tbuckley/cabot-search huggingface dataset:
Interleukin-6 Regulates Androgen Synthesis in Prostate Cancer Cells
Authors: Jae Yeon Chun, Nagalakshmi Nadiminty, Smitha Dutt, Wei Lou, Joy C. Yang, Hsing-Jien Kung, Christopher P. Evans, Allen C. Gao
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The standard systemic treatment for prostate cancer patients is androgen deprivation therapy. Although serum testosterone concentrations were significantly reduced after androgen deprivation therapy, levels of intraprostatic androgens are reproducibly measured at concentrations sufficient to activate androgen receptor and stimulate tumor growth, suggesting that prostate cancer cells may survive androgen deprivation therapies by increasing intracrine androgen synthesis within the prostate. However, factors that regulate de novo intracrine androgen synthesis have not been identified. Interleukin-6 (IL-6) has been implicated in the modulation of androgen receptor activation and growth and differentiation in prostate cancer. In this study, we investigate whether IL-6 regulates intraprostatic androgen synthesis in prostate cancer cells. Experimental Design: Quantitative reverse transcription-PCR and Western blotting were done to detect expression levels of steroidogenic enzymes. AKR1C3 promoter reporter was constructed and analyzed for IL-6–mediated AKR1C3 transcriptional activity. IL-6–mediated signaling was knocked down using small interfering RNA specific to IL-6 receptor and gp130, and the effect on AKR1C3 expression was examined. Intraprostatic androgen levels in prostate cancer cells in culture and in tumors were measured by an enzyme immunoassay (Testosterone EIA kit). Results: We found that IL-6 increases the expression of genes encoding many steroidogenic enzymes, including HSD3B2 and AKR1C3, involved in androgen biosynthesis. Down-regulation of IL-6 receptor and gp130 expression using specific small interfering RNA abolished IL-6–mediated AKR1C3 expression, suggesting that IL-6 signaling is responsible for AKR1C3 expression. IL-6 increases AKR1C3 promoter activity, indicating that the increase in IL-6–mediated AKR1C3 expression is in part at the transcriptional level. Treatment of IL-6 increased testosterone level in LNCaP cells. The tumor testosterone levels were detected at 378 pg/g in tumors generated from IL-6–overexpressing LNCaP-IL6+ cells inoculated orthotopically into the prostates of castrated male nude mice. Conclusions: These results suggest that IL-6 increases levels of intracrine androgens through enhanced expression of genes mediating androgen metabolism in prostate cancer cells.
A common mitochondrial DNA variant associated with left ventricular hypertrophy in type 2 diabetes mellitus
Authors: Yukihiko Momiyama, Michiko Furutani, Yoshihiko Suzuki, Shin-ichirou Imamura, Kazuhiro Hosokawa, Yoshihito Atsumi, Kempei Matsuoka, Mitsuru Kimura, Fumitaka Ohsuzu, Rumiko Matsuoka
Journal: Journal of the American College of Cardiology (2003)
Direct Detection of Bacterial Biofilms on the Middle-Ear Mucosa of Children With Chronic Otitis Media
Authors: Luanne Hall-Stoodley, Fen Ze Hu, Armin Gieseke, Laura Nistico, Duc Nguyen, Jay Hayes, Michael Forbes, David P. Greenberg, Bethany Dice, Amy Burrows, P. Ashley Wackym, Paul Stoodley, J. Christopher Post, Garth D. Ehrlich, Joseph E. Kerschner
Journal: JAMA (2006)

ContextChronic otitis media (OM) is a common pediatric infectious disease. Previous studies demonstrating that metabolically active bacteria exist in culture-negative pediatric middle-ear effusions and that experimental infection with Haemophilus influenzae in the chinchilla model of otitis media results in the formation of adherent mucosal biofilms suggest that chronic OM may result from a mucosal biofilm infection.ObjectiveTo test the hypothesis that chronic OM in humans is biofilm-related.Design, Setting, and PatientsMiddle-ear mucosa (MEM) biopsy specimens were obtained from 26 children (mean age, 2.5 [range, 0.5-14] years) undergoing tympanostomy tube placement for treatment of otitis media with effusion (OME) and recurrent OM and were analyzed using microbiological culture, polymerase chain reaction (PCR)-based diagnostics, direct microscopic examination, fluorescence in situ hybridization, and immunostaining. Uninfected (control) MEM specimens were obtained from 3 children and 5 adults undergoing cochlear implantation. Patients were enrolled between February 2004 and April 2005 from a single US tertiary referral otolaryngology practice.Main Outcome MeasuresConfocal laser scanning microscopic (CLSM) images were obtained from MEM biopsy specimens and were evaluated for biofilm morphology using generic stains and species-specific probes for H influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. Effusions, when present, were evaluated by PCR and culture for evidence of pathogen-specific nucleic acid sequences and bacterial growth, respectively.ResultsOf the 26 children undergoing tympanostomy tube placement, 13 (50%) had OME, 20 (77%) had recurrent OM, and 7 (27%) had both diagnoses; 27 of 52 (52%) of the ears had effusions, 24 of 24 effusions were PCR-positive for at least 1 OM pathogen, and 6 (22%) of 27 effusions were culture-positive for any pathogen. Mucosal biofilms were visualized by CLSM on 46 (92%) of 50 MEM specimens from children with OME and recurrent OM using generic and pathogen-specific probes. Biofilms were not observed on 8 control MEM specimens obtained from the patients undergoing cochlear implantation.ConclusionDirect detection of biofilms on MEM biopsy specimens from children with OME and recurrent OM supports the hypothesis that these chronic middle-ear disorders are biofilm-related.
Long-Term Weight Loss and Changes in Blood Pressure: Results of the Trials of Hypertension Prevention, Phase II
Authors: Victor J. Stevens
Journal: Annals of Internal Medicine (2001)

Weight loss appears to be an effective method for primary prevention of hypertension. However, the long-term effects of weight loss on blood pressure have not been extensively studied.To present detailed results from the weight loss arm of Trials of Hypertension Prevention (TOHP) II.Multicenter, randomized dinical trial testing the efficacy of lifestyle interventions for reducing blood pressure over 3 to 4 years. Participants in TOHP II were randomly assigned to one of four groups. This report focuses only on participants assigned to the weight loss (n = 595) and usual care control (n = 596) groups.Men and women 30 to 54 years of age who had nonmedicated diastolic blood pressure of 83 to 89 mm Hg and systolic blood pressure less than 140 mm Hg and were 110% to 165% of their ideal body weight at baseline.The weight loss intervention included a 3-year program of group meetings and individual counseling focused on dietary change, physical activity, and social supportWeight and blood pressure data were collected every 6 months by staff who were blinded to treatment assignmentMean weight change from baseline in the intervention group was -4.4 kg at 6 months, -2.0 kg at 18 months, and -0.2 kg at 36 months. Mean weight change in the control group at the same time points was 0.1, 0.7, and 1.8 kg. Blood pressure was significantly lower in the intervention group than in the control group at 6, 18, and 36 months. The risk ratio for hypertension in the intervention group was 0.58 (95% CI, 0.36 to 0.94) at 6 months, 0.78 (CI, 0.62 to 1.00) at 18 months, and 0.81 (CI, 0.70 to 0.95) at 36 months. In subgroup analyses, intervention participants who lost at least 4.5 kg at 6 months and maintained this weight reduction for the next 30 months had the greatest reduction in blood pressure and a relative risk for hypertension of 0.35 (CI, 0.20 to 0.59).Clinically significant long-term reductions in blood pressure and reduced risk for hypertension can be achieved with even modest weight loss.
SUICIDE AND SUICIDAL ATTEMPTS IN CHILDREN AND ADOLESCENTS
Authors: JAMES M. TOOLAN
Journal: American Journal of Psychiatry (1962)

A study of 102 children and adolescents who presented suicidal thoughts and actions is described. They represented approximately 11% of all admissions under 16 years of age. The majority were adolescent females diagnosed as character disorders, who were reacting to stressful situations. The majority came from chaotic homes where one or both parents were absent. It is our belief that suicidal thoughts and attempts are either ignored or undervalued in adolescents because of the erroneously accepted tenet that adolescents do not become depressed, ergo, suicide is unlikely. If we can successfully recognize the signs by which depression is manifested in younger persons we shall then be in a position to prevent many serious suicidal attempts.
Growth hormone as a risk for premature mortality in healthy subjects: data from the Paris prospective study
Authors: P. Maison, B. Balkau, D. Simon, P. Chanson, G. Rosselin, E. Eschwege
Journal: BMJ (1998)

between H pylori seropositivity and these vascular risk factors are largely due to chance, or selective publication, or both.The clinical implication is that if there is any relation between chronic H pylori infection and coronary heart disease, 1 then it is not likely to be dependent on the risk factors described here.
Strategies to Address Low Drug Solubility in Discovery and Development
Authors: Hywel D. Williams, Natalie L. Trevaskis, Susan A. Charman, Ravi M. Shanker, William N. Charman, Colin W. Pouton, Christopher J. H. Porter
Journal: Pharmacological Reviews (2013)

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.
Chronic obstructive pulmonary disease is characterized with suppressed lipoxin A4 and increased lipoxin receptor expression in lungs
Authors: Liga Balode, Darja Isajeva, Agnese Kislina, Sergejs Isajevs, Gunta Strazda, Normunds Jurka, Uldis Kopeika, Maris Bukovskis, Immanuels Taivans
Journal: European Respiratory Journal (2012)

Persistent inflammation of COPD could be influenced by disorders of arachidonic acid metabolism when synthesis of leukotrienes does not switch to lipoxin generation, and thereby promotes further inflammation process.  The aim: to estimate concentration of lipoxin A4 (LXA4), leukotriene B4 (LtB4), as well as expression of LXA4 receptor (FPRL-1) in induced sputum (IS) of COPD patients and healthy controls.  Materials and methods: 17 COPD patients and 7 healthy controls. LXA4 and LtB4 concentration in IS was assessed with ELISA. FPRL-1 expression was detected immunocytochemically.  Results: Concentration of LXA4 in COPD patient9s IS was decreased compared to healthy controls (0,909+/-0,43 ng/ml vs 2,198+/-1,189 ng/ml; p=0,009). Ratio LtB4/LXA4 in COPD patients was three times greater compared to healthy persons (8,884+/-2,789 vs 3,328+/-2,94; p=0,0071).  In COPD patient9s IS FPRL-1 positive polinuclear cells (PPC) were in greater amount compared to healthy controls (8,802+/-5,758 cells/mm2 vs 2,123+/-2,232 cells/mm2; p=0,0109). Also, in COPD patients a count of FPRL-1 positive mononuclear cells (PMC) in IS was increased compared to healthy controls (2,563+/-1,711 cells/mm2 vs 0,655+/-0,522 cells/mm2; p=0,0311).  Correlation between FPRL-1 PPC and LtB4 concentration in IS (r=0,628; p=0,0013).  Conclusions: Increased LtB4/LXA4 indicate a disbalance of inflammatory mediators in COPD patients that could be one of the causes of inflammation persistence. In turn, increased LXA4 receptor expression and its correlation with LtB4 concentration in COPD patients could denote mechanism of inflammation adaption that is initiated by LtB4.
Ovarian cancer progression is controlled by phenotypic changes in dendritic cells
Authors: Uciane K. Scarlett, Melanie R. Rutkowski, Adam M. Rauwerdink, Jennifer Fields, Ximena Escovar-Fadul, Jason Baird, Juan R. Cubillos-Ruiz, Ana C. Jacobs, Jorge L. Gonzalez, John Weaver, Steven Fiering, Jose R. Conejo-Garcia
Journal: The Journal of Experimental Medicine (2012)

We characterized the initiation and evolution of the immune response against a new inducible p53-dependent model of aggressive ovarian carcinoma that recapitulates the leukocyte infiltrates and cytokine milieu of advanced human tumors. Unlike other models that initiate tumors before the development of a mature immune system, we detect measurable anti-tumor immunity from very early stages, which is driven by infiltrating dendritic cells (DCs) and prevents steady tumor growth for prolonged periods. Coinciding with a phenotypic switch in expanding DC infiltrates, tumors aggressively progress to terminal disease in a comparatively short time. Notably, tumor cells remain immunogenic at advanced stages, but anti-tumor T cells become less responsive, whereas their enduring activity is abrogated by different microenvironmental immunosuppressive DCs. Correspondingly, depleting DCs early in the disease course accelerates tumor expansion, but DC depletion at advanced stages significantly delays aggressive malignant progression. Our results indicate that phenotypically divergent DCs drive both immunosurveillance and accelerated malignant growth. We provide experimental support for the cancer immunoediting hypothesis, but we also show that aggressive cancer progression after a comparatively long latency period is primarily driven by the mobilization of immunosuppressive microenvironmental leukocytes, rather than loss of tumor immunogenicity.
An <i>In Vivo</i> Functional Screen Identifies ST6GalNAc2 Sialyltransferase as a Breast Cancer Metastasis Suppressor
Authors: Nirupa Murugaesu, Marjan Iravani, Antoinette van Weverwijk, Aleksandar Ivetic, Damian A. Johnson, Aristotelis Antonopoulos, Antony Fearns, Mariam Jamal-Hanjani, David Sims, Kerry Fenwick, Costas Mitsopoulos, Qiong Gao, Nick Orr, Marketa Zvelebil, Stuart M. Haslam, Anne Dell, Helen Yarwood, Christopher J. Lord, Alan Ashworth, Clare M. Isacke
Journal: Cancer Discovery (2014)

To interrogate the complex mechanisms involved in the later stages of cancer metastasis, we designed a functional in vivo RNA interference (RNAi) screen combined with next-generation sequencing. Using this approach, we identified the sialyltransferase ST6GalNAc2 as a novel breast cancer metastasis suppressor. Mechanistically, ST6GalNAc2 silencing alters the profile of O-glycans on the tumor cell surface, facilitating binding of the soluble lectin galectin-3. This then enhances tumor cell retention and emboli formation at metastatic sites leading to increased metastatic burden, events that can be completely blocked by galectin-3 inhibition. Critically, elevated ST6GALNAC2, but not galectin-3, expression in estrogen receptor-negative breast cancers significantly correlates with reduced frequency of metastatic events and improved survival. These data demonstrate that the prometastatic role of galectin-3 is regulated by its ability to bind to the tumor cell surface and highlight the potential of monitoring ST6GalNAc2 expression to stratify patients with breast cancer for treatment with galectin-3 inhibitors.
Acute pneumonitis starting 2 hours after intramuscular gold administration in a patient with rheumatoid arthritis
Authors: A Hafejee
Journal: Annals of the Rheumatic Diseases (2004)

Gold salts have been used for the treatment of rheumatoid arthritis (RA) for over 50 years.1 Their use is limited by the incidence of adverse reactions, including pneumonitis. Most case reports describe pneumonitis developing after a cumulative dose of several hundred milligrams.2 Only four cases of lung disease have been reported with a cumulative dose of <100 mg.3

Here we report a case of gold pneumonitis, starting only 2 hours after the first maintenance dose of 20 mg was administered.

A 54 year old woman with RA had been followed up since 1984, her arthritis being well controlled with chloroquine. In 1997 her disease had flared up, and alternative disease modifying drugs were introduced—sulfasalazine, then methotrexate (both of …
Hypoxia differentially regulated CXCR4 and CXCR7 signaling in colon cancer
Authors: Benoît Romain, Muriel Hachet-Haas, Serge Rohr, Cécile Brigand, Jean-Luc Galzi, Marie-Pierre Gaub, Erwan Pencreach, Dominique Guenot
Journal: Molecular Cancer (2014)

HIF-1α and CXCR4/CXCL12 have crucial roles in the metastatic process of colorectal cancer. Our aim was to study the significance of targeting HIF-1α and the CXCR4/CXCL12 axis in colorectal cancer to prevent the dissemination process in vitro. We investigated CXCR4 and CXCR7 mRNA and protein expression in human colon carcinomas and the modulation of their expression by hypoxia and HIF-1α in colon cancer cell lines. The migration of tumor cells in a Boyden chamber was studied after CXCR4 inhibition with siRNA or the CXCR4/CXCL12 neutraligand, chalcone 4. Analysis of a cohort of colon polyps and chromosome-unstable carcinomas showed that the expression of CXCR4 and CXCR7 was similar to that of the normal mucosa in the polyps and early-stage carcinomas but significantly increased in late stage carcinomas. Our data demonstrate that hypoxia strongly induced the expression of CXCR4 transcript and protein at the cell membrane, both regulated by HIF-1α, whereas CXCR7 expression was independent of hypoxia. After transient hypoxia, CXCR4 levels remained stable at the cell membrane up to 48 hours. Furthermore, reducing CXCR4 expression impaired CXCL12-induced Akt phosphorylation, whereas Erk activation remained unchanged. In contrast, reducing CXCR7 expression did not affect Akt nor Erk activation. In the presence of CXCR4 or CXCR7 siRNAs, a significant reduction in cell migration occurred (37% and 17%, respectively). Although irinotecan inhibited cell migration by 20% (p <0.001), the irinotecan and chalcone 4 combination further increased inhibition to 40% (p <0.001). We demonstrated, for the first time, that hypoxia upregulated CXCR4 but not CXCR7 expression in tumor cells and that the CXCR4 receptor protein level remains high at the cell membrane when the tumor cells return to normoxia for up to 48 hours. In addition we showed the interest to inhibit the CXCR4 signaling by inhibiting both the HIF-1α and CXCR4/CXCL12 pathway. CXCR4 seems to be a relevant target because it is continuously expressed and functional both in normoxic and hypoxic conditions in tumor cells.
Intestinal Pseudo-Obstruction Syndrome
Authors: Sinn Anuras
Journal: Annual Review of Medicine (1988)

Intestinal pseudo-obstruction is a syndrome of many causes. Attempts must be made to determine the cause and the extent of the involvement of the gastrointestinal tract in each patient, because they will dictate the method of treatment for that patient. Family history must be taken from all primary chronic intestinal pseudo-obstruction patients. If it is positive, genetic counseling and proper medical management can be given to newly identified cases in the family.
<i>Yersinia pseudotuberculosis</i> disseminates directly from a replicating bacterial pool in the intestine
Authors: Penelope D. Barnes, Molly A. Bergman, Joan Mecsas, Ralph R. Isberg
Journal: The Journal of Experimental Medicine (2006)

Dissemination of Yersinia pseudotuberculosis within mice after oral inoculation was analyzed. Y. pseudotuberculosis translocated to organs such as the liver and spleen shortly after oral inoculation, but was quickly cleared. In contrast, a second temporally distinct bacterial translocation event resulted in successful hepatosplenic replication of the bacteria. Replicating pools of bacteria could be established in these organs in mouse mutants that lacked Peyer's patches. These animals frequently had sterile mesenteric lymph nodes, a finding consistent with translocation taking place independently of regional lymph node colonization. In further contradiction to accepted models for dissemination of enteropathogens, clonal analysis revealed that bacteria causing disease in the spleen and liver of C57BL/6J mice were derived from populations located outside the intestinal lymph nodes. Replication of bacteria in the intestine before translocation appeared critical for dissemination, as transient selective suppression by streptomycin of bacterial growth in the intestine delayed dissemination of Y. pseudotuberculosis. These results collectively indicate that hepatosplenic colonization appears intimately connected with the ability of Y. pseudotuberculosis to successfully establish replication in the intestinal lumen and does not result from ordered spread leading from the intestine to regional lymph nodes before dissemination.
FUNCTIONAL AND STRUCTURAL COMPLEXITY OF SIGNAL TRANSDUCTION VIA G-PROTEIN-COUPLED RECEPTORS
Authors: Thomas Gudermann, Torsten Schöneberg, Günter Schultz
Journal: Annual Review of Neuroscience (1997)

▪ Abstract A prerequisite for the maintenance of homeostasis in a living organism is fine-tuned communication between different cells. The majority of extracellular signaling molecules, such as hormones and neurotransmitters, interact with a three-protein transmembrane signaling system consisting of a receptor, a G protein, and an effector. These single components interact sequentially and reversibly. Considering that hundreds of G-protein-coupled receptors interact with a limited repertoire of G proteins, the question of coupling specificity is worth considering. G-protein-mediated signal transduction is a complex signaling network with diverging and converging transduction steps at each coupling interface. The recent realization that classical signaling pathways are intimately intertwined with growth-factor–signaling cascades adds another level of complexity. Elaborate studies have significantly enhanced our knowledge of the functional anatomy of G-protein-coupled receptors, and the concept has emerged that receptor function can be modulated with high specificity by coexpressed receptor fragments. These results may have significant clinical impact in the future.