tbuckley/cabot-search huggingface dataset:
<i>APOE4</i>-VLDL Inhibits the HDL-Activated Phosphatidylinositol 3-Kinase/Akt Pathway via the Phosphoinositol Phosphatase SHIP2
Authors: Robert DeKroon, Jennifer B. Robinette, Anita B. Hjelmeland, Emma Wiggins, Morven Blackwell, Mirta Mihovilovic, Makoto Fujii, John York, Janet Hart, Christopher Kontos, Jeremy Rich, Warren J. Strittmatter
Journal: Circulation Research (2006)

Endothelial cell dysfunction and apoptosis are critical in the pathogenesis of atherosclerotic cardiovascular disease (CVD). Both endothelial cell apoptosis and atherosclerosis are reduced by high-density lipoprotein (HDL). Low HDL levels increase the risk of CVD and are also a key characteristic of the metabolic syndrome. The apolipoprotein E4 (APOE4) allele also increases the risk of atherosclerosis and CVD. We previously demonstrated that the antiapoptotic activity of HDL is inhibited by APOE4 very-low-density lipoprotein (APOE4-VLDL) in endothelial cells, an effect similar to reducing the levels of HDL. Here we establish the intracellular mechanism by which APOE4-VLDL inhibits the antiapoptotic pathway activated by HDL. We show that APOE4-VLDL diminishes the phosphorylation of Akt by HDL but does not alter phosphorylation of c-Jun N-terminal kinase, p38, or Src family kinases by HDL. Furthermore APOE4-VLDL inhibits Akt phosphorylation by reducing the phosphatidylinositol 3-kinase product phosphatidylinositol-(3,4,5)-triphosphate (PI[3,4,5]P3). We further demonstrate that APOE4-VLDL reduces PI(3,4,5)P3, through the phosphoinositol phosphatase SHIP2, and not through PTEN. SHIP2 is already implicated as an independent risk factor for type II diabetes, hypertension and obesity, which are also all components of the metabolic syndrome and independent risk factors for CVD. Significantly, the association between CVD and type 2 diabetes or hypertension is further increased by the APOE4 allele. Therefore the activation of SHIP2 by APOE4-VLDL, with the subsequent inhibition of the HDL/Akt pathway, is a novel and significant biological mechanism and may be a critical intermediate by which APOE4 increases the risk of atherosclerotic CVD.
Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension
Authors: G Ghobadi, B Bartelds, S J van der Veen, M G Dickinson, S Brandenburg, R M F Berger, J A Langendijk, R P Coppes, P van Luijk
Journal: Thorax (2011)

<h3>Background</h3> Pulmonary arterial hypertension (PAH) is a commonly fatal pulmonary vascular disease that is often diagnosed late and is characterised by a progressive rise in pulmonary vascular resistance resulting from typical vascular remodelling. Recent data suggest that vascular damage plays an important role in the development of radiation-induced pulmonary toxicity. Therefore, the authors investigated whether irradiation of the lung also induces pulmonary hypertension. <h3>Methods</h3> Different sub-volumes of the rat lung were irradiated with protons known to induce different levels of pulmonary vascular damage. <h3>Results</h3> Early loss of endothelial cells and vascular oedema were observed in the irradiation field and in shielded parts of the lung, even before the onset of clinical symptoms. 8 weeks after irradiation, irradiated volume-dependent vascular remodelling was observed, correlating perfectly with pulmonary artery pressure, right ventricle hypertrophy and pulmonary dysfunction. <h3>Conclusions</h3> The findings indicate that partial lung irradiation induces pulmonary vascular remodelling resulting from acute pulmonary endothelial cell loss and consequential pulmonary hypertension. Moreover, the close resemblance of the observed vascular remodelling with vascular lesions in PAH makes partial lung irradiation a promising new model for studying PAH.
Cardiovascular Effects of Sevelamer in Stage 3 CKD
Authors: Colin D. Chue, Jonathan N. Townend, William E. Moody, Daniel Zehnder, Nadezhda A. Wall, Lorraine Harper, Nicola C. Edwards, Richard P. Steeds, Charles J. Ferro
Journal: Journal of the American Society of Nephrology (2013)

Serum phosphate independently predicts cardiovascular mortality in the general population and CKD, even when levels are in the normal range. Associations between serum phosphate, arterial stiffness, and left ventricular (LV) mass suggest a possible pathophysiological mechanism, potentially mediated by the phosphaturic hormone fibroblast growth factor-23 (FGF-23). To what extent the phosphate binder sevelamer modulates these effects is not well understood. In this single-center, randomized, double-blind, placebo-controlled trial, we enrolled 120 patients with stage 3 nondiabetic CKD. After a 4-week open-label run-in period, during which time all patients received sevelamer carbonate, we randomly assigned 109 patients to sevelamer (n=55) or placebo (n=54) for an additional 36 weeks. We assessed LV mass and systolic and diastolic function with cardiovascular magnetic resonance imaging and echocardiography, and we assessed arterial stiffness by carotid-femoral pulse wave velocity. The mean age was 55 years, and the mean eGFR was 50 ml/min per 1.73 m(2). After 40 weeks, we found no statistically significant differences between sevelamer and placebo with regard to LV mass, systolic and diastolic function, or pulse wave velocity. Only 56% of subjects took ≥ 80% of prescribed therapy; in this compliant subgroup, treatment with sevelamer associated with lower urinary phosphate excretion and serum FGF-23 but not serum phosphate, klotho, vitamin D, or cardiovascular-related outcomes of interest. In conclusion, this study does not provide evidence that sevelamer carbonate improves LV mass, LV function, or arterial stiffness in stage 3 nondiabetic CKD.
Mesangial expression of angiotensin II receptor in IgA nephropathy and its regulation by polymeric IgA1
Authors: Kar Neng Lai, Loretta Y.Y. Chan, Sydney C.W. Tang, Anita W.L. Tsang, Felix F.K. Li, Man Fai Lam, Sing Leung Lui, Joseph C.K. Leung
Journal: Kidney International (2004)
Long term results of endoscopic dilatation for corrosive oesophageal strictures.
Authors: S L Broor, G S Raju, P P Bose, D Lahoti, G N Ramesh, A Kumar, G K Sood
Journal: Gut (1993)

Although dilatation is the treatment of choice for most patients with benign oesophageal strictures, there is little information on its efficacy and safety in corrosive oesophageal strictures. Of 123 adults with benign oesophageal strictures treated by endoscopic dilatation, 52 (42.3%) had strictures after corrosive ingestion and 39 (31.7%) had peptic strictures. Treatment was considered adequate if the oesophageal lumen could be dilated to 15 mm and there was complete relief of dysphagia. If dysphagia recurred after adequate initial dilatation, the stricture was dilated again up to 15 mm. Initial dilatation was adequate in 93.6% of patients with corrosive strictures and this success rate was comparable with that of the peptic stricture group (100%, p > 0.05). Long term success after adequate initial dilatation was studied in 36 patients with corrosive strictures (mean follow up 32.36 (17.12) months, range 6-60) and 33 patients with peptic strictures (mean follow up 36.32 (17.9) months, range 6-60). The mean (SEM) number of symptomatic recurrences per patient month during the total follow up period in the corrosive group was significantly higher than that in the peptic group (0.27 (0.04) v 0.07 (0.02), p < 0.001). The recurrence rate in the corrosive group, however, decreased over time, and after 12 months it was significantly (p < 0.001) lower than the recurrence rate in the first six months. After 36 months, the difference in the recurrence rate in the two groups was not significant (p > 0.05). Only nine oesophageal perforations occurred during a total of 1373 dilatation treatments (procedure related incidence 0.66%), and eight of these were in the corrosive stricture group. These patients were managed conservatively and subsequently strictures were dilated adequately in all. Endoscopic dilatation is safe and effective for short and long term relief of dysphagia in patients with corrosive oesophageal strictures.
Hypoxic Epithelial Necrosis Triggers Neutrophilic Inflammation via IL-1 Receptor Signaling in Cystic Fibrosis Lung Disease
Authors: Benedikt Fritzsching, Zhe Zhou-Suckow, Joanna B. Trojanek, Susanne C. Schubert, Jolanthe Schatterny, Stephanie Hirtz, Raman Agrawal, Thomas Muley, Nicolas Kahn, Carsten Sticht, Nikolas Gunkel, Tobias Welte, Scott H. Randell, Florian Länger, Philipp Schnabel, Felix J. F. Herth, Marcus A. Mall
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Rationale: In many organs, hypoxic cell death triggers sterile neutrophilic inflammation via IL-1R signaling. Although hypoxia is common in airways from patients with cystic fibrosis (CF), its role in neutrophilic inflammation remains unknown. We recently demonstrated that hypoxic epithelial necrosis caused by airway mucus obstruction precedes neutrophilic inflammation in Scnn1b-transgenic (Scnn1b-Tg) mice with CF-like lung disease.Objectives: To determine the role of epithelial necrosis and IL-1R signaling in the development of neutrophilic airway inflammation, mucus obstruction, and structural lung damage in CF lung disease.Methods: We used genetic deletion and pharmacologic inhibition of IL-1R in Scnn1b-Tg mice and determined effects on airway epithelial necrosis; levels of IL-1α, keratinocyte chemoattractant, and neutrophils in bronchoalveolar lavage; and mortality, mucus obstruction, and structural lung damage. Furthermore, we analyzed lung tissues from 21 patients with CF and chronic obstructive pulmonary disease and 19 control subjects for the presence of epithelial necrosis.Measurements and Main Results: Lack of IL-1R had no effect on epithelial necrosis and elevated IL-1α, but abrogated airway neutrophilia and reduced mortality, mucus obstruction, and emphysema in Scnn1b-Tg mice. Treatment of adult Scnn1b-Tg mice with the IL-1R antagonist anakinra had protective effects on neutrophilic inflammation and emphysema. Numbers of necrotic airway epithelial cells were elevated and correlated with mucus obstruction in patients with CF and chronic obstructive pulmonary disease.Conclusions: Our results support an important role of hypoxic epithelial necrosis in the pathogenesis of neutrophilic inflammation independent of bacterial infection and suggest IL-1R as a novel target for antiinflammatory therapy in CF and potentially other mucoobstructive airway diseases.
No Effect of the Altered Peptide Ligand NBI-6024 on β-Cell Residual Function and Insulin Needs in New-Onset Type 1 Diabetes
Authors: Markus Walter, Areti Philotheou, François Bonnici, Anette-G. Ziegler, Roland Jimenez
Journal: Diabetes Care (2009)

OBJECTIVE This randomized, four-arm, placebo-controlled, dose-ranging phase 2 trial was conducted to determine whether repeated subcutaneous injections of the altered peptide ligand, NBI-6024, designed to inhibit autoreactive T-cells, improves β-cell function in patients with recently diagnosed type 1 diabetes. RESEARCH DESIGN AND METHODS A total of 188 patients, aged 10–35 years, with recently diagnosed type 1 diabetes were randomly assigned for a treatment consisting of the subcutaneous administration of placebo or 1, 0.5, or 0.1 mg NBI-6024 at baseline, weeks 2 and 4, and then monthly until month 24. Fasting, peak, and area under the curve (AUC) C-peptide concentrations during a 2-h mixed-meal tolerance test were measured at 3-month intervals during treatment. Immune function parameters (islet antibodies and CD4 and CD8 T-cells) were also studied. RESULTS The mean peak C-peptide concentration at 24 months after study entry showed no significant difference between the groups treated with 0.1 mg (0.59 pmol/ml), 0.5 mg (0.57 pmol/ml), and 1.0 mg NBI-6024 (0.48 pmol/ml) and the placebo group (0.54 pmol/ml). Fasting, stimulated peak, and AUC C-peptide concentrations declined linearly in all groups by ∼60% over the 24-month treatment period. The average daily insulin needs at month 24 were also comparable between the four groups. No treatment-related changes in islet antibodies and T cell numbers were observed. CONCLUSIONS Treatment with altered peptide ligand NBI-6024 at repeated doses of 0.1, 0.5, or 1.0 mg did not improve or maintain β-cell function.
Cell Motility in Chronic Lymphocytic Leukemia: Defective Rap1 and αLβ2 Activation by Chemokine
Authors: Kathleen J. Till, Robert J. Harris, Andrea Linford, David G. Spiller, Mirko Zuzel, John C. Cawley
Journal: Cancer Research (2008)

Abstract Chemokine-induced activation of α4β1 and αLβ2 integrins (by conformational change and clustering) is required for lymphocyte transendothelial migration (TEM) and entry into lymph nodes. We have previously reported that chemokine-induced TEM is defective in chronic lymphocytic leukemia (CLL) and that this defect is a result of failure of the chemokine to induce polar clustering of αLβ2; engagement of α4β1 and autocrine vascular endothelial growth factor (VEGF) restore clustering and TEM. The aim of the present study was to characterize the nature of this defect in αLβ2 activation and determine how it is corrected. We show here that the αLβ2 of CLL cells is already in variably activated conformations, which are not further altered by chemokine treatment. Importantly, such treatment usually does not cause an increase in the GTP-loading of Rap1, a GTPase central to chemokine-induced activation of integrins. Furthermore, we show that this defect in Rap1 GTP-loading is at the level of the GTPase and is corrected in CLL cells cultured in the absence of exogenous stimuli, suggesting that the defect is the result of in vivo stimulation. Finally, we show that, because Rap1-induced activation of both α4β1 and αLβ2 is defective, autocrine VEGF and chemokine are necessary to activate α4β1 for ligand binding. Subsequently, this binding and both VEGF and chemokine stimulation are all needed for αLβ2 activation for motility and TEM. The present study not only clarifies the nature of the αLβ2 defect of CLL cells but is the first to implicate activation of Rap1 in the pathophysiology of CLL. [Cancer Res 2008;68(20):8429–36]
Developmental Switches in Chemokine Response Profiles during B Cell Differentiation and Maturation
Authors: Edward P. Bowman, James J. Campbell, Dulce Soler, Zengjun Dong, Natasha Manlongat, Dominic Picarella, Richard R. Hardy, Eugene C. Butcher
Journal: The Journal of Experimental Medicine (2000)

Developing B cells undergo dramatic changes in their responses to chemoattractant cytokines (chemokines) and in expression of chemokine receptors. Bone marrow pre–pro-B cells (AA4.1+/natural killer 1.1− Fraction A cells) and cells capable of generating pro-B colonies in the presence of interleukin 7 and flt3 ligand migrate to thymus-expressed chemokine (TECK), a response lost in later stages of B cell development. B cell–attracting chemokine 1 (BCA-1) responses correlate with CXC chemokine receptor (CXCR)5 expression, are first displayed by a pro-B cell subset, are lost in pre-B cells, and then are regained just before and after egress from the marrow. All peripheral B cell subsets, including follicular and germinal center as well as marginal zone and peritoneal B1 B cells, respond to BCA-1, implying that responsiveness to this follicular chemokine is not sufficient to predict follicle localization. Responses to the CC chemokine receptor (CCR)7 ligands secondary lymphoid tissue chemoattractant (SLC) and macrophage inflammatory protein (MIP)-3β, implicated in homing to lymphoid tissues, are upregulated before B cell exit from the marrow, but increase further in the periphery and are shared by all peripheral B cells. In contrast, responsiveness to MIP-3α and expression of CCR6 are acquired only after emigration to the periphery and during maturation into the recirculating B cell pool. Chemotaxis to stromal cell–derived factor 1α is observed at all stages of B cell differentiation. Thus, unique patterns of chemokine responses may help define developing B cell populations and direct their maturation in the marrow and migration to the periphery.
Acupuncture Versus Venlafaxine for the Management of Vasomotor Symptoms in Patients With Hormone Receptor–Positive Breast Cancer: A Randomized Controlled Trial
Authors: Eleanor M. Walker, Alba I. Rodriguez, Beth Kohn, Ronald M. Ball, Jan Pegg, Jeffrey R. Pocock, Ramon Nunez, Ed Peterson, Susan Jakary, Robert A. Levine
Journal: Journal of Clinical Oncology (2009)

Vasomotor symptoms are common adverse effects of antiestrogen hormone treatment in conventional breast cancer care. Hormone replacement therapy is contraindicated in patients with breast cancer. Venlafaxine (Effexor), the therapy of choice for these symptoms, has numerous adverse effects. Recent studies suggest acupuncture may be effective in reducing vasomotor symptoms in menopausal women. This randomized controlled trial tested whether acupuncture reduces vasomotor symptoms and produces fewer adverse effects than venlafaxine.Fifty patients were randomly assigned to receive 12 weeks of acupuncture (n = 25) or venlafaxine (n = 25) treatment. Health outcomes were measured for up to 1 year post-treatment.Both groups exhibited significant decreases in hot flashes, depressive symptoms, and other quality-of-life symptoms, including significant improvements in mental health from pre- to post-treatment. These changes were similar in both groups, indicating that acupuncture was as effective as venlafaxine. By 2 weeks post-treatment, the venlafaxine group experienced significant increases in hot flashes, whereas hot flashes in the acupuncture group remained at low levels. The venlafaxine group experienced 18 incidences of adverse effects (eg, nausea, dry mouth, dizziness, anxiety), whereas the acupuncture group experienced no negative adverse effects. Acupuncture had the additional benefit of increased sex drive in some women, and most reported an improvement in their energy, clarity of thought, and sense of well-being.Acupuncture appears to be equivalent to drug therapy in these patients. It is a safe, effective and durable treatment for vasomotor symptoms secondary to long-term antiestrogen hormone use in patients with breast cancer.
Improvement of long-term survival in extensive small-cell lung cancer.
Authors: D V Jackson, L D Case, P J Zekan, B L Powell, R D Caldwell, J D Bearden, E C Nelson, H B Muss, M R Cooper, F Richards
Journal: Journal of Clinical Oncology (1988)

The effect of adding the epipodophyllotoxin etoposide (VP-16-213) to a standard chemotherapy regimen for patients with extensive stage small-cell lung cancer was evaluated during a randomized trial. Chemotherapy consisted of vincristine, doxorubicin, and cyclophosphamide (VAC) alone or with etoposide (EVAC). Of 139 patients enrolled, 136 patients were eligible for study and all but five were evaluable for response. The overall objective response was 46% in the VAC group v 70% in the etoposide-treated group (P = .008) with complete response (CR) rates of 12% v 29%, respectively (P = .030). Although the time to the observation of disease progression was significantly longer in the group of patients receiving etoposide (9.6 v 6.5 months, P = .010), overall survival was similar; this was probably due to administration of other agents including etoposide at the time of VAC failure. However, there were noteworthy differences in long-term (greater than or equal to 2 year) survival. Whereas only four (6%) patients treated with VAC lived 2 years, 11 (16%) of the etoposide-treated group did so (P = .100). Two-year failure-free survival was attained in one (2%) of the VAC patients and eight (11%) of the patients treated with etoposide (P = .034). Long-term survivorship, heretofore usually reported in patients with limited stage disease after a variety of treatments, may be possible with this drug combination in the setting of extensive disease.
Plasma Surfactant Protein-B
Authors: Carmine G. De Pasquale, Leonard F. Arnolda, Ian R. Doyle, Philip E. Aylward, Derek P. Chew, Andrew D. Bersten
Journal: Circulation (2004)

Background— In chronic heart failure (CHF), elevated pulmonary microvascular pressure (P mv ) results in pulmonary edema. Because elevated P mv may alter the integrity of the alveolocapillary barrier, allowing leakage of surfactant protein-B (SP-B) from the alveoli into the circulation, we aimed to determine plasma levels of SP-B in CHF and their relation to clinical status. Methods and Results— Fifty-three outpatients with CHF had plasma SP-B and N-terminal proBNP (NT-proBNP) assayed, in addition to a formalized clinical assessment at each clinic review over a period of 18 months. The control group comprised 19 normal volunteers. Plasma SP-B was elevated in CHF ( P &lt;0.001), and levels increased with New York Heart Association classification ( P &lt;0.001). SP-B correlated with objective clinical status parameters and NT-proBNP. During follow-up, major cardiovascular events occurred in patients with higher plasma SP-B ( P &lt;0.01) and NT-proBNP ( P &lt;0.05). Furthermore, on conditional logistic regression analysis, only SP-B was independently associated with CHF hospitalization ( P =0.005). The 53 patients underwent a total of 210 outpatient visits. When the diuretic dosage was increased on clinical grounds, SP-B had increased 39% ( P &lt;0.001) and NT-proBNP had increased 32% ( P &lt;0.001). Conversely, at the next visit, SP-B fell 12% ( P &lt;0.001), whereas NT-proBNP fell 39% ( P &lt;0.001). Conclusions— Plasma SP-B is increased in CHF, and levels are related to clinical severity. Furthermore, within individual patients, SP-B levels vary with dynamic clinical status and NT-proBNP levels. Because plasma SP-B is independently associated with CHF hospitalization, it may, by virtue of its differing release mechanism to NT-proBNP, be a clinically useful biomarker of the pulmonary consequences of raised P mv .
Diabetes in Hispanic American Youth
Authors: Jean M. Lawrence, Elizabeth J. Mayer-Davis, Kristi Reynolds, Jennifer Beyer, David J. Pettitt, Ralph B. D'Agostino, Santica M. Marcovina, Giuseppina Imperatore, Richard F. Hamman
Journal: Diabetes Care (2009)

To report the 2001 prevalence and 2002-2005 incidence of type 1 and type 2 diabetes in Hispanic American youth and to describe the demographic, clinical, and behavioral characteristics of these youth.Data from the SEARCH for Diabetes in Youth Study, a population-based multicenter observational study of youth aged 0-19 years with physician-diagnosed diabetes, were used to estimate the prevalence and incidence of type 1 and type 2 diabetes. Information obtained by questionnaire, physical examination, and blood and urine collection was analyzed to describe the characteristics of youth who completed a study visit.Among Hispanic American youth, type 1 diabetes was more prevalent than type 2 diabetes, including in youth aged 10-19 years. There were no significant sex differences in type 1 or type 2 diabetes prevalence. The incidence of type 2 diabetes for female subjects aged 10-14 years was twice that of male subjects (P < 0.005), while among youth aged 15-19 years the incidence of type 2 diabetes exceeded that of type 1 diabetes for female subjects (P < 0.05) but not for male subjects. Poor glycemic control, defined as A1C >or=9.5%, as well as high LDL cholesterol and triglycerides were common among youth aged >or=15 years with either type of diabetes. Forty-four percent of youth with type 1 diabetes were overweight or obese.Factors such as poor glycemic control, elevated lipids, and a high prevalence of overweight and obesity may put Hispanic youth with type 1 and type 2 diabetes at risk for future diabetes-related complications.