tbuckley/cabot-search huggingface dataset:
Uptake and Metabolism of Tritiated Norepinephrine in the Isolated Canine Heart
Authors: CHARLES A. CHIDSEY, RICHARD L. KAHLER, LESLIE L. KELMINSON, EUGENE BRAUNWALD
Journal: Circulation Research (1963)

Using an isolated canine heart preparation, the myocardial norepinephrine pool was labeled by injecting tritiated norepinephrine into the blood perfusing the heart. The extraction of the norepinephrine during a single circulation through the coronary bed was shown to be large (74%). As the isotopic material, which was extracted, was released spontaneously from the norepinephrine pool 75% to 88% of it was metabolized before appearing in the coronary venous blood. The chief metabolite has been demonstrated to be normetanephrine which accounts for 39.0% to 61.7% of the spontaneously released norepinephrine. Because of this it is concluded that catechol-O-methyl transferase is the enzyme primarily responsible for the metabolic inactivation of norepinephrine in the canine heart. When release was increased by the injection of tyramine, more of the released norepinephrine appeared unmetabolized in coronary venous blood, suggesting that the enzymatic process by which norepinephrine is inactivated may be limited. Therefore, the extent to which enzymatic processes contribute to the termination of augmented adrenergic activity in the heart may be questioned.
Death versus survival: functional interaction between the apoptotic and stress-inducible heat shock protein pathways
Authors: H. M. Beere
Journal: Journal of Clinical Investigation (2005)

Induction of heat shock proteins (Hsps) following cellular damage can prevent apoptosis induced by both the intrinsic and the extrinsic pathways. The intrinsic pathway is characterized by mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, apoptosome assembly, and caspase activation. Hsps promote cell survival by preventing MOMP or apoptosome formation as well as via regulation of Akt and JNK activities. Engagement of the TNF death receptors induces the extrinsic pathway that is characterized by Fas-associated death domain–dependent (FADD-dependent) caspase-8 activation or induction of NF-κB to promote cellular survival. Hsps can directly suppress proapoptotic signaling events or stabilizing elements of the NF-κB pathway to promote cellular survival.
Major Histocompatibility Complex Class I Viral Antigen Processing in the Secretory Pathway Defined by the <i>trans</i>-Golgi Network Protease Furin
Authors: Beatriz C. Gil-Torregrosa, A. Raúl Castaño, Margarita Del  Val
Journal: The Journal of Experimental Medicine (1998)

Classical antigen presentation by major histocompatibility complex class I molecules involves cytosolic processing of endogenously synthesized antigens by proteasomes and translocation of processed peptides into the endoplasmic reticulum (ER) by transporters associated with antigen presentation (TAP). Alternative pathways for processing of endogenous antigens, generally involving the ER, have been suggested but not fully proved. We analyzed the potential for class I presentation of proteolytic maturation of secretory antigens in the exocytic pathway. We found that hepatitis B (HB) virus secretory core protein HBe can efficiently deliver COOH-terminally located antigenic peptides for endogenous class I loading in the absence of TAP. Antigen presentation to specific cytotoxic T lymphocytes correlates with protein maturation at the COOH terminus, since modification of maturation and transport of HBe through the secretory pathway alters antigen presentation. Both maturation and a necessary processing step occur in the Golgi or post-Golgi compartment. Antigen presentation is independent of proteasome activity, but inhibitors of the trans-Golgi network resident protease furin inhibit both HBe maturation and antigen presentation. These results define a new antigen processing pathway located in the secretory route, with a central role for proteolytic maturation mediated by the subtilisin protease family member furin as an efficient source for antigen presentation.
Impact of Body Mass Index on the Efficacy of Endocrine Therapy in Premenopausal Patients With Breast Cancer: An Analysis of the Prospective ABCSG-12 Trial
Authors: Georg Pfeiler, Robert Königsberg, Christian Fesl, Brigitte Mlineritsch, Herbert Stoeger, Christian F. Singer, Sabine Pöstlberger, Guenther G. Steger, Michael Seifert, Peter Dubsky, Susanne Taucher, Hellmut Samonigg, Vesna Bjelic-Radisic, Richard Greil, Christian Marth, Michael Gnant
Journal: Journal of Clinical Oncology (2011)

Aromatase inhibitors are effective as endocrine treatment for patients with hormone receptor-positive breast cancer. According to the hypothesis that overweight patients have higher levels of aromatase enzyme availability, we investigated the influence of body mass index (BMI) on the efficacy of adjuvant endocrine therapy in premenopausal patients in a retrospective analysis of the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 12 trial.ABCSG-12 examined the efficacy of ovarian suppression using goserelin (3.6 mg subcutaneously every 28 days) in combination with anastrozole or tamoxifen with or without zoledronic acid (4 mg intravenously every 6 months) in premenopausal women with endocrine-responsive breast cancer. BMI was calculated using the prospectively collected data on patients' height and weight at study entry. BMI categories have been differentiated according to the WHO definition.Overweight patients treated with anastrozole had a 60% increase in the risk of disease recurrence (hazard ratio [HR], 1.60; 95% CI, 1.06 to 2.41; P = .02) and more than a doubling in the risk of death (HR, 2.14; 95% CI, 1.17 to 3.92; P = .01) compared with normal weight patients treated with anastrozole. In the overweight group, patients treated with anastrozole had a nearly 50% increase in the risk of disease recurrence (HR, 1.49; 95% CI, 0.93 to 2.38; P = .08) and a three-fold increase in the risk of death (HR, 3.03; 95% CI, 1.35 to 6.82; P = .004) compared with patients treated with tamoxifen.BMI significantly impacts on the efficacy of anastrozole plus goserelin in premenopausal patients with breast cancer, probably through influencing aromatase availability and/or ovarian suppression by goserelin.
Phase I Study of a Bispecific Ligand-Directed Toxin Targeting CD22 and CD19 (DT2219) for Refractory B-cell Malignancies
Authors: Veronika Bachanova, Arthur E. Frankel, Qing Cao, Dixie Lewis, Bartosz Grzywacz, Michael R. Verneris, Celalettin Ustun, Aleksandr Lazaryan, Brian McClune, Erica D. Warlick, Hagop Kantarjian, Daniel J. Weisdorf, Jeffrey S. Miller, Daniel A. Vallera
Journal: Clinical Cancer Research (2015)

Abstract Purpose: The novel bispecific ligand-directed toxin (BLT) DT2219 consists of a recombinant fusion between the catalytic and translocation enhancing domain of diphtheria toxin (DT) and bispecific single-chain variable fragments (scFV) of antibodies targeting human CD19 and CD22. We conducted a phase I dose-escalation study to assess the safety, maximum tolerated dose, and preliminary efficacy of DT2219 in patients with relapsed/refractory B-cell lymphoma or leukemia. Experimental Design: DT2219 was administered intravenously over 2 hours every other day for 4 total doses. Dose was escalated from 0.5 μg/kg/day to 80 μg/kg/day in nine dose cohorts until a dose-limiting toxicity (DLT) was observed. Results: Twenty-five patients with mature or precursor B-cell lymphoid malignancies expressing CD19 and/or CD22 enrolled to the study. Patients received median 3 prior lines of chemotherapy and 8 failed hematopoietic transplantation. All patients received a single course of DT2219; one patient was retreated. The most common adverse events, including weight gain, low albumin, transaminitis, and fever were transient grade 1–2 and occurred in patients in higher dose cohorts (≥40 μg/kg/day). Two subjects experienced DLT at dose levels 40 and 60 μg/kg. Durable objective responses occurred in 2 patients; one was complete remission after 2 cycles. Correlative studies showed a surprisingly low incidence of neutralizing antibody (30%). Conclusions: We have determined the safety of a novel immunotoxin DT2219 and established its biologically active dose between 40 and 80 μg/kg/day ×4. A phase II study exploring repetitive courses of DT2219 is planned. Clin Cancer Res; 21(6); 1267–72. ©2015 AACR.
The Prevalence of the Metabolic Syndrome Among Arab Americans
Authors: Linda A. Jaber, Morton B. Brown, Adnan Hammad, Qian Zhu, William H. Herman
Journal: Diabetes Care (2004)

To estimate the prevalence of the metabolic syndrome in Arab Americans by age, sex, and BMI and to examine the association between insulin resistance and each of the components of the metabolic syndrome.We studied a representative, cross-sectional, population-based sample of 542 Arab Americans aged 20-75 years. The metabolic syndrome was defined by Adult Treatment Panel III (ATP III) and World Health Organization (WHO) diagnostic criteria. Insulin resistance was estimated by homeostasis model assessment (HOMA-IR).The age-adjusted prevalence of the metabolic syndrome was 23% (95% CI 19-26%) by the ATP III definition and 28% (24-32%) by the WHO definition. Although the prevalence increased significantly with age and BMI in both sexes by both definitions, differences in estimates were noted. With ATP III, the age-specific rates were similar for men and women aged 20-49 years but were significantly higher for women aged >/=50 years. With WHO, rates were higher for men than women aged 20-49 years and similar for those aged >/=50 years. The most common component of the metabolic syndrome in men and women was low HDL cholesterol with the ATP III and the presence of glucose intolerance and HOMA-IR with the WHO. Strong associations between HOMA-IR and individual components of the metabolic syndrome were observed. After fitting a model with HOMA-IR as the outcome, waist circumference, triglyceride level, and fasting plasma glucose level were significantly associated with HOMA-IR.The metabolic syndrome is common among Arab Americans and is related to modifiable risk factors.
The phosphoinositide-binding protein p40<i>phox</i> activates the NADPH oxidase during FcγIIA receptor–induced phagocytosis
Authors: Chang-Il Suh, Natalie D. Stull, Xing Jun Li, Wei Tian, Marianne O. Price, Sergio Grinstein, Michael B. Yaffe, Simon Atkinson, Mary C. Dinauer
Journal: The Journal of Experimental Medicine (2006)

Superoxide produced by the phagocyte reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is essential for host defense. Enzyme activation requires translocation of p67phox, p47phox, and Rac-GTP to flavocytochrome b558 in phagocyte membranes. To examine the regulation of phagocytosis-induced superoxide production, flavocytochrome b558, p47phox, p67phox, and the FcγIIA receptor were expressed from stable transgenes in COS7 cells. The resulting COSphoxFcγR cells produce high levels of superoxide when stimulated with phorbol ester and efficiently ingest immunoglobulin (Ig)G-coated erythrocytes, but phagocytosis did not activate the NADPH oxidase. COS7 cells lack p40phox, whose role in the NADPH oxidase is poorly understood. p40phox contains SH3 and phagocyte oxidase and Bem1p (PB1) domains that can mediate binding to p47phox and p67phox, respectively, along with a PX domain that binds to phosphatidylinositol-3-phosphate (PI(3)P), which is generated in phagosomal membranes. Expression of p40phox was sufficient to activate superoxide production in COSphoxFcγR phagosomes. FcγIIA-stimulated NADPH oxidase activity was abrogated by point mutations in p40phox that disrupt PI(3)P binding, or by simultaneous mutations in the SH3 and PB1 domains. Consistent with an essential role for PI(3)P in regulating the oxidase complex, phagosome NADPH oxidase activation in primary macrophages ingesting IgG-coated beads was inhibited by phosphatidylinositol 3 kinase inhibitors to a much greater extent than phagocytosis itself. Hence, this study identifies a role for p40phox and PI(3)P in coupling FcγR-mediated phagocytosis to activation of the NADPH oxidase.
809 SUSTAINED VIROLOGICAL RESPONSE IS ASSOCIATED WITH ERADICATION OF HEPATITIS C VIRUS AND DECREASE IN ANTI-HCV TITER IN PATIENTS TREATED FOR CHRONIC HEPATITIS C
Authors: M. Martinot-Peignoux, S. Maylin, N. Boyer, A.C. Cardoso, M.P. Ripault, N. Giuily, C. Castelnau, M. Pouteau, P. Bedossa, P. Marcellin
Journal: Journal of Hepatology (2008)
Pulmonary and extrapulmonary acute respiratory distress syndrome are different
Authors: P. Pelosi, D. D'Onofrio, D. Chiumello, S. Paolo, G. Chiara, V.L. Capelozzi, C.S.V. Barbas, M. Chiaranda, L. Gattinoni
Journal: European Respiratory Journal (2003)

Acute respiratory distress syndrome (ARDS) can be derived from two pathogenetic pathways: a direct insult on lung cells (pulmonary ARDS (ARDSp)) or indirectly (extrapulmonary ARDS (ARDSexp)). This review reports and discusses differences in biochemical activation, histology, morphological aspects, respiratory mechanics and response to different ventilatory strategies between ARDSp and ARDSexp. In ARDSp the direct insult primarily affects the alveolar epithelium with a local alveolar inflammatory response while in ARDSexp the indirect insult affects the vascular endothelium by inflammatory mediators through the bloodstream. Radiological pattern in ARDSp is characterised by a prevalent alveolar consolidation while the ARDSexp by a prevalent ground-glass opacification. In ARDSp the lung elastance, while in ARDSexp the chest wall and intra-abdominal chest elastance are increased. The effects of positive end-expiratory pressure, recruitment manoeuvres and prone position are clearly greater in ARDSexp. Although these two types of acute respiratory distress syndrome have different pathogenic pathways, morphological aspects, respiratory mechanics, and different response to ventilatory strategies, at the present, is still not clear, if this distinction can really ameliorate the outcome.
Bmi-1 Is a Novel Molecular Marker of Nasopharyngeal Carcinoma Progression and Immortalizes Primary Human Nasopharyngeal Epithelial Cells
Authors: Li-Bing Song, Mu-Sheng Zeng, Wen-Ting Liao, Ling Zhang, Hao-Yuan Mo, Wan-Li Liu, Jian-Yong Shao, Qiu-Liang Wu, Man-Zhi Li, Yun-Fei Xia, Li-Wu Fu, Wen-Lin Huang, Goberdhan P. Dimri, Vimla Band, Yi-Xin Zeng
Journal: Cancer Research (2006)

The Bmi-1 oncoprotein regulates proliferation and oncogenesis in human cells. Its overexpression leads to senescence bypass in human fibroblasts and immortalization of human mammary epithelial cells. In this study, we report that compared with normal nasopharyngeal epithelial cells (NPEC), Bmi-1 is overexpressed in nasopharyngeal carcinoma cell lines. Importantly, Bmi-1 was also found to be overexpressed in 29 of 75 nasopharyngeal carcinoma tumors (38.7%) by immunohistochemical analysis. In contrast to nasopharyngeal carcinoma, there was no detectable expression of Bmi-1 in noncancerous nasopharyngeal epithelium. Moreover, high Bmi-1 expression positively correlated with poor prognosis of nasopharyngeal carcinoma patients. We also report that the overexpression of Bmi-1 leads to bypass of senescence and immortalization of NPECs, which normally express p16(INK4a) and exhibit finite replicative life span. Overexpression of Bmi-1 in NPECs led to the induction of human telomerase reverse transcriptase activity and reduction of p16(INK4a) expression. Mutational analysis of Bmi-1 showed that both RING finger and helix-turn-helix domains of it are required for immortalization of NPECs. Our findings suggest that Bmi-1 plays an important role in the development and progression of nasopharyngeal carcinoma, and that Bmi-1 is a valuable marker for assessing the prognosis of nasopharyngeal carcinoma patients. Furthermore, this study provides the first cellular proto-oncogene immortalized nasopharyngeal epithelial cell line, which may serve as a cell model system for studying the mechanisms involved in the tumorigenesis of nasopharyngeal carcinoma.
Association of Achieved Dialysis Dose with Mortality in the Hemodialysis Study
Authors: Tom Greene, John Daugirdas, Thomas Depner, Michael Allon, Gerald Beck, Cameron Chumlea, James Delmez, Frank Gotch, John W. Kusek, Nathan Levin, William Owen, Gerald Schulman, Robert Star, Robert Toto, Garabed Eknoyan
Journal: Journal of the American Society of Nephrology (2005)

In the intention-to-treat analysis of the Hemodialysis Study, all-cause mortality did not differ significantly between the high versus standard hemodialysis dose groups. The association of mortality with delivered dose within each of the two randomized treatment groups was examined, and implications for observational studies were considered. Time-dependent Cox regression was used to relate the relative risk (RR) for mortality to the running mean of the achieved equilibrated Kt/V (eKt/V) over the preceding 4 mo. eKt/V was categorized by quintiles within each dose group. Analyses were controlled for case-mix factors and baseline anthropometric volume. Within each randomized dose group, mortality was elevated markedly when achieved eKt/V was in the lowest quintile (RR, 1.93; 95% confidence interval [CI], 1.40 to 2.66; P < 0.0001 in the standard-dose group; RR, 2.04; 95% CI, 1.50 to 2.76; P < 0.0001 in the high-dose group; RR relative to the middle quintiles). The mortality rate in the lowest eKt/V quintile of the high-dose group was higher than in the full standard-dose group (RR, 1.59; 95% CI, 1.29 to 1.96; P < 0.0001). Each 0.1 eKt/V unit below the group median was associated with a 58% higher mortality in the standard-dose group (P < 0.001) and a 37% higher mortality in the high-dose group (P < 0.001). The magnitude of these dose-mortality effects was seven- to 12-fold higher than the upper limit of the 95% CI from the intention-to-treat analysis. The effects were attenuated in lagged analyses but did not disappear. When dialysis dose is targeted closely, as under the controlled conditions of the Hemodialysis Study, patients with the lowest achieved dose relative to their target dose experience markedly increased mortality, to a degree that is not compatible with a biologic effect of dose. The possibility of similar (albeit smaller) biases should be considered when analyzing observational data sets relating mortality to achieved dose of dialysis.
An fMRI Stroop Task Study of Ventromedial Prefrontal Cortical Function in Pathological Gamblers
Authors: Marc N. Potenza, Hoi-Chung Leung, Hilary P. Blumberg, Bradley S. Peterson, Robert K. Fulbright, Cheryl M. Lacadie, Pawel Skudlarski, John C. Gore
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Function of the ventromedial prefrontal cortex has been implicated in impulse control. The authors used the Stroop paradigm to test attention and response inhibition during the presentation of congruent and incongruent stimuli in male pathological gamblers and a group of comparison subjects. METHOD: Event-related functional magnetic resonance imaging was used to examine ventromedial prefrontal cortex function during Stroop performance. RESULTS: In response to infrequent incongruent stimuli, pathological gamblers demonstrated decreased activity in the left ventromedial prefrontal cortex relative to the comparison subjects. Both groups demonstrated similar activity changes in multiple brain regions, including activation of the dorsal anterior cingulate and dorsolateral frontal cortex. CONCLUSIONS: Pathological gamblers share many neural correlates of Stroop task performance with healthy subjects but differ in a brain region previously implicated in disorders characterized by poor impulse control.
Cannabis Smoking and Periodontal Disease Among Young Adults
Authors: W. Murray Thomson, Richie Poulton, Jonathan M. Broadbent, Terrie E. Moffitt, Avshalom Caspi, James D. Beck, David Welch, Robert J. Hancox
Journal: JAMA (2008)

Tobacco smoking is a recognized behavioral risk factor for periodontal disease (through its systemic effects), and cannabis smoking may contribute in a similar way.To determine whether cannabis smoking is a risk factor for periodontal disease.Prospective cohort study of the general population, with cannabis use determined at ages 18, 21, 26, and 32 years and dental examinations conducted at ages 26 and 32 years. The most recent data collection (at age 32 years) was completed in June 2005.A complete birth cohort born in 1972 and 1973 in Dunedin, New Zealand, and assessed periodically (with a 96% follow-up rate of the 1015 participants who survived to age 32 years). Complete data for this analysis were available from 903 participants (comprising 89.0% of the surviving birth cohort).Periodontal disease status at age 32 years (and changes from ages 26 to 32 years) determined from periodontal combined attachment loss (CAL) measured at 3 sites per tooth.Three cannabis exposure groups were determined: no exposure (293 individuals, or 32.3%), some exposure (428; 47.4%), and high exposure (182; 20.2%). At age 32 years, 265 participants (29.3%) had 1 or more sites with 4 mm or greater CAL, and 111 participants (12.3%) had 1 or more sites with 5 mm or greater CAL. Incident attachment loss between the ages of 26 and 32 years in the none, some, and high cannabis exposure groups was 6.5%, 11.2%, and 23.6%, respectively. After controlling for tobacco smoking (measured in pack-years), sex, irregular use of dental services, and dental plaque, the relative risk estimates for the highest cannabis exposure group were as follows: 1.6 (95% confidence interval [CI], 1.2-2.2) for having 1 or more sites with 4 mm or greater CAL; 3.1 (95% CI, 1.5-6.4) for having 1 or more sites with 5 mm or greater CAL; and 2.2 (95% CI, 1.2-3.9) for having incident attachment loss (in comparison with those who had never smoked cannabis). Tobacco smoking was strongly associated with periodontal disease experience, but there was no interaction between cannabis use and tobacco smoking in predicting the condition's occurrence.Cannabis smoking may be a risk factor for periodontal disease that is independent of the use of tobacco.
The COPD assessment test: a systematic review
Authors: Nisha Gupta, Lancelot M. Pinto, Andreea Morogan, Jean Bourbeau
Journal: European Respiratory Journal (2014)

The COPD assessment test (CAT) is a self-administered questionnaire that measures health-related quality of life. We aimed to systematically evaluate the literature for reliability, validity, responsiveness and minimum clinically important difference (MCID) of the CAT. Multiple databases were searched for studies analysing the psychometric properties of the CAT in adults with chronic obstructive pulmonary disease. Two reviewers independently screened, selected and extracted data, and assessed methodological quality of relevant studies using the COSMIN checklist. From 792 records identified, 36 studies were included. The number of participants ranged from 45 to 6469, mean age from 56 to 73 years, and mean forced expiratory volume in 1 s from 39% to 98% predicted. Internal consistency (reliability) was 0.85–0.98, and test–retest reliability was 0.80–0.96. Convergent and longitudinal validity using Pearson’s correlation coefficient were: SGRQ-C 0.69–0.82 and 0.63, CCQ 0.68–0.78 and 0.60, and mMRC 0.29–0.61 and 0.20, respectively. Scores differed with GOLD stages, exacerbation and mMRC grades. Mean scores decreased with pulmonary rehabilitation (2.2–3 units) and increased at exacerbation onset (4.7 units). Only one study with adequate methodology reported an MCID of 2 units and 3.3–3.8 units using the anchor-based approach and distribution-based approach, respectively. Most studies had fair methodological quality. We conclude that the studies support the reliability and validity of the CAT and that the tool is responsive to interventions, although the MCID remains debatable.