tbuckley/cabot-search huggingface dataset:
Sialyltransferase ST3Gal-IV controls CXCR2-mediated firm leukocyte arrest during inflammation
Authors: David Frommhold, Andreas Ludwig, M. Gabriele Bixel, Alexander Zarbock, Inna Babushkina, Melitta Weissinger, Sandra Cauwenberghs, Lesley G. Ellies, Jamey D. Marth, Annette G. Beck-Sickinger, Michael Sixt, Bärbel Lange-Sperandio, Alma Zernecke, Ernst Brandt, Christian Weber, Dietmar Vestweber, Klaus Ley, Markus Sperandio
Journal: The Journal of Experimental Medicine (2008)

Recent in vitro studies have suggested a role for sialylation in chemokine receptor binding to its ligand (Bannert, N., S. Craig, M. Farzan, D. Sogah, N.V. Santo, H. Choe, and J. Sodroski. 2001. J. Exp. Med. 194:1661–1673). This prompted us to investigate chemokine-induced leukocyte adhesion in inflamed cremaster muscle venules of α2,3 sialyltransferase (ST3Gal-IV)-deficient mice. We found a marked reduction in leukocyte adhesion to inflamed microvessels upon injection of the CXCR2 ligands CXCL1 (keratinocyte-derived chemokine) or CXCL8 (interleukin 8). In addition, extravasation of ST3Gal-IV−/− neutrophils into thioglycollate-pretreated peritoneal cavities was significantly decreased. In vitro assays revealed that CXCL8 binding to isolated ST3Gal-IV−/− neutrophils was markedly impaired. Furthermore, CXCL1-mediated adhesion of ST3Gal-IV−/− leukocytes at physiological flow conditions, as well as transendothelial migration of ST3Gal-IV−/− leukocytes in response to CXCL1, was significantly reduced. In human neutrophils, enzymatic desialylation decreased binding of CXCR2 ligands to the neutrophil surface and diminished neutrophil degranulation in response to these chemokines. In addition, binding of α2,3-linked sialic acid–specific Maackia amurensis lectin II to purified CXCR2 from neuraminidase-treated CXCR2-transfected HEK293 cells was markedly impaired. Collectively, we provide substantial evidence that sialylation by ST3Gal-IV significantly contributes to CXCR2-mediated leukocyte adhesion during inflammation in vivo.
Metabolic Syndrome, Independent of Its Components, Is a Risk Factor for Stroke and Death But Not for Coronary Heart Disease Among Hypertensive Patients in the ASCOT-BPLA
Authors: Ajay K. Gupta, Bjorn Dahlof, Peter S. Sever, Neil R. Poulter
Journal: Diabetes Care (2010)

OBJECTIVE To evaluate whether in hypertensive patients the risk of cardiovascular disease is greater in association with the metabolic syndrome (MetS) or the sum of its individual components. RESEARCH DESIGN AND METHODS Cox regression analysis models were developed to assess the influence of age, sex, ethnicity, and the individual components of MetS on risk associated with the MetS (using several definitions) of coronary outcomes, stroke, and all-cause mortality. RESULTS MetS was significantly associated with coronary outcomes, stroke, and all-cause mortality after adjusting for age, sex, and ethnicity. However, when the model was further adjusted for the individual components, MetS was associated with significantly increased risk of stroke (hazard ratio 1.34 [95% CI 1.07–1.68]) and all-cause mortality (1.35 [1.16–1.58]) but not coronary outcomes (fatal coronary heart disease plus nonfatal myocardial infarction 1.16 [0.95–1.43] and total coronary events 1.06 [0.91–1.24]). CONCLUSIONS MetS, independent of its individual components, is associated with increased risk of stroke and all-cause mortality but not coronary outcomes.
Genotype-phenotype relationships in the low-phospholipid-associated cholelithiasis syndrome: A study of 156 consecutive patients
Authors: Raoul Poupon, Olivier Rosmorduc, Pierre Yves Boëlle, Yves Chrétien, Christophe Corpechot, Olivier Chazouillères, Chantal Housset, Véronique Barbu
Journal: Hepatology (2013)

The low-phospholipid-associated cholelithiasis syndrome (LPAC; OMIM 171060) is a peculiar form of intrahepatic cholelithiasis occurring in young adults, associated with ABCB4/MDR3 gene sequence variations. Our aim was to determine the genotype-phenotype relationships in 156 consecutive patients with the criteria of LPAC syndrome. A variant was detected in 79 (61 missense and 18 truncating sequence variants), 63 being monoallelic. The clinical features (age at onset, high prevalence in women, frequency and severity of acute and chronic complications, intrahepatic cholestasis of pregnancy [ICP]) were similar in the patients with or without ABCB4 gene sequence variation. Truncating variations were associated with an earlier onset of symptoms both in women and men. Acute and chronic biliary complications were variant-independent. Half of the women who had pregnancy developed ICP. The frequency of ICP and fetal complications were similar in patients with missense and truncating variants.The LPAC syndrome is more frequent in women and highly associated with ICP. Half of the patients harbored missense or truncating variants of the ABCB4 gene. The characteristics of the patients without detectable variant are similar to those with variant, indicating that yet unexplored regions of the ABCB4 and other genes may be involved.
Warfarin plus Aspirin after Myocardial Infarction or the Acute Coronary Syndrome: Meta-Analysis with Estimates of Risk and Benefit
Authors: Michael B. Rothberg, Carmel Celestin, Louis D. Fiore, Elizabeth Lawler, James R. Cook
Journal: Annals of Internal Medicine (2005)

Background: After the acute coronary syndrome, adding warfarin to standard aspirin therapy decreases myocardial infarction and stroke but increases major bleeding. Purpose: To quantify the risks and benefits of warfarin therapy after the acute coronary syndrome. Data Sources: MEDLINE from 1990 to October 2004. Additional data were obtained from study authors. Clinical risk factors were used to classify hypothetical patients into cardiovascular and bleeding risk groups on the basis of published data. Study Selection: Randomized trials comparing intensive warfarin therapy (international normalized ratio > 2.0) plus aspirin with aspirin alone after the acute coronary syndrome. Data Extraction: Two reviewers independently selected studies and extracted data on study design; quality; and clinical outcomes, including myocardial infarction, stroke, revascularization, death, and major and minor bleeding. Rate ratios for outcomes were calculated and pooled by using the method of DerSimonian and Laird. Data Synthesis: Ten trials involving a total of 5938 patients (11 334 patient-years) met the study criteria. Compared with aspirin alone, warfarin plus aspirin was associated with a decrease in the annual rate of myocardial infarction (0.022 vs. 0.041; rate ratio, 0.56 [95% CI, 0.46 to 0.69]), ischemic stroke (0.004 vs. 0.008; rate ratio, 0.46 [CI, 0.27 to 0.77]), and revascularization (0.115 vs. 0.135; rate ratio, 0.80 [CI, 0.67 to 0.95]). Warfarin was associated with an increase in major bleeding (0.015 vs. 0.006; rate ratio, 2.5 [CI, 1.7 to 3.7]). Mortality did not differ. Limitations: Two large studies provided most of the data. Studies did not include coronary stenting, and results should not be applied to patients with stents. Relative risk reductions may not be consistent across risk groups. Conclusions: For patients with the acute coronary syndrome who are at low or intermediate risk for bleeding, the cardiovascular benefits of warfarin outweigh the bleeding risks.
Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival
Authors: Véronique Witko-Sarsat, Julie Mocek, Dikra Bouayad, Nicola Tamassia, Jean-Antoine Ribeil, Céline Candalh, Noélie Davezac, Nathalie Reuter, Luc Mouthon, Olivier Hermine, Magali Pederzoli-Ribeil, Marco A. Cassatella
Journal: The Journal of Experimental Medicine (2010)

Neutrophil apoptosis is a highly regulated process essential for inflammation resolution, the molecular mechanisms of which are only partially elucidated. In this study, we describe a survival pathway controlled by proliferating cell nuclear antigen (PCNA), a nuclear factor involved in DNA replication and repairing of proliferating cells. We show that mature neutrophils, despite their inability to proliferate, express high levels of PCNA exclusively in their cytosol and constitutively associated with procaspases, presumably to prevent their activation. Notably, cytosolic PCNA abundance decreased during apoptosis, and increased during in vitro and in vivo exposure to the survival factor granulocyte colony-stimulating factor (G-CSF). Peptides derived from the cyclin-dependent kinase inhibitor p21, which compete with procaspases to bind PCNA, triggered neutrophil apoptosis thus demonstrating that specific modification of PCNA protein interactions affects neutrophil survival. Furthermore, PCNA overexpression rendered neutrophil-differentiated PLB985 myeloid cells significantly more resistant to TNF-related apoptosis-inducing ligand– or gliotoxin-induced apoptosis. Conversely, a decrease in PCNA expression after PCNA small interfering RNA transfection sensitized these cells to apoptosis. Finally, a mutation in the PCNA interdomain-connecting loop, the binding site for many partners, significantly decreased the PCNA-mediated antiapoptotic effect. These results identify PCNA as a regulator of neutrophil lifespan, thereby highlighting a novel target to potentially modulate pathological inflammation.
Clinical significance of anti-GM-CSF antibodies in idiopathic pulmonary alveolar proteinosis
Authors: F-C Lin
Journal: Thorax (2006)

The role of anti-granulocyte-macrophage colony stimulating factor (GM-CSF) antibodies as a diagnostic marker in idiopathic pulmonary alveolar proteinosis (iPAP) remains unclear.Anti-GM-CSF antibodies were detected in blood and bronchoalveolar lavage fluid (BAL) fluid in 13 patients with iPAP. Three patients with secondary PAP, 35 with other pulmonary disorders, and 10 subjects without lung lesions acted as controls. Blood samples only were obtained from 30 healthy medical personnel. Anti-GM-CSF antibodies were detected using immunoblotting and measured semi-quantitatively by serial dilution or concentration methods. The relationship between antibodies and reported severity indicators for iPAP was analysed.Anti-GM-CSF antibodies could be detected in both blood and BAL fluid samples in 12 of 13 iPAP patients and were undetectable in blood and/or BAL fluid from the other subjects studied. BAL fluid levels of anti-GM-CSF antibodies were highly correlated with the severity indicators for iPAP, including serum lactate dehydrogenase (LDH) levels, arterial oxygen tension, alveolar-arterial oxygen tension difference, (AaPO2), lung carbon monoxide transfer factor, and some lesion scores on chest radiographs and computed tomographic scans. In contrast, blood anti-GM-CSF antibodies were not significantly correlated with the severity indicators evaluated. In addition, patients with iPAP who required subsequent therapeutic lung lavage had significantly higher values of serum LDH, AaPO2, and BAL fluid anti-GM-CSF antibodies, and significantly lower values of PaO2.In addition to serum LDH levels, PaO2 and AaPO2, BAL fluid levels of anti-GM-CSF antibodies might reflect disease severity in patients with iPAP and predict the need for subsequent therapeutic lung lavage. These findings may expand the role of anti-GM-CSF antibodies in iPAP.
Retropubic versus Transobturator Midurethral Slings for Stress Incontinence
Authors: Holly E. Richter, Michael E. Albo, Halina M. Zyczynski, Kimberly Kenton, Peggy A. Norton, Larry T. Sirls, Stephen R. Kraus, Toby C. Chai, Gary E. Lemack, Kimberly J. Dandreo, R. Edward Varner, Shawn Menefee, Chiara Ghetti, Linda Brubaker, Ingrid Nygaard, Salil Khandwala, Thomas A. Rozanski, Harry Johnson, Joseph Schaffer, Anne M. Stoddard, Robert L. Holley, Charles W. Nager, Pamela Moalli, Elizabeth Mueller, Amy M. Arisco, Marlene Corton, Sharon Tennstedt, T. Debuene Chang, E. Ann Gormley, Heather J. Litman
Journal: New England Journal of Medicine (2010)

Midurethral slings are increasingly used for the treatment of stress incontinence, but there are limited data comparing types of slings and associated complications.We performed a multicenter, randomized equivalence trial comparing outcomes with retropubic and transobturator midurethral slings in women with stress incontinence. The primary outcome was treatment success at 12 months according to both objective criteria (a negative stress test, a negative pad test, and no retreatment) and subjective criteria (self-reported absence of symptoms, no leakage episodes recorded, and no retreatment). The predetermined equivalence margin was +/-12 percentage points.A total of 597 women were randomly assigned to a study group; 565 (94.6%) completed the 12-month assessment. The rates of objectively assessed treatment success were 80.8% in the retropubic-sling group and 77.7% in the transobturator-sling group (3.0 percentage-point difference; 95% confidence interval [CI], -3.6 to 9.6). The rates of subjectively assessed success were 62.2% and 55.8%, respectively (6.4 percentage-point difference; 95% CI, -1.6 to 14.3). The rates of voiding dysfunction requiring surgery were 2.7% in those who received retropubic slings and 0% in those who received transobturator slings (P=0.004), and the respective rates of neurologic symptoms were 4.0% and 9.4% (P=0.01). There were no significant differences between groups in postoperative urge incontinence, satisfaction with the results of the procedure, or quality of life.The 12-month rates of objectively assessed success of treatment for stress incontinence with the retropubic and transobturator approaches met the prespecified criteria for equivalence; the rates of subjectively assessed success were similar between groups but did not meet the criteria for equivalence. Differences in the complications associated with the two procedures should be discussed with patients who are considering surgical treatment for incontinence. (ClinicalTrials.gov number, NCT00325039.)
Endogenous Circadian Rhythm of Pulmonary Function in Healthy Humans
Authors: CHRISTINA M. SPENGLER, STEVEN A. SHEA
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Numerous studies have demonstrated a diurnal rhythm in indices of pulmonary function in both healthy subjects and subjects with asthma, with minima occurring during the night. To determine whether such diurnal changes are caused by an endogenous circadian rhythm or by diurnal alterations in behavior or the environment, we measured indices of pulmonary function throughout a “constant routine” protocol designed to unmask underlying circadian rhythms. After two acclimation days in the laboratory, 10 healthy adults maintained relaxed wakefulness in a semirecumbent posture in a constant environment with low light (10 lux) for 41 h. Measurements of FEV1, FEVC, PEF, blood cortisol, and core body temperature (CBT) were performed every 2 h. Results of cosinor analysis of group data aligned to CBT circadian minimum revealed significant circadian variations in FEV1 and FEV1/FEVC, cortisol, and CBT, and lack of significant circadian variations in FEVC and PEF. The ranges (peak to trough) of mean circadian changes in spirometric variables were 2.0–3.2% of the mesor. The circadian minima of all variables occurred within the usual sleep period (although subjects remained awake). Because of differences in phase relationships between CBT and pulmonary function among subjects, the circadian rhythms within subjects were generally larger than the group average circadian changes, being significant for FEV1/FEVC in 5 of 10 subjects and for PEF in 6 of 10 subjects. Sleep deprivation (24 h) failed to cause a significant change in any pulmonary function variable (when controlled for circadian phase). Thus, endogenous circadian rhythms contribute to diurnal changes in pulmonary function in healthy subjects.
Possible involvement and the mechanisms of excess trans-fatty acid consumption in severe NAFLD in mice
Authors: Noriyuki Obara, Koji Fukushima, Yoshiyuki Ueno, Yuta Wakui, Osamu Kimura, Keiichi Tamai, Eiji Kakazu, Jun Inoue, Yasuteru Kondo, Norihiko Ogawa, Kenta Sato, Tsuyoshi Tsuduki, Kazuyuki Ishida, Tooru Shimosegawa
Journal: Journal of Hepatology (2010)
TR3 Modulates Platinum Resistance in Ovarian Cancer
Authors: Andrew J. Wilson, Annie Y. Liu, Joseph Roland, Oluwafunmilayo B. Adebayo, Sarah A. Fletcher, James C. Slaughter, Jeanette Saskowski, Marta A. Crispens, Howard W. Jones, Samuel James, Oluwole Fadare, Dineo Khabele
Journal: Cancer Research (2013)

In metastatic ovarian cancer, resistance to platinum chemotherapy is common. Although the orphan nuclear receptor TR3 (nur77/NR4A1) is implicated in mediating chemotherapy-induced apoptosis in cancer cells, its role in ovarian cancer has not been determined. In an ovarian cancer tissue microarray, TR3 protein expression was elevated in stage I tumors, but downregulated in a significant subset of metastatic tumors. Moreover, TR3 expression was significantly lower in platinum-resistant tumors in patients with metastatic disease, and low TR3 staining was associated with poorer overall and progression-free survival. We have identified a direct role for TR3 in cisplatin-induced apoptosis in ovarian cancer cells. Nucleus-to-cytoplasm translocation of TR3 was observed in cisplatin-sensitive (OVCAR8, OVCAR3, and A2780PAR) but not cisplatin-resistant (NCI/ADR-RES and A2780CP20) ovarian cancer cells. Immunofluorescent analyses showed clear overlap between TR3 and mitochondrial Hsp60 in cisplatin-treated cells, which was associated with cytochrome c release. Ovarian cancer cells with stable shRNA- or transient siRNA-mediated TR3 downregulation displayed substantial reduction in cisplatin effects on apoptotic markers and cell growth in vitro and in vivo. Mechanistic studies showed that the cisplatin-induced cytoplasmic TR3 translocation required for apoptosis induction was regulated by JNK activation and inhibition of Akt. Finally, cisplatin resistance was partially overcome by ectopic TR3 overexpression and by treatment with the JNK activator anisomycin and Akt pathway inhibitor, wortmannin. Our results suggest that disruption of TR3 activity, via downregulation or nuclear sequestration, likely contributes to platinum resistance in ovarian cancer. Moreover, we have described a treatment strategy aimed at overcoming platinum resistance by targeting TR3.
Risk Factors of Trastuzumab Induced Cardiotoxicity in Her2-Positive Early Breast Cancer
Authors: M.A. Sendur, S. Aksoy, H. Yorgun, N. Ozdemir, F.M. Yilmaz, O. Yazici, C. Zungun, K. Aytemir, N. Zengin, M.K. Altundag
Journal: Annals of Oncology (2014)
Prognostic and predictive factors in a randomized phase III trial comparing cisplatin–pemetrexed versus cisplatin–gemcitabine in advanced non-small-cell lung cancer
Authors: K.N. Syrigos, J. Vansteenkiste, P. Parikh, J. von Pawel, C. Manegold, R.G. Martins, L. Simms, K.P. Sugarman, C. Visseren-Grul, G.V. Scagliotti
Journal: Annals of Oncology (2009)
Modulation of Cerebral Arteriolar Diameter by Intraluminal Flow and Pressure
Authors: Al C. Ngai, H. Richard Winn
Journal: Circulation Research (1995)

We determined whether cerebral arterioles in vitro adjust their diameters in response to changes in intraluminal flow rate and pressure. Intracerebral arterioles (38- to 55-microns diameter) were isolated from Sprague-Dawley rats and cannulated with a perfusion system that permitted separate control of intraluminal pressure and flow rates. Increasing pressure at 0 flow, in 20 mm Hg steps from 20 to 100 mm Hg, resulted in myogenic constriction, which was greatest at 60 mm Hg (approximately 20%). Increasing flow rate at a constant pressure of 60 mm Hg elicited a biphasic response. At flow rates of up to 10 microL/min, the arterioles dilated by up to 14.5 +/- 2.2% of their control diameter. At higher (> 10 microL/min) flow rates, however, a progressive restoration of resting diameter was observed. Application of the nitric oxide synthase inhibitor NG-mono-methyl-L-arginine (L-NMMA, 0.1 mmol/L) caused a 15.4 +/- 1.7% decrease in control diameter (at 60 mm Hg, zero flow). Although L-NMMA did not affect the responses to increases in pressure or to vasodilators (adenosine and pH 6.8 buffer), it abolished the dilator responses to flow rate increases and to acetylcholine. In contrast, inhibition of prostaglandin synthesis by indomethacin (10 mumol/L) had no effect on flow-induced dilation. These results show that changes in intraluminal flow rates and pressure can independently influence cerebral arteriolar tone and suggest that the flow-induced dilator responses of cerebral arterioles are mediated by an arginine metabolite, such as nitric oxide.
Ki-67 is a strong predictor of central nervous system relapse in patients with mantle cell lymphoma (MCL)
Authors: D. Chihara, N. Asano, K. Ohmachi, M. Nishikori, M. Okamoto, M. Sawa, R. Sakai, Y. Okoshi, N. Tsukamoto, Y. Yakushijin, S. Nakamura, T. Kinoshita, M. Ogura, R. Suzuki
Journal: Annals of Oncology (2015)
Cloning of a group 3 allergen from <i>Blomia tropicalis</i> mites
Authors: N. Cheong, L. Yang, B. W. Lee, K. Y. Chua
Journal: Allergy (2003)

Blomia tropicalis is an important mite species in the tropics and subtropical regions of the world. It is well established that the allergen from this species of mite is one of the triggering factors for allergic asthma. The isolation and characterization of allergens in this mite species is desired to provide sensitive and specific reagents for diagnostic as well as therapeutic purposes.The SMART (Clontech Laboratories, Palo Alto, CA, USA) rapid amplification of complementary DNA ends (RACE cDNA amplification) method was used to isolate the putative Blo t 3 gene. Polymerase chain reactions (PCR) were performed in the presence of specific gene primers to obtain the full-length gene, and were confirmed by DNA sequencing. The putative gene was cloned into E. coli expression vector GST-4T-1 and expressed as a fusion protein with glutathione-S-transferase (GST). The allergenicity of the GST-Blo t 3 recombinant protein was evaluated by human IgE enzyme-linked immunoassay (ELISA) and skin pricks tests.The full length Blo t 3 gene had 1138 base pairs, including a 105-bp long 5' nontranslated region, an ATG start codon at positions 106-108, and a stop codon TAA at positions 904-906, with an open reading frame coding for a polypeptide of 266 amino acids. Protein analysis revealed that it was a serine protease that had a prepro-mature structure that shared high sequence homology with group 3 dust mite allergens. The predicted molecular weight of the matured protein was approximately 23.8 kD with a theoretical pI of 8.87. The frequency of IgE reactivity of the recombinant protein showed up to 50% of IgE reactivity with mite allergic subjects but IgE titer was generally low.We had isolated and fully characterized the cDNA encoding an important B. tropicalis allergen that was highly homologous to Group 3 dust mite allergens and we proposed that it should be designated as Blo t 3. Its clinical importance was implicated by the high frequency of IgE reactivity with allergic sera.
Influence of age and ABO blood groups in the precipitation of bleeding peptic ulcers
Authors: M. Berg
Journal: Gut (1969)

In a series of patients admitted to hospital for bleeding duodenal ulcer, the mean age at onset for patients belonging to blood group O was significantly lower than for those of blood group A. This raises the question of the significance of age and ABO blood group substances in increasing the liability to, or protecting against, bleeding.