tbuckley/cabot-search huggingface dataset:
X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production
Authors: Orchidée Filipe-Santos, Jacinta Bustamante, Margje H. Haverkamp, Emilie Vinolo, Cheng-Lung Ku, Anne Puel, David M. Frucht, Karin Christel, Horst von Bernuth, Emmanuelle Jouanguy, Jacqueline Feinberg, Anne Durandy, Brigitte Senechal, Ariane Chapgier, Guillaume Vogt, Ludovic de Beaucoudrey, Claire Fieschi, Capucine Picard, Meriem Garfa, Jalel Chemli, Mohamed Bejaoui, Maria N. Tsolia, Necil Kutukculer, Alessandro Plebani, Luigi Notarangelo, Christine Bodemer, Frédéric Geissmann, Alain Israël, Michel Véron, Maike Knackstedt, Ridha Barbouche, Laurent Abel, Klaus Magdorf, Dominique Gendrel, Fabrice Agou, Steven M. Holland, Jean-Laurent Casanova
Journal: The Journal of Experimental Medicine (2006)

Germline mutations in five autosomal genes involved in interleukin (IL)-12-dependent, interferon (IFN)-gamma-mediated immunity cause Mendelian susceptibility to mycobacterial diseases (MSMD). The molecular basis of X-linked recessive (XR)-MSMD remains unknown. We report here mutations in the leucine zipper (LZ) domain of the NF-kappaB essential modulator (NEMO) gene in three unrelated kindreds with XR-MSMD. The mutant proteins were produced in normal amounts in blood and fibroblastic cells. However, the patients' monocytes presented an intrinsic defect in T cell-dependent IL-12 production, resulting in defective IFN-gamma secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-kappaB/c-Rel-mediated CD40 signaling after the stimulation of monocytes and dendritic cells by CD40L-expressing T cells and fibroblasts, respectively. However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells and the proliferation and immunoglobulin class switch of B cells were normal. Moreover, the patients' blood and fibroblastic cells responded to other NF-kappaB activators, such as tumor necrosis factor-alpha, IL-1beta, and lipopolysaccharide. These two mutations in the NEMO LZ domain provide the first genetic etiology of XR-MSMD. They also demonstrate the importance of the T cell- and CD40L-triggered, CD40-, and NEMO/NF-kappaB/c-Rel-mediated induction of IL-12 by monocyte-derived cells for protective immunity to mycobacteria in humans.
A dominant role for glucose in β cell compensation of insulin resistance
Authors: Gordon C Weir, Susan Bonner-Weir
Journal: Journal of Clinical Investigation (2007)

Increased insulin secretion and expansion of pancreatic β cell mass work together to maintain normal glucose levels when insulin resistance develops. Changes in glucose concentration have long been known to have profound effects upon the rates of insulin secretion and β cell mass, but various other agents can also cause changes, raising questions about which mechanisms are dominant. Evidence favoring a dominant role for glucose is provided by Terauchi et al. in this issue of the JCI (see the related article beginning on page 246). Mice haploinsufficient for β cell glucokinase (Gck) were unable to increase their β cell mass in response to insulin resistance produced by high-fat feeding. Gck is known to be the glucose sensor for glucose metabolism in β cells. The study also provides strong evidence that insulin receptor substrate 2 (Irs2), which is known to have major effects on β cell growth and survival, is a key downstream mediator of the effects of glucose found in this study.
MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
Authors: Stephanie Ma, Yuen Piu Chan, Pak Shing Kwan, Terence K. Lee, Mingxia Yan, Kwan Ho Tang, Ming Tat Ling, Juergen R. Vielkind, Xin-Yuan Guan, Kwok Wah Chan
Journal: Cancer Research (2011)

Abstract Expression of microRNA genes is profoundly altered in cancer but their role in the development of androgen-independent prostate cancer has received limited attention as yet. In this study, we report a functional impact in prostate cancer cells for overexpression of the microRNA miR-616, which occurred consistently in cells that were androgen-independent (AI) versus androgen-dependent (AD). miR-616 overexpression was confirmed in malignant prostate tissues as opposed to benign prostate specimens. Stable miR-616 overexpression in LNCaP cells by a lentiviral-based approach stimulated AI prostate cancer cell proliferation in vitro whereas concomitantly reducing androgen-induced cell growth. More importantly, miR-616 overexpressing LNCaP cells overcame castration resistance as shown by an enhanced ability to proliferate in vivo after bilateral orchiectomy. Conversely, antagonizing miR-616 in AI prostate cancer cells yielded opposite effects. Microarray profiling and bioinformatics analysis identified the tissue factor pathway inhibitor TFPI-2 mRNA as a candidate downstream target of miR-616. In support of this candidacy, we documented interactions between miR-616 and the 3′UTR of TFPI-2 and determined TFPI-2 expression to be inversely correlated to miR-616 in a series of prostate cell lines and clinical specimens. Notably, reexpression of TFPI-2 in LNCaP cells with stable miR-616 overexpression rescued the AD phenotype, as shown by a restoration of androgen dependence and cell growth inhibition. Taken together, our findings define a functional involvement for miR-616 and TFPI-2 in the development and maintenance of androgen-independent prostate cancer. Cancer Res; 71(2); 583–92. ©2011 AACR.
Cytokines in chronic obstructive pulmonary disease
Authors: K.F. Chung
Journal: European Respiratory Journal (2001)

Chronic obstructive pulmonary disease (COPD) is characterized by chronic obstruction of expiratory flow affecting peripheral airways, associated with chronic bronchitis (mucus hypersecretion with goblet cell and submucosal gland hyperplasia) and emphysema (destruction of airway parenchyma), together with fibrosis and tissue damage, and inflammation of the small airways. Cytokines are extracellular signalling proteins. Increased levels of interleukin (IL)-6, IL-1beta, tumour necrosis factor-alpha (TNF-alpha) and IL-8 have been measured in sputum, with further increases during exacerbations, and the bronchiolar epithelium over-expresses monocyte chemotactic protein (MCP)-1 and IL-8. IL-8 can account for some chemotactic activity of sputum, and sputum IL-8 levels correlate with airway bacterial load and blood myeloperoxidase levels. The expression of chemokines such as regulated on activation, normal T-cell expressed and secreted (RANTES) may underlie the airway eosinophilia observed in some COPD patients. Cytokines may be involved in tissue remodelling. TNF-alpha and IL-1beta stimulate macrophages to produced matrix metalloproteinase-9 (MMP-9), and bronchial epithelial cells to produce extracellular matrix glycoproteins such as tenascin. Increased expression of transforming growth factor-beta (TGFbeta) and of epidermal growth factor (EGF) occurs in the epithelium and submucosal cells of patients with chronic bronchitis. TGFbeta and EGF activate proliferation of fibroblasts, while activation of the EGF receptor leads to mucin gene expression. The cytokine profile seen in chronic obstructive pulmonary disease is different from that observed in asthma. The role of these cytokines needs to be defined and there is a potential for anticytokine therapy in chronic obstructive pulmonary disease.
Polio immunisation in pregnancy.
Authors: J Twomey
Journal: BMJ (1977)

treatment of abscesses of different aetiology, with which we dealt in our second report.;We regard this omission as dangerous.Your preoccupation with a single chemo- therapeutic agent, effective only against strict anaerobes, is misleading, since we have demonstrated that aerobic and microaerophilic organisms predominate in cerebral abscesses.Of the patients in our study, 76 0 were infected only with microbes that were demonstrably resistant to metronidazole.Further, we remind you that lincomycin and chloramphenicol are effective against anaerobic bacteria and that they were used in the treatment of some abscesses in both series of cases discussed in the leading article.Carbenicillin, not used in either series, and fusidic acid also have some activity against anaerobic bacteria.The treatment of cerebral abscesses is primarily surgical and it remains so.Rapid and accurate location of the lesion followed by prompt evacuation of the pus and internal decompression continues to save lives.Factors other than the choice of antibiotics, such as measures taken against cerebral oedema, should be taken into account in any discussion of mortality.
A novel reflux inhibitor lesogaberan (AZD3355) as add-on treatment in patients with GORD with persistent reflux symptoms despite proton pump inhibitor therapy: a randomised placebo-controlled trial
Authors: G. E. Boeckxstaens, H. Beaumont, J. G. Hatlebakk, D. G. Silberg, K. Bjorck, M. Karlsson, H. Denison
Journal: Gut (2011)

<h3>Objective</h3> To evaluate the efficacy and tolerability of add-on treatment with lesogaberan (AZD3355), a novel reflux inhibitor, in patients with persistent gastro-oesophageal reflux disease (GORD) symptoms despite proton pump inhibitor (PPI) therapy. <h3>Methods</h3> A double-blind, placebo-controlled, randomised, parallel-group, multicentre phase IIA study was carried out in outpatient clinics. The study group comprised 244 adult patients with persistent GORD symptoms (heartburn and/or regurgitation) of at least mild intensity and for 3 days of 7 days before enrolment, despite ≥6 weeks of continuous PPI therapy. Patients received either lesogaberan (65 mg twice daily) or placebo in addition to PPI therapy for a period of 4 weeks. Symptom intensity, based on the Reflux Disease Questionnaire, was recorded twice daily. Treatment response (defined as at most one 24 h period with heartburn or regurgitation of not more than mild intensity during the last 7 days of treatment). Time to response, proportion of symptom-free days and measures of tolerability were also analysed. <h3>Results</h3> A total of 232 (114 lesogaberan- and 118 placebo-treated patients) of the 244 randomised patients were analysed for efficacy. Treatment with lesogaberan, compared with placebo, resulted in a significantly larger proportion of responders to treatment (16% vs 8% of patients; p=0.026) and cumulative proportion of responders over time (log-rank p=0.0195). Lesogaberan was well tolerated: adverse events of mostly mild to moderate intensity were reported in 45% of patients on lesogaberan and in 37% on placebo. <h3>Conclusions</h3> Lesogaberan add-on therapy to PPIs significantly improved heartburn and regurgitation symptoms; however, the proportion of responders was small. <h3>Clinical trial number</h3> NCT00394472.
Altered levels of Ets-1 transcription factor and matrix metalloproteinases in melanocytes from patients with vitiligo
Authors: R. Kumar, D. Parsad, A.J. Kanwar, D. Kaul
Journal: British Journal of Dermatology (2011)

Vitiligo is characterized by the loss of functional melanocytes from the epidermis. Repigmentation in vitiligo is initiated by activation, proliferation and migration of melanoblasts from the outer root sheath of hair follicles, or melanocytes from the border area of vitiligo lesions, into the depigmented epidermis. Cell migration plays a crucial role during repigmentation in vitiligo.To investigate the role of matrix metalloproteinases (MMPs) and their transcription factor Ets-1 in vitiligo.Skin biopsies were taken from 15 patients with vitiligo and six controls to culture melanocytes from clinically active perilesional and normal skin. Expression of MMP-1, MMP-2, MMP-9 and Ets-1 was examined by reverse transcriptase-polymerase chain reaction analysis. Expression of Ets-1 was also confirmed with Western blot analysis. Activity of MMP-2 and MMP-9 was assessed using gelatin zymography.The activity of MMP-2 and MMP-9 was significantly lower in patients with vitiligo compared with the controls. The expression of MMP-2 and MMP-9 was also significantly lower in patients with vitiligo. There was no expression of Ets-1 transcription factor at either the transcriptional or translational level in melanocytes cultured from patients with vitiligo.The absence of a basal level of expression of Ets-1 significantly decreases the expression and activity of MMP-2 and MMP-9. Significant decreases in MMP-2 and MMP-9 activity could possibly reduce the migration of melanocyte precursors (melanoblasts) from the outer root sheath of hair follicles or migration of melanocytes from the border of vitiligo lesions into clinically depigmented epidermis which is crucial to the repigmentation of vitiliginous skin.
Pitx2 confers left morphological, molecular, and functional identity to the sinus venosus myocardium
Authors: Grazia Ammirabile, Alessandra Tessari, Viviana Pignataro, Dorota Szumska, Fabio Sutera Sardo, Jiri Benes, Mariangela Balistreri, Shoumo Bhattacharya, David Sedmera, Marina Campione
Journal: Cardiovascular Research (2011)

The sinus venous myocardium, comprising the sinoatrial node (SAN) and sinus horns (SH), is a region subject to congenital malformations and cardiac arrhythmias. It differentiates from symmetric bilateral mesenchymal precursors, but morphological, molecular, and functional left/right differences are progressively established through development. The role of the laterality gene Pitx2 in this process is unknown. We aimed to elucidate the molecular events driving left/right patterning in the sinus venosus (SV) myocardium by using a myocardial Pitx2 knockout mouse.We generated a myocardial specific Pitx2 knockout model (cTP mice). cTP embryos present several features of Pitx2 null, including right atrial isomerism with bilateral SANs and symmetric atrial entrance of the systemic veins. By in situ hybridization and optical mapping analysis, we compared throughout development the molecular and functional properties of the SV myocardium in wt and mutant embryos. We observed that Pitx2 prevents the expansion of the left-SAN primordium at the onset of its differentiation into myocardium; Pitx2 promotes expansion of the left SH through development; Pitx2 dose-dependently represses the autorhythmic properties of the left SV myocardium at mid-gestation (E14.5); Pitx2 modulates late foetal gene expression at the left SH-derived superior caval vein.Pitx2 drives left/right patterning of the SV myocardium through multiple developmental steps. Overall, Pitx2 plays a crucial functional role by negatively modulating a nodal-type programme in the left SV myocardium.
Abstract 921: Small-molecule inhibitor BMS-777607 induces breast cancer cell polyploidy with increased resistance to cytotoxic chemotherapy agents.
Authors: Sharad Sharma, Jun-Yin Zeng, Chunmei Zhunag, Ruiwen Zhang, Ming-hai Wang
Journal: Cancer Research (2013)

Abstract The RON receptor tyrosine kinase is a therapeutic target for cancer treatment. Here we report therapeutic effect and phenotypic change of breast cancer cells in response to BMS-777607, a RON tyrosine kinase inhibitor. Treatment of breast cancer cells with BMS-777607 at therapeutic doses inhibited cancerous clonogenic growth but had only minimal effect on cell apoptosis. Significantly, BMS-777607 induced extensive polyploidy with multiple sets of chromosomes in cancer cells. This effect is independent of RON expression. Knockdown of RON in T-47D and ZR-75-1 cells by specific siRNA did not prevent polyploid formation. Immunofluorescent analysis of α-tubulin and γ-tubulin expression in polyploid cells revealed that BMS-777607 disrupts bi-polar spindle formation and causes multi-polar-like microtubule assembly. Also, both metaphase equatorial alignment and chromosomal segregation were absent in polyploid cells. These results suggest that cellular mitosis arrests at prophase/pro-metaphase and fails to undergo cytokinesis. By analyzing kinase-inhibitory profiles, aurora kinase B was identified as the target molecule inhibited by BMS-777607. In BMS-777607 treated cells, aurora kinase B was inhibited followed by protein degradation. Moreover, BMS-777607 inhibited Ser10 phosphorylation of histone H3, a substrate of aurora kinase B. Chemosensitivity analysis indicated the resistance of polyploid cells towards chemotherapeutics. Treatment with doxorubicin, bleomycin,cisplatin, methotrexate, and paclitaxel significantly increased cellular IC50 values. These findings highlight the theory that BMS-777607 acts as a multi-kinase inhibitor at therapeutic doses and is capable of inducing polyploidy by inhibiting aurora kinase B. Increased resistance of polyploid cells to cytotoxic chemotherapeutics could have a negative impact on targeted cancer therapy using BMS-777607. Citation Format: Sharad Sharma, Jun-Yin Zeng, Chunmei Zhunag, Ruiwen Zhang, Ming-hai Wang. Small-molecule inhibitor BMS-777607 induces breast cancer cell polyploidy with increased resistance to cytotoxic chemotherapy agents. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 921. doi:10.1158/1538-7445.AM2013-921
Long-Lived Antitumor CD8+ Lymphocytes for Adoptive Therapy Generated Using an Artificial Antigen-Presenting Cell
Authors: Marcus O. Butler, Jeng-Shin Lee, Sascha Ansén, Donna Neuberg, F. Stephen Hodi, Andrew P. Murray, Linda Drury, Alla Berezovskaya, Richard C. Mulligan, Lee M. Nadler, Naoto Hirano
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Antitumor lymphocytes can be generated ex vivo unencumbered by immunoregulation found in vivo. Adoptive transfer of these cells is a promising therapeutic modality that could establish long-term antitumor immunity. However, the widespread use of adoptive therapy has been hampered by the difficulty of consistently generating potent antitumor lymphocytes in a timely manner for every patient. To overcome this, we sought to establish a clinical grade culture system that can reproducibly generate antigen-specific cytotoxic T lymphocytes (CTL). Experimental Design: We created an off-the-shelf, standardized, and renewable artificial antigen-presenting cell (aAPC) line that coexpresses HLA class I, CD54, CD58, CD80, and the dendritic cell maturation marker CD83. We tested the ability of aAPC to generate tumor antigen-specific CTL under optimal culture conditions. The number, phenotype, effector function, and in vitro longevity of generated CTL were determined. Results: Stimulation of CD8+ T cells with peptide-pulsed aAPC generated large numbers of functional CTL that recognized a variety of tumor antigens. These CTLs, which possess a phenotype consistent with in vivo persistence, survived ex vivo for prolonged periods of time. Clinical grade aAPC33, produced under current Good Manufacturing Practices guidelines, generated sufficient numbers of CTL within a short period of time. These CTL specifically lysed a variety of melanoma tumor lines naturally expressing a target melanoma antigen. Furthermore, antitumor CTL were easily generated in all melanoma patients examined. Conclusions: With clinical grade aAPC33 in hand, we are now poised for clinical translation of ex vivo generated antitumor CTL for adoptive cell transfer.
Early Undifferentiated Connective Tissue Disease: III. Outcome and Prognostic Indicators in Early Scleroderma (Systemic Sclerosis)
Authors: Ken J. Bulpitt
Journal: Annals of Internal Medicine (1993)

Objective: To characterize the course of early scleroderma and to delineate prognostic factors present within 1 year of disease onset that might identify patients at high risk. Design: Inception cohort study. Setting: Ten university-based rheumatology clinics participating in the Cooperative Systematic Studies of Rheumatic Diseases Program. Patients: Forty-eight patients who had had scleroderma for less than 1 year. Measurements: Fifteen patients with early scleroderma who died were compared with those still living during the initial study period (1982 to 1992). Kaplan-Meier survival estimation and Cox proportional-hazards analysis were used to analyze baseline variables for their ability to predict survival duration. Results: Eight of 15 deaths were due to cardiac or pulmonary system failure. The estimated 5-year survival rate was 68%. Baseline factors that were the most predictive of a poor outcome included the presence of abnormal cardiopulmonary signs and abnormal urine sediment (pyuria, hematuria). Conclusion: Evidence of early cardiopulmonary disease, renal disease, inflammation, or immune activation may identify a subset of patients with scleroderma who will experience rapidly progressive disease and early death.
Identification of Genes with Differential Expression in Acquired Drug-Resistant Gastric Cancer Cells Using High-Density Oligonucleotide Microarrays
Authors: Hio Chung Kang, Il-Jin Kim, Jae-Hyun Park, Yong Shin, Ja-Lok Ku, Mi Sun Jung, Byong Chul Yoo, Hark Kyun Kim, Jae-Gahb Park
Journal: Clinical Cancer Research (2004)

Abstract Purpose: A major obstacle in chemotherapy is treatment failure due to anticancer drug resistance. The emergence of acquired resistance results from host factors and genetic or epigenetic changes in the cancer cells. The purpose of this study was to identify differentially expressed genes associated with acquisition of resistance in human gastric cancer cells. Experimental Design: We performed global gene expression analysis in the acquired drug-resistant gastric cancer cell lines to the commonly used drugs 5-fluorouracil, doxorubicin, and cisplatin using Affymetrix HG-U133A microarray. The gene expression patterns of 10 chemoresistant gastric cancer cell lines were compared with those of four parent cell lines using fold-change and Wilcoxon’s test for data analysis. Results: We identified over 250 genes differentially expressed in 5-fluorouracil-, cisplatin-, or doxorubicin-resistant gastric cancer cell lines. Our expression analysis also identified eight multidrug resistance candidate genes that were associated with resistance to two or more of the tested chemotherapeutic agents. Among these, midkine (MDK), a heparin-binding growth factor, was overexpressed in all drug-resistant cell lines, strongly suggesting that MDK might contribute to multidrug resistance in gastric cancer cells. Conclusions: Our investigation provides comprehensive gene information associated with acquired resistance to anticancer drugs in gastric cancer cells and a basis for additional functional studies.
PULMONARY FUNCTION STUDIES IN MITRAL STENOSIS BEFORE AND AFTER COMMISSUROTOMY
Authors: M. Henry Williams
Journal: Journal of Clinical Investigation (1953)

Decreased arterial oxygen saturation may occur in the blood of patients with mitral stenosis. This unsaturation might be due to impairment of diffusion of oxygen across the alveolar membrane or to impairment of ventilation-perfusion relationships in the lung. Both such abnormalities have been found in patients with mitral stenosis (1, 2, 3), but it is highly unlikely that appreciable unsaturation could occur during the breathing of room air as a result of impaired diffusion. This report deals with the pulmonary diffusing capacity and ventilation-perfusion relationships in nine patients with mitral stenosis before and after mitral commissurotomy.