tbuckley/cabot-search huggingface dataset:
MicroRNA-223 is a crucial mediator of PPARγ-regulated alternative macrophage activation
Authors: Wei Ying, Alexander Tseng, Richard Cheng-An Chang, Andrew Morin, Tyler Brehm, Karen Triff, Vijayalekshmi Nair, Guoqing Zhuang, Hui Song, Srikanth Kanameni, Haiqing Wang, Michael C. Golding, Fuller W. Bazer, Robert S. Chapkin, Stephen Safe, Beiyan Zhou
Journal: Journal of Clinical Investigation (2015)

Polarized activation of adipose tissue macrophages (ATMs) is crucial for maintaining adipose tissue function and mediating obesity-associated cardiovascular risk and metabolic abnormalities; however, the regulatory network of this key process is not well defined. Here, we identified a PPARγ/microRNA-223 (miR-223) regulatory axis that controls macrophage polarization by targeting distinct downstream genes to shift the cellular response to various stimuli. In BM-derived macrophages, PPARγ directly enhanced miR-223 expression upon exposure to Th2 stimuli. ChIP analysis, followed by enhancer reporter assays, revealed that this effect was mediated by PPARγ binding 3 PPARγ regulatory elements (PPREs) upstream of the pre-miR-223 coding region. Moreover, deletion of miR-223 impaired PPARγ-dependent macrophage alternative activation in cells cultured ex vivo and in mice fed a high-fat diet. We identified Rasa1 and Nfat5 as genuine miR-223 targets that are critical for PPARγ-dependent macrophage alternative activation, whereas the proinflammatory regulator Pknox1, which we reported previously, mediated miR-223-regulated macrophage classical activation. In summary, this study provides evidence to support the crucial role of a PPARγ/miR-223 regulatory axis in controlling macrophage polarization via distinct downstream target genes.
The Pattern of Recovery of Renal Function Following Renal Artery Occlusion in the Dog
Authors: SYDNEY M. FRIEDMAN, R. L. JOHNSON, CONSTANCE L. FRIEDMAN
Journal: Circulation Research (1954)

The pattern of recovery of renal function following two hours of complete ischemia was studied in a series of dogs. A marked functional ischemia persisted for several hours after release of the clamp, but restoration of blood flow was substantially complete in 24 hours. Other renal functions returned slowly over a period of weeks, reflecting the rate of repair of damaged tubules. Two important phases of recovery are thus to be considered: (a) a brief but significant period of continuing ischemia immediately following the trauma, and (b) a period of slow repair of those nephrons damaged but not destroyed in the first phase of the insult.
Latent Epstein-Barr Virus Infection of Tumor Cells in Classical Hodgkin's Lymphoma Predicts Adverse Outcome in Older Adult Patients
Authors: Arjan Diepstra, Gustaaf W. van Imhoff, Michael Schaapveld, Henrike Karim-Kos, Anke van den Berg, Edo Vellenga, Sibrand Poppema
Journal: Journal of Clinical Oncology (2009)

Purpose In classical Hodgkin's lymphoma (cHL), the impact of tumor cell Epstein-Barr virus (EBV) status on clinical outcome is controversial. Patients and Methods We assessed failure-free survival (FFS) and relative survival (RS) in 412 patients with cHL and age-defined subgroups in a population-based study in the northern Netherlands. Tumor cell EBV status was positive in 34%, and the median follow-up time was 7.1 years. Patients' median age at diagnosis was 35 years (range, 7 to 91 years), and 63% had Ann Arbor stage I or II, 24% had stage III, and 12% had stage IV disease. Results EBV status influenced 5-year FFS and RS only in patients from the age group 50 to 74 years. Five-year FFS was 60% in patients with EBV-positive versus 85% in EBV-negative tumors (P = .01). Five-year RS was 69% in patients with EBV-positive versus 82% in EBV-negative tumors (P = .03). After adjusting for histology, HLA class II expression by tumor cells, stage, presence of extranodal localizations and treatment, and the effect of positive EBV tumor status remained significant in FFS multivariate analysis (hazard ratio, 3.11; 95% CI, 1.28 to 7.53; P = .01). Conclusion This study indicates that treatment failure in older adult patients with cHL is associated with positive tumor cell EBV status.
Short-Term Dynamics and Metabolic Impact of Abdominal Fat Depots After Bariatric Surgery
Authors: Ram Weiss, Liat Appelbaum, Chaya Schweiger, Idit Matot, Naama Constantini, Alon Idan, Noam Shussman, Jacob Sosna, Andrei Keidar
Journal: Diabetes Care (2009)

Bariatric surgery is gaining acceptance as an efficient treatment modality for obese patients. Mechanistic explanations regarding the effects of bariatric surgery on body composition and fat distribution are still limited.Intra-abdominal and subcutaneous fat depots were evaluated using computed tomography in 27 obese patients prior to and 6 months following bariatric surgery. Associations with anthropometric and clinical changes were evaluated.Excess weight loss 6 months following surgery was 47% in male and 42.6% in female subjects. Visceral fat and subcutaneous fat were reduced by 35% and 32%, respectively, in both sexes, thus the visceral-to-subcutaneous fat ratio remained stable. The strongest relation between absolute and relative changes in visceral and subcutaneous fat was demonstrated for the excess weight loss following the operations (r approximately 0.6-0.7), and these relations were strengthened further following adjustments for sex, baseline BMI, and fat mass. Changes in waist circumference and fat mass had no relation to changes in abdominal fat depots. All participants met the criteria of the metabolic syndrome at baseline, and 18 lost the diagnosis on follow-up. A lower baseline visceral-to-subcutaneous fat ratio (0.43 +/- 0.15 vs. 0.61 +/- 0.21, P = 0.02) was associated with clinical resolution of metabolic syndrome parameters.The ratio between visceral and subcutaneous abdominal fat remains fairly constant 6 months following bariatric procedures regardless of sex, procedure performed, or presence of metabolic complications. A lower baseline visceral-to-abdominal fat ratio is associated with improvement in metabolic parameters.
Potential Mechanisms of Low Sodium Diet–Induced Cardiac Disease
Authors: Nobuhiro Suematsu, Caroline Ojaimi, Fabio A. Recchia, Zipping Wang, Yester Skayian, Xiaobin Xu, Suhua Zhang, Pawel M. Kaminski, Dong Sun, Michael S. Wolin, Gabor Kaley, Thomas H. Hintze
Journal: Circulation Research (2009)

Patients on a low salt (LS) diet have increased mortality.
Evaluation of anti-HBV drug resistant mutations among patients with acute symptomatic hepatitis B in the United States
Authors: Dwayne M. Baxa, Ashish D. Thekdi, Alicia Golembieski, Prashant V. Krishnan, Omar Sharif, Anne Kizy, Lynne Shetron-Rama, John Jovanovich, Brandi J. Chappell, Andrea Snow-Lampart, Katyna Borroto-Esoda, Stuart C. Gordon
Journal: Journal of Hepatology (2012)
Pazopanib Enhances Paclitaxel-Induced Mitotic Catastrophe in Anaplastic Thyroid Cancer
Authors: Crescent R. Isham, Ayoko R. Bossou, Vivian Negron, Kelly E. Fisher, Rakesh Kumar, Laura Marlow, Wilma L. Lingle, Robert C. Smallridge, Eric J. Sherman, Vera J. Suman, John A. Copland, Keith C. Bible
Journal: Science Translational Medicine (2013)

Anaplastic thyroid cancer (ATC) has perhaps the worst prognosis of any cancer, with a median survival of only about 5 months regardless of stage. Pazopanib monotherapy has promising clinical activity in differentiated thyroid cancers (generally attributed to vascular endothelial growth factor receptor inhibition), yet has less effective single-agent activity in ATC. We now report that combining pazopanib with microtubule inhibitors such as paclitaxel produced heightened and synergistic antitumor effects in ATC cells and xenografts that were associated with potentiated mitotic catastrophe. We hypothesized that combined effects may reflect enhanced paclitaxel-induced cytotoxicity mediated by cell cycle regulatory kinase inhibition by pazopanib. Indeed, pazopanib potently inhibited aurora A, with pazopanib/paclitaxel synergy recapitulated by aurora A short hairpin RNA knockdown or by specific aurora A pharmacological inhibition. Pazopanib/paclitaxel synergy was reversed by aurora A knockdown. Moreover, aurora A (but not B or C) message and protein levels were significantly increased in patient ATCs, and durable benefit resulted from pilot clinical translation of pazopanib/paclitaxel therapy in a patient with metastatic ATC. Collectively, these results suggest that the pazopanib/paclitaxel combination is a promising candidate therapeutic approach in ATC and that aurora A may represent a potentially viable therapeutic molecular target in ATC.
Expression of Cocaine- and Amphetamine-Regulated Transcript Is Associated with Worse Survival in Small Bowel Carcinoid Tumors
Authors: Kalle Landerholm, Liliya Shcherbina, Sture E. Falkmer, Johannes Järhult, Nils Wierup
Journal: Clinical Cancer Research (2012)

Cocaine- and amphetamine-regulated transcript (CART) peptide exerts several regulatory functions acting both as neurotransmitter and hormone. We recently showed that CART is expressed in various neuroendocrine tumors, including small bowel carcinoids. The main objective of the present study was to examine whether CART expression is associated with survival in patients with small bowel carcinoid. Secondary aims were to assess whether CART expression is associated with other tumor characteristics or clinical symptoms.Specimens from 97 patients with small bowel carcinoids were examined for CART expression using immunohistochemistry. A CART score was introduced on the basis of the proportion of CART immunoreactive cells. On inclusion, specimens were examined by routine histopathologic methods and detailed clinical patient data were retrieved. The effect of CART on cell viability was assessed in vitro using two intestinal tumor cell lines.Expression of CART (P = 0.011) and increasing CART score (P = 0.033) were associated with worse disease-specific survival. Adjusting for age, disease stage, and tumor grade in multivariable analysis, CART expression was still associated with worse survival [Low CART HR, 5.47; 95% confidence interval (CI), 0.71-42.46; and High CART HR, 9.44; 95% CI, 1.14-78.14]. CART expression was not associated with patient age, disease stage, tumor grade, or any presenting symptom. Supporting our clinical data, we found that CART promoted tumor cell viability in vitro in two different tumor cell lines.Expression of CART in small bowel carcinoid tumors is associated with worse survival.
Sensitivity and exposure to indoor allergens in adults with differing asthma severity
Authors: WS Tunnicliffe, TJ Fletcher, K Hammond, K Roberts, A Custovic, A Simpson, A Woodcock, JG Ayres
Journal: European Respiratory Journal (1999)

In asthma, it is uncertain whether there is an association between degrees of exposure to domestic allergens and asthma severity. The pattern of sensitivity and exposure to common indoor allergens was examined in subjects with differing asthma severity. Sensitivity to house dust mite, dog and cat allergen and exposure to Der p 1, Can f 1 and Fel d 1 were assessed by skin prick tests and settled dust analysis in 28 subjects with severe asthma and 28 age- and sex-matched subjects with mild asthma (two declined skin prick test). All severe asthmatic subjects had at least one positive skin test and 20 of the 28 subjects were positive to all three allergens. Fourteen of the 26 subjects with mild asthma who took skin prick tests were positive to at least one, and one of these subjects was positive to the three allergens tested. Except for bedroom Fel d 1, the proportion of severe asthmatics both sensitized and exposed to each allergen at each site was significantly greater than the proportion sensitized and exposed in the mild asthma group. The geometric mean allergen concentrations, with the exception of bedroom Fel d 1, were greater in sensitized severe asthmatics than the sensitized mild asthmatics, which was significant for Der p 1 in bedroom samples and Can f 1 in bedroom and living room samples. These results support an association between the degrees of domestic allergen exposure in sensitized individuals and asthma severity.
Comparison of effects of three types of endurance, resistance and combination training on (cTnT and CKMB) in active males
Authors: Fakhreddin Rajaei, Hossein Mojtahedi, Amir Akbari, Mohammad Marandi
Journal: British Journal of Sports Medicine (2010)

The aim of this present study was to compare three types of endurance (E), resistance (R) and combined (C) exercise on cardiac biomarkers (cardiac troponin T and creatine kinase isoenzymes MB) in active men. 15 healthy and active young men (mean age ± SD of 23 ± 1.604 years, height 173 ± 3.751 m, weight 69 ± 8.742 kg and VO 2 max 51.48 ± 1.847 ml/kg/min) voluntarily participated. Each of the subjects did three types of exercise in 7 days interval. All of the subjects using the analysis of blood samples before and immediately after exercise were evaluated. Blood samples for biochemical indicators of cardiac (cTnT and CKMB) were analysed. Statistical analysis was performed using paired T independent and repeated measures analysis of variance (p≤0.05). Results indicate that CKMB increased significantly after all three types of exercise than before exercise levels. cTnT was also significantly elevated immediately after endurance training than the values before exercise, while they were not significantly different between the levels of cTnT after resistance and combination exercise than the values before exercise. Results show that short-term intense endurance training increased cTnT and CK MB that show the least sign of heart damage or exercise-induced cardiac fatigue, but resistance and combination exercise with the lack of significant change in cTnT levels after exercise do not induce physiologically important degenerative changes in myocardium. However, the clinical significance of these results requires further research.
PTU-136 Prevalence of Functional Gastrointestinal Disorders in Consecutive New Patient Referrals to a Gastroenterology Clinic: Abstract PTU-136 Table 1
Authors: U Shivaji, D Gracie, A Sainsbury, A C Ford
Journal: Gut (2013)

<h3>Introduction</h3> Functional gastrointestinal disorders (FGIDs), such as irritable bowel syndrome (IBS) and functional dyspepsia (FD), are common in the community. However, the amount of time that a Gastroenterologist spends dealing with these conditions in the outpatient department has not been well-described. We aimed to examine this issue. <h3>Methods</h3> Review of consecutive unselected new patient referrals to a single Gastroenterologist’s outpatient clinic during a 2-year period, from January 2010 to December 2011. All clinic letters were reviewed retrospectively, and symptoms reported by the patient at the initial consultation were recorded. Radiology, endoscopy, chemical pathology, and histopathology databases were then cross-examined in order to ascertain the final diagnosis following full investigation, to the level deemed appropriate by the consulting physician. <h3>Results</h3> There were 397 consecutive unselected new patient referrals (mean age 53.2 years, 231 (58.2%) female) to a single Gastroenterologist between January 2010 and December 2011. Of these, 155 (39.0%) were judged as being entirely due to an FGID after investigation, and another 12 (3.0%) were deemed as being partially related to FGIDs, meaning that 167 (42.0%) patients reported symptoms compatible with an FGID. The final diagnoses are listed in Table 1, with some patients reporting symptoms consistent with more than one FGID. The commonest FGID was IBS, followed by FD. Functional bowel disorders accounted for 38.9% of FGIDs seen in clinic. Number (n = 167) Percentage <h3>Conclusion</h3> FGIDs accounted for over 40% of a Gastroenterologist’s workload in clinic. Given that some of these conditions have a similar prevalence in the community, the disparity in prevalence among individual FGIDs seen in a Gastroenterology outpatient clinic suggests that General Practitioners are more comfortable dealing with some FGIDs than others. <h3>Disclosure of Interest</h3> None Declared
Influence of steady-state alterations in acid-base equilibrium on the fate of administered bicarbonate in the dog.
Authors: H J Adrogué, J Brensilver, J J Cohen, N E Madias
Journal: Journal of Clinical Investigation (1983)

Previous workers have shown that metabolic acidosis increases the apparent space through which administered bicarbonate is distributed. This finding has been ascribed to the accompanying acidemia and to the consequent availability of a large quantity of hydrogen ion that accumulates on nonbicarbonate tissue buffers during the development of acidosis. To test this hypothesis, bicarbonate space was measured in dogs with a broad range of steady-state plasma [HCO-3] in association with alkalemia as well as with acidemia. Appropriate combinations of pH and plasma [HCO-3] were achieved by pretreating the animals to produce graded degrees of each of the four cardinal, chronic acid-base disorders. Metabolic acidosis (n = 15) was produced by prolonged HCl-feeding; metabolic alkalosis (n = 17) by diuretics and a chloride-free diet; and respiratory acidosis (n = 9) and alkalosis (n = 8) by means of an environmental chamber. Animals with normal acid-base status (n = 4) were also studied. Sodium bicarbonate (5 mmol/kg) was infused over 10 min to the unanesthetized animals; observations were carried out over 90 min. The results obtained from animals with metabolic acid-base disturbances demonstrated an inverse relationship between bicarbonate space and initial plasma pH, confirming the previous findings of others. By contrast, the results obtained in animals with respiratory acid-base disturbances demonstrated a direct relationship between bicarbonate space and initial plasma pH. The pooled data revealed that bicarbonate space is, in fact, quite independent of the initial pH but is highly correlated with the initial level of extracellular [HCO-3]; dogs with low extracellular [HCO-3] (congruent to 10 meq/liter) whether acidemic or alkalemic, have a bicarbonate space that is 25% larger than normal and some 50% larger than in dogs with high extracellular [HCO-3] (congruent to 50 meq/liter). We conclude from these results that the increased bicarbonate space in metabolic acidosis (and respiratory alkalosis) does not reflect the availability of more hydrogen ions for release during bicarbonate administration, but merely evidences the wider range of titration (delta pH) of nonbicarbonate buffers that occurs during alkali loading whenever plasma [HCO-3] is low.
Contrasting effects of static and pulsatile pressure on carotid baroreceptor activity in dogs.
Authors: M W Chapleau, F M Abboud
Journal: Circulation Research (1987)

The purpose of this study was to contrast the effects of static and pulsatile pressure on carotid baroreceptor activity over a wide range of mean arterial pressure. Static and pulsatile pressure were applied to the isolated carotid sinus of dogs anesthetized with chloralose. Recordings were obtained from single baroreceptor units as well as from the whole sinus nerve or a large strand of the nerve. Three observations are reported. First, in single units the pulsatile pressure threshold, which averaged 48 +/- 8 (SEM) mm Hg, was far below the static pressure threshold, which averaged 79 +/- 8 mm Hg (p less than 0.05, n = 15). Thus, pulsatility decreased the threshold by an average of 31 mm Hg in contrast to the minimal or lack of decrease in threshold reported by others in aortic baroreceptors. Second, at moderate arterial pressures a shift from static to pulsatile pressure caused a decrease in single and multiple unit activities. In single units, the decrease approximated 15% (from 42.0 +/- 2.1 to 35.5 +/- 1.9 spikes/sec, p less than 0.05, n = 25). In all units, there was no diastolic nerve activity ("silence") when diastolic pressure was 1 to 10 mm Hg above static pressure threshold; 80% of the units exhibited "diastolic silence" when diastolic pressure was 20-30 mm Hg above threshold and 40% of the units showed silence at diastolic pressures 40-50 mm Hg above threshold. In whole nerve recordings, pulsatility increased activity from 57 +/- 15 to 142 +/- 29 spikes/sec (p less than 0.05) at low mean arterial pressures (50 and 75 mm Hg), as expected from the reduction in pressure threshold noted in single units, and decreased activity by approximately 15% (from 373 +/- 69 to 320 +/- 55 spikes/sec, p less than 0.05, n = 9) at mean arterial pressures of 125 and 150 mm Hg. This decrease in activity with a shift from static to pulsatile pressure at moderate arterial pressures has not been reported previously. Third, the static pressure-activity curve was sigmoid, and its gain peaked sharply at 75-100 mm Hg; in contrast, the pulsatile pressure-activity curve was linear between 25 and 150 mm Hg, and its maximum gain was half the maximum gain during static pressure. These differences between the static pressure-activity curve and the pulsatile pressure-activity curve were noted during both increases and decreases in carotid sinus pressure; both curves exhibited some hysteresis during the decreases in pressure.
The small GTPase RhoG mediates glioblastoma cell invasion
Authors: Aneta Kwiatkowska, Sebastien Didier, Shannon Fortin, Yayu Chuang, Timothy White, Michael E Berens, Elisabeth Rushing, Jennifer Eschbacher, Nhan L Tran, Amanda Chan, Marc Symons
Journal: Molecular Cancer (2012)

The invasion of glioblastoma cells into regions of the normal brain is a critical factor that limits current therapies for malignant astrocytomas. Previous work has identified roles for the Rho family guanine nucleotide exchange factors Trio and Vav3 in glioblastoma invasion. Both Trio and Vav3 act on the small GTPase RhoG. We therefore examined the role of RhoG in the invasive behavior of glioblastoma cells.We found that siRNA-mediated depletion of RhoG strongly inhibits invasion of glioblastoma cells through brain slices ex vivo. In addition, depletion of RhoG has a marginal effect on glioblastoma cell proliferation, but significantly inhibits glioblastoma cell survival in colony formation assays. We also observed that RhoG is activated by both HGF and EGF, two factors that are thought to be clinically relevant drivers of glioblastoma invasive behavior, and that RhoG is overexpressed in human glioblastoma tumors versus non-neoplastic brain. In search of a mechanism for the contribution of RhoG to the malignant behavior of glioblastoma cells, we found that depletion of RhoG strongly inhibits activation of the Rac1 GTPase by both HGF and EGF. In line with this observation, we also show that RhoG contributes to the formation of lamellipodia and invadopodia, two functions that have been shown to be Rac1-dependent.Our functional analysis of RhoG in the context of glioblastoma revealed a critical role for RhoG in tumor cell invasion and survival. These results suggest that targeting RhoG-mediated signaling presents a novel avenue for glioblastoma therapy.
BCR-ABL fusion transcript types and levels and their interaction with secondary genetic changes in determining the phenotype of Philadelphia chromosome–positive leukemias
Authors: Dan Jones, Rajyalakshmi Luthra, Jorge Cortes, Deborah Thomas, Susan O'Brien, Carlos Bueso-Ramos, Seema Hai, Farhad Ravandi, Marcos de Lima, Hagop Kantarjian, Jeffrey L. Jorgensen
Journal: Blood (2008)