) but also by local perfusion conditions. The reviews covered in this Spotlight Issue provide a broad survey on many fundamental aspects of the control of microvascular exchange processes under both physiological and pathological conditions.

Although hyperpermeability and oedema formation …
Testosterone Effects on the Breast: Implications for Testosterone Therapy for Women
Authors: Woraluk Somboonporn, Susan R. Davis
Journal: Endocrine Reviews (2004)

Androgens have important physiological effects in women. Postmenopausal androgen replacement, most commonly as testosterone therapy, is becoming increasingly widespread. This is despite the lack of clear guidelines regarding the diagnosis of androgen insufficiency, optimal therapeutic doses, and long-term safety data. With respect to the breast specifically, there is the potential for exogenous testosterone to exert either androgenic or indirect estrogenic actions, with the latter potentially increasing breast cancer risk. In experimental studies, androgens exhibit growth-inhibitory and apoptotic effects in some, but not all, breast cancer cell lines. Differing effects between cell lines appear to be due primarily to variations in concentrations of specific coregulatory proteins at the receptor level. In rodent breast cancer models, androgen action is antiproliferative and proapoptotic, and is mediated via the androgen receptor, despite the potential for testosterone and dehydroepiandrosterone to be aromatized to estrogen. The results from studies in rhesus monkeys suggest that testosterone may serve as a natural endogenous protector of the breast and limit mitogenic and cancer-promoting effects of estrogen on mammary epithelium. Epidemiological studies have significant methodological limitations and provide inconclusive results. The strongest data for exogenous testosterone therapy comes from primate studies. Based on such simulations, inclusion of testosterone in postmenopausal estrogen-progestin regimens has the potential to ameliorate the stimulating effects of combined estrogen-progestin on the breast. Research addressing this is warranted; however, the number of women that would be required for an adequately powered randomized controlled trial renders such a study unlikely.
Primary structure and alternative splice variants of gephyrin, a putative glycine receptor-tubulin linker protein
Authors: P. Prior, B. Schmitt, G. Grenningloh, I. Pribilla, G. Multhaup, K. Beyreuther, Y. Maulet, P. Werner, D. Langosch, J. Kirsch, H. Betz
Journal: Neuron (1992)

A 93 kd polypeptide associated with the mammalian inhibitory glycine receptor (GlyR) is localized at central synapses and binds with high affinity to polymerized tubulin. This protein, named gephyrin (from the Greek gamma epsilon phi upsilon rho alpha, bridge), is thought to anchor the GlyR to subsynaptic microtubules. Here we report its primary structure deduced from cDNA and show that corresponding transcripts are found in all rat tissues examined. In brain, at least five different gephyrin mRNAs are generated by alternative splicing. Expression of gephyrin cDNAs in 293 kidney cells yields polypeptides reactive with a gephyrin-specific antibody, which coprecipitate with polymerized tubulin. Thus, gephyrin may define a novel type of microtubule-associated protein involved in membrane protein-cytoskeleton interactions.