tbuckley/cabot-search huggingface dataset:
Targeting the XIAP/caspase-7 complex selectively kills caspase-3–deficient malignancies
Authors: Yuan-Feng Lin, Tsung-Ching Lai, Chih-Kang Chang, Chi-Long Chen, Ming-Shyan Huang, Chih-Jen Yang, Hon-Ge Liu, Jhih-Jhong Dong, Yi-An Chou, Kuo-Hsun Teng, Shih-Hsun Chen, Wei-Ting Tian, Yi-Hua Jan, Michael Hsiao, Po-Huang Liang
Journal: Journal of Clinical Investigation (2013)

Caspase-3 downregulation (CASP3/DR) in tumors frequently confers resistance to cancer therapy and is significantly correlated with a poor prognosis in cancer patients. Because CASP3/DR cancer cells rely heavily on the activity of caspase-7 (CASP7) to initiate apoptosis, inhibition of activated CASP7 (p19/p12-CASP7) by X-linked inhibitor of apoptosis protein (XIAP) is a potential mechanism by which apoptosis is prevented in those cancer cells. Here, we identify the pocket surrounding the Cys246 residue of p19/p12-CASP7 as a target for the development of a protein-protein interaction (PPI) inhibitor of the XIAP:p19/p12-CASP7 complex. Interrupting this PPI directly triggered CASP7-dependent apoptotic signaling that bypassed the activation of the apical caspases and selectively killed CASP3/DR malignancies in vitro and in vivo without adverse side effects in nontumor cells. Importantly, CASP3/DR combined with p19/p12-CASP7 accumulation correlated with the aggressive evolution of clinical malignancies and a poor prognosis in cancer patients. Moreover, targeting of this PPI effectively killed cancer cells with multidrug resistance due to microRNA let-7a-1–mediated CASP3/DR and resensitized cancer cells to chemotherapy-induced apoptosis. These findings not only provide an opportunity to treat CASP3/DR malignancies by targeting the XIAP:p19/p12-CASP7 complex, but also elucidate the molecular mechanism underlying CASP3/DR in cancers.
Classification of Patients With Chronic Myeloid Leukemia on Basis of <i>BCR-ABL</i> Transcript Level at 3 Months Fails to Identify Patients With Low Organic Cation Transporter-1 Activity Destined to Have Poor Imatinib Response
Authors: Deborah L. White, Timothy P. Hughes
Journal: Journal of Clinical Oncology (2012)

considered when assessing a noncarrier or any other woman.As tests for modifier alleles enter clinical practice, risk assessment for all patients should improve.
Catecholamine-dependent cyclic adenosine monophosphate and renin in the dog kidney.
Authors: N Beck, K S Kim, B B Davies
Journal: Circulation Research (1975)

Lithium inhibits the catecholamine-dependent cyclic adenosine monophosphate (AMP) generation in the kidney but not the hemodynamic effects of beta-adrenergic stimulation. Therefore, the possible role of catecholamine-dependent cyclic AMP in the release of renin was investigated in lithium-treated dogs both in vivo and vitro. Lithium therapy had no measurable effect on the increase in plasma renin activity induced by an injection of isoproterenol (2.6 plus and minus 1.2 (SE) ng/hour in control dogs vs. 3.0 plus and minus 1.2 ng/hour in lithium-treated dogs, P greater than 0.05). However, lithium inhibited the isoproterenol-induced increase in urinary excretion of cyclic AMP in vivo (791 plus and minus 199 pmoles/min in control dogs vs. 123 plus and minus 129 pmoles/min in lithium-treated dogs, P less than 0.05) and the increase in cyclic AMP concentration in renal tissue in vitro (4.50 plus and minus 0.15 pmoles/ng wet tissue in control dogs vs. 0.34 plus and minus 0.26 pmoles/mg in lithium-treated dogs, P less than 0.01). The finding that, in the lithium-treated dogs, isoproternol increased plasma renin activity but not cyclic AMP generation in the kidney suggests that the increase in plasma renin activity observed after an injection of isoproterenol is probably not mediated through the beta-adrenergic stimulus-dependent cyclic AMP system in the kidney.
Prognostic role of epidermal growth factor receptor in stage III nonsmall cell lung cancer
Authors: T. Berghmans
Journal: European Respiratory Journal (2005)

New biological factors have not been extensively studied in stage III nonsmall cell lung cancer (NSCLC). The aim of the present retrospective study was to determine the role of epidermal growth factor receptor (EGF-R) as a prognostic factor in stage III NSCLC, in addition to the stage and other known clinical factors. Clinical characteristics were retrieved from the patients' charts. Membrane immunostaining for EGF-R was evaluated by three independent observers. The Cox multivariate model, including all variables with a p-value of <0.2 in univariate analysis, was used to assess the impact of clinical and biological factors on patients survival. Between January 1987 and July 2002, 99 assessable stage III NSCLC patients were included in the study. A total of 23 patients were positive for EGF-R (squamous 39.6% versus nonsquamous 7.8%). In multivariate analysis, only three factors were statistically significantly associated with survival: performance status, surgery and creatinine. In conclusion, good performance status, surgical resection and creatinine were found to be independent favourable prognostic factors for survival in a retrospective analysis of stage III nonsmall cell lung cancer, while epidermal growth factor receptor was not even in the univariate analysis.
Heart disease and rheumatoid arthritis: understanding the risks
Authors: S E Gabriel
Journal: Annals of the Rheumatic Diseases (2009)

Patients with rheumatoid arthritis (RA) are at increased risk of mortality compared with the general population. Evidence suggests that this increased mortality can largely be attributed to increased cardiovascular death. In a retrospective study of an inception cohort of RA patients in Rochester, MN, the contribution of traditional and RA-specific risk factors was investigated to this increased risk of cardiovascular morbidity and mortality. Several traditional cardiovascular risk factors were found to behave differently in RA patients. In addition, their associations with cardiovascular disease are weaker in RA patients as increased inflammation associated with RA also appears to contribute substantially to the increased cardiovascular mortality. Furthermore, the impact of disease-modifying antirheumatic drugs and biologicals on cardiovascular disease in RA patients is unclear. Cardiovascular risk scores for the general population may underestimate the risk for RA patients. Together with other studies that have demonstrated similar associations between RA and cardiovascular mortality, these data suggest that optimal control of cardiovascular risk factors is important, but not sufficient in RA patients. RA-specific cardiovascular risk prediction tools are needed, as well as clinical trials to assess the impact of therapies and tight control of inflammation in RA patients on cardiovascular outcomes and mortality.
C-Reactive Protein and Risk of Breast Cancer
Authors: S. M. Zhang, J. Lin, N. R. Cook, I-M. Lee, J. E. Manson, J. E. Buring, P. M. Ridker
Journal: JNCI Journal of the National Cancer Institute (2007)

Chronic inflammation is hypothesized to be associated with breast cancer development. However, data evaluating the association between C-reactive protein (CRP), a marker of systemic inflammation, and breast cancer risk are sparse. In the Women's Health Study, 27919 apparently healthy women aged 45 years and older who were free of cancer and cardiovascular disease had plasma CRP levels measured at baseline. During a mean of 10 years of follow-up, a total of 892 women developed invasive breast cancer. All statistical tests were two-sided. Baseline plasma CRP level was not statistically significantly associated with breast cancer risk (highest versus lowest quintile of CRP, multivariable hazard ratio = 0.90, 95% confidence interval = 0.71 to 1.16; Ptrend = .19; crude incidence rates: 273 versus 305 per 100000 person-years). Our data suggest that baseline plasma CRP levels are not associated with the increased risk of breast cancer in apparently healthy women.
Airway Distensibility in Adults with Asthma and Healthy Adults, Measured by Forced Oscillation Technique
Authors: Nathan J Brown, Cheryl M Salome, Norbert Berend, C William Thorpe, Gregory G King
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: Reduced airway distensibility in subjects with asthma compared with control subjects may be related to differences in lung elastic recoil and bronchomotor tone.Objectives: To examine the contribution of lung elastic recoil and bronchomotor tone to airway distensibility.Methods: We compared airway distensibility in 18 subjects with asthma with 19 control subjects before and after bronchodilator administration and, in a subgroup of 7 subjects with asthma and 8 control subjects, correlated distensibility with pressure–volume parameters.Measurements and Main Results: Distensibility was measured, using the forced oscillation technique, as the linear slope of conductance versus volume between total lung capacity (TLC) and 75% TLC and between 75% TLC and FRC. Transpulmonary pressure was recorded concurrently with distensibility, using an esophageal balloon. Pressure–conductance data were described using linear regressions and pressure–volume data were described using exponential equations. Subjects with asthma had lower baseline FEV1 (p = 0.0003) and conductance (p = 0.002) than did control subjects. Distensibility above 75% TLC was less in subjects with asthma than in control subjects (p < 0.0001), but there was no difference below 75% TLC. Bronchodilator administration did not alter distensibility despite increases in FEV1 (p = 0.0002) and conductance (p < 0.0001) in subjects with asthma, and conductance (p = 0.0004) in control subjects. After bronchodilator administration, subjects with asthma had reduced lung elastic recoil compared with control subjects (p = 0.03) and a reduced pressure–conductance slope (p = 0.01), but there were no correlations between pressure–volume characteristics and airway distensibility.Conclusions: Airway distensibility measured by forced oscillation technique is reduced in subjects with asthma compared with subjects without asthma, is not related to lung elastic recoil, and is unchanged by bronchodilator administration. Airway wall remodeling remains the most likely cause of reduced airway distensibility in asthma.
Generation of Anti-Hirudin Antibodies in Heparin-Induced Thrombocytopenic Patients Treated With R-Hirudin
Authors: Xuehong Song, Günter Huhle, Lianchun Wang, Ursula Hoffmann, Job Harenberg
Journal: Circulation (1999)

Hirudin is a small protein with strong thrombin inhibition that may be antigenic. The generation and disappearance of anti-hirudin antibodies were investigated in patients with heparin-induced thrombocytopenia who were treated with recombinant hirudin (r-hirudin) for >/=5 days.The IgA, IgE, IgG, and IgM isotypes of anti-hirudin antibodies were determined by ELISA before and after the start of r-hirudin therapy. A total of 56% of patients (13 of 23) developed >/=1 antibody isotype during therapy. No IgE antibodies were generated. IgA, IgG, and IgM antibodies were detected in 30% (7 of 23), 52% (12 of 23), and 17% (4 of 23) of patients, respectively. Four patients generated only IgG, 2 patients developed either IgM or IgG and IgM, 5 patients IgG and IgA, and 2 patients IgG, IgM, and IgA antibodies. IgM antibodies disappeared within 8 days of the cessation of r-hirudin. IgA and IgG antibodies disappeared within 1 year in all but 1 patient. Binding of purified IgG to r-hirudin in IgG antibody-positive patients (n=7) was demonstrated by competitive ELISA for r-hirudin. Of the 7 IgG antibody samples, 1 each neutralized or enhanced the anticoagulant activity of r-hirudin.R-hirudin may be antigenic in patients with heparin-induced thrombocytopenia. More comprehensive investigations will be required to determine the biological relevance of this and to establish the antibody-generation pattern in other diseases.
Predictive value of enzyme‐linked immunoassay platelet crossmatching for transfusion of platelet concentrates to alloimmunized recipients
Authors: Daniel B. Brubaker, James C. Duke, Maxine Romine
Journal: American Journal of Hematology (1987)

Some evidence has shown that platelet crossmatching is useful in multitransfused patients with hypoplastic bone marrows who are refractory to platelet therapy through alloimmunization. Several immunoglobulin binding assays other than enzyme-linked immunospecific assay (ELISA) have been studied previously. We performed 51 ELISA crossmatches on six patients receiving single donor platelets. One bone marrow transplant patient receiving 33 single donor HLA matched (related and unrelated) was also studied. Effectiveness of transfusion was closely monitored by patient evaluation and corrected platelet count increment (CCI) at 1-2 and 18-24 hours posttransfusion. We found the ELISA method very sensitive, specific, and predictive, 85, 96, and 95.6% respectively in the 51 crossmatches studied in six patients with either leukemia, solid tumors, or aplastic anemia. However, variation existed among individual recipients, with sensitivity ranging from 70-100%. The distribution of true positives and negatives and false positives and negatives in the 33 crossmatches performed in the bone marrow transplant patient differed significantly (chi 2 = 101.2; P less than 0.001) from single donor recipients. The specificity in the 51 crossmatches on the six patients was also significantly different from the 33 crossmatches performed in the bone marrow transplant (96 vs 74%). This suggests individual variation occurs as well as differences in diseases and bone marrow suppressive agents affecting platelet crossmatching.
One-Hour Postload Plasma Glucose Levels and Left Ventricular Mass in Hypertensive Patients
Authors: Angela Sciacqua, Sofia Miceli, Giuseppe Carullo, Laura Greco, Elena Succurro, Franco Arturi, Giorgio Sesti, Francesco Perticone
Journal: Diabetes Care (2011)

OBJECTIVE Left ventricular hypertrophy (LVH), an independent risk factor for cardiovascular (CV) morbidity and mortality, recognizes a multifactorial pathogenesis. A plasma glucose value ≥155 mg/dL for the 1-h postload plasma glucose during an oral glucose tolerance test (OGTT) identifies subjects with normal glucose tolerance (NGT) at high risk for type 2 diabetes. We addressed the question if glucose tolerance status, particularly 1-h postload plasma glucose levels, affects left ventricular mass (LVM) and cardiac geometry in essential hypertension. RESEARCH DESIGN AND METHODS We enrolled 767 never-treated hypertensive subjects, 393 women and 374 men (mean age 49.6 ± 8.5 years). All patients underwent an OGTT for the evaluation of glucose tolerance and standard echocardiography. LVM was calculated using the Devereux formula and normalized by body surface area (LVM index [LVMI]). Insulin sensitivity was assessed by the Matsuda index. Among all participants, 514 had NGT, 168 had impaired glucose tolerance (IGT), and 85 had type 2 diabetes. According to the 1-h postload plasma glucose cutoff point of 155 mg/dL, we divided normotolerant subjects into two groups: NGT &amp;lt;155 mg/dL (n = 356) and NGT ≥155 mg/dL (n = 158). RESULTS Subjects in the NGT ≥155 mg/dL group had worse insulin sensitivity than subjects in the NGT &amp;lt;155 mg/dL group (Matsuda index 63.9 vs. 88.8; P &amp;lt; 0.0001). Men with NGT ≥155 mg/dL had a higher LVMI than men with NGT &amp;lt;155 mg/dL (126.6 vs. 114.3 g/m2; P = 0.002) and a different LVH prevalence (41.1 vs. 25.8%; P &amp;lt; 0.0001). At multiple regression analysis, 1-h glucose resulted in the major determinant of LVMI in normotolerant, IGT, and diabetic groups. CONCLUSIONS These data show that NGT ≥155 mg/dL subjects, compared with NGT &amp;lt;155 mg/dL subjects, have a higher LVMI and a greater prevalence of LVH similar to that of IGT and diabetic patients.
Protein Kinase D1 Suppresses Epithelial-to-Mesenchymal Transition through Phosphorylation of Snail
Authors: Cheng Du, Chuanyou Zhang, Sazzad Hassan, Md. Helal Uddin Biswas, K.C. Balaji
Journal: Cancer Research (2010)

Cancer cells undergo epithelial-mesenchymal transition (EMT) as a program of increased invasion and metastasis during cancer progression. Here, we report that a novel regulator of EMT in cancer cells is protein kinase D1 (PKD1), which is downregulated in advanced prostate, breast, and gastric cancers. Ectopic reexpression of PKD1 in metastatic prostate cancer cells reversibly suppressed expression of mesenchyme-specific genes and increased epithelial markers such as E-cadherin, whereas small interfering RNA-mediated knockdown of PKD1 increased expression of mesenchyme markers. Further, PKD1 inhibited tumor growth and metastasis in a tumor xenograft model. PKD1 phosphorylates Ser(11) (S11) on transcription factor Snail, a master EMT regulator and repressor of E-cadherin expression, triggering nuclear export of Snail via 14-3-3σ binding. Snail S11 mutation causes acquisition of mesenchymal traits and expression of stem cell markers. Together, our results suggest that PKD1 functions as a tumor and metastasis suppressor, at least partly by regulating Snail-mediated EMT, and that loss of PKD1 may contribute to acquisition of an aggressive malignant phenotype.
Quantitative computed tomography–derived clusters: Redefining airway remodeling in asthmatic patients
Authors: Sumit Gupta, Ruth Hartley, Umair T. Khan, Amisha Singapuri, Beverly Hargadon, William Monteiro, Ian D. Pavord, Ana R. Sousa, Richard P. Marshall, Deepak Subramanian, David Parr, James J. Entwisle, Salman Siddiqui, Vimal Raj, Christopher E. Brightling
Journal: Journal of Allergy and Clinical Immunology (2013)

Asthma heterogeneity is multidimensional and requires additional tools to unravel its complexity. Computed tomography (CT)-assessed proximal airway remodeling and air trapping in asthmatic patients might provide new insights into underlying disease mechanisms.The aim of this study was to explore novel, quantitative, CT-determined asthma phenotypes.Sixty-five asthmatic patients and 30 healthy subjects underwent detailed clinical, physiologic characterization and quantitative CT analysis. Factor and cluster analysis techniques were used to determine 3 novel, quantitative, CT-based asthma phenotypes.Patients with severe and mild-to-moderate asthma demonstrated smaller mean right upper lobe apical segmental bronchus (RB1) lumen volume (LV) in comparison with healthy control subjects (272.3 mm(3) [SD, 112.6 mm(3)], 259.0 mm(3) [SD, 53.3 mm(3)], 366.4 mm(3) [SD, 195.3 mm(3)], respectively; P = .007) but no difference in RB1 wall volume (WV). Air trapping measured based on mean lung density expiratory/inspiratory ratio was greater in patients with severe and mild-to-moderate asthma compared with that seen in healthy control subjects (0.861 [SD, 0.05)], 0.866 [SD, 0.07], and 0.830 [SD, 0.06], respectively; P = .04). The fractal dimension of the segmented airway tree was less in asthmatic patients compared with that seen in control subjects (P = .007). Three novel, quantitative, CT-based asthma clusters were identified, all of which demonstrated air trapping. Cluster 1 demonstrates increased RB1 WV and RB1 LV but decreased RB1 percentage WV. On the contrary, cluster 3 subjects have the smallest RB1 WV and LV values but the highest RB1 percentage WV values. There is a lack of proximal airway remodeling in cluster 2 subjects.Quantitative CT analysis provides a new perspective in asthma phenotyping, which might prove useful in patient selection for novel therapies.
The role of the shared epitope in arthralgia with anti-cyclic citrullinated peptide antibodies (anti-CCP), and its effect on anti-CCP levels
Authors: W H Bos, J Ursum, N de Vries, G M Bartelds, G J Wolbink, M T Nurmohamed, I E van der Horst-Bruinsma, R J van de Stadt, J B A Crusius, P P Tak, B A C Dijkmans, D van Schaardenburg
Journal: Annals of the Rheumatic Diseases (2007)

Patients presenting with both arthralgia and antibodies to cyclic citrullinated peptide (anti-CCP) have an increased risk of developing rheumatoid arthritis (RA). To further characterise this patient group and shed more light on its relationship with clinically manifest early arthritis and established RA, an immunogenetic and serological analysis was performed.In a group of 111 patients with anti-CCP-positive arthralgia, anti-CCP levels and shared epitope (SE) status were determined. Data were compared with 125 and 128 patients with anti-CCP-positive early arthritis and established RA respectively.In patients with anti-CCP-positive arthralgia, the frequency of SE allele positivity is significantly lower when compared with anti-CCP-positive early arthritis and established RA (58% vs 80%, and 58% vs 92%, respectively, both p<0.001). Median anti-CCP levels were higher in the group of patients with SE-positive arthralgia compared with the group of patients with SE-negative arthralgia (p = 0.02). Median anti-CCP levels were similar in the groups of patients with SE-positive arthralgia and arthritis.The lower frequency of SE positivity in patients with arthralgia compared with patients with RA indicates that, compared with patients who were SE positive, patients who were SE negative as a group go through a longer arthralgia phase, or alternatively have a lower risk for transition from anti-CCP positive arthralgia to RA. Furthermore, the present results suggest that in this early stage the effect of the SE on disease risk may be mediated through higher anti-CCP levels.
P45 * LIPID SIGNATURES IN MENINGIOMA - METABOLIC CLUES TO REVEAL POTENTIAL THERAPEUTIC TARGETS
Authors: H. Hatchell, M. Hill, C. Lawrence, C. Rolph
Journal: Neuro-Oncology (2014)

INTRODUCTION: A preliminary study involving human meningioma tissue revealed unusually high levels of phosphatidylserine (PS) enriched with Docosahexaenoic acid (DHA) compared to other areas of the Brain. In study this phenomenon further in terms of cellular proliferation, metabolism and apoptosis, we have developed an oleaginous yeast paradigm. METHOD: Radiochemistry Yeast cells supplemented with DHA and/or serine incubated with [1-14C] acetate; rate of uptake determined. Lipids were extracted from the remainder of the cells and analysed on Silica Gel 60 high performance Thin-layer Chromatography followed by scintillation counting.High Performance Liquid Chromatography Lipid extracts taken at varying growth phases with DHA and/or serine supplementation for phospholipid molecular species analysis. RESULTS: To date, results show both serine and DHA alter carbon-flux within biosynthetic pathways, alongside increased cholesterol ester production and triacylglycerol accumulation. Interestingly, serine prematurely promotes the expression of a phospholipid profile typical to that seen in stationary phase at early exponential phase. CONCLUSION: Both serine and DHA alter carbon-flux within biosynthetic pathways associated with both acyl and isoprenoid metabolic routes which may further define cellular survival. Of interest is that both serine and DHA increased TAG accumulation during the stationary phase; a phenomenon seen in many human disease processes. In addition, both supplementations resulted in increased cholesterol ester production which could potentially initiate SREBP based signalling processes. Work presented will focus the effect serine and DHA has upon phospholipid profile and molecular species enrichment.