tbuckley/cabot-search huggingface dataset:
Paracrine Activation of Hepatic CB1 Receptors by Stellate Cell-Derived Endocannabinoids Mediates Alcoholic Fatty Liver
Authors: Won-il Jeong, Douglas Osei-Hyiaman, Ogyi Park, Jie Liu, Sándor Bátkai, Partha Mukhopadhyay, Norio Horiguchi, Judith Harvey-White, Giovanni Marsicano, Beat Lutz, Bin Gao, George Kunos
Journal: Cell Metabolism (2008)
Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease
Authors: E. Sidransky, M.A. Nalls, J.O. Aasly, J. Aharon-Peretz, G. Annesi, E.R. Barbosa, A. Bar-Shira, D. Berg, J. Bras, A. Brice, C.-M. Chen, L.N. Clark, C. Condroyer, E.V. De Marco, A. Dürr, M.J. Eblan, S. Fahn, M.J. Farrer, H.-C. Fung, Z. Gan-Or, T. Gasser, R. Gershoni-Baruch, N. Giladi, A. Griffith, T. Gurevich, C. Januario, P. Kropp, A.E. Lang, G.-J. Lee-Chen, S. Lesage, K. Marder, I.F. Mata, A. Mirelman, J. Mitsui, I. Mizuta, G. Nicoletti, C. Oliveira, R. Ottman, A. Orr-Urtreger, L.V. Pereira, A. Quattrone, E. Rogaeva, A. Rolfs, H. Rosenbaum, R. Rozenberg, A. Samii, T. Samaddar, C. Schulte, M. Sharma, A. Singleton, M. Spitz, E.-K. Tan, N. Tayebi, T. Toda, A.R. Troiano, S. Tsuji, M. Wittstock, T.G. Wolfsberg, Y.-R. Wu, C.P. Zabetian, Y. Zhao, S.G. Ziegler
Journal: New England Journal of Medicine (2009)

Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease.Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers.All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations.Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.
Genetic variations in EGF and EGFR and glioblastoma outcome
Authors: S. Sjostrom, U. Andersson, Y. Liu, T. Brannstrom, H. Broholm, C. Johansen, H. Collatz-Laier, R. Henriksson, M. Bondy, B. Melin
Journal: Neuro-Oncology (2010)

Few prognostic factors have been associated with glioblastoma survival. We analyzed a complete tagging of the epidermal growth factor (EGF) and EGF receptor (EGFR) gene polymorphisms as potential prognostic factors. Thirty tagging single-nucleotide polymorphisms (SNPs) in EGF and 89 tagging SNPs in EGFR were analyzed for association with survival in 176 glioblastoma cases. Validation analyses were performed for 4 SNPs in a set of 638 glioblastoma patients recruited at The University of Texas M. D. Anderson Cancer Center (MDACC). Three hundred and seventy-four glioblastoma patients aged 50 years or older at diagnosis were subanalyzed to enrich for de novo arising glioblastoma. We found 7 SNPs in haplotype 4 in EGF that were associated with prognosis in glioblastoma patients. In EGFR, 4 of 89 SNPs were significantly associated with prognosis but judged as false positives. Four of the significantly associated EGF polymorphisms in haplotype block 4 were validated in a set from MDACC; however, none of the associations were clearly replicated. rs379644 had a hazard ratio (HR) of 1.19 (0.94–1.51) in the whole population with 18.6 months survival in the risk genotype compared with 24.5 in the reference category. As the median age differed slightly between the 2 study sets, the MDACC cases aged 50 or older at diagnosis were analyzed separately (rs379644, HR 1.32 [0.99–1.78]), which is marginally significant and partially validates our findings. This study is, to our knowledge, the first to perform a comprehensive tagging of the EGF and EGFR genes, and the data give some support that EGF polymorphisms might be associated with poor prognosis. Further confirmation in independent data sets of prospective studies is necessary to establish EGF as prognostic risk factor.
Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004)
Authors: T. Ruers, C. Punt, F. Van Coevorden, J.P.E.N. Pierie, I. Borel-Rinkes, J.A. Ledermann, G. Poston, W. Bechstein, M.A. Lentz, M. Mauer, E. Van Cutsem, M.P. Lutz, B. Nordlinger
Journal: Annals of Oncology (2012)
Tissue Doppler Echocardiographic Evidence of Reverse Remodeling and Improved Synchronicity by Simultaneously Delaying Regional Contraction After Biventricular Pacing Therapy in Heart Failure
Authors: Cheuk-Man Yu, Elaine Chau, John E. Sanderson, Katherine Fan, Man-Oi Tang, Wing-Hong Fung, Hong Lin, Shun-Ling Kong, Yui-Ming Lam, Michael R.S. Hill, Chu-Pak Lau
Journal: Circulation (2002)

Background — Biventricular pacing has been proposed to improve symptoms and exercise capacity in patients with advanced heart failure and wide electrocardiographic wave complexes. This study investigated the effect of biventricular pacing on reverse remodeling and the underlying mechanisms. Methods and Results — Twenty-five patients with NYHA class III to IV heart failure and electrocardiographic wave complex duration &gt;140 ms receiving biventricular pacing therapy were assessed serially up to 3 months after pacing and when pacing was withheld for 4 weeks. Tissue Doppler echocardiography was performed using a 6-basal, 6-mid segmental model to assess the time to peak sustained systolic contraction (T S ). There was significant improvement of ejection fraction, dP/dt, and myocardial performance index; decrease in mitral regurgitation, left ventricular (LV) end-diastolic (205±68 versus 168±67 mL, P &lt;0.01) and end-systolic volume (162±54 versus 122±42 mL, P &lt;0.01); and improved 6-minute hall-walk distance and quality of life score after pacing for 3 months. The mechanisms of benefits were as follows: (1) improved LV synchrony, as evident by homogeneous delay of T S to a timing close to the latest (usually the lateral) segment abolishing the intersegmental difference in T S and decreasing the standard deviation of T S within the left ventricle (37.7±10.9 versus 29.3±8.3 ms, P &lt;0.05); (2) improved interventricular synchrony; and (3) shortened isovolumic contraction time (122±57 versus 82±36 ms, P &lt;0.05) but increased diastolic filling time. These benefits are pacing dependent, because withholding the pacing resulted in varying speeds in the loss of cardiac improvements. Conclusions — Biventricular pacing reverses LV remodeling and improves cardiac function. Improvement of LV mechanical synchrony seems to be the predominant mechanism.
Genome-wide analysis reveals rapid and dynamic changes in miRNA and siRNA sequence and expression during ovule and fiber development in allotetraploid cotton (Gossypium hirsutum L.)
Authors: Mingxiong Pang, Andrew W Woodward, Vikram Agarwal, Xueying Guan, Misook Ha, Vanitharani Ramachandran, Xuemei Chen, Barbara A Triplett, David M Stelly, Z Jeffrey Chen
Journal: Genome biology (2009)
Stage-Specific Outcomes of Patients With Uterine Leiomyosarcoma: A Comparison of the International Federation of Gynecology and Obstetrics and American Joint Committee on Cancer Staging Systems
Authors: Oliver Zivanovic, Mario M. Leitao, Alexia Iasonos, Lindsay M. Jacks, Qin Zhou, Nadeem R. Abu-Rustum, Robert A. Soslow, Margrit M. Juretzka, Dennis S. Chi, Richard R. Barakat, Murray F. Brennan, Martee L. Hensley
Journal: Journal of Clinical Oncology (2009)

Uterine leiomyosarcoma (LMS) is staged by the modified International Federation of Gynecology and Obstetrics (FIGO) staging system for uterine cancer. We aimed to determine whether the American Joint Committee on Cancer (AJCC) soft tissue sarcoma (STS) staging system is more accurate in predicting progression-free survival (PFS) and overall survival (OS).Patients with uterine LMS who presented at our institution from 1982 to 2005 were staged retrospectively according to a modified FIGO staging system and the AJCC STS staging system. The predictive accuracy of the two staging systems was compared using concordance estimation.Two hundred nineteen patients had sufficient clinical and pathologic information to be staged under both systems; 132 patients were upstaged using the AJCC staging system, whereas only four were downstaged. Stage-specific PFS and OS rates for stages I, II, and III differed substantially between the two staging systems. In both systems, there was prognostic overlap between stages II and III. Thus, despite the marked stage-specific differences in 5-year PFS and OS rates for stages I, II, and III, both systems had similar concordance indices.Estimates of stage-specific PFS and OS for uterine LMS were altered substantially when using the AJCC versus FIGO staging system. Adjuvant treatment strategies should be tested in patients at substantial risk for disease progression and death. Neither the FIGO nor AJCC staging system is ideal for identifying such patients, suggesting a need for a uterine LMS-specific staging system to better target patients for trials of adjuvant therapies.
Rituximab Therapy for Refractory Scleritis
Authors: Eric B. Suhler, Lyndell L. Lim, Robert M. Beardsley, Tracy R. Giles, Sirichai Pasadhika, Shelly T. Lee, Alexandre de Saint Sardos, Nicholas J. Butler, Justine R. Smith, James T. Rosenbaum
Journal: Ophthalmology (2014)
Gastric mucosal secretion of interleukin-10: relations to histopathology, Helicobacter pylori status, and tumour necrosis factor-alpha secretion.
Authors: K Bodger, J I Wyatt, R V Heatley
Journal: Gut (1997)

BACKGROUND: Interleukin-10 (IL-10) is an 18 kDa peptide with a range of anti-inflammatory and immunosuppressive properties. AIM: To determine whether this cytokine is involved in gastric mucosal inflammation in Helicobacter pylori infection. METHODS: The production of IL-10 by antral mucosal biopsy specimens during short term in vitro culture was determined by measuring IL-10 content of supernatants by enzyme linked immunosorbent assay (ELISA). H pylori status was determined by serology and histology, with gastritis scored using the Sydney system. Tumour necrosis factor-alpha (TNF-alpha) content of supernatants was also determined in a subgroup of patients. RESULTS: IL-10 secretion was significantly greater in patients with H pylori associated chronic gastritis than in patients who were H pylori negative with normal mucosa/reactive changes, and those with H pylori negative chronic gastritis (p &lt; 0.01 and &lt; 0.05 respectively). There was a significant correlation overall between IL-10 secretion and chronic inflammation score (r = 0.40). Secretion of TNF-alpha, which was significantly higher in H pylori infected patients than uninfected patients with a normal mucosa (p &lt; 0.04), correlated with scores for chronic inflammation and activity (r = 0.39 and 0.38 respectively), but was only weakly correlated with IL-10 secretion (r = 0.22, NS). CONCLUSIONS: Gastric mucosal production of IL-10 and TNF-alpha are increased in chronic gastritis associated with H pylori infection, and mucosal cytokine secretion varies with important histopathological aspects of gastric inflammation. Whereas the secretion of IL-10 in H pylori infection may be protective, limiting tissue damage caused by inflammation, it may also contribute towards failure of the immune response to eliminate the organism.
Consumer receptive alternative preparations (CRAP)
Authors: L. Farrell
Journal: BMJ (2010)

Spleen tyrosine kinase (SYK) has an important role in immunoreceptor signaling, and SYK inhibition has accordingly attenuated immune-mediated injury in several <i>in vivo</i> models. However, the effect of SYK inhibition on autoantibody production remains unclear, and SYK inhibition has not been studied in an autoimmune model of renal disease. We, therefore, studied the effect of SYK inhibition in experimental autoimmune GN, a rodent model of antiglomerular basement membrane disease. We show glomerular SYK expression and activation by immunohistochemistry in both experimental and clinical disease, and we show that treatment with fostamatinib, a small molecule kinase inhibitor selective for SYK, completely prevents the induction of experimental autoimmune GN. In established experimental disease, introduction of fostamatinib treatment led to cessation of autoantibody production, reversal of renal injury, preservation of biochemical renal function, and complete protection from lung hemorrhage. B cell ELISpot and flow cytometric analysis suggest that short-term fostamatinib treatment inhibits the generation and activity of antigen-specific B cells without affecting overall B-cell survival. Additionally, fostamatinib inhibited proinflammatory cytokine production by nephritic glomeruli <i>ex vivo</i> and cultured bone marrow-derived macrophages <i>in vitro</i>, suggesting additional therapeutic effects independent of effects on autoantibody production that are likely related to inhibited Fc receptor signaling within macrophages in diseased glomeruli. Given these encouraging results in an <i>in vivo</i> model that is highly applicable to human disease, we believe clinical studies targeting SYK in GN are now warranted.
Receptor Binding Properties and Biologic Activity In Vitro of Biosynthetic Human Insulin
Authors: Linda M Keefer, Marie AgnÈs Piron, Pierre De Meyts
Journal: Diabetes Care (1981)

The interaction of biosynthetic human insulin with human cultured lymphocytes, human circulating erythrocytes, and isolated rat fat cells was examined. The binding of the biosynthetic insulin to human cells was identical to that of native human or pork insulins, with respect to affinity, kinetics of association and dissociation, negative cooperativity, and downregulation of lymphocyte receptors. The biosynthetic insulin also had equal potency in stimulating the incorporation of [3H]-glucose into the lipids of isolated rat fat cells. These data suggest that the structure of the biosynthetic insulin has been integrally reconstituted.
Overnight Glucose Control With an Automated, Unified Safety System in Children and Adolescents With Type 1 Diabetes at Diabetes Camp
Authors: Trang T. Ly, Marc D. Breton, Patrick Keith-Hynes, Daniel De Salvo, Paula Clinton, Kari Benassi, Benton Mize, Daniel Chernavvsky, Jéróme Place, Darrell M. Wilson, Boris P. Kovatchev, Bruce A. Buckingham
Journal: Diabetes Care (2014)

To determine the safety and efficacy of an automated unified safety system (USS) in providing overnight closed-loop (OCL) control in children and adolescents with type 1 diabetes attending diabetes summer camps.The Diabetes Assistant (DIAS) USS used the Dexcom G4 Platinum glucose sensor (Dexcom) and t:slim insulin pump (Tandem Diabetes Care). An initial inpatient study was completed for 12 participants to evaluate safety. For the main camp study, 20 participants with type 1 diabetes were randomized to either OCL or sensor-augmented therapy (control conditions) per night over the course of a 5- to 6-day diabetes camp.Subjects completed 54 OCL nights and 52 control nights. On an intention-to-treat basis, with glucose data analyzed regardless of system status, the median percent time in range, from 70-150 mg/dL, was 62% (29, 87) for OCL nights versus 55% (25, 80) for sensor-augmented pump therapy (P = 0.233). A per-protocol analysis allowed for assessment of algorithm performance. The median percent time in range, from 70-150 mg/dL, was 73% (50, 89) for OCL nights (n = 41) versus 52% (24, 83) for control conditions (n = 39) (P = 0.037). There was less time spent in the hypoglycemic range <50, <60, and <70 mg/dL during OCL compared with the control period (P = 0.019, P = 0.009, and P = 0.023, respectively).The DIAS USS algorithm is effective in improving time spent in range as well as reducing nocturnal hypoglycemia during the overnight period in children and adolescents with type 1 diabetes in a diabetes camp setting.
Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis
Authors: Lennart Greiff, Cecilia Ahlstrom-Emanuelsson, Gun Almqvist, Morgan Andersson, Anders Cervin, Jan Dolata, Leif Eriksson, Anders Kallen, Per Norlen, Inga-Lisa Sjolin, Henrik Widegren
Journal: European Respiratory Journal (2011)

Background:  The TLR7 agonist AZD8848 was developed as a treatment for allergic airway disease with the rationale of suppressing allergic (Th2-like) immune responses by triggering innate immune responses through TLRs. Intranasal administration of AZD8848 has demonstrated protection against allergen challenge in animal models of asthma and allergic rhinitis. AZD8848 is rapidly hydrolysed  in vivo  to a metabolite that is over 100-fold less active, to minimise the risk of undesirable systemic effects.   Methods:  Five once-weekly intranasal doses of AZD8848 (60 μg) were given in a randomised, placebo-controlled, double-blind, parallel group clinical trial to patients with allergic rhinitis (AR) off season (NCT00770003). Nasal symptoms were recorded during a 7-day nasal allergen challenge period starting 24 hours post last dose of AZD8848 to assess clinical effect. Biomarkers of TLR7 activation and plasma exudation were monitored in plasma or nasal lavage. Safety, tolerability and pharmacokinetics were also monitored.   Results:  Successful stimulation of TLR7 was indicated by reversible reductions in blood lymphocytes and increased plasma levels of IL-1Ra 24 hrs after administration of AZD8848. Some patients reported transient flu-like symptoms, as expected based on mechanism of action. AZD8848 reduced total nasal symptoms of allergic rhinitis as recorded 10 minutes after allergen challenge on days 5, 6, 7 and 8 after the last dose of AZD8848. Levels of α 2 -macroglobulin in nasal lavage were also reduced by AZD8848.   Conclusion:  Repeated intranasal administration of AZD8848 activated TLR7 and this resulted in a sustained reduction in responsiveness to allergen in patients with AR.
Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease
Authors: Hans Zischka, Josef Lichtmannegger, Sabine Schmitt, Nora Jägemann, Sabine Schulz, Daniela Wartini, Luise Jennen, Christian Rust, Nathanael Larochette, Lorenzo Galluzzi, Veronique Chajes, Nathan Bandow, Valérie S. Gilles, Alan A. DiSpirito, Irene Esposito, Martin Goettlicher, Karl H. Summer, Guido Kroemer
Journal: Journal of Clinical Investigation (2011)

Wilson disease (WD) is a rare hereditary condition that is caused by a genetic defect in the copper-transporting ATPase ATP7B that results in hepatic copper accumulation and lethal liver failure. The present study focuses on the structural mitochondrial alterations that precede clinical symptoms in the livers of rats lacking Atp7b, an animal model for WD. Liver mitochondria from these Atp7b–/– rats contained enlarged cristae and widened intermembrane spaces, which coincided with a massive mitochondrial accumulation of copper. These changes, however, preceded detectable deficits in oxidative phosphorylation and biochemical signs of oxidative damage, suggesting that the ultrastructural modifications were not the result of oxidative stress imposed by copper- dependent Fenton chemistry. In a cell-free system containing a reducing dithiol agent, isolated mitochondria exposed to copper underwent modifications that were closely related to those observed in vivo. In this cell-free system, copper induced thiol modifications of three abundant mitochondrial membrane proteins, and this correlated with reversible intramitochondrial membrane crosslinking, which was also observed in liver mitochondria from Atp7b–/– rats. In vivo, copper-chelating agents reversed mitochondrial accumulation of copper, as well as signs of intra-mitochondrial membrane crosslinking, thereby preserving the functional and structural integrity of mitochondria. Together, these findings suggest that the mitochondrion constitutes a pivotal target of copper in WD.
TSH-Lowering Effect of Metformin in Type 2 Diabetic Patients
Authors: Carlo Cappelli, Mario Rotondi, Ilenia Pirola, Barbara Agosti, Elena Gandossi, Umberto Valentini, Elvira De Martino, Antonio Cimino, Luca Chiovato, Enrico Agabiti-Rosei, Maurizio Castellano
Journal: Diabetes Care (2009)

OBJECTIVE To assess the interplay between metformin treatment and thyroid function in type 2 diabetic patients. RESEARCH DESIGN AND METHODS The acute and long-term effects of metformin on thyroid axis hormones were assessed in diabetic patients with primary hypothyroidism who were either untreated or treated with levothyroxine (L-T4), as well as in diabetic patients with normal thyroid function. RESULTS No acute changes were found in 11 patients with treated hypothyroidism. After 1 year of metformin administration, a significant thyrotropin (TSH) decrease (P &amp;lt; 0.001) was observed in diabetic subjects with hypothyroidism who were either treated (n = 29; from 2.37 ± 1.17 to 1.41 ± 1.21 mIU/l) or untreated (n = 18; 4.5 ± 0.37 vs. 2.93 ± 1.48) with L-T4, but not in 54 euthyroid subjects. No significant change in free T4 (FT4) was observed in any group. CONCLUSIONS Metformin administration influences TSH without change of FT4 in patients with type 2 diabetes and concomitant hypothyroidism. The need for reevaluation of thyroid function in these patients within 6–12 months after starting metformin is indicated.
Adenosine Diphosphate (ADP)-Ribosylation of the Guanosine Triphosphatase (GTPase) Rho in Resting Peripheral Blood Human T Lymphocytes Results in Pseudopodial Extension and the Inhibition of T Cell Activation
Authors: Darren G. Woodside, David K. Wooten, Bradley W. McIntyre
Journal: The Journal of Experimental Medicine (1998)

Scrape loading Clostridium botulinum C3 exoenzyme into primary peripheral blood human T lymphocytes (PB T cells) efficiently adenosine diphosphate (ADP)-ribosylates and thus inactivates the guanosine triphosphatase (GTPase) Rho. Basal adhesion of PB T cells to the β1 integrin substrate fibronectin (Fn) was not inhibited by inactivation of Rho, nor was upregulation of adhesion using phorbol myristate acetate (PMA; 10 ng/ml) or Mn++ (1 mM) affected. Whereas untreated PB T cells adherent to Fn remain spherical, C3-treated PB T cells extend F-actin–containing pseudopodia. Inactivation of Rho delayed the kinetics of PMA-dependent PB T cell homotypic aggregation, a process involving integrin αLβ2. Although C3 treatment of PB T cells did not prevent adhesion to the β1 integrin substrate Fn, it did inhibit β1 integrin/CD3-mediated costimulation of proliferation. Analysis of intracellular cytokine production at the single cell level demonstrated that ADP-ribosylation of Rho inhibited β1 integrin/ CD3 and CD28/CD3 costimulation of IL-2 production within 6 h of activation. Strikingly, IL-2 production induced by PMA and ionomycin was unaffected by C3 treatment. Thus, the GTPase Rho is a novel regulator of T lymphocyte cytoarchitecture, and functional Rho is required for very early events regulating costimulation of IL-2 production in PB T cells.