tbuckley/cabot-search huggingface dataset:
Altered Glutamate Metabolism Is Associated with Reduced Muscle Glutathione Levels in Patients with Emphysema
Authors: MARIËLLE P. K. J. ENGELEN, ANNEMIE M. W. J. SCHOLS, JOAN D. DOES, NICOLAAS E. P. DEUTZ, EMIEL F. M. WOUTERS
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Chronic obstructive pulmonary disease (COPD) is often characterized by an impaired skeletal muscle energy metabolism, which is at least partly related to chronic hypoxia and a reduced diffusing capacity. We have found that muscle glutamate (Glu), which is negatively influenced by these conditions, was reduced in patients with severe COPD. The aim of this study was to investigate whether the reduced intracellular Glu level in patients with emphysema is associated with an increased muscle glycolytic metabolism. Since Glu is an important substrate in the synthesis of glutamine (Gln) and glutathione (GSH), the influence of Glu status on muscle GSH and Gln was also examined. In 13 patients with emphysema and 25 control patients, arterial blood and biopsies from the vastus lateralis muscle were obtained. Expressed as a percentage of the control values, the patients with emphysema had reduced values for muscle Glu (64 +/- 12%; p < 0.001), GSH (76 +/- 23%; p < 0.01), and Gln (93 +/- 5%; p < 0.01), and higher values for lactate (p < 0.01) and pyruvate (p < 0.05). No differences were found in plasma values. Muscle Glu was highly associated with GSH (R(2) = 0.61; p < 0.001), but not with Gln. This study illustrates that reduced Glu levels in skeletal muscle of patients with emphysema are possibly related to an enhanced glycolytic activity and associated with decreased GSH levels.
DNA-Protein Cross-links and Replication-Dependent Histone H2AX Phosphorylation Induced by Aminoflavone (NSC 686288), a Novel Anticancer Agent Active against Human Breast Cancer Cells
Authors: Ling-hua Meng, Glenda Kohlhagen, Zhi-yong Liao, Smitha Antony, Edward Sausville, Yves Pommier
Journal: Cancer Research (2005)

Abstract Aminoflavone (5-amino-2,3-fluorophenyl)-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one) (NSC 686288) is a candidate for possible advancement to phase I clinical trial. Aminoflavone has a unique activity profile in the NCI 60 cell lines (COMPARE analysis; http://www.dtp.nci.nih.gov/docs/dtp_search.html), and exhibits potent cellular and animal antitumor activity. To elucidate the mechanism of action of aminoflavone, we studied DNA damage in MCF-7 cells. Aminoflavone induced DNA-protein cross-links (DPC) and DNA single-strand breaks (SSB). Aminoflavone induced high levels of DPC and much lower level of SSB than camptothecin, which induces equal levels of DPC and SSB due to the trapping topoisomerase I-DNA complexes. Accordingly, neither topoisomerase I nor topoisomerase II were detectable in the aminoflavone-induced DPC. Aminoflavone also induced dose- and time-dependent histone H2AX phosphorylation (γ-H2AX). γ-H2AX foci occurred with DPC formation, and like DPC, persisted after aminoflavone removal. Aphidicolin prevented γ-H2AX formation, suggesting that γ-H2AX foci correspond to replication-associated DNA double-strand breaks. Accordingly, no γ-H2AX foci were found in proliferating cell nuclear antigen–negative or in mitotic cells. Bromodeoxyuridine incorporation and fluorescence-activated cell sorting analyses showed DNA synthesis inhibition uniformly throughout the S phase after exposure to aminoflavone. Aminoflavone also induced RPA2 and p53 phosphorylation, and induced p21Waf1/Cip1 and MDM2, demonstrating S-phase checkpoint activation. These studies suggest that aminoflavone produces replication-dependent DNA lesions and S-phase checkpoint activation following DPC formation. γ-H2AX may be a useful clinical marker for monitoring the efficacy of aminoflavone in tumor therapies.
p53 Upregulates Death Receptor 4 Expression through an Intronic p53 Binding Site
Authors: Xiangguo Liu, Ping Yue, Fadlo R. Khuri, Shi-Yong Sun
Journal: Cancer Research (2004)

Abstract Death receptor 4 (DR4) is one of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors and triggers apoptosis on ligation with TRAIL or overexpression. Our previous study demonstrated that DR4 expression could be regulated in a p53-dependent fashion. In the present study, we have demonstrated that DR4 is a p53 target gene and is regulated by p53 through a functional intronic p53 binding site (p53BS) based on the following lines of evidence: (a) the p53BS in the DR4 gene is almost identical to the one found in the first intron of the DR5 gene in terms of their locations and sequences; (b) DR4 p53BS bound to p53 protein in intact cells upon p53 activation as demonstrated by a chromatin immunoprecipitation assay; (c) a luciferase reporter vector carrying the DR4 p53BS upstream of an SV40 promoter exhibited enhanced luciferase activity when transiently cotransfected with a wild-type p53 expression vector in p53-null cell lines or stimulated with DNA-damaging agents in a cell line having wild-type p53; and (d) when the DR4 p53BS, together with its own corresponding promoter region in the same orientation as it sits in its natural genomic locus, was cloned into a basic luciferase vector without a promoter element, its transcriptional activity was strikingly increased by cotransfection of a wild-type p53 expression vector or treatment with DNA-damaging agents. However, wild-type p53 or DNA-damaging agents completely lost their activity to increase transcriptional activity of a reporter construct with deleted DR4 p53BS. Thus, we conclude that p53 directly regulates the expression of the DR4 gene via the novel intronic p53BS.
Angiotensin-converting enzyme genotype and the ventilatory responseto exertional hypoxia
Authors: S. Patel, D.R. Woods, N.J. Macleod, A. Brown, K.R. Patel, H.E. Montgomery, A.J. Peacock
Journal: European Respiratory Journal (2003)

The “insertion” (I) rather than “deletion” (D) variant of the human angiotensin-converting enzyme (ACE) gene is associated with both lower tissue ACE activity and elite performance at high altitude. Three genotypes, II, ID and DD, are thus represented in the population. The authors examined whether an improved ventilatory response to hypoxic exercise may contribute to this effect. Subjects (n=60; 37 male, mean±sem age 23.6±0.6 yrs, 14 II, 30 ID, 16 DD) underwent incremental cardiopulmonary exercise testing to establish maximal oxygen uptake and ventilatory threshold (VT). Four hours later, subjects exercised for 6 mins at 50% of the workload at VT. The protocol was repeated 15 mins later while breathing 12.5±0.5% oxygen in nitrogen. All subject characteristics were independent of genotype, as were data during normoxic exercise. However, the hypoxia-induced rise in minute ventilation was significantly greater among those of II genotype (39.6±4.1% versus 27.9±2.0% versus 28.4±2.2% for II versus ID versus DD, respectively). These data are supported by a significantly greater decrease in end tidal carbon dioxide (consistent with an increase in alveolar ventilation) among those homozygous for the I allele (II −18.7±1.3%, ID −15.7±0.4%, DD −15.1%±1.1). The ventilatory response to hypoxic exercise is influenced by angiotensin-converting enzyme genotype. Potential implications concern high altitude performance and the pathogenesis and management of hypoxic lung disease.
Increased myothermal economy of isometric force generation in compensated cardiac hypertrophy induced by pulmonary artery constriction in the rabbit. A characterization of heat liberation in normal and hypertrophied right ventricular papillary muscles.
Authors: N R Alpert, L A Mulieri
Journal: Circulation Research (1982)

because the controls in the earlier series of five muscles liberated 40% more initial heat per gram of muscle than did the present controls.We believe the present values, obtained from a much larger population, to be a better representation of rabbit papillary muscle energetics. Methods Animals and Surgical PreparationExperiments were performed on 38 male albino rabbits weighing 2.44 ± 0.09 kg at the time of sacrifice.Experimental animals (1.7 ± 0.04 kg body weight) were anesthetized with Phenergan (20 mg/animal) and sodium pentobarbitol (20 mg/kg).Positive pressure respiration with 95% C>2-5% CO2, partially saturated with halothane, was established after tracheal intubation.The central end of the pulmonary artery was exposed and freed of surrounding connective tissue through an incision at the second intercostal space on the left side of the animal.A spiral monel metal coil (inside diameter 2.9 mm; length 6.6 mm; 2.5 turns; 0.7 mm diameter wire) was applied to the outside surface of the artery by threading the spiral around the artery in a screw-like manner (Hamrell and Alpert, 1977).Animals recovered (3-5 hours) in a warm compartment (28 °C) which was continuously supplied with a moisturized, 95% C>2-5% CO2 gas mixture.The surgical trauma and the 67% constriction of the pulmonary artery caused 50% of the animals to die within 72 hours of surgery.Experiments were performed 32 days after surgery.Right ventricular blood pressure was measured directly in five representative experimental and control animals under standard anesthesia by needle puncture of the thorax and right ventricular wall (18-gauge, 5-cm hypodermic needle connected to the AILTECH, MSIOD pressure transducer).Papillary muscles were not taken from these animals.
Immunogenic Tumor Cell Death Induced by Chemoradiotherapy in Patients with Esophageal Squamous Cell Carcinoma
Authors: Yoshiyuki Suzuki, Kousaku Mimura, Yuya Yoshimoto, Mitsuaki Watanabe, Yu Ohkubo, Shinichirou Izawa, Kazutoshi Murata, Hideki Fujii, Takashi Nakano, Koji Kono
Journal: Cancer Research (2012)

Although it has been shown that chemoradiotherapy may induce immunogenic cell death, which could trigger T-cell immunity mediated by high-mobility group box 1 protein (HMGB1) and calreticulin, there is still limited information to support this theory directly in a clinical setting. In the present study, we evaluated antigen-specific T-cell responses against six cancer-testis antigens in peripheral blood lymphocytes from patients with esophageal squamous cell carcinoma (ESCC) receiving chemoradiation. Expression of HMGB1 and calreticulin within tumor microenvironment was also analyzed in resected samples with and without chemoradiotherapy in relation to patients survival. Tumor antigen-specific T-cell responses were confirmed in six (38%) of 16 patients with ESCC after chemoradiotherapy coexisting with elevated serum HMGB1. In addition, HMGB1 within tumor microenvironment was significantly upregulated in patients with ESCC with preoperative chemoradiotherapy, but not in those without chemoradiotherapy, and the degree of HMGB1 positively correlated with patient survival (n=88). Both irradiation and chemotherapeutic drugs induced upregulation of HMGB1 and calreticulin in nine ESCC cell lines. Furthermore, HMGB1 was able to induce maturation of dendritic cells. Together, our findings indicate that chemoradiation induces tumor antigen-specific T-cell responses, and HMGB1 production is related to clinical outcome after chemoradiation.
Neutrophils use both shared and distinct mechanisms to adhere to selectins under static and flow conditions.
Authors: K D Patel, K L Moore, M U Nollert, R P McEver
Journal: Journal of Clinical Investigation (1995)

Both P-selectin glycoprotein ligand-1 (PSGL-1) and L-selectin are localized on the microvilli of neutrophils and have been implicated in the attachment of neutrophils to P-selectin or E-selectin. We directly compared the attachment and rolling of neutrophils on P-selectin and E-selectin under flow, with emphasis on the functions of PSGL-1 and L-selectin. Flowing neutrophils attached more avidly and rolled at lower velocities on P-selectin than on E-selectin at matched densities. Studies with purified molecules indicated that P-selectin and E-selectin bound to a related site on PSGL-1 that overlapped the epitope for the anti-PSGL-1 mAb PL1. E-selectin bound with lower affinity than P-selectin to this site and also bound to an additional site(s) on PSGL-1.PL1 abolished adhesion of neutrophils to P-selectin under shear or static conditions, whereas DREG-56, a mAb to L-selectin, had no effect on adhesion to P-selectin. PL1 inhibited attachment of neutrophils to E-selectin under flow but not static conditions. DREG-56 also inhibited attachment of flowing neutrophils to E-selectin, and a combination of DREG-56 and PL1 nearly eliminated attachment to E-selectin under flow. These data suggest that PSGL-1 functions cooperatively with L-selectin to mediate optimal attachment of flowing neutrophils to E-selectin but not to P-selectin. Neutrophils attach more efficiently and with greater strength to P-selectin, perhaps because of the higher affinity of P-selectin for the PL1-defined site on PSGL-1.
Expression of Synovial Sarcoma X (SSX) Antigens in Epithelial Ovarian Cancer and Identification of SSX-4 Epitopes Recognized by CD4+ T Cells
Authors: Danila Valmori, Feng Qian, Maha Ayyoub, Christoph Renner, Andrea Merlo, Sacha Gjnatic, Elisabeth Stockert, Deborah Driscoll, Shashikant Lele, Lloyd J. Old, Kunle Odunsi
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Synovial sarcoma X (SSX) breakpoint genes are expressed in a variety of cancers but not in normal tissues, except for testis, and are potential targets for immunotherapy. The aims of this study were to determine the expression and immunogenicity of these antigens in patients with epithelial ovarian cancer (EOC). Experimental Design: SSX-1-, SSX-2-, and SSX-4-specific reverse transcription-PCR were done on a panel of EOC specimens. Sera from a subgroup of the patients were tested for SSX-2 and SSX-4 antibody by ELISA and recombinant antigen expression on yeast surface (RAYS). In vitro stimulation of peripheral blood mononuclear cells from a patient bearing SSX-4-expressing tumor with a pool of long peptides spanning the protein sequence was used for assessment of SSX-4-specific CD4+ T cells recognizing distinct antigenic sequences restricted by HLA class II alleles. Results: Our results indicate expression of SSX-1, SSX-2, and SSX-4 in 2.5%, 10%, and 16% of 120 EOC specimens, respectively. When all three SSX antigens are considered, aberrant expression was found in 26% of ovarian tumors. Antibodies to SSX-2 and SSX-4 were detectable by ELISA and RAYS in two patients. SSX-4-specific CD4+ T cells recognizing two previously undescribed SSX-4-derived T-cell epitopes in association with HLA-DR (SSX-4: 51-70 and SSX-4: 61-180) were identified. Conclusions: Our study shows aberrant expression of SSX antigens in a proportion of patients with EOC. The evidence of humoral immunity to SSX-2 and SSX-4, and SSX-4-specific CD4+ T cells among circulating lymphocytes in patients with antigen expressing EOC suggest that these antigens are attractive targets for specific immunotherapy in EOC.
Dose-Intense Adjuvant Treatment of High-Risk Breast Cancer
Authors: G. Bonadonna, P. Valagussa
Journal: JNCI Journal of the National Cancer Institute (1990)

During the past two decades, we have witnessed a dramatic revolution in the strategic approach for primary breast cancer. The introduction of systemic adjuvant therapy was considered conceptually important in given high-risk subsets to control and, if possible, to eradicate distant micrometastases that were responsible for the failure of local-regional therapy, regardless of the extent of surgery and the intensity of radiation (1). For the same biologic and clinical reasons that indicate the prevalent systemic nature of this complex disease, surgeons (2,3) decided to test conservative versus mutilating procedures in small breast tumors. The 5to 10-year results of prospective randomized trials have successfully validated the proposed alternative hypothesis. Systemic adjuvant therapy can significantly improve relapse-free and total survival in given subsets of patients (4). Mutilating surgery is an unnecessary procedure in the treatment of breast tumors less than 4 cm at their largest diameter. These important achievements have further stimulated laboratory and clinical investigators to improve their selection of candidate patients for systemic adjuvant therapy, to intensify treatment in the poor-risk subsets, and to increase the frequency of breast-saving procedures by primary (neoadjuvant) chemotherapy.
Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation
Authors: P Revent R Ecurrent, E Vents T Rial
Journal: New England Journal of Medicine (2001)

A BSTRACT Background Despite current treatments, patients who have acute coronary syndromes without ST-segment elevation have high rates of major vascular events. We evaluated the efficacy and safety of the antiplatelet agent clopidogrel when given with aspirin in such patients. Methods We randomly assigned 12,562 patients who had presented within 24 hours after the onset of symptoms to receive clopidogrel (300 mg immediately, followed by 75 mg once daily) (6259 patients) or placebo (6303 patients) in addition to aspirin for 3 to 12 months. Results The first primary outcome — a composite of death from cardiovascular causes, nonfatal myocardial infarction, or stroke — occurred in 9.3 percent of the patients in the clopidogrel group and 11.4 percent of the patients in the placebo group (relative risk with clopidogrel as compared with placebo, 0.80; 95 percent confidence interval, 0.72 to 0.90; P<0.001). The second primary outcome — the first primary outcome or refractory ischemia — occurred in 16.5 percent of the patients in the clopidogrel group and 18.8 percent of the patients in the placebo group (relative risk, 0.86, P<0.001). The percentages of patients with in-hospital refractory or severe ischemia, heart failure, and revascularization procedures were also significantly lower with clopidogrel. There were significantly more patients with major bleeding in the clopidogrel group than in the placebo group (3.7 percent vs. 2.7 percent; relative risk, 1.38; P=0.001), but there were not significantly more patients with episodes of life-threatening bleeding (2.1 percent vs. 1.8 percent, P=0.13) or hemorrhagic strokes. Conclusions The antiplatelet agent clopidogrel has beneficial effects in patients with acute coronary syndromes without ST-segment elevation. However, the risk of major bleeding is increased among patients treated with clopidogrel. (N Engl J Med 2001;345: 494-502.)
Factor inhibiting HIF limits the expression of hypoxia-inducible genes in podocytes and distal tubular cells
Authors: Johannes Schödel, Daniela Bohr, Bernd Klanke, Gunnar Schley, Ursula Schlötzer-Schrehardt, Christina Warnecke, Armin Kurtz, Kerstin Amann, Kai-Uwe Eckardt, Carsten Willam
Journal: Kidney International (2010)
Combination of the Framingham Risk Score and Carotid Intima-Media Thickness Improves the Prediction of Cardiovascular Events in Patients With Type 2 Diabetes
Authors: Michiko Yoshida, Tomoya Mita, Risako Yamamoto, Tomoaki Shimizu, Fuki Ikeda, Chie Ohmura, Akio Kanazawa, Takahisa Hirose, Ryuzo Kawamori, Hirotaka Watada
Journal: Diabetes Care (2011)

The aim of this study was to investigate whether carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) add value to the Framingham risk score (FRS) in predicting the development of cardiovascular diseases (CVDs) in type 2 diabetic patients with a negative history of CVD.Type 2 diabetic patients (n = 783) were retrospectively recruited and followed for CVD.During a 5.4-year follow-up period, 85 incidences of CVD were recorded (10.9%). After adjustment for conventional arterial risk factors, multivariate analysis with the Cox proportional hazards model identified IMT, but not baPWV, as a significant determinant of CVD. In addition, the combination of FRS with IMT, but not with baPWV, improved the prediction of CVD.Carotid IMT is a significant predictor of CVD in asymptomatic type 2 diabetic patients, and the combination of FRS and IMT improves the prediction of CVD in these patients.
Evaluation of swallowing function by two screening tests in primary COPD
Authors: K. Ohta, K. Murata, T. Takahashi, S. Minatani, S. Sako, Y. Kanada
Journal: European Respiratory Journal (2009)

<h3>Abstract</h3> <h3>Background</h3> COVID-19 is spreading quickly, causing great deal of fear and unrest in the public. <h3>Methods</h3> This web-based, cross-sectional study was conducted among students of four renowned Pakistani education institutions. Google forms were used to disseminate the online questionnaire to assess anxiety (generalized anxiety disorder 7-item scale), depression (9-item patient health questionnaire), sources of distress (14-items) and the coping strategies (Brief-COPE). <h3>Results</h3> A total of 1134 responses (age 21.7 ± 3.5 years, 70.5% females) were included. The frequency of students having moderate-severe anxiety and depression (score ≥ 10) were ≈ 34% and 45%, respectively. The respondents’ aged ≥ 31 years had significantly lower depression score than those below 30 years. Males had significantly less anxiety and depression scores than females. Additionally, those having a family member, friend or acquaintance infected with disease had significantly higher anxiety score. The main sources of distress were related to adverse effects of ongoing pandemic on daily life followed by the rapid disease spread. Regarding coping strategies, majority of respondents were found to have adopted religious/spiritual coping followed by acceptance. <h3>Conclusions</h3> COVID-19 have significant adverse impact on students’ mental health. The most frequent coping strategy adopted by them are religious/spiritual coping, acceptance, self-distraction and active coping. It is suggested that mental health of students should not be neglected during epidemics.
Sarcoidosis and cancer revisited: a long-term follow-up study of 555 Danish sarcoidosis patients
Authors: FK Romer, P Hommelgaard, G Schou
Journal: European Respiratory Journal (1998)

For more than 20 yrs it has been debated whether the systemic disease sarcoidosis predisposes to malignant neoplasms. The aim of this study was to examine the occurrence of cancer in Danish sarcoidosis patients observed for 9-30 yrs. The clinical data of 555 consecutive sarcoidosis patients were linked with the nationwide Danish Cancer Registry in a database, comparing the results with the expected incidence in the Danish population, adjusted for sex, age and calendar time. The sarcoidosis patients were diagnosed in two areas during the periods of 1960-1971 and 1970-1981, respectively, and followed until December 31, 1991. No excess of cancer was observed in sarcoidosis patients. A total number of 48 patients were observed with cancer (20 males and 28 females). Cancer occurred 1-29 yrs after sarcoidosis diagnosis (median 14 yrs) The observed versus expected (O/E) ratio was 1.16 (95% confidence interval (CI) 0.75-1.79) in males and 1.28 (95% CI 0.88-1.86) in females. No increased occurrence of lung cancer or malignant lymphoma (O/E ratios 0.23, 95% CI 0.00-1.25 and 1.25, 95% CI 0.02-6.95, respectively) was found. Neither age at diagnosis of sarcoidosis nor clinical sarcoidosis features were indicators of later occurrence of malignancy. The study could not confirm previous reports of an increased occurrence of malignant neoplasms in Danish sarcoidosis patients.