tbuckley/cabot-search huggingface dataset:
RhoA Influences the Nuclear Localization of Extracellular Signal–Regulated Kinases to Modulate p21 <sup>Waf/Cip1</sup> Expression
Authors: Brian S. Zuckerbraun, Richard A. Shapiro, Timothy R. Billiar, Edith Tzeng
Journal: Circulation (2003)

The 42/44-kD mitogen-activated protein kinases (extracellular signal-regulated kinases, ERKs) regulate smooth muscle cell (SMC) cell-cycle progression and can either promote or inhibit proliferation depending on the activation status of the small GTPase RhoA. RhoA is involved in the regulation of the actin cytoskeleton and converges on multiple signaling pathways. However, the mechanism by which RhoA modulates ERK signaling is not well defined. The purpose of this investigation was to examine whether RhoA regulates ERK downstream signaling and cellular proliferation through its effects on the cytoskeleton and the nuclear localization of ERK.Treatment of SMCs with Clostridia botulinum C3 exoenzyme, which inhibits RhoA activation, decreased SMC proliferation to 24+/-7% of that of controls and increased p21Waf1/Cip1 transcription and protein levels. These effects of RhoA were reversed by inhibition of ERK phosphorylation. However, inactivation of RhoA did not alter levels of ERK phosphorylation but did increase nuclear localization of phosphorylated ERK. In addition, immunostaining demonstrated that phosphorylated ERK associated with the actin cytoskeleton, which was disrupted by C3 exoenzyme. Leptomycin B, an inhibitor of Crm1 that results in ERK nuclear accumulation, similarly increased p21Waf1/Cip1.RhoA inhibition increased levels of phosphorylated ERK in the cell nucleus. Inhibition of RhoA or pharmacological inhibition of nuclear export resulted in increased p21Waf1/Cip1 expression and decreased SMC proliferation, effects that were partially dependent on ERK. RhoA regulation of the actin cytoskeleton may determine ERK subcellular localization and its subsequent effects on SMC proliferation.
Cognition and Quality-of-Life Outcomes in the Targeted Temperature Management Trial for Cardiac Arrest
Authors: Venkatesh Aiyagari, Michael N. Diringer
Journal: JAMA Neurology (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Treating Idiopathic Intracranial Hypertension
Authors: Susan P. Mollan, Michael A. Burdon, Alex J. Sinclair
Journal: JAMA Neurology (2014)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
First Human Trial of FTY720, a Novel Immunomodulator, in Stable Renal Transplant Patients
Authors: Klemens Budde, Robert L. Schmouder, Reinhard Brunkhorst, Bjorn Nashan, Peter W. Lu[Combining Diaeresis]cker, Thomas Mayer, Somesh Choudhury, Andrej Skerjanec, Gerolf Kraus, Hans H. Neumayer
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. FTY720 is a novel immunomodulator to be developed for use in organ transplantation. The primary objective of this study was to measure safety, single-dose pharmacokinetics, and pharmacodynamics in stable renal transplant patients—the first human use of FTY720. This study used a randomized, double-blind, placebo-controlled design that explored single oral doses of FTY720 from 0.25 to 3.5 mg in 20 stable renal transplant patients on a cyclosporine-based regimen. Safety assessments and blood samples were taken predose and at multiple time points during a 96-h period postdose. Standard pharmacokinetic parameters were derived from the FTY720 whole blood concentrations, measured by HPLC/MS/MS. FTY720 was well tolerated, with no serious adverse events. Transient, asymptomatic bradycardia occurred after administration in 10 of 24 doses of FTY720. Pharmacokinetics are characterized by a prolonged absorption phase; the terminal elimination phase started 36 h after the administration, with elimination half-life (t1/2) ranging from 89 to 157 h independent of dose. Maximum plasma concentration and AUC were proportional to dose with low intersubject variability, the apparent volume of distribution (Vd/F) ranged from 1116 to 1737 L. FTY pharmacodynamics were characterized by a reversible transient lymphopenia within 6 h, the nadir being 42% of baseline. The lymphocyte count returned to baseline within 72 h in all dosing cohorts except the highest. Single oral doses of FTY720 ranging from 0.25 to 3.5 mg were well tolerated and caused a reversible selective lymphopenia. Transient, but asymptomatic bradycardia was the most common adverse event. The long t1/2 suggests less frequent dosing intervals. The size of Vd/F is in excess of blood volume, consistent with widespread tissue distribution
Influence of Tumor Size and Surgical Resection on Cell-Mediated Immunity in Mice2
Authors: Richard B. Whitney, Julia G. Levy, Anajane G. Smith
Journal: JNCI Journal of the National Cancer Institute (1974)

Tumor-specific immunity and general lymphoid cell competence were assessed in mice with 3-methylcholanthrene- induced transplantable tumors at various stages of development and after surgical resection. A significant level of tumor-specific immunity developed before palpable tumors were observed. The level of immunity increased slightly as tumors became palpable, then decreased, and finally disappeared completely when tumors were >10% of the total body weight. Resection rapidly increased the level of immunity. The response to both T- and B-cell mitogens decreased progressively with increasing tumor size but returned to normal levels after resection.
*Inhaled formoterol dry powder in the treatment of patients with reversible obstructive airway disease
Authors: I. Steffensen, P. Faurschou, H. Riska, J. Rostrup, T. Wegener
Journal: Allergy (1995)

Inhaled formoterol is a potent selective β 2 ‐agonist with rapid onset and at least 12‐h duration of bronchodilation. The aim of the study was to compare the bronchodilating effect of inhaled formoterol dry powder ‘dp) 12 μg b.i.d. with salbutamol dp 400 μg q.i.d. and placebo in patients with reversible obstructive airway disease ‘ROAD). The study design consisted of a closed 12‐week double‐blind, placebo‐controlled, multicenter trial followed by an open noncomparative, multicenter, 12‐month follow‐up trial, in which the tolerability of formoterol dp was assessed. A total of 304 patients ‘146 men, 158 women) aged 18‐79 years, ill during 0.1‐64 years, were randomized. No demographic or baseline differences were found among the different treatment groups. The bronchodilating effect of formoterol, assessed by morning premedication PEFR, was significantly superior to placebo ‘ P &lt; 0.0001) and salbutamol ‘ P &lt; 0.0001). Efficacy was maintained during the open follow‐up study with 12 μg b.i.d. in most of the patients. A few patients, however, needed 24 μg b.i.d. to control their ROAD. Formoterol 12 μg b.i.d. significantly reduced morning and evening asthma symptoms and sleep disturbances, and reduced significantly the need for rescue medication. The tolerability of the three treatment groups was comparable. In conclusion, formoterol 12 μg dp b.i.d. was significantly superior to both salbutamol 400 μg dp q.i.d. and placebo, and reduced asthma symptoms significantly. Overall, formoterol showed a tolerability profile comparable to that of salbutamol, and no tachyphylaxis was observed during 1 year of treatment.
Isolation and properties of the leukocytosis- and lymphocytosis-promoting factor of Bordetella pertussis.
Authors: S I Morse, J H Morse
Journal: The Journal of Experimental Medicine (1976)

The leukocytosis- and lymphocytosis-promoting factor (LPF) of Bordetella pertussis has been isolated to near homogeneity by physical, chemical, and electron microscopical criteria. LPF contains 14.5% nitrogen and is lipid and carbohydrate free. It is apparently composed of four polypeptide subunits. LPF caused leukocytosis and lymphocytosis in "nude" as well as in normal mice. In addition, purified LPF also induced histamine sensitization and hypoglycemia and refractoriness to the hyperglycemic effect of epinephrine. A monospecific LPF antiserum blocked these reactions as well as leukocytosis and lymphocytosis. LPF is clearly distinct from the hemagglutinating pili of B. pertussis.
Alpha-1-antitrypsin deficiency: a biological enigma.
Authors: A G Bearn
Journal: Gut (1978)

The association of certain forms of liver disease and a deficiency of alpha-1-antitrypsin is an observation which raises the possibility that other forms of liver disease ultimately will be found to have as their proximate cause a defined metabolic aberration, which may in turn be inherited. Although alpha-1-antitrypsin deficiency is a genetically determined error of protein synthesis, environmental factors, unrecognised at present, are required for the disease to become overt. Thus, this interesting association may herald an increasing number of clinical diseases in which the interaction of environmental stimuli and single genetically determined aberrations are crucially important. The diseases to which we succumb may be largely determined by a genetically determined susceptibility, a point of view which was stated so well by Archibalt Garrod in his essay Inborn Factors in Disease published nearly half a century ago.
Comment on Genuth. Should Sulfonylureas Remain an Acceptable First-Line Add-on to Metformin Therapy in Patients With Type 2 Diabetes? No, It’s Time to Move On! Diabetes Care 2015;38:170–175
Authors: Dennis Schrijnders, Sebastiaan T. Houweling, Gijs W.D. Landman
Journal: Diabetes Care (2015)

Genuth (1) discusses in a Counterpoint article several arguments against the use of sulfonylureas (SUs) as an add-on therapy to metformin. We understand that in this format he makes arguments against the use of SUs; however, we could not appreciate his oversimplification by ignoring within-class differences. Specifically, the safety of gliclazide is not recognized.

In the 2013 Dutch type 2 diabetes guidelines from the …
Disparity in Outcomes of Surgical Revascularization for Limb Salvage
Authors: Louis L. Nguyen, Nathanael Hevelone, Selwyn O. Rogers, Dennis F. Bandyk, Alexander W. Clowes, Gregory L. Moneta, Stuart Lipsitz, Michael S. Conte
Journal: Circulation (2008)

Background— Vein bypass surgery is an effective therapy for atherosclerotic occlusive disease in the coronary and peripheral circulations; however, long-term results are limited by progressive attrition of graft patency. Failure of vein bypass grafts in patients with critical limb ischemia results in morbidity, limb loss, and additional resource use. Although technical factors are known to be critical to the success of surgical revascularization, patient-specific risk factors are not well defined. In particular, the relationship of race/ethnicity and gender to the outcomes of peripheral bypass surgery has been controversial. Methods and Results— We analyzed the Project of Ex Vivo Vein Graft Engineering via Transfection III (PREVENT III) randomized trial database, which included 1404 lower extremity vein graft operations performed exclusively for critical limb ischemia at 83 North American centers. Trial design included intensive ultrasound surveillance of the bypass graft and clinical follow-up to 1 year. Multivariable modeling (Cox proportional hazards and propensity score) was used to examine the relationships of demographic variables to clinical end points, including perioperative (30-day) events and 1-year outcomes (vein graft patency, limb salvage, and patient survival). Final propensity score models adjusted for 16 covariates (including type of institution, technical factors, selected comorbidities, and adjunctive medications) to examine the associations between race, gender, and outcomes. Among the 249 black patients enrolled in PREVENT III, 118 were women and 131 were men. Black men were at increased risk for early graft failure (hazard ratio [HR], 2.832 for 30-day failure; 95% confidence interval [CI], 1.393 to 5.759; P =0.0004), even when the analysis was restricted to exclude high-risk venous conduits. Black patients experienced reduced secondary patency (HR, 1.49; 95% CI, 1.08 to 2.06; P =0.016) and limb salvage (HR, 2.02; 95% CI, 1.27 to 3.20; P =0.003) at 1 year. Propensity score models demonstrate that black women were the most disadvantaged, with an increased risk for loss of graft patency (HR, 2.02 for secondary patency; 95% CI, 1.27 to 3.20; P =0.003) and major amputation (HR, 2.38; 95% CI, 1.18 to 4.83; P =0.016) at 1 year. Perioperative mortality and 1-year mortality were similar across race/gender groups. Conclusions— Black race and female gender are risk factors for adverse outcomes after vein bypass surgery for limb salvage. Graft failure and limb loss are more common events in black patients, with black women being a particularly high-risk group. These data suggest the possibility of an altered biological response to vein grafting in this population; however, further studies are needed to determine the mechanisms underlying these observed disparities in outcome.
Adipose-derived resistin and gut-derived resistin-like molecule–β selectively impair insulin action on glucose production
Authors: Michael W. Rajala, Silvana Obici, Philipp E. Scherer, Luciano Rossetti
Journal: Journal of Clinical Investigation (2003)

The adipose-derived hormone resistin is postulated to link obesity to insulin resistance and diabetes. Here, the infusion of either resistin or the resistin-like molecule-beta (RELMbeta) rapidly induced severe hepatic but not peripheral insulin resistance. In the presence of physiologic hyperinsulinemia, the infusion of purified recombinant resistin, increasing circulating resistin levels by approximately twofold to 15-fold, inhibited glucose metabolism such that lower rates of glucose infusion were required to maintain the plasma glucose concentration at basal levels. The effects of resistin and RELMbeta on in vivo insulin action were completely accounted for by a marked increase in the rate of glucose production. These results support the notion that a novel family of fat- and gut-derived circulating proteins modulates hepatic insulin action.
Variability of peak expiratory flow rate in children: short and long term reproducibility.
Authors: T Frischer, R Meinert, R Urbanek, J Kuehr
Journal: Thorax (1995)

BACKGROUND--Variability of peak expiratory flow (PEF) has been proposed as a surrogate for bronchial hyperresponsiveness. The normal range of variability of PEF for children has been reported and the test has been used to screen for asthma in population based studies. However, there is little information on the reproducibility of the method in epidemiological settings. METHODS--In a cohort study of primary school children the variability in PEF was recorded in two consecutive years for one week (first survey) and two weeks (second survey) using mini Wright peak flow meters. PEF was recorded twice daily (morning and evening) and average amplitude as a percentage of mean was calculated as a standard measure of PEF variability for each single week of PEF measurement. Children with PEF variability exceeding the 90% percentile of the distribution for the specific time period were regarded as having increased variability of PEF. RESULTS--Of 66 children with increased PEF variability in the first year, 13 (19.7%) had an abnormal test in the first week of the second year. Of 543 children with normal PEF variability in the first year, 44 (8.1%) had an abnormal test in the second study year (odds ratio 2.8, confidence interval (CI) 1.4 to 5.4). Of 646 children in the second survey 61 (9.4%) were abnormal during the first week and 68 (10.5%) had an increased PEF variability during the second week, but only 24 (3.7%) children had an increased PEF variability in both weeks. The sensitivity (specificity) for doctor-diagnosed asthma (12 month period prevalence) was 36.4% (91.0%) in the first week of the second survey. When measurements of both weeks of the second survey were used to calculate PEF variability there was little improvement in the sensitivity (38.1%) and specificity (91.5%), mainly because of decreased compliance in the second measurement week. CONCLUSIONS--In young children assessment of PEF variability in order to screen for asthma is of limited value because of the low reproducibility of the method.
Phase I Study of the Novel Epothilone Analog Ixabepilone (BMS-247550) in Patients With Advanced Solid Tumors and Lymphomas
Authors: Carol Aghajanian, Howard A. Burris, Suzanne Jones, David R. Spriggs, Marvin B. Cohen, Ronald Peck, Paul Sabbatini, Martee L. Hensley, F. Anthony Greco, Jakob Dupont, Owen A. O'Connor
Journal: Journal of Clinical Oncology (2007)

To establish the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or relapsed/refractory non-Hodgkin's lymphoma. Dosing schedules of 40 mg/m2 and 50 mg/m2 over 3 hours were also evaluated.Sixty-one patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase, with doses of ixabepilone ranging from 7.4 to 65 mg/m2. The pharmacokinetics of ixabepilone and two of its chemical degradation products were evaluated. Plasma pharmacodynamics were evaluated for both 1- and 3-hour infusions using an assay that measures the amount of endogenous tubulin in peripheral-blood mononuclear cells that exists in the polymerized versus the unpolymerized state. Response evaluation was performed every 6 weeks.The most common DLTs were neutropenia, stomatitis/pharyngitis, myalgia, and arthralgia. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The maximum plasma concentration and area under the plasma concentration time curve appeared to increase less than proportionally to dose. Durable objective responses were seen in eight patients, including two complete responses. Five of the responders had experienced treatment failure with a taxane.The recommended dose of ixabepilone for the initiation of phase II studies on the basis of these results is 50 mg/m2 over 1 hour every 3 weeks. The promising efficacy and tolerability results demonstrated by ixabepilone in this study warrant its continued development.
The Clinician as Investigator
Authors: Ellis W. Lader, Christopher P. Cannon, E. Magnus Ohman, L. Kristin Newby, Daniel P. Sulmasy, Robyn J. Barst, Joan M. Fair, Marcus Flather, Jane E. Freedman, Robert L. Frye, Mary M. Hand, Robert L. Jesse, Frans Van de Werf, Fernando Costa
Journal: Circulation (2004)

The American Heart Association makes every effort to avoid
APE1 and XRCC1 Protein Expression Levels Predict Cancer-Specific Survival Following Radical Radiotherapy in Bladder Cancer
Authors: Sei C. Sak, Patricia Harnden, Colin F. Johnston, Alan B. Paul, Anne E. Kiltie
Journal: Clinical Cancer Research (2005)

Abstract Introduction: Radiotherapy offers the potential of bladder preservation in muscle-invasive bladder cancer, but only a proportion of tumors respond, and there are no accurate predictive methods. The ability of tumor cells to repair DNA damage induced by ionizing radiation influences radiosensitivity. We therefore investigated the prognostic value of the DNA repair proteins APE1 and XRCC1 in patients with muscle-invasive bladder cancer treated by radical radiotherapy. Materials and Methods: The tumors of 90 patients with muscle-invasive transitional cell carcinoma and known clinical outcomes were immunostained with APE1 and XRCC1 antibodies. Levels of protein expression were assessed as a percentage of tumor cells with positive nuclear staining (1,000 cells per tumor). Results: The median percentage of nuclear staining for APE1 was 98.7% (range, 42.2-100%) and for XRCC1 was 96.5% (range, 0.6-99.6%). High expression levels of APE1 or XRCC1 (≥95% positivity) were associated with improved patient cancer-specific survival (log-rank, P = 0.02 and 0.006, respectively). In a multivariate Cox regression model, APE1 and XRCC1 expression and hydronephrosis were the only independent predictors of patient survival. Conclusions: Expression levels of both APE1 and XRCC1 proteins were strongly associated with patient outcome following radiotherapy, separating patients with good outcome from the 50% with poor outcome (82% and 44%, 3-year cause-specific survival, respectively). If prospectively validated, this simple test could be incorporated into clinical practice to select patients likely to respond to radiotherapy and consider alternative forms of therapy for those unlikely to respond.
Pentraxin-3: A novel biomarker for the differentiation of parapneumonic effusion and malignant pleural effusion
Authors: Savas Ozsu, Yasin Abul, Ahmet Mentese, Hayriye Bektas, Aysegül Uzun, Tevfik Ozlu
Journal: European Respiratory Journal (2012)

Pentraxin-3(PTX-3) is a new marker of inflammation. Pentraxins like C-reactive protein are key components of the innate immune system. Diagnostic value of PTX-3 in parapneumonic pleural effusion (PPPE) and malign pleural effusion(MPE) has not been examined before.

The concentrations of pleural fluid PTX-3 were measured in a total of 61 patients: 20 with PPPE and 41 with MPE. A diagnosis PPPE was based upon the presence of an effusion in patients with clinical and radiological evidence of acute pneumonia. A malignant pleural effusion(PE) was defined by pleural biopsy or the presence of malignant cells on PE cytology. The area under the curve (AUC) quantified the overall diagnostic accuracy of the tests.

The study demonstrated that PTX-3 concentration was higher in pleural fluid of PPPE patients compared with MPE patients (31.8 ng/mL vs 6.9 ng/mL, respectively, p<0.001). Pleural effusion PTX-3 demonstrated AUCs of 0.802 (95% CI: 0.683–0.921, P<0.001) for diagnosing effusions due to PPPE. The sensitivity and specificity of PE-PTX-3 for PPPE at the cut-off concentration of 8.5 ng/mL was 80% and 64 %, respectively.

Measuring PTX-3 concentrations in pleural fluid may be helpful in distinguishing pleural effusion due to a PPPE or MPE aetiology.