tbuckley/cabot-search huggingface dataset:
Serum 8-Hydroxy-Guanine Levels Are Increased in Diabetic Patients
Authors: Chan Soo Shin, Byung Sool Moon, Kyong Soo Park, Seong Yeon Kim, Su Jin Park, Myung Hee Chung, Hong Kyu Lee
Journal: Diabetes Care (2001)

OBJECTIVE—The production of reactive oxygen species is increased in diabetic patients, especially in those with poor glycemic control. We have investigated oxidative damage in type 2 diabetic patients using serum 8-hydroxyguanine (8-OHG) as a biomarker. RESEARCH DESIGN AND METHODS—We studied 41 type 2 diabetic patients and compared them with 33 nondiabetic control subjects. Serum 8-OHG concentration was assayed using high-pressure liquid chromatography. RESULTS—The type 2 diabetic patients had significantly higher concentrations of 8-OHG in their serum than the control subjects (5.03 ± 0.69 vs. 0.96 ± 0.15 pmol/ml; P &amp;lt; 0.01). There was no association between the levels of 8-OHG and HbA1c. We also could not find any correlation between serum 8-OHG levels and age, duration of diabetes, serum lipids, or creatinine or albumin excretion rate. Creatinine clearance showed marginal correlation with serum 8-OHG levels (P = 0.06). Among the diabetic patients, those with proliferative retinopathy had significantly higher 8-OHG levels than those with nonproliferative retinopathy or without retinopathy. Likewise, the serum 8-OHG levels in patients who had advanced nephropathy (azotemia) were higher than in patients with normoalbuminuria, microalbuminuria, or overt proteinuria. CONCLUSIONS—Our findings show that measuring serum 8-OHG is a novel convenient method for evaluating oxidative DNA damage. Diabetic patients, especially those with advanced microvascular complications, had significantly higher serum 8-OHG levels; this suggests that such changes may contribute to the development of microvascular complications of diabetes.
Circulating Oncometabolite 2-Hydroxyglutarate Is a Potential Surrogate Biomarker in Patients with Isocitrate Dehydrogenase-Mutant Intrahepatic Cholangiocarcinoma
Authors: Darrell R. Borger, Lipika Goyal, Thomas Yau, Ronnie T. Poon, Marek Ancukiewicz, Vikram Deshpande, David C. Christiani, Hannah M. Liebman, Hua Yang, Hyeryun Kim, Katharine Yen, Jason E. Faris, A. John Iafrate, Eunice L. Kwak, Jeffrey W. Clark, Jill N. Allen, Lawrence S. Blaszkowsky, Janet E. Murphy, Supriya K. Saha, Theodore S. Hong, Jennifer Y. Wo, Cristina R. Ferrone, Kenneth K. Tanabe, Nabeel Bardeesy, Kimberly S. Straley, Sam Agresta, David P. Schenkein, Leif W. Ellisen, David P. Ryan, Andrew X. Zhu
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Mutations in the IDH1 and IDH2 (IDH1/2) genes occur in approximately 20% of intrahepatic cholangiocarcinoma and lead to accumulation of 2-hydroxyglutarate (2HG) in the tumor tissue. However, it remains unknown whether IDH1/2 mutations can lead to high levels of 2HG circulating in the blood and whether serum 2HG can be used as a biomarker for IDH1/2 mutational status and tumor burden in intrahepatic cholangiocarcinoma. Experimental Design: We initially measured serum 2HG concentration in blood samples collected from 31 patients with intrahepatic cholangiocarcinoma in a screening cohort. Findings were validated across 38 resected patients with intrahepatic cholangiocarcinoma from a second cohort with tumor volume measures. Circulating levels of 2HG were evaluated relative to IDH1/2 mutational status, tumor burden, and a number of clinical variables. Results: Circulating levels of 2HG in the screening cohort were significantly elevated in patients with IDH1/2-mutant (median, 478 ng/mL) versus IDH1/2–wild-type (median, 118 ng/mL) tumors (P &amp;lt; 0.001). This significance was maintained in the validation cohort (343 ng/mL vs. 55 ng/mL, P &amp;lt; 0.0001) and levels of 2HG directly correlated with tumor burden in IDH1/2-mutant cases (P &amp;lt; 0.05). Serum 2HG levels ≥170 ng/mL could predict the presence of an IDH1/2 mutation with a sensitivity of 83% and a specificity of 90%. No differences were noted between the allelic variants IDH1 or IDH2 in regard to the levels of circulating 2HG. Conclusions: This study indicates that circulating 2HG may be a surrogate biomarker of IDH1 or IDH2 mutation status in intrahepatic cholangiocarcinoma and that circulating 2HG levels may correlate directly with tumor burden. Clin Cancer Res; 20(7); 1884–90. ©2014 AACR.
Nitric Oxide Synthase Inhibition Restores Hypoxic Pulmonary Vasoconstriction in Sepsis
Authors: STEFANIE R. FISCHER, DONALD J. DEYO, HANS G. BONE, ROY McGUIRE, LILLIAN D. TRABER, DANIEL L. TRABER
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Hypoxic pulmonary vasoconstriction (HPV) is inhibited by inhaled nitric oxide (NO) in healthy animals and is blunted in endotoxemia. We investigated whether the loss of HPV during sepsis could be reversed by NO synthase (NOS) inhibition. Hypoxic challenges were induced in intubated, awake sheep breathing 100% nitrogen to the left lung and 100% oxygen to the right lung. HPV was assessed as the decrease in left pulmonary blood flow during hypoxia, measured with an ultrasonic flow probe around the left pulmonary artery. Group I (n = 5) received carrier solutions and Groups II (n = 6) and III (n = 8) received an infusion containing Pseudomonas aeruginosa. After 24 h, Group III also received an infusion of 6.6 mg.kg.h-1 N omega-monomethyl-L-arginine (L-NMMA). After 24 h of sepsis, HPV decreased from 60 +/- 9% in Group II and 56 +/- 4% in Group III to 27 +/- 2% and 26 +/- 4%, respectively. Group I showed no change in HPV. During infusion of L-NMMA, HPV increased to 38 +/- 4%. Pulmonary shunt during hypoxia increased in Group III to 161 +/- 10% of its baseline value, and decreased to 121 +/- 11% during infusion of L-NMMA. We conclude that L-NMMA improves but does not restore HPV, indicating that other vasodilatory mediators besides NO also influence HPV in sepsis.
Planning for implementation and translation: seek first to understand the end-users' perspectives
Authors: A Donaldson, CF Finch
Journal: British Journal of Sports Medicine (2011)

<h3>Background</h3> Women aged ≤35 years with breast cancer have a poor prognosis, but their prognostic factors have not been clearly defined. <h3>Aims</h3> To evaluate whether the molecular markers used in age-unspecified breast cancer could also be applied to women ≤35 years. <h3>Methods</h3> Archival tumours from patients aged ≤35 years with stage I–III breast cancer were collected. Oestrogen receptor (ER), progesterone receptor (PR), HER2, Ki67 and P53 protein expression profiles in paraffin-embedded tissue sections were determined by immunohistochemistry. Tumours with an HER2 score of 2+ were further evaluated by fluorescence in situ hybridisation. Mutational analysis of exons 4–9 of the TP53 gene and exons 9 and 20 of the PIK3CA gene was carried out using direct sequencing analysis. <h3>Results</h3> 116 patients with a median follow-up duration of 62.7 months were included. In addition to tumour size and axillary lymph node status, univariate analysis showed that high Ki67 expression, ER-negative, HER2 overexpression, and TP53 mutations were associated with shorter overall survival. Multivariate analysis showed that high Ki67 expression (HR=3.93, p=0.005), HER2 overexpression (HR=3.21, p=0.013) and TP53 mutations (HR=4.44, p=0.005) were associated with shorter overall survival. PR expression and PIK3CA mutations were not associated with survival. <h3>Conclusions</h3> For women ≤35 years, TP53 mutations, Ki67 and HER2 expressions are strong prognostic factors. The limited prognostic value of hormone receptors suggests that the prognostic markers used in age-unspecified breast cancer may not be completely fit for this population.
Neoadjuvant Treatment Response As an Early Response Indicator for Patients With Rectal Cancer
Authors: In Ja Park, Y. Nancy You, Atin Agarwal, John M. Skibber, Miguel A. Rodriguez-Bigas, Cathy Eng, Barry W. Feig, Prajnan Das, Sunil Krishnan, Christopher H. Crane, Chung-Yuan Hu, George J. Chang
Journal: Journal of Clinical Oncology (2012)

Neoadjuvant chemoradiotherapy for rectal cancer is associated with improved local control and may result in complete tumor response. Associations between tumor response and disease control following radical resection should be established before tumor response is used to evaluate treatment strategies. The purpose of this study was to assess and compare oncologic outcomes associated with the degree of pathologic response after chemoradiotherapy.All patients with locally advanced (cT3-4 or cN+ by endorectal ultrasonography, computed tomography, or magnetic resonance imaging) rectal carcinoma diagnosed from 1993 to 2008 at our institution and treated with preoperative chemoradiotherapy and radical resection were identified, and their records were retrospectively reviewed. The median radiation dose was 50.4 Gy with concurrent chemotherapy. Recurrence-free survival (RFS), distant metastasis (DM), and local recurrence (LR) rates were compared among patients with complete (ypT0N0), intermediate (ypT1-2N0), or poor (ypT3-4 or N+) response by using Kaplan-Meier survival analysis and multivariate Cox proportional hazards regression.In all, 725 patients were classified by tumor response: complete (131; 18.1%), intermediate (210; 29.0%), and poor (384; 53.0%). Age, sex, cN stage, and tumor location were not related to tumor response. Tumor response (complete v intermediate v poor) was associated with 5-year RFS (90.5% v 78.7% v 58.5%; P < .001), 5-year DM rates (7.0% v 10.1% v 26.5%; P < .001), and 5-year LR only rates (0% v 1.4% v 4.4%; P = .002).Treatment response to neoadjuvant chemoradiotherapy among patients with locally advanced rectal cancer undergoing radical resection is an early surrogate marker and correlate to oncologic outcomes. These data provide guidance with response-stratified oncologic benchmarks for comparisons of novel treatment strategies.
Methylnaltrexone for Reversal of Constipation Due to Chronic Methadone Use
Authors: Chun-Su Yuan, Joseph F. Foss, Michael O'Connor, Joachim Osinski, Theodore Karrison, Jonathan Moss, Michael F. Roizen
Journal: JAMA (2000)

Constipation is the most common chronic adverse effect of opioid pain medications in patients who require long-term opioid administration, such as patients with advanced cancer, but conventional measures for ameliorating constipation often are insufficient.To evaluate the efficacy of methylnaltrexone, the first peripheral opioid receptor antagonist, in treating chronic methadone-induced constipation.Double-blind, randomized, placebo-controlled trial conducted between May 1997 and December 1998.Clinical research center of a university hospital.Twenty-two subjects (9 men and 13 women; mean [SD] age, 43.2 [5.5] years) enrolled in a methadone maintenance program and having methadone-induced constipation.Laxation response, oral-cecal transit time, and central opioid withdrawal symptoms were compared between the 2 groups.The 11 subjects in the placebo group showed no laxation response, and all 11 subjects in the intervention group had laxation response after intravenous methylnaltrexone administration (P<.001). The oral-cecal transit times at baseline for subjects in the methylnaltrexone and placebo groups averaged 132.3 and 126.8 minutes, respectively. The average (SD) change in the methylnaltrexone-treated group was -77.7 (37.2) minutes, significantly greater than the average change in the placebo group (-1.4 [12.0] minutes; P<.001). No opioid withdrawal was observed in any subject, and no significant adverse effects were reported by the subjects during the study.Our data demonstrate that intravenous methylnaltrexone can induce laxation and reverse slowing of oral cecal-transit time in subjects taking high opioid dosages. Low-dosage methylnaltrexone may have clinical utility in managing opioid-induced constipation.
MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18
Authors: Rosalba Salcedo, Andrea Worschech, Marco Cardone, Yava Jones, Zsofia Gyulai, Ren-Ming Dai, Ena Wang, Winnie Ma, Diana Haines, Colm O'hUigin, Francesco M. Marincola, Giorgio Trinchieri
Journal: The Journal of Experimental Medicine (2010)

Signaling through the adaptor protein myeloid differentiation factor 88 (MyD88) promotes carcinogenesis in several cancer models. In contrast, MyD88 signaling has a protective role in the development of azoxymethane (AOM)/dextran sodium sulfate (DSS) colitis-associated cancer (CAC). The inability of Myd88−/− mice to heal ulcers generated upon injury creates an altered inflammatory environment that induces early alterations in expression of genes encoding proinflammatory factors, as well as pathways regulating cell proliferation, apoptosis, and DNA repair, resulting in a dramatic increase in adenoma formation and progression to infiltrating adenocarcinomas with frequent clonal mutations in the β-catenin gene. Others have reported that toll-like receptor (Tlr) 4–deficient mice have a similar susceptibility to colitis to Myd88-deficient mice but, unlike the latter, are resistant to CAC. We have observed that mice deficient for Tlr2 or Il1r do not show a differential susceptibility to colitis or CAC. However, upon AOM/DSS treatment Il18−/− and Il18r1−/− mice were more susceptible to colitis and polyp formation than wild-type mice, suggesting that the phenotype of Myd88−/− mice is, in part, a result of their inability to signal through the IL-18 receptor. This study revealed a previously unknown level of complexity surrounding MyD88 activities downstream of different receptors that impact tissue homeostasis and carcinogenesis.
Hodgkin lymphoma: 2014 update on diagnosis, risk‐stratification, and management
Authors: Stephen M. Ansell
Journal: American Journal of Hematology (2014)

Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 9,200 new patients annually and representing approximately 11.5% of all lymphomas in the United States.HL is composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte-predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups under the designation of classical HL.An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence, as well as the response to therapy as determined by positron emission tomography scan, are used to optimize therapy.Initial therapy for HL patients is based on the histology of the disease, the anatomical stage, and the presence of poor prognostic features. Patients with early stage disease are treated with combined modality strategies using abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. Management of relapsed/refractory disease: High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, palliative chemotherapy, nonmyeloablative allogeneic transplant, or participation in a clinical trial should be considered.
Efficacy of Duloxetine on Cognition, Depression, and Pain in Elderly Patients With Major Depressive Disorder: An 8-Week, Double-Blind, Placebo-Controlled Trial
Authors: Joel Raskin, Curtis G. Wiltse, Alan Siegal, Javaid Sheikh, Jimmy Xu, James J. Dinkel, Benjamin T. Rotz, Richard C. Mohs
Journal: American Journal of Psychiatry (2007)

This study compared the effects of duloxetine, 60 mg/day, versus placebo on cognition, depression, and pain in elderly patients with recurrent major depressive disorder.Patients were randomly assigned (2:1) to duloxetine, 60 mg/day (N=207), or placebo (N=104) for 8 weeks in a double-blind study. The primary outcome measure was a prespecified composite cognitive score composed of four individual tests. Secondary measures included the Geriatric Depression Scale, the Hamilton Depression Rating Scale, the Visual Analogue Scale assessing pain, and standard safety and tolerability assessments.Patients had a median age of 72 years (range=65-90). Duloxetine demonstrated significantly greater improvement in the composite cognitive score versus placebo (least-squares mean change from baseline to endpoint: 1.95 versus 0.76), driven by improved verbal learning and memory. Duloxetine treatment showed significantly greater baseline-to-endpoint reductions in both Hamilton depression scale (-6.49 versus -3.72) and Geriatric Depression Scale (-4.07 versus -1.34) total scores compared with placebo. Hamilton depression scale response (37.3% versus 18.6%) and remission (27.4% versus 14.7%) rates at endpoint were significantly higher for duloxetine than for placebo. Duloxetine significantly improved Visual Analogue Scale scores for back pain and time in pain while awake versus placebo. Significantly fewer patients receiving duloxetine withdrew from the study because of lack of efficacy (2.9% versus 9.6%); the incidences of discontinuation due to adverse events were similar for duloxetine and placebo (9.7% versus 8.7%).Duloxetine improved cognition, depression, and some pain measures and was safe and well tolerated in elderly patients with recurrent major depressive disorder.
Club cells inhibit alveolar epithelial wound repair<i>via</i>TRAIL-dependent apoptosis
Authors: Khondoker M. Akram, Nicola J. Lomas, Monica A. Spiteri, Nicholas R. Forsyth
Journal: European Respiratory Journal (2012)

Club cells (Clara cells) participate in bronchiolar wound repair and regeneration. Located in the bronchioles, they become activated during alveolar injury in idiopathic pulmonary fibrosis (IPF) and migrate into the affected alveoli, a process called alveolar bronchiolisation. The purpose of this migration and the role of club cells in alveolar wound repair is controversial. This study was undertaken to investigate the role of club cells in alveolar epithelial wound repair and pulmonary fibrosis. A direct-contact co-culture in vitro model was used to evaluate the role of club cells (H441 cell line) on alveolar epithelial cell (A549 cell line) and small airway epithelial cell (SAEC) wound repair. Immunohistochemistry was conducted on lung tissue samples from patients with IPF to replicate the in vitro findings ex vivo . Our study demonstrated that club cells induce apoptosis in alveolar epithelial cells and SAECs through a tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent mechanism resulting in significant inhibition of wound repair. Furthermore, in IPF lungs, TRAIL-expressing club cells were detected within the affected alveolar epithelia in areas of established fibrosis, together with widespread alveolar epithelial cell apoptosis. From these findings, we hypothesise that the extensive pro-fibrotic remodelling associated with IPF could be driven by TRAIL-expressing club cells inducing apoptosis in alveolar epithelial cells through a TRAIL-dependent mechanism.
Autopsy findings in 42 consecutive patients with idiopathic pulmonary fibrosis
Authors: C. E. Daniels, E. S. Yi, J. H. Ryu
Journal: European Respiratory Journal (2008)

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive lung disease that commonly results in respiratory failure and death. However, the cause of death in these patients has not previously been fully defined. The current study reviews the clinical records and pathological findings of 42 consecutive patients with IPF who underwent a post mortem at the Mayo Clinic (Rochester, MN, USA) over a 9-yr period, from January 1996 to December 2004. The median (range) age at post mortem for the patients was 74 (46–98 yrs) yrs, which included 25 (60%) males. A total of 31 (74%) patients died in the hospital. The immediate causes of death were reported as: respiratory (64%), cardiovascular (21%), or noncardiopulmonary (14%). Acute exacerbation of IPF was the most common immediate cause of death (29%). Pneumonia, aspiration and drug-induced lung disease were identified as other causes of respiratory death. Evidence of pulmonary hypertension was present in the post mortem of 19 (45%) patients and was the immediate cause of death in two of these patients. The immediate cause of death was clinically unsuspected in five (12%) patients and IPF was diagnosed post mortem in nine (21%) patients. The majority of patients with idiopathic pulmonary fibrosis who had undergone a post mortem were found to have died from respiratory causes. Acute exacerbation of idiopathic pulmonary fibrosis was found to be the most common cause of death whilst death from the gradual progression of idiopathic pulmonary fibrosis was found to be less common.
Factors affecting adherence of end-stage renal disease patients to an exercise programme.
Authors: A Williams, R Stephens, T McKnight, S Dodd
Journal: British Journal of Sports Medicine (1991)

Recently it has been shown that regular exercise is both physiologically and psychologically beneficial to patients with end-stage renal disease (ESRD). However, ESRD patients traditionally have a high non-adherence level to their self-care and medical regimens. To date, their adherence to exercise programmes has not been studied. Background information about employment, medical history, previous exercise habits and locus of control was obtained from 40 volunteer ESRD patients who started exercise at home. Twenty-eight participants maintained the exercise programme, consisting of aerobic activity lasting an average of 25 min, four times per week, for 12 weeks. The adherent patients were found to have encouraging support groups (75 versus 25%), to be between 41 and 60 years of age (64 versus 33%), to have been on dialysis for between 2 and 5 years, and to have loci of control (feeling of control over life events) classed as 'internal' (68 versus 25%). Factors such as sex, race, employment status and depression were found to have little influence on adherence. The major finding of this study was that patients adherent to exercise could be distinguished by unique psychological and psychosocial factors, and that adherence in this population was higher (70 compared with 50%) than some estimates for the general population.
Multifocal lymphangioendotheliomatosis with thrombocytopenia: Phenotypic variant and course with propranolol, corticosteroids, and aminocaproic acid
Authors: Edward M. Esparza, Gail Deutsch, Luana Stanescu, Edward Weinberger, Heather A. Brandling-Bennett, Robert Sidbury
Journal: Journal of the American Academy of Dermatology (2012)