tbuckley/cabot-search huggingface dataset:
A Critical Role for p130<sup>Cas</sup> in the Progression of Pulmonary Hypertension in Humans and Rodents
Authors: Ly Tu, Frances S. De Man, Barbara Girerd, Alice Huertas, Marie-Camille Chaumais, Florence Lecerf, Charlène François, Frédéric Perros, Peter Dorfmüller, Elie Fadel, David Montani, Saadia Eddahibi, Marc Humbert, Christophe Guignabert
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Rationale: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by pulmonary arterial muscularization due to excessive pulmonary vascular cell proliferation and migration, a phenotype dependent upon growth factors and activation of receptor tyrosine kinases (RTKs). p130Cas is an adaptor protein involved in several cellular signaling pathways that control cell migration, proliferation, and survival.Objectives: We hypothesized that in experimental and human PAH p130Cas signaling is overactivated, thereby facilitating the intracellular transmission of signal induced by fibroblast growth factor (FGF)2, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF).Measurements and Main Results: In patients with PAH, levels of p130Cas protein and/or activity are higher in the serum, in the walls of distal pulmonary arteries, in cultured smooth muscle cells (PA-SMCs), and in pulmonary endothelial cells (P-ECs) than in control subjects. These abnormalities in the p130Cas signaling were also found in the chronically hypoxic mice and monocrotaline-injected rats as models of human PAH. We obtained evidence for the convergence and amplification of the growth-stimulating effect of the EGF-, FGF2-, and PDGF-signaling pathways via the p130Cas signaling pathway. We found that daily treatment with the EGF-R inhibitor gefitinib, the FGF-R inhibitor dovitinib, and the PDGF-R inhibitor imatinib started 2 weeks after a subcutaneous monocrotaline injection substantially attenuated the abnormal increase in p130Cas and ERK1/2 activation and regressed established pulmonary hypertension.Conclusions: Our findings demonstrate that p130Cas signaling plays a critical role in experimental and idiopathic PAH by modulating pulmonary vascular cell migration and proliferation and by acting as an amplifier of RTK downstream signals.
Exenatide Affects Circulating Cardiovascular Risk Biomarkers Independently of Changes in Body Composition
Authors: Mathijs C. Bunck, Michaela Diamant, Bjorn Eliasson, Anja Cornér, Rimma M. Shaginian, Robert J. Heine, Marja-Riitta Taskinen, Hannele Yki-Järvinen, Ulf Smith
Journal: Diabetes Care (2010)

OBJECTIVE To study the effect of exenatide on body composition and circulating cardiovascular risk biomarkers. RESEARCH DESIGN AND METHODS Metformin-treated patients with type 2 diabetes (N = 69) were randomized to exenatide or insulin glargine and treated for 1 year. Body composition was evaluated by dual-energy X-ray absorptiometry. Additionally, body weight, waist circumference, and cardiovascular biomarkers were measured. RESULTS Treatment with exenatide for 1 year significantly reduced body weight, waist circumference, and total body and trunkal fat mass by 6, 5, 11, and 13%, respectively. In addition, exenatide increased total adiponectin by 12% and reduced high-sensitivity C-reactive protein by 61%. Insulin glargine significantly reduced endothelin-1 by 7%. These changes were statistically independent of the change in total body fat mass and body weight. CONCLUSIONS Exenatide treatment for 1 year reduced body fat mass and improved the profile of circulating biomarkers of cardiovascular risk. No significant changes were seen with insulin glargine except a trend for reduced endothelin-1 levels.
Regression of Electrocardiographic Left Ventricular Hypertrophy During Antihypertensive Treatment and the Prediction of Major Cardiovascular Events
Authors: Peter M Okin, Richard B Devereux, Sverker Jern, Sverre E Kjeldsen, Stevo Julius, Markku S Nieminen, Steven Snapinn, Katherine E Harris, Peter Aurup, Jonathan M Edelman, Hans Wedel, Lars H Lindholm, Björn Dahlöf
Journal: JAMA (2004)

Electrocardiographic left ventricular hypertrophy (LVH) is a strong predictor of cardiovascular (CV) morbidity and mortality. However, the predictive value of changes in the magnitude of electrocardiographic LVH criteria during antihypertensive therapy remains unclear.To test the hypothesis that lesser severity of electrocardiographic LVH during antihypertensive treatment is associated with decreased CV morbidity and mortality, independent of blood pressure levels and reduction and treatment modality.Double-blind, randomized, parallel-group study conducted in 1995-2001 among 9193 men and women with hypertension aged 55 through 80 years (mean, 67 years), with electrocardiographic LVH by Cornell voltage-duration product or Sokolow-Lyon voltage criteria and enrolled in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study.Losartan- or atenolol-based treatment regimens, with follow-up assessments for at least 4 (mean, 4.8 [SD, 0.9]) years.Composite end point of CV death, myocardial infarction (MI), or stroke in relation to severity of electrocardiographic LVH determined at baseline and on subsequent electrocardiograms obtained at 1 or more annual revisits.Cardiovascular death, nonfatal MI, or stroke occurred in 1096 patients (11.9%). In Cox regression models controlling for treatment type, baseline Framingham risk score, baseline and in-treatment blood pressure, and severity of baseline electrocardiographic LVH by Cornell product and Sokolow-Lyon voltage, less-severe in-treatment LVH by Cornell product and Sokolow-Lyon voltage were associated with 14% and 17% lower rates, respectively, of the composite CV end point (adjusted hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.82-0.90; P<.001 for every 1050-mm x ms [1-SD] decrease in Cornell product; and HR, 0.83; 95% CI, 0.78-0.88; P<.001 for every 10.5-mm [1-SD] decrease in Sokolow-Lyon voltage). In parallel analyses, lower Cornell product and Sokolow-Lyon voltage were each independently associated with lower risks of CV mortality (HR, 0.78; 95% CI, 0.73-0.83; P<.001; and HR, 0.80; 95% CI, 0.73-0.87; P<.001, respectively), MI (HR, 0.90; 95% CI, 0.82-0.98; P=.01; and HR, 0.90; 95% CI, 0.81-1.00; P = .04), and stroke (HR, 0.90; 95% CI, 0.84-0.96; P=.002; and HR, 0.81; 95% CI, 0.75-0.89; P<.001).Less-severe electrocardiographic LVH by Cornell product and Sokolow-Lyon voltage criteria during antihypertensive therapy is associated with lower likelihoods of CV morbidity and mortality, independent of blood pressure lowering and treatment modality in persons with essential hypertension. Antihypertensive therapy targeted at regression or prevention of electrocardiographic LVH may improve prognosis.
Ultrasonographic evaluation of mediastinal lymph nodes using endobronchial ultrasound
Authors: Hanaa Shafiek, Federico Fiorentino, Alejandro Peralta, Jaume Sauleda, Borja G. Cosio
Journal: European Respiratory Journal (2013)

Background: Endobronchial ultrasound (EBUS) has the ability to visualize the mediastinal and hilar lymph nodes (LN). Preliminary studies have shown that ultrasonographic (US) appearance might have predictive value for malignancy. Objectives: To evaluate the utility of the EBUS ultrasonographic features in predicting benign and malignant LN and validate the previously proposed score of combined US criteria as a score for clinical application. Methods: The study enrolled 142 patients with 189 hilar/mediastinal LN. The following US features were evaluated: short axis ≥1cm, round shape, heterogenicity, distinct margin, absence of central hilar structure (CHS) and the presence of hyperechoic density inside the LN. A simplified score was generated where the presence of each criteria was scored as 1 except for the distinct margin that was scored between (0= indistinct to 2= well distinct). These criteria were correlated with the histopathological results and the sensitivity, specificity, positive and negative predictive values were calculated. Results: Malignancy was the diagnosis in 54% of the involved LN. It was found that heterogenicity had the best sensitivity (99%) in predicting malignant LN and the presence of hyperechoic density inside LN had the best specificity (78%). Both the heterogenicity and the absence of CHS (with or without blood vessels) had the best negative predictive value (93% and 89% respectively). A score >4 of the different criteria had a sensitivity of 86% in predicting malignant LN and that >5 showed a specificity of 80%. Conclusion: The proposed score of the US features of the LN is easy for onsite clinical application and have a good prediction for malignant LN.
Intrarenal Renin-Angiotensin System Is Upregulated in Experimental Model of Progressive Renal Disease Induced by Chronic Inhibition of Nitric Oxide Synthesis
Authors: Miguel Luis Graciano, Rita de Cassia Cavaglieri, Humberto Dellê, Wagner Vasquez Dominguez, Dulce Elena Casarini, Denise Maria Avancini Costa Malheiros, Irene L Noronha
Journal: Journal of the American Society of Nephrology (2004)

Locally generated angiotensin II (AngII) may be involved in the pathogenic mechanisms of chronic renal diseases. Renal expression of AngII and other components of the renin-angiotensin system (RAS) were analyzed by immunohistochemistry and Western blot in a model of chronic progressive nephropathy induced by inhibition of nitric oxide synthesis. Renal injury was evaluated by histology and albumin excretion. Systemic RAS status was evaluated through plasma renin activity (PRA) and plasma AngII concentration. In addition, the effects of enalapril, losartan, and mycophenolate mofetil (MMF) on AngII expression in animals with chronic renal disease was also analyzed. Plasma renin activity and plasma AngII were not different between rats with nephropathy and controls (2.08 +/- 0.7 versus 2.03 +/- 0.5 ng/ml/h and 94.3 +/- 18 versus 78.9 +/- 16 fmol/ml, respectively). However, rats with chronic progressive nephropathy showed augmented renal content of angiotensinogen protein (13.5 +/- 3.5 versus 2.2 +/- 0.4 pixels in control rats; P < 0.05), enhanced expression of cathepsin D-a renin-like enzyme-in cortical collecting tubules (103.5 +/- 27.0 versus 66.2 +/- 3.6 cells/mm2 in controls; P < 0.01), and increased expression of AT1 receptor in interstitium (54.7 +/- 7.8 versus 1.3 +/- 0.4 cells/mm2 in controls; P < 0.001). Kidney angiotensin-converting enzyme content did not differ among the groups. Notably, an increased number of interstitial cells expressing AngII was detected in the renal interstitium (9.5 +/- 1.6 versus 1.7 +/- 0.6 cells/mm2 in controls; P < 0.05). Rats treated with Nomega-nitro-L-arginine-methyl-esther and losartan presented a decreased local AngII formation, in contrast to its known effect on plasma AngII. Moreover, mycophenolate mofetil lowered interstitial AngII expression, suggesting that inflammatory signaling may be involved in interstitial AngII generation. This study demonstrates the upregulation of local RAS in the kidney in a model of chronic progressive nephropathy.
The class of surface immunoglobulin on cells carrying IgG memory in rat thoracic duct lymph: the size of the subpopulation mediating IgG memory.
Authors: D W Mason
Journal: The Journal of Experimental Medicine (1976)

The fluorescence activated cell sorter was used to determine the class of immunoglobulin on the thoracic duct lymphocytes (TDL) which carried IgG memory. Although only about 3% of all TDL carried membrane IgG these cells accounted for most, if not all, of the adoptive IgG anti-DNP response. It is concluded that both CR+ and CR- cells mediating IgG memory in rat TDL bear the same class of membrane immunoglobulin as that secreted by their differentiated progeny. The class of membrane immunoglobulin on CR+ and CR- rat TDL was also examined. It was found that IgM+ cells, which made up over 80% of all Ig+ cells, were virtually all CR+. In contrast, the few percent of IgG+ and IgA+ cells present were to be found in both subpopulations. There was no evidence of a large population of B cells bearing exclusively heavy chains other than IgA, IgG, of IgM. The observation that some IgG+ cells as well as IgM+ cells possess a receptor for C3 appears to rule out the hypothesis that this receptor is involved in blocking a switch from IgM to IgG synthesis.
Comparative effects of calcipotriol (MC903) solution and placebo (vehicle of MC903) in the treatment of psoriasis of the scalp
Authors: C. GREEN, M. GANPULE, D. HARRIS, G. KAVANAGH, G. KENNEDY, R. MALLETT, M. RUSTIN, N. DOWNES
Journal: British Journal of Dermatology (1994)

The efficacy and safety of calcipotriol solution in the treatment of scalp psoriasis was compared with placebo (vehicle solution), in a multicentre double-blind, randomized, parallel-group study of 49 adult patients. Calcipotriol solution (50 micrograms/ml), or placebo, was applied twice daily over a 4-week period. At the end of the study period 60% of patients on calcipotriol showed clearance or marked improvement of their psoriasis compared with 17% on placebo. Overall assessment of treatment response showed that calcipotriol was superior to placebo in both investigator (P < 0.001; 95% confidence interval for difference 19.0-67.6) and patient (P < 0.001; 95% confidence interval for difference 18.3-68.0) assessments. Total sign score for psoriasis (i.e. the sum of the scores for redness, thickness and scaliness) decreased by 48.9% in the calcipotriol group, and by 18.6% in the placebo group (P = 0.005). Calcipotriol was significantly superior to placebo in reducing redness, thickness, scaliness and extent of psoriasis, and in the patients' assessment in reducing scalp flaking and itching. No statistically significant changes in blood biochemistry were detected during the study, and the solution was generally well tolerated.
Does "A" stand for alveolization?
Authors: J.S. Torday, V.K. Rehan
Journal: European Respiratory Journal (2003)

The current issue of the European Respiratory Journal (ERJ) publishes a report by Hind and Maden 1 showing vitamin A induction of alveolization which has been read with great interest. Vitamin A is a nutrient that is important for lung organogenesis, homeostasis and repair. It was more than 60 years ago that Wolbach and Howe 2 first demonstrated that vitamin A deprivation caused squamous metaplasia of conducting airway epithelium, that could be reversed by vitamin A repletion. Since this report many clinical studies and animal models, have supported the importance of dietary retinoids in lung morphogenesis and repair. These studies have generated optimism that retinoic acid might be useful for promoting alveolization in both the premature neonatal and emphysematous adult lung. Premature infants who are at risk of developing bronchopulmonary dysplasia (BPD) have low retinoid liver stores and blood levels at birth 3, 4. In fact, infants who develop BPD show squamous metaplasia of the conducting airways and show alveolar arrest, findings similar to those occurring in vitamin A-depleted animals. Therefore, it is not surprising that several investigators suggest that thecourse of BPD in very low birth-weight infants can be ameliorated by supplemental vitamin A 5, 6. In a randomised, controlled multicentre clinical trial, vitamin A supplementation caused a small, but significant reduction in BPD 7.

The involvement of vitamin A, not only as a preventive but also as a therapeutic role in lung injury, has previously been suggested by many investigators. For example, …
Doxorubicin Cardiotoxicity in the Elderly: Old Drugs and New Opportunities
Authors: Joseph R. Carver, Stephen J. Schuster, John H. Glick
Journal: Journal of Clinical Oncology (2008)

Non-Hodgkin's lymphoma is a frequent disease in older patients, and at least half of non-Hodgkin's lymphoma diagnoses occur in patients older than 65 years. 1 This diagnosis presents special challenges in the older population because of pre-existing comorbidities, changes in drug pharmacokinetics, and poorer response rates and other outcomes.In addition, the lack of enrollment of older patients with existing comorbidities, such as cardiac disease, onto clinical trials has limited the accumulation of evidence-based clinical knowledge. 2nthracycline-based chemotherapy improves survival in multiple solid and hematologic malignancies.Doxorubicin is the anthracycline used most frequently in the treatment of diffuse large B-cell lymphoma as part of the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen, with or without rituximab (R-CHOP).The use of doxorubicin is associated with, and often limited by, a risk of cardiotoxicity manifested by left ventricular dysfunction.
β-Catenin Signaling Controls Metastasis in Braf-Activated Pten-Deficient Melanomas
Authors: William E. Damsky, David P. Curley, Manjula Santhanakrishnan, Lara E. Rosenbaum, James T. Platt, Bonnie E. Gould Rothberg, Makoto M. Taketo, David Dankort, David L. Rimm, Martin McMahon, Marcus Bosenberg
Journal: Cancer Cell (2011)

Malignant melanoma is characterized by frequent metastasis, however, specific changes that regulate this process have not been clearly delineated. Although it is well known that Wnt signaling is frequently dysregulated in melanoma, the functional implications of this observation are unclear. By modulating β-catenin levels in a mouse model of melanoma that is based on melanocyte-specific Pten loss and BrafV600E mutation, we demonstrate that β-catenin is a central mediator of melanoma metastasis to the lymph nodes and lungs. In addition to altering metastasis, β-catenin levels control tumor differentiation and regulate both MAPK/Erk and PI3K/Akt signaling. Highly metastatic tumors with β-catenin stabilization are very similar to a subset of human melanomas. Together these findings establish Wnt signaling as a metastasis regulator in melanoma.
Islet-Specific Antibody Seroconversion in Patients With Long Duration of Permanent Neonatal Diabetes Caused by Mutations in the <i>KCNJ</i>11 Gene
Authors: Agnieszka Gach, Krystyna Wyka, Maciej T. Malecki, Anna Noczynska, Jan Skupien, Joanna Nazim, Mieczyslaw Szalecki, Jerzy Bodalski, Jacek Sieradzki, Wojciech Mlynarski
Journal: Diabetes Care (2007)

Heterozygous activating mutations in the KCNJ 11 gene are a common cause of permanent neonatal diabetes (PNDM) (1,2). In contrast to the autoimmune type 1 diabetes, patients with KCNJ 11 mutations do not have serological markers of autoimmune β-cell destruction at disease onset (1,3–5). In such patients, hyperglycemia does not result from insulin-secreting cell destruction but rather from impaired insulin secretion. In addition, the majority of cases can be corrected with sulfonylurea therapy (2,6). Here, we report that carriers of the KCNJ 11 mutation that are immunonegative at onset may show presence of islet antibodies in the further course of the disease.

We sought to evaluate the clinical and genetic characteristics of patients with neonatal diabetes in Poland, using the Nationwide Registry, which was established in 2005 (7,8). Automatic sequencing of the KCNJ 11 gene allowed identification of 15 patients with heterozygous mutations that cause neonatal diabetes. Sera from 11 carriers of the KCNJ 11 gene mutation were available for the present study. None of the patients had a family history of type 1 diabetes. Informed consent was obtained from all subjects or their parents. The study was conducted in accordance with the Declaration of Helsinki (revised in 2000) and accepted by the local ethics committee in Lodz, Poland.

### β-Cell antibody analysis

#### At diabetes onset.

Available data on …
Structural requirements for class I MHC molecule-mediated antigen presentation and cytotoxic T cell recognition of an immunodominant determinant of the human immunodeficiency virus envelope protein.
Authors: H Takahashi, R Houghten, S D Putney, D H Margulies, B Moss, R N Germain, J A Berzofsky
Journal: The Journal of Experimental Medicine (1989)

In H-2d mice, the immunodominant determinant of the HIV-1-IIIB gp160 envelope glycoprotein recognized by CD8+ CTL is represented by a 15-residue synthetic peptide (315-329: RIQRGPGRAFVTIGK). This peptide is seen in association with the Dd class I MHC molecule expressed on H-2k L cell fibroblast targets. We explored the structural requirements for CTL recognition of this peptide at the levels of both the peptide molecule and the class I MHC molecule. Using several transfectants expressing recombinant Dd/Ld molecules, we found that presentation of this epitope required both the alpha 1 and alpha 2 domains of the Dd molecule, in contrast to certain instances of allorecognition for which alpha 1 of Dd was sufficient in association with alpha 2 of Ld. Because this peptide derives from a hypervariable segment of the HIV envelope, substituted peptides could be used to define not only the structures affecting interaction of peptide with class I MHC molecule and with the TCR, but also the structural basis for the effect of naturally occurring viral variation on CTL recognition. The CTL-LINE specific for this HIV-1-IIIB-derived sequence could not recognize the HIV-1-RF variant-derived sequence from exactly the same site (315-329:--HIGPGRVIYATGQ). Peptides with single amino acid substitutions from the HIV-1-IIIB sequence toward the HIV-1-RF sequence were made to test the effect of each residue significantly affected recognition, and only one, 324(F), was obligatory. Moreover, both 322(R) and 324(F) substituted peptides failed to inhibit the binding of the wild type peptide to the MHC molecule. Therefore, the amino-acids 322(R) and 324(F) seem to be involved in regulating peptide interaction with the Dd class I MHC molecule. In contrast, 325(V) appeared to affect interaction with the TCR. We suggest that sequence variations among known HIV-1 isolates that affect peptide binding to MHC such as those described here, if occurring during the course of infection of an individual, could result in failure of the MHC molecules of that individual to present the peptide. If the number of dominant HIV CTL epitopes is indeed very limited, such a blind spot could allow the virus to escape immune control, proliferate rapidly, and cause AIDS.
Mechanistic study of the adjuvant effect of biodegradable nanoparticles in mucosal vaccination
Authors: Bram Slütter, Laurence Plapied, Virgine Fievez, Maria Alonso Sande, Anne des Rieux, Yves-Jacques Schneider, Elly Van Riet, Wim Jiskoot, Véronique Préat
Journal: Journal of Controlled Release (2009)
Rapid Clearance Of JAK2 V617F Allele Burden In Patient With Advanced Polycythemia Vera (PV) During Combination Therapy With Ruxolitinib and Peg-Interferon Alpha-2a
Authors: Mads Emil Bjørn, Karin de Stricker, Lasse Kjær, Karsten Ellemann, Hans Carl Hasselbalch
Journal: Blood (2013)
Is There Room for Improvement in Adverse Event Reporting in the Era of Targeted Therapies?
Authors: M. Edgerly, T. Fojo
Journal: JNCI Journal of the National Cancer Institute (2008)

The Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, and its predecessors, the Common Toxicity Criteria (CTC) versions 1.0 and 2.0, were developed under the direction of the Cancer Therapy Evaluation Program of the National Cancer Institute (NCI) in an effort to provide standard language for reporting adverse events that occur in NCI-sponsored clinical trials. Each successive version of the CTC has improved the accuracy, precision, and completeness of the criteria in an effort to standardize reporting. We believe that the current version of the CTCAE cannot adequately code the subacute adverse events that commonly occur with today's targeted therapies.