tbuckley/cabot-search huggingface dataset:
Antineutrophil Cytoplasm Antibody–Stimulated Neutrophil Adhesion Depends on Diacylglycerol Kinase–Catalyzed Phosphatidic Acid Formation
Authors: Julie M. Williams, Trevor R. Pettitt, Wendy Powell, Joseph Grove, Caroline O.S. Savage, Michael J.O. Wakelam
Journal: Journal of the American Society of Nephrology (2007)

Patients with certain forms of systematic vasculitis, such as Wegener's granulomatosis, have circulating antineutrophil cytoplasmic antibodies (ANCA). These inappropriately stimulate circulating neutrophils adhere to and thereby obstruct small vessels. This, together with ANCA-induced degranulation and an oxidative burst, leads to local tissue damage. The signaling pathways that are activated by ANCA IgG are distinct from those that are involved in normal neutrophil activation. This study shows that diacylglycerol kinase is selectively activated by ANCA and that the generated phosphatidic acid is responsible for promoting neutrophil adhesion, in part through integrin activation. The data presented point to diacylglycerol kinase alpha as a novel but selective target for the development of drugs to treat this potentially fatal disorder.
Protein Kinase D1–Mediated Phosphorylation and Subcellular Localization of β-Catenin
Authors: Cheng Du, Meena Jaggi, Chuanyou Zhang, K.C. Balaji
Journal: Cancer Research (2009)

beta-Catenin is essential for E-cadherin-mediated cell adhesion in epithelial cells and also acts as a key cofactor for transcription activity. We previously showed that protein kinase D1 (PKD1), founding member of the PKD family of signal transduction proteins, is down-regulated in advanced prostate cancer and interacts with E-cadherin. This study provides evidence that PKD1 interacts with and phosphorylates beta-catenin at Thr(112) and Thr(120) residues in vitro and in vivo; mutation of Thr(112) and Thr(120) results in increased nuclear localization of beta-catenin and is associated with altered beta-catenin-mediated transcription activity. It is known that mutation of Thr(120) residue abolishes binding of beta-catenin to alpha-catenin, which links to cytoskeleton, suggesting that PKD1 phosphorylation of Thr(120) could be critical for cell-cell adhesion. Overexpression of PKD1 represses beta-catenin-mediated transcriptional activity and cell proliferation. Epistatic studies suggest that PKD1 and E-cadherin are within the same signaling pathway. Understanding the molecular basis of PKD1-beta-catenin interaction provides a novel strategy to target beta-catenin function in cells including prostate cancer.
The Role of Calcitonin in the Development and Treatment of Osteoporosis*
Authors: MICHAEL T. McDERMOTT, GERALD S. KIDD
Journal: Endocrine Reviews (1987)

CALCITONIN (CT) was first discovered in 1962 and named because of its ability to lower plasma calcium concentrations (1). In 1964, the thyroid was established as its major source (2). Since then, extensive investigation has greatly enhanced our understanding of the structure, biosynthesis, physiology, and pharmacology of the hormone (3–9). Despite this progress, the physiological function of CT remains uncertain, although current theories include a role as one of several hormones involved in the chronic regulation of skeletal homeostasis and calcium balance. There has also been a great deal of interest in the relationship of CT to osteoporosis, both as a possible pathogenetic factor and as a potential therapeutic agent. In order to carefully examine this important area of investigation, we have undertaken a critical assessment of the published literature concerning the role of CT in the development and treatment of osteoporosis. CT is a 32-amino acid peptide hormone with a 1–7 disulfide bridge at the amino terminus and a carboxyterminal proline amide (9).
Treatment of Toxoplasmic Encephalitis in Patients with AIDS
Authors: Brian Dannemann, J. Allen McCutchan, Dennis Israelski, Diane Antoniskis, Catherine Leport, Benjamin Luft, Joseph Nussbaum, Nathan Clumeck, Philippe Morlat, Joseph Chiu, Jean-Louis Vilde, Manuel Orellana, David Feigal, Angie Bartok, Peter Heseltine, John Leedom, Jack Remington
Journal: Annals of Internal Medicine (1992)

Objective: To compare pyrimethamine plus clindamycin (PC) to pyrimethamine plus sulfadiazine (PS) as a treatment for toxoplasmic encephalitis (TE) in patients with the acquired immunodeficiency syndrome (AIDS). Design: Randomized, unblinded phase II, multi-center trial with provision for crossover for failure or intolerance of the assigned regimen. Setting: University hospitals. Patients: Eighty-four patients with presumptive TE were entered. Thirteen were excluded when they were found to have another diagnosis, and 12 were excluded because they did not meet entry criteria. The baseline characteristics in the remaining 26 patients randomized to PC and 33 randomized to PS were comparable. Interventions: Patients were treated for 6 weeks with pyrimethamine and folinic acid plus either sulfadiazine or clindamycin. Clindamycin was given intravenously during the first 3 weeks. Measurements and Main Results: There was a trend toward greater survival in patients randomized to PS (hazard ratio, 3.25; 95% Cl, 0.63 to 16.8; P = 0.13), but most study deaths were not directly related to TE. In contrast, patients randomized to PC appeared more likely to achieve complete clinical (odds ratio, 0.67; Cl, 0.2 to 1.97; P > 0.2) and radiologic responses (odds ratio, 0.28; Cl, 0.08 to 0.96; P = 0.02). Multivariate analysis revealed drug effects to be largely independent of other variables. Similar efficacy of the treatments was also suggested by a hazard analysis of resolution of abnormal mental status, fever, and headache. Skin rash was the most common adverse event in both treatment arms. Because of toxicity, six patients randomized to PC and 11 patients randomized to PS had to switch to the alternate treatment, but only three were unable to complete therapy after crossover. Conclusions: The results of several end points of efficacy, taken together, suggest that the relative efficacy of PC approximately equals that of PS. PC appears to be an acceptable alternative in patients unable to tolerate PS.
Vascular consequences of menopause and hormone therapy: Importance of timing of treatment and type of estrogen
Authors: R DUBEY, B IMTHURN, M BARTON, E JACKSON
Journal: Cardiovascular Research (2005)

Premenopausal women have a lower risk for cardiovascular events, and mortality due to coronary vascular disease (CVD) in premenopausal women is rare. These facts suggest that endogenous estrogens, such as estradiol, protect the cardiovascular system, and several observational studies and a few small clinical studies conducted in healthy and younger postmenopausal women support this hypothesis. In contrast, two large randomized clinical trials (RCTs), using conjugated equine estrogens and conducted in older women with established CVD or without overt CVD, failed to demonstrate protection against CVD by exogenous estrogens. These divergent findings have resulted in confusion with regard to the association between estrogen deficiency and CVD in postmenopausal women. In order to reconcile these contradictory findings, it is necessary to examine the pathophysiology associated with age-dependent changes within the vessel wall and to compare the pharmacology of different types of estrogens. Understanding age-dependent changes in vascular pathology and the pharmacology of different estrogens may facilitate the development of therapeutic strategies for hormone replacement therapy (HRT) that would be effective in delaying vascular remodeling leading to CVD following menopause. In this review we provide an overview of the impact of menopause and estrogen deficiency on vascular remodeling and emphasize the importance of timing and type of estrogen to achieve maximum benefits with regard to reducing the risk of CVD.
PWE-041 Obesity is associated with improved survival in surgically resected oesophageal cancer
Authors: T S Athwal, S Love, S Bruce, R Page, M Hartley, N Howes
Journal: Gut (2012)

<h3>Introduction</h3> Obesity is an increasing health burden in the western world and a known risk factor for oesophageal cancer. The aim of this study was to determine the impact of obesity on circumferential resection margin (CRM), lymph node yield (LNY) and survival among a 10 year cohort of surgically resected oesophageal cancer patients. <h3>Methods</h3> All patients who underwent transthoracic oesophagectomy for histologically proven adenocarcinoma or squamous cell carcinoma, performed at a supra-regional upper GI cancer centre, were registered on a prospective database between 2002 and 2012. Total LNY, CRM and survival was compared between different BMI groups: normal (18.5–24.9), overweight (25–30), and obese (&gt;30). Patients who were malnourished prior to surgery were excluded from the analysis. <h3>Results</h3> A total of 482 consecutive patients underwent oesphagectomy during the study period, of which the complete dataset was available for 441 (91%); normal (155), overweight (177) and obese (91). The median lymph node yield was 16 (IQR 11–22), normal 15 (10–23), overweight 17 (12–23) and obese 15 (10–21), with no significant difference seen between the three groups (p=0.4565, χ<sup>2</sup> test). The CRM was involved in 30 (27%) of the obese patients compared to 55 (31%), 54 (35%) and of overweight, healthy patients respectively (p=0.0615, χ<sup>2</sup> test). <h3>Conclusion</h3> Obesity appears to confer a survival advantage in patients undergoing surgical resection for oesophageal cancer. Interestingly, there appeared to be a trend towards an uninvolved CRM in obese patients but no significant impact on the lymph node yield. <h3>Competing interests</h3> None declared.
Smooth Muscle α-Actin Is a Direct Target of Notch/CSL
Authors: Michela Noseda, YangXin Fu, Kyle Niessen, Fred Wong, Linda Chang, Graeme McLean, Aly Karsan
Journal: Circulation Research (2006)

Intercellular signaling mediated by Notch receptors is essential for proper cardiovascular development and homeostasis. Notch regulates cell fate decisions that affect proliferation, survival, and differentiation of endothelial and smooth muscle cells. It has been reported that Jagged1-Notch interactions may participate in endocardial cushion formation by inducing endothelial-to-mesenchymal transformation. Here, we show that Notch directly regulates expression of the mesenchymal and smooth muscle cell marker smooth muscle alpha-actin (SMA) in endothelial and vascular smooth muscle cells via activation of its major effector, CSL. Notch/CSL activation induces SMA expression during endothelial-to-mesenchymal transformation, and Notch activation is required for expression of SMA in vascular smooth muscle cells. CSL directly binds a conserved cis element in the SMA promoter, and this consensus sequence is required for Notch-mediated SMA induction. This is the first evidence of the requirement for Notch activation in the regulation of SMA expression.
Investigation of intravenous delivery of nanoliposomal topotecan for activity against orthotopic glioblastoma xenografts
Authors: L. P. Serwer, C. O. Noble, K. Michaud, D. C. Drummond, D. B. Kirpotin, T. Ozawa, M. D. Prados, J. W. Park, C. D. James
Journal: Neuro-Oncology (2011)

Achieving effective treatment outcomes for patients with glioblastoma (GBM) has been impeded by many obstacles, including the pharmacokinetic limitations of antitumor agents, such as topotecan (TPT). Here, we demonstrate that intravenous administration of a novel nanoliposomal formulation of TPT (nLS-TPT) extends the survival of mice with intracranial GBM xenografts, relative to administration of free TPT, because of improved biodistribution and pharmacokinetics of the liposome-formulated drug. In 3 distinct orthotopic GBM models, 3 weeks of biweekly intravenous therapy with nLS-TPT was sufficient to delay tumor growth and significantly extend animal survival, compared with treatment with free TPT (P ≤ .03 for each tumor tested). Analysis of intracranial tumors showed increased activation of cleaved caspase-3 and increased DNA fragmentation, both indicators of apoptotic response to treatment with nLS-TPT. These results demonstrate that intravenous delivery of nLS-TPT is a promising strategy in the treatment of GBM and support clinical investigation of this therapeutic approach.
HIV Therapy and Diabetes Risk
Authors: Samuel Dagogo-Jack
Journal: Diabetes Care (2008)

The use of combination antiretroviral therapy (cART) has yielded dramatic clinical benefits for individuals with HIV infection. Benefits include suppression of viral load, improvement in CD4 lymphocyte counts, decrease in the number of opportunistic infections and length of hospital stay, and reduction in AIDS-related mortality (1,2). These advantages have come at the price of increased incidence of unanticipated adverse metabolic effects, including insulin resistance, diabetes, dyslipidemia, and lipodystrophy (2). The clinical presentation of antiretroviral-associated diabetes is consistent with that of type 2 diabetes, and evidence of islet autoimmunity is distinctly uncommon in patients with antiretroviral-associated diabetes (3). Early studies fostered the understanding that inclusion of HIV-1 protease inhibitors most likely accounts for the adverse metabolic effects. The association between protease inhibitors and diabetes was further strengthened by studies showing that switching patients to other regimens improved the hyperglycemia and hyperlipidemia observed during use of protease inhibitor–containing regimens. Focusing almost exclusively on the role …
Low renal papillary plasma flow in both Dahl and Kyoto rats with spontaneous hypertension.
Authors: M Ganguli, L Tobian, L Dahl
Journal: Circulation Research (1976)

Abnormally low plasma flow to renal papilla characterizes Dahl hypertension. When eating a normal Na diet (0.3% NaCl) both hypertension-sensitive (S) rats and hypertension-resistant (R) rats, 16 weeks old, have fairly normal blood pressure (BP), averaging 144 and 129 mm Hg, respectively. However, even in this barely hypertensive state, 18 S rats had a 31% lower papillary plasma flow (Lilienfield method) than 22 R rats, 19.2 ml/100 g of papilla per min compared to 25.6 (P less than 0.001). When a high (8%) NaCl diet was fed for 7 days, R rats increased papillary plasma flow from 25.6 on 0.3% NaCl to 33.8 on 8% NaCl, a 32% rise (P less than 0.001). S rats increased papillary flow from 20.4 to 24.8, a 22% rise (P less than 0.05). When a high (8%) NaCl diet was fed for 4 weeks, R rats increased papillary plasma flow from 25.7 ml/100 g per min on 0.3% NaCl to 29.5 ml/100 g per min on 8% NaCl, a 15% rise (P less than 0.025). S rats increased papillary flow from 17.7 to 20.0 ml/100 g per min (not significant). S rats on 8% NaCl had a papillary flow 32% lower than R rats on 8% NaCl (P less than 0.001). BP of S rats rose to 162 mm Hg after 4 weeks on 8% NaCl; in R rats, BP did not rise at all. S rats on 0.3% NaCl have a low papillary flow even in a borderline hypertensive state. When challenged with 8% NaCl, R rats increased papillary flow, an adaptation possibly important for the natriuresis. S rats failed to achieve this same high papillary flow. Lacking this adaptation, hypertension may then conceivably occur in S rats to accomplish natriuresis through a "pressure natriuresis" mechanism. Papillary flow also decreased by 11% in 26 Kyoto 17-week-old spontaneously hypertensives (BP, 182 mm Hg) compared to 24 Kyoto normotensives (BP, 118 mm Hg), 29.5 vs 33.2 ml/100 g per min (P less than 0.001). Thus, low papillary flow exists in both hypertensions.
Malignant mesenchymoma of the chest wall in an adult.
Authors: S K Jain, M Afzal, M Mathew, S K Ramani
Journal: Thorax (1993)

Mesenchymoma (hamartoma) of the chest wall is an extremely rare tumour presenting in early infancy or fetal life. Pleural, pulmonary, and lymph node metastases developed in a young man with malignant mesenchymoma of the chest wall. The tumour had several characteristics that differ from the mesenchymoma reported from the other parts of the body.
Overnight variations in cortisol, interleukin 6, tumour necrosis factor α and other cytokines in people with rheumatoid arthritis
Authors: M G Perry, J R Kirwan, D S Jessop, L P Hunt
Journal: Annals of the Rheumatic Diseases (2008)

Objective: To investigate overnight variations in absolute values and patterns of cytokines including interleukin 6 (IL6) and tumour necrosis factor α (TNFα) in rheumatoid arthritis (RA), and to relate any changes to those occurring in blood cortisol. Methods: A total of 16 people (8 female) with active RA and who had received no recent glucocorticoids were admitted overnight. Blood samples were obtained at 13 time points between 21.00 and 10.00. Results: The geometric mean IL6 concentration rose significantly from 35 pg/ml at 22:00 to 64 pg/ml at 07:15 (repeated measures analysis of variance (ANOVA), p&lt;0.001). The geometric mean cortisol concentration rose significantly overnight from 57 ng/ml at 01:00 to 229 ng/ml at 07:15 (repeated measures ANOVA, p&lt;0.001). Neither TNFα nor the other cytokines measured changed significantly. Using cubic regression modelling IL6 began to rise before cortisol (range 0.01 to 4.83 h) in eight participants and after cortisol (range 1.11 to 5.14 h) in three participants. In a random coefficient model including data from all participants, the estimated mean IL6 value began to rise 3.05 h before the estimated mean cortisol value, with the IL6 peak occurring 0.70 h before the cortisol peak. Conclusion: The mean IL6 and cortisol concentrations showed a significant overnight variation. Neither TNFα nor the other cytokines measured changed significantly. In a random coefficient model IL6 began to rise approximately 3 h, and reached a peak about 40 min, before cortisol. These studies confirm that there are abnormalities in plasma cortisol and IL6 concentrations and dynamics. The data also link the overnight rise in IL6 to the circadian variation in symptoms.
Time to first cigarette and lung cancer risk in Japan
Authors: H. Ito, S. Gallus, S. Hosono, I. Oze, K. Fukumoto, Y. Yatabe, T. Hida, T. Mitsudomi, E. Negri, K. Yokoi, K. Tajima, C. La Vecchia, H. Tanaka, K. Matsuo
Journal: Annals of Oncology (2013)
Fish Oil and Glycemic Control in Diabetes: A meta-analysis
Authors: Cylla E Friedberg, Martien J F M Janssen, Robert J Heine, Diederick E Grobbee
Journal: Diabetes Care (1998)

Hypertriglyceridemia is associated with cardiovascular disease in diabetes. Fibrates effectively lower, but do not always normalize, serum triglyceride levels. Fish oil supplements may then be added to lower serum triglyceride levels. Doubt remains whether the net effect of fish oil intake on glycemic control is beneficial in diabetes. We therefore performed a meta-analysis from published clinical trials.Data sources were Medline (Cologne, Germany), Excerpta Medica, Current Contents, review articles, and published reference lists. Publications of 26 trials were selected, and all trials included more than five diabetes (IDDM and NIDDM) patients and addressed the effects of fish oil (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) on serum lipids and glucose tolerance. We (C.E.F., M.J.F.M.J.) extracted data independently based on predetermined criteria. Studies were classified according to design.All studies combined showed a decrease in mean triglyceride concentrations in association with fish oil: -0.60 mmol/l (95% CI, -0.84 to -0.33, P < 0.01) and a slight but significant increase in serum LDL cholesterol: 0.18 mmol/l (95% CI, 0.04-0.32, P = 0.01), with both findings most prominent in NIDDM. No significant changes in HbA1c percentages occurred in diabetic subjects treated with fish oil. Fasting blood glucose levels were increased with borderline significance in NIDDM subjects (0.43 mmol/l [95% CI, 0.00-0.87], P = 0.06) and were significantly lower in IDDM subjects (-1.86 mmol/l [95% CI, -3.1 to -0.61], P < 0.05). Significant dose-response effects of EPA (g/day) on HbA1c and triglycerides and of DHA (g/day) on fasting blood glucose levels, HbA1c, and triglycerides were demonstrated only in NIDDM subjects.The use of fish oil has no adverse affects on HbA1c in diabetic subjects and lowers triglyceride levels effectively by almost 30%. However, this may be accompanied by a slight increase in LDL cholesterol concentration. Fish oil may be useful in treating dyslipidemia in diabetes.
Dose-Ranging Pharmacodynamic Study of Tipifarnib (R115777) in Patients With Relapsed and Refractory Hematologic Malignancies
Authors: Todd M. Zimmerman, Helena Harlin, Olatoyosi M. Odenike, Seth Berk, Evie Sprague, Theodore Karrison, Wendy Stock, Richard A. Larson, Mark J. Ratain, Thomas F. Gajewski
Journal: Journal of Clinical Oncology (2004)

Tipifarnib, an orally bioavailable inhibitor of farnesyl transferase, has activity in hematologic malignancies, but the dose required to achieve the proposed biologic end point, inhibition of farnesylation, is unknown.The impact on post-translational farnesylation was assessed in 42 patients with refractory hematologic malignancies and bone marrow involvement. Tipifarnib was taken orally for 21 days of a 28-day cycle. For cycle 1, patients were randomly assigned to one of four dose levels: 100 mg bid, 200 mg bid, 300 mg bid, and 600 mg bid. In cycle 1, peripheral blood and bone marrow mononuclear cells were analyzed for inhibition of HDJ2 prenylation by Western blot analysis at baseline and on day 21.Twenty-three patients were assessable for analysis of HDJ2 prenylation before and after therapy. Inhibition of farnesylation was noted at all dose levels, although the highest level of inhibition was noted at the 300-mg-bid dose. The inhibition of farnesylation in the peripheral blood correlated with the inhibition in the bone marrow (r = 0.62). Of the 26 patients assessable for clinical activity after cycle 1, three patients had a significant decrease in total blasts count (acute myeloid leukemia in two patients, and chronic myelogenous leukemia in one patient). The inhibition of farnesylation was greater in the three responders than the nonresponders (P = .03).Farnesylation as measured by HDJ2 analysis was inhibited at all dose levels administered. Clinical activity may correlate with the degree of farnesylation inhibition, rather than dose of tipifarnib, and escalation beyond 300 mg bid might not result in additional clinical activity.
Hemodynamic effects after conversion of arrhythmias
Authors: Robert J. Corliss, David H. McKenna, Charles W. Crumpton, George G. Rowe
Journal: Journal of Clinical Investigation (1968)

Systemic and coronary hemodynamic parameters were determined during an arrhythmia and immediately after a direct current transthoracic shock given in an attempt to convert the arrhythmia to a sinus mechanism. No anesthesia or drugs were administered between the two studies. 16 patients with atrial fibrillation converted to sinus rhythm and five did not. In two patients with atrial flutter and one with supraventricular tachycardia, the arrhythmia was corrected. The arrhythmia persisted in a single patient with ventricular tachycardia. Utilizing each patient as his own control, we compared statistically various hemodynamic parameters before and after the shock. In addition, the group of patients whose atrial fibrillation terminated was compared to the group treated in the same manner but in which the atrial fibrillation persisted. Pressures in the right side of the heart decreased in both groups so that the changes appeared to be caused by factors associated with the transthoracic direct current shock or the catheterization procedure. The differences between those with atrial fibrillation who converted to sinus rhythm as compared to those who did not were a decrease in heart rate, an increase in stroke volume, and an increase in cardiac efficiency. There was no immediate effect on the cardiac output or coronary blood flow.