tbuckley/cabot-search huggingface dataset:
Conserved Synteny Between the Ciona Genome and Human Paralogons Identifies Large Duplication Events in the Molecular Evolution of the Insulin-Relaxin Gene Family
Authors: Robert Piotr Olinski, Lars-Gustav Lundin, Finn Hallböök
Journal: Molecular Biology and Evolution (2005)

The aims of the study were to outline the sequence of events that gave rise to the vertebrate insulin-relaxin gene family and the chromosomal regions in which they reside. We analyzed the gene content surrounding the human insulin/relaxin genes with respect to what family they belonged to and if the duplication history of investigated families parallels the evolution of the insulin-relaxin family members. Markov Clustering and phylogenetic analysis were used to determine family identity. More than 15% of the genes belonged to families that have paralogs in the regions, defining two sets of quadruplicate paralogy regions. Thereby, the localization of insulin/relaxin genes in humans is in accordance with those regions on human chromosomes 1, 11, 12, 19q (insulin/insulin-like growth factors) and 1, 6p/15q, 9/5, 19p (insulin-like factors/relaxins) were formed during two genome duplications. We compared the human genome with that of Ciona intestinalis, a species that split from the vertebrate lineage before the two suggested genome duplications. Two insulin-like orthologs were discovered in addition to the already described Ci-insulin gene. Conserved synteny between the Ciona regions hosting the insulin-like genes and the two sets of human paralogons implies their common origin. Linkage of the two human paralogons, as seen in human chromosome 1, as well as the two regions hosting the Ciona insulin-like genes suggests that a segmental duplication gave rise to the region prior to the genome doublings. Thus, preserved gene content provides support that genome duplication(s) in addition to segmental and single-gene duplications shaped the genomes of extant vertebrates.
Farnesyl transferase inhibitors induce extended remissions in transgenic mice with mature B cell lymphomas
Authors: Kenneth A Field, Soratree Charoenthongtrakul, J Michael Bishop, Yosef Refaeli
Journal: Molecular Cancer (2008)

We have used a mouse model based on overexpression of c-Myc in B cells genetically engineered to be self-reactive to test the hypothesis that farnesyl transferase inhibitors (FTIs) can effectively treat mature B cell lymphomas. FTIs are undergoing clinical trials to treat both lymphoid and non-lymphoid malignancies and we wished to obtain evidence to support the inclusion of B cell lymphomas in future trials. We report that two FTIs, L-744,832 and SCH66336, blocked the growth of mature B cell lymphoma cells in vitro and in vivo. The FTI treatment affected the proliferation and survival of the transformed B cells to a greater extent than naïve B cells stimulated with antigen. In syngeneic mice transplanted with the transgenic lymphoma cells, L-744,832 treatment prevented the growth of the tumor cells and the morbidity associated with the resulting lymphoma progression. Tumors that arose from transplantation of the lymphoma cells regressed with as little as three days of treatment with L-744,832 or SCH66336. Treatment of these established lymphomas with L-744,832 for seven days led to long-term remission of the disease in approximately 25% of animals. FTI treatment can block the proliferation and survival of self-reactive transformed B cells that overexpress Myc. In mice transplanted with mature B cell lymphomas, we found that FTI treatment led to regression of disease. FTIs warrant further consideration as therapeutic agents for mature B cell lymphomas and other lymphoid tumors.
Stem cell therapy for diabetes mellitus
Authors: Júlio C. Voltarelli, Carlos E.B. Couri, Maria C. Oliveira, Daniela A. Moraes, Ana B.P.L. Stracieri, Fabiano Pieroni, George M.N. Barros, Kelen C.R. Malmegrim, Belinda P. Simões, Angela M.O. Leal, Milton C. Foss
Journal: Kidney International Supplements (2011)
Response to D.M. Marcus's comment on the TRIFRA study (comparison of<i>Tripterygium wilfordii</i>Hook F vs methotrexate in the treatment of active rheumatoid arthritis)
Authors: Qian-wen Lv, Wen Zhang, Qun Shi, Wen-jie Zheng, Peter E Lipsky, Xuan Zhang
Journal: Annals of the Rheumatic Diseases (2014)

We appreciate the comments of Dr Marcus1 concerning our article on the treatment of patients with rheumatoid arthritis with an extract of Tripterygium wilfordii Hook F (TwHF).2 While we agree that patient safety is of paramount concern, we would like to clarify a number of issues.

First, our study did not examine the efficacy of ‘the herb’ TwHF, but rather a pharmaceutical extract of specific parts of the plant. Various extracts of TwHF have been used in traditional Chinese medicine for hundreds of years for various symptoms. Because the plant contains hundreds of components, many of which have biological activity, standardisation has been difficult.3 However, over the past 30 years, intensive work by Chinese and …
Kinetic Preservation of Dual Specificity of Coprogrammed Minor Histocompatibility Antigen-Reactive Virus-Specific T Cells
Authors: Marleen M. van Loenen, Renate S. Hagedoorn, Michel G.D. Kester, Manja Hoogeboom, Roel Willemze, J.H. Frederik Falkenburg, Mirjam H.M. Heemskerk
Journal: Cancer Research (2009)

Adoptive transfer of antigen-specific T cells is an attractive strategy for the treatment of hematologic malignancies. It has been shown that T cells recognizing minor histocompatibility antigens (mHag) selectively expressed on hematopoietic cells mediate antileukemic reactivity after allogeneic stem cell transplantation. However, large numbers of T cells with defined specificity are difficult to attain. An attractive strategy to obtain large numbers of leukemia-reactive T cells is retroviral transfer of mHag-specific T-cell receptors (TCR). TCR transfer into T cells specific for persistent viruses may enable these T cells to proliferate both after encountering with viral antigens as well as mHags, increasing the possibility of in vivo survival. We analyzed whether the dual specificity of the TCR-transferred T cells after repetitive stimulation via either the introduced antileukemic HA-2-TCR or the endogenous cytomegalovirus (CMV) specific CMV-TCR was preserved. We show that after repetitive stimulation, T cells skew to a population predominantly expressing the triggered TCR. However, HA-2-TCR-transferred CMV-specific T cells with high antileukemic HA-2-TCR expression but low CMV-TCR expression were able to persist and proliferate after repetitive stimulation with pp65. Moreover, HA-2-TCR-transferred CMV-specific T cells remained dual specific after repetitive stimulation and TCR expression could be reverted after additional stimulation via the previously nonstimulated TCR, restoring high-avidity interactions. These data imply persistence of TCR-transferred virus-specific T cells with both antileukemic and antivirus reactivity in vivo.
Effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: the BCG-REVAC cluster-randomised trial
Authors: Laura C Rodrigues, Susan M Pereira, Sergio S Cunha, Bernd Genser, Maria Yury Ichihara, Silvana C de Brito, Miguel A Hijjar, Alvaro A Cruz, Clemax Sant'Anna, Ana Luiza Bierrenbach, Mauricio L Barreto, Ines Dourado
Journal: The Lancet (2005)
Clinical and immunological parameters in patients with newly diagnosed sarcoidosis
Authors: Natalya Demyanenko, Vladimir Romanov, Svetlana Sheluhina, Eugene Shmelev, Olga Lovacheva, Michael Averbach
Journal: European Respiratory Journal (2013)

Purpose: to study the clinical and immunological features of the flow of new-onset sarcoidosis (at the level of synthesis of interleukins) for different modes of anti-inflammatory therapy.  Materials and Methods: The study involved 80 patients with sarcoidosis: a clinical (history, physical examination), laboratory (blood count, inflammatory proteins), x-rays and CT pulmonary study of immunological status and respiratory function, bronchoscopy study taking BAL and transbronchial intrapulmonary biopsy. Group 1 (40 patients) received prednisolone with a maximum daily dose of 20 mg, group 2 (38 patients) received erespal 240 mg per day. Control of the above parameters has been carried out on 1st, 3rd and 6th monthss of the therapy. After 6 months of treatment, all patients was noticed with a decreased levels of erythrocyte sedimentation rate and with a positive radiological dynamics.  6-month treatment with prednisolone reduced the production of proinflammatory cytokines (IL-1 beta, IL-6, 12 and 8) and increased in production of IL-2, 4.5, and IL-10. Therapy by erespal resulted into a reduction of pro-inflammatory cytokines (IL- 1 beta, TNF-alpha, IFN-gamma, IL-8 and 2) and an increasement in production of IL-4, IL-5, and 10.  After 6 months of treatment with erespal it was noticed asignificant increase of IL-10 (2.5 times higher than in group 1), which indicates a more efficient suppression of excessive immune inflammatory component as a result of the treatment.
Increase of sympathetic outflow measured by neuropeptide Y and decrease of the hypothalamic-pituitary-adrenal axis tone in patients with systemic lupus erythematosus and rheumatoid arthritis: another example of uncoupling of response systems
Authors: P Harle
Journal: Annals of the Rheumatic Diseases (2005)

To study in parallel the outflow of the sympathetic nervous system (SNS) and the hypothalamic-pituitary adrenal (HPA) axis tone in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).32 patients with SLE, 62 with RA, and 65 healthy subjects (HS) were included. To measure the tone of the HPA axis, plasma ACTH and serum cortisol were determined. Serum neuropeptide Y (NPY) was used to evaluate the sympathetic outflow.Patients with SLE had increased NPY levels in comparison with HS, irrespective of prior prednisolone treatment (p<0.001). For patients with RA, only those with prednisolone treatment had increased NPY levels in comparison with HS (p = 0.016). Daily prednisolone dose correlated positively with serum NPY in RA (R(Rank) = 0.356, p = 0.039). In contrast, plasma ACTH levels were generally decreased significantly in comparison with HS in SLE with prednisolone, and in RA with/without prednisolone. Similarly, serum cortisol levels were also decreased in SLE with/without prednisolone, and in RA with prednisolone. The NPY/ACTH ratio was increased in SLE and RA, irrespective of prior prednisolone treatment. The NPY/cortisol ratio was increased in SLE with/without prednisolone, and in RA with prednisolone. Twelve weeks' anti-TNF antibody treatment with adalimumab did not decrease NPY levels in RA, irrespective of prednisolone treatment.An increased outflow of the SNS was shown and a decreased tone of the HPA axis in patients with SLE and RA. Low levels of cortisol in relation to SNS neurotransmitters may be proinflammatory because cooperative anti-inflammatory coupling of the two endogenous response axes is missing.
Vacuolar H+-ATPase Plays a Crucial Role in Growth and Phenotypic Modulation of Myofibroblasts in Cultured Human Saphenous Vein
Authors: H. Otani, T. Yamamura, Y. Nakao, R. Hattori, H. Fujii, H. Ninomiya, M. Kido, H. Kawaguchi, M. Osako, H. Imamura, T. Ohta, S. Ohkuma
Journal: Circulation (2000)

The molecular mechanism of neointimal hyperplasia after vein graft surgery remains elusive. Vacuolar H(+)-ATPase (V-ATPase) is involved in intracellular trafficking and may play a crucial role in neointimal cell growth.Cultured human saphenous vein segments developed neointimal formation within 10 days. Neointimal cells were positive for vimentin and alpha-smooth muscle actin but negative for desmin, which is indicative of myofibroblasts. Those myofibroblasts were found to have originated from periadventitial fibroblasts, which upregulated the expression of 16-kDa proteolipid of V-ATPase before proliferation and phenotypic modulation. Neointimal myofibroblast growth and survival were highly sensitive to inhibition of V-ATPase by bafilomycin A(1) (BA(1)), because the incorporation of [(3)H]thymidine into the myofibroblasts was significantly inhibited by nanomolar concentrations of BA(1) and apoptotic cell death was induced by a similar concentration range of BA(1). In contrast, endothelial cells and differentiated smooth muscle cells were resistant to apoptosis by BA(1).These results suggest that V-ATPase plays a crucial role in growth and phenotypic modulation of myofibroblasts that contributes to neointimal formation in cultured human saphenous vein.
Critical role of endothelial CXCR2 in LPS-induced neutrophil migration into the lung
Authors: J. Reutershan
Journal: Journal of Clinical Investigation (2006)

In models of acute lung injury, CXC chemokine receptor 2 (CXCR2) mediates migration of polymorphonuclear leukocytes (PMNs) into the lung. Since CXCR2 ligands, including CXCL1 and CXCL2/3, are chemotactic for PMNs, CXCR2 is thought to recruit PMNs by inducing chemotactic migration. In a model of PMN recruitment to the lung, aerosolized bacterial LPS inhalation induced PMN recruitment to the lung in wild-type mice, but not in littermate CXCR2–/– mice. Surprisingly, lethally irradiated wild-type mice reconstituted with CXCR2–/– BM still showed about 50% PMN recruitment into bronchoalveolar lavage fluid and into lung interstitium, but CXCR2–/– mice reconstituted with CXCR2–/– BM showed no PMN recruitment. Conversely, CXCR2–/– mice reconstituted with wild-type BM showed a surprisingly large defect in PMN recruitment, inconsistent with a role of CXCR2 on PMNs alone. Cell culture, immunohistochemistry, flow cytometry, and real-time RT-PCR were used to show expression of CXCR2 on pulmonary endothelial and bronchial epithelial cells. The LPS-induced increase in lung microvascular permeability as measured by Evans blue extravasation required CXCR2 on nonhematopoietic cells. Our data revealed what we believe to be a previously unrecognized role of endothelial and epithelial CXCR2 in LPS-induced PMN recruitment and lung injury.
Leisure-Time Physical Activity and the Metabolic Syndrome in the Finnish Diabetes Prevention Study
Authors: Pirjo Ilanne-Parikka, David E. Laaksonen, Johan G. Eriksson, Timo A. Lakka, Jaanaöm Lindstr, Markku Peltonen, Sirkka Aunola, Sirkka Keinánen-Kiukaanniemi, Matti Uusitupa, Jaakko Tuomilehto
Journal: Diabetes Care (2010)

OBJECTIVE To assess the effects of leisure-time physical activity (LTPA) and resistance training on metabolic syndrome (MetS) and its components in a post hoc analysis of the Finnish Diabetes Prevention Study, a randomized controlled lifestyle counseling trial. RESEARCH DESIGN AND METHODS A cohort of 486 middle-aged overweight men and women with impaired glucose tolerance were followed for an average of 4.1 years. The intervention and control groups were combined in the analyses. LTPA was assessed by questionnaires, dietary intake by food records, and features of the MetS by anthropometric and biochemical measures annually. Resistance training sessions were documented for 137 participants. RESULTS Increased moderate-to-vigorous LTPA, even after adjustments for changes in dietary intakes of total and saturated fat, fiber, and energy, and change in BMI was associated with a greater likelihood for resolution (29.7 vs. 19.1%; P = 0.004 in the upper versus lower third of change) and a lesser likelihood for development (23.5 vs. 44.7%; P = 0.041) of the MetS. Of the components of the MetS, the increase in moderate-to-vigorous LTPA was associated most strongly with improvement of glycemia. Among the 137 participants who participated in resistance training, MetS components were favorable in individuals who were in the upper third of participation rate (median 51 times/year) compared with individuals in the lowest third (median 8.5 times/year). CONCLUSIONS Increased moderate-to-vigorous LTPA was associated with a decreased likelihood of developing the MetS and an increased likelihood of its resolution in individuals at high risk for type 2 diabetes.
Beta-Testing of PI3-Kinase Inhibitors: Is Beta Better?
Authors: Peter R. Shepherd, William A. Denny
Journal: Cancer Discovery (2012)

Although it has been known for some time that PTEN-null tumors require expression of the p110β isoform of phosphoinositide 3-kinase for growth, the corollary demonstration that small-molecule inhibitors of p110β are effective drugs for such tumors has not been shown. This has now been rectified by the demonstration that the TGX221 analogue KIN-193 is effective in mouse xenografts of HCC70 and PC3 human tumor cell lines.
Identification of a rare coding variant in complement 3 associated with age-related macular degeneration
Authors: Xiaowei Zhan, David E Larson, Chaolong Wang, Daniel C Koboldt, Yuri V Sergeev, Robert S Fulton, Lucinda L Fulton, Catrina C Fronick, Kari E Branham, Jennifer Bragg-Gresham, Goo Jun, Youna Hu, Hyun Min Kang, Dajiang Liu, Mohammad Othman, Matthew Brooks, Rinki Ratnapriya, Alexis Boleda, Felix Grassmann, Claudia von Strachwitz, Lana M Olson, Gabriëlle H S Buitendijk, Albert Hofman, Cornelia M van Duijn, Valentina Cipriani, Anthony T Moore, Humma Shahid, Yingda Jiang, Yvette P Conley, Denise J Morgan, Ivana K Kim, Matthew P Johnson, Stuart Cantsilieris, Andrea J Richardson, Robyn H Guymer, Hongrong Luo, Hong Ouyang, Christoph Licht, Fred G Pluthero, Mindy M Zhang, Kang Zhang, Paul N Baird, John Blangero, Michael L Klein, Lindsay A Farrer, Margaret M DeAngelis, Daniel E Weeks, Michael B Gorin, John R W Yates, Caroline C W Klaver, Margaret A Pericak-Vance, Jonathan L Haines, Bernhard H F Weber, Richard K Wilson, John R Heckenlively, Emily Y Chew, Dwight Stambolian, Elaine R Mardis, Anand Swaroop, Goncalo R Abecasis
Journal: Nature Genetics (2013)
The kappa opioid receptor is associated with the perception of visceral pain
Authors: D BLACK, M TREVETHICK
Journal: Gut (1998)

μ-, δ- and κ-opioid receptors are widely expressed in the central nervous system where they mediate the strong analgesic and mood-altering actions of opioids, and modulate numerous endogenous functions. To investigate the contribution of the κ-opioid receptor (KOR) to opioid function in vivo , we have generated KOR-deficient mice by gene targeting. We show that absence of KOR does not modify expression of the other components of the opioid system, and behavioural tests indicate that spontaneous activity is not altered in mutant mice. The analysis of responses to various nociceptive stimuli suggests that the KOR gene product is implicated in the perception of visceral chemical pain. We further demonstrate that KOR is critical to mediate the hypolocomotor, analgesic and aversive actions of the prototypic κ-agonist U-50,488H. Finally, our results indicate that this receptor does not contribute to morphine analgesia and reward, but participates in the expression of morphine abstinence. Together, our data demonstrate that the KOR -encoded receptor plays a modulatory role in specific aspects of opioid function.
Sedentary behaviour interventions in young people: a meta-analysis
Authors: Stuart JH Biddle, Sophie O'Connell, Rock E Braithwaite
Journal: British Journal of Sports Medicine (2011)

Background There is increasing concern about the time young people spend in sedentary behaviour (‘sitting time’), especially with the development of attractive home-based electronic entertainment. This may have deleterious health effects. Purpose To ascertain, through a meta-analytic review, whether interventions targeted at reducing sedentary behaviours in young people are successful. Method ERIC, MedLine, PsychInfo, SportDiscus and the Cochrane Library databases were searched up to 2010. Titles and abstracts of identified papers were examined against inclusion criteria. Included papers were coded by three researchers. Results 17 papers, including 17 independent samples (N=4976), met the inclusion criteria and were analysed. There was a small but significant effect in favour of sedentary behaviour reduction for intervention groups (Hedges' g = − 0.192; SE = 0.056; 95% CI = −0.303 to −0.082; p = 0.001). Moderator analyses produced no significant between-moderator results for any of the intervention or study characteristics, although trends were evident. Conclusion Behaviour change interventions targeting reductions in sedentary behaviour have been shown to be successful, although effects are small. More needs to be known about how best to optimise intervention effects.
T cell receptor-mediated recognition of self-ligand induces signaling in immature thymocytes before negative selection.
Authors: R Abe, Y Ishida, K Yui, M Katsumata, T M Chused
Journal: The Journal of Experimental Medicine (1992)

Shaping of the T cell repertoire by selection during intrathymic maturation involves T cell receptor (TCR) recognition of major histocompatibility complex/self-antigen complexes. In this communication, we studied the ability of minor lymphocyte stimulating (Mls) determinants to act as self-tolerogens in the selection of the T cell repertoire. We demonstrate that unprimed T cells from normal as well as TCR transgenic mice form Mls-specific conjugates with antigen-presenting cells, and that this TCR-ligand interaction leads to elevation of intercellular Ca2+ ([Ca2+]i). Peripheral T cells from TCR transgenic mice expressing receptors specific for self-Mls antigen show no reactivities to Mlsa. However, a proportion of immature thymocytes from these mice show specific binding and strong [Ca2+]i elevation in response to self-antigen-presenting cells, although these thymocytes do not proliferate. This self-reactivity of thymocytes is inhibited by antibodies specific for TCR, CD4, CD8, class II molecules, lymphocyte function-associated antigen 1, and intercellular adhesion molecule 1. These results demonstrate for the first time that before thymic negative selection, immature T cells can specifically interact with cells bearing self-antigen, and suggest that the resulting TCR-dependent signal transduction events provide a basis for negative selection of self-reactive T cells.
Ferroportin/IREG-1/MTP-1/SLC40A1 modulates the uptake of iron at the apical membrane of enterocytes
Authors: C Thomas
Journal: Gut (2003)

Background: Absorption of non-haeme iron occurs mainly in the duodenum. It involves the divalent metal transporter 1 (DMT1) in the uptake of ferrous Fe(II) iron and the basolateral transporter ferroportin/IREG-1/MTP-1/SLC40A1 in its release. Whether ferroportin functions in this process at other sites in the enterocyte is unknown. In this study the effect of a blocking antibody to ferroportin on the uptake and release of iron was evaluated in enterocyte-like cells (IEC-6 and Caco-2) and in freshly isolated duodenal enterocytes from rats. Methods: Uptake of 1 μM Fe(II) and its release by cells was studied in the presence of the antibody. Ferroportin expression was determined by western blot analysis of duodenal mucosa enriched microvillus membranes, Caco-2 cells, IEC-6 cells, and freshly isolated enterocytes. Immunofluorescent detection of ferroporitn was performed on frozen sections of duodenum from rats with variations in body iron stores. Results: Ferroportin was expressed in all cell types. In these cells, the antibody significantly reduced (p<0.05) uptake of Fe(II) by 40–50% but had no effect on the release of iron. In Caco-2 cells, Fe(II) uptake was reduced only when the antibody was in contact with the apical membrane. Ferroportin protein was enriched in microvillus membrane preparations. In enterocytes from iron deficient rats, ferroportin was expressed along the brush border where it colocalised with lactase. Ferroportin was seen in the basal cytoplasm and along the basolateral membranes. Iron loading markedly reduced intracellular expression of ferroportin. In Caco-2 cells, ferroportin also localised to the microvillus and lateral and basal membranes. Conclusions: In addition to release, ferroportin functions in the uptake of iron at the apical membrane, possibly by modulating the activity of DMT1.