tbuckley/cabot-search huggingface dataset:
Increased Spontaneous and Lymphokine–Conditioned Iga and Igg Synthesis by B Cells From Alcoholic Cirrhotic Patients
Authors: José Antonio Girón, Melchor Alvarez-Mon, José Luis Menéndez-Caro, Luis Abreu, Agustín Albillos, Luis Manzano, Alberto Durántez
Journal: Hepatology (1992)

Immunoglobulin secretion by B lymphocytes is a complex process in which lymphokines secreted by T lymphocytes play an important regulatory role. Increased serum levels of IgA and IgG have been characteristically detected in patients with alcoholic cirrhosis. We have studied the functional alterations of T and B lymphocytes implicated in the physiopathology of this common immunoglobulin abnormality. After activation with phytohemagglutinin, purified T cells from alcoholic cirrhotic patients showed significantly enhanced secretion of B–cell differentiation factors for IgG and IgA with respect to those secreted by T cells from healthy controls (p &lt; 0.05). Simultaneously, normal secretion of B–cell differentiation factor for IgM was demonstrated in T lymphocytes from these patients. The pattern of secretion of the lymphokines involved in the regulation of the B–cell differentiation pathway found in alcoholic cirrhotic patients was different from that of the primary biliary cirrhotic patients studied. Purified B cells from patients with alcoholic cirrhosis secreted significantly higher amounts of IgA and IgG than did those found in healthy controls, both spontaneously (p &lt; 0.05) and after sequential activation with immunoglobulin ligands ( Staphylococcus aureus Cowan I) and a standard B–cell differentiation factor preparation (p &lt; 0.05). By contrast, the IgM secretion and regulatory pathway were normal in alcoholic cirrhotic patients. These results support a physiopathological explanation for the characteristic hyperimmunoglobulinemia found in patients with alcoholic cirrhosis. (Hepatology 1992;16:664-670.)
Proliferation and Apoptosis as Markers of Benefit in Neoadjuvant Endocrine Therapy of Breast Cancer
Authors: Mitch Dowsett, Ian E. Smith, Steve R. Ebbs, J. Michael Dixon, Anthony Skene, Clive Griffith, Irene Boeddinghaus, Janine Salter, Simone Detre, Margaret Hills, Susan Ashley, Stephen Francis, Geraldine Walsh, Roger A'Hern
Journal: Clinical Cancer Research (2006)

Abstract The study of changes in proliferation as a marker of treatment benefit during presurgical endocrine treatment of breast cancer has become increasingly popular, particularly using the nuclear marker Ki67, and holds the potential for prioritizing new treatments for full clinical development. There are weakly significant relationships between Ki67 change and clinical response that differ according to data handling. In the neoadjuvant Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen trial, suppression of Ki67 at both 2 and 12 weeks was greater with the aromatase inhibitor anastrozole than with either tamoxifen or the combination of anastrozole and tamoxifen. We report here that absolute values of Ki67 after 2 weeks were also significantly lower with anastrozole than with tamoxifen and the combination. This indicates that it may be possible to make such comparisons using surgical samples only. We argue that these changes in proliferation and concurrent changes in apoptosis may be expected to be more predictive of adjuvant benefit from endocrine therapy than clinical response.
Protein kinase D2 is a crucial regulator of tumour cell-endothelial cell communication in gastrointestinal tumours
Authors: N. Azoitei, G. V. Pusapati, A. Kleger, P. Moller, R. Kufer, F. Genze, M. Wagner, J. van Lint, P. Carmeliet, G. Adler, T. Seufferlein
Journal: Gut (2010)

<h3>Background</h3> Tumour angiogenesis is crucially dependent on the communication between the tumour and the associated endothelium. Protein kinase D (PKD) isoenzymes mediate vascular endothelial growth factor-A (VEGF-A) induced endothelial cell proliferation and migration and are also highly expressed in various tumours. <h3>Aim</h3> To examine the role of PKDs for tumour proliferation and angiogenesis selectively in pancreatic and gastric tumours and in tumour-associated endothelium in vitro and in vivo. <h3>Methods</h3> PKD2 expression in human tumours was determined by immunohistochemistry. The effect of PKD2 depletion in endothelial cells by siRNAs was examined in sprouting assays, the chorioallantois model (CAM) and tumour xenografts. In murine endothelium in vivo PKD2 was knocked-down by splice switching oligonucleotides. Human PKD2 was depleted in xenografts by siRNAs and PKD2-miRs. PKD2 activation by hypoxia and its role for hypoxia-induced NR4/TR3- and VEGF-A promoter activity, expression and secretion was investigated in cell lines. <h3>Results</h3> PKD2 is expressed in gastrointestinal tumours and in the tumour-associated endothelium. Tumour growth and angiogenesis in the CAM and in tumour xenografts require PKD expression in endothelial cells. Conversely, hypoxia activates PKD2 in pancreatic cancer cells and PKD2 was identified as the major mediator of hypoxia-stimulated VEGF-A promoter activity, expression and secretion in tumour cells. PKD2 depletion in pancreatic tumours inhibited tumour-driven blood vessel formation and tumour growth in the CAM and in orthotopic pancreatic cancer xenografts. <h3>Conclusion</h3> PKD2 regulates hypoxia-induced VEGF-A expression/secretion by tumour cells and VEGF-A stimulated blood vessel formation. PKD2 is a novel, essential mediator of tumour cell–endothelial cell communication and a promising therapeutic target to inhibit angiogenesis in gastrointestinal cancers.
Efficacy of Quadrivalent HPV Vaccine against HPV Infection and Disease in Males
Authors: Anna R. Giuliano, Joel M. Palefsky, Stephen Goldstone, Edson D. Moreira, Mary E. Penny, Carlos Aranda, Eftyhia Vardas, Harald Moi, Heiko Jessen, Richard Hillman, Yen-Hwa Chang, Daron Ferris, Danielle Rouleau, Janine Bryan, J. Brooke Marshall, Scott Vuocolo, Eliav Barr, David Radley, Richard M. Haupt, Dalya Guris
Journal: New England Journal of Medicine (2011)

Infection with human papillomavirus (HPV) and diseases caused by HPV are common in boys and men. We report on the safety of a quadrivalent vaccine (active against HPV types 6, 11, 16, and 18) and on its efficacy in preventing the development of external genital lesions and anogenital HPV infection in boys and men.
Renal Structure in Normoalbuminuric and Albuminuric Patients With Type 2 Diabetes and Impaired Renal Function
Authors: Elif I. Ekinci, George Jerums, Alison Skene, Paul Crammer, David Power, Karey Y. Cheong, Sianna Panagiotopoulos, Karen McNeil, Scott T. Baker, Paola Fioretto, Richard J. MacIsaac
Journal: Diabetes Care (2013)

The structural basis of normoalbuminuric renal insufficiency in patients with type 2 diabetes remains to be elucidated. We compared renal biopsy findings in patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) and measured GFR of <60 mL/min/1.73 m2, associated with either normo-, micro-, or macroalbuminuria.In patients with normo- (n = 8) or microalbuminuria (n = 6), renal biopsies were performed according to a research protocol. In patients with macroalbuminuria (n = 17), biopsies were performed according to clinical indication. Findings were categorized according to the Fioretto classification: category 1 (C1), normal/near normal; category 2 (C2), typical diabetic nephropathy (DN) with predominantly glomerular changes; and category 3 (C3), atypical with disproportionately severe interstitial/tubular/vascular damage and with no/mild diabetic glomerular changes.In our study population (mean eGFR 35 mL/min/1.73 m2), typical glomerular changes (C2) of DN were observed in 22 of 23 subjects with micro- or macroalbuminuria compared with 3 of 8 subjects with normoalbuminuria (P = 0.002). By contrast, predominantly interstitial or vascular changes (C3) were seen in only 1 of 23 subjects with micro- or macroalbuminuria compared with 3 of 8 normoalbuminuric subjects (P = 0.08). Mesangial area increased progressively from normal controls to patients with type 2 diabetes and normo-, micro-, and macroalbuminuria. Varying degrees of arteriosclerosis, although not necessarily the predominant pattern, were seen in seven of eight subjects with normoalbuminuria.Typical renal structural changes of DN were observed in patients with type 2 diabetes and elevated albuminuria. By contrast, in normoalbuminuric renal insufficiency, these changes were seen less frequently, likely reflecting greater contributions from aging, hypertension, and arteriosclerosis.
A Negative Progesterone Receptor in Luminal Her-2 Negative Breast Cancer by Age at Diagnosis: 10 Years Follow-Up
Authors: S. Olbrecht, K. Van Asten, A. Laenen, C. Remmerie, H. Wildiers, G. Floris, M.R. Christiaens, I. Vergote, P. Neven
Journal: Annals of Oncology (2014)
Nonlinearities of the human carotid baroreceptor-cardiac reflex.
Authors: D L Eckberg
Journal: Circulation Research (1980)

Carotid baroreceptors of nine healthy young men and women were stretched or compressed with neck suction or pressure, before and after beta-adrenergic and cholinergic blockade, to evaluate several nonlinearities of sinus node baroreflex responses. Sinus node inhibition was related linearly to the intensity of brief baroreceptor stimuli over a range extending from carotid-distending pressures of about 101 +/- 5 (mean +/- SE) to 160 +/- 6 mm Hg (the subject's average systolic pressure was 108 +/- 2 mm Hg). Sinus node response to sustained (5 seconds) neck suction or pressure were strikingly asymmetrical. Responses were abolished by atropine, or by atropine and propranolol. Propranolol alone augmented sinus node responses to both neck suction and pressure. These results suggest that, in normal human subjects, sinus node responses to abrupt alterations of afferent baroreceptor traffic are nonlinear and are mediated by fluctuations of efferent cholinergic activity. Most of the observed nonlinear behavior of the integrated reflex can be explained on the basis of known properties of afferent and central portions of the baroreflex arc.
Impact of use of hormone replacement therapy on false positive recall in the NHS breast screening programme: results from the million women study
Authors: Emily Banks, Gillian Reeves, Valerie Beral, Diana Bull, Barbara Crossley, Moya Simmonds, Elizabeth Hilton, Stephen Bailey, Nigel Barrett, Peter Briers, Ruth English, Alan Jackson, Elizabeth Kutt, Janet Lavelle, Linda Rockall, Matthew G Wallis, Mary Wilson, Julietta Patnick
Journal: BMJ (2004)

About half of the women attending the NHS breast screening programme have used hormone replacement therapy.1 Although previous studies have reported that use of hormone replacement therapy increases the risk of being recalled after mammography for further assessment, with no subsequent diagnosis of breast cancer (“false positive recall”), the effect of different patterns of use is unclear.2



Relative risk of false positive recall in postmenopausal women in relation to time since last use of hormone replacement therapy. (Relative risk compared with never users (1057/44 427 recalled) stratified by screening centre, age, previous screening, body mass index, previous breast operation, and time since menopause in: current users of hormone replacement therapy (relative risk 1.64, 95% confidence interval 1.50 to 1.80; 1157/28 634 recalled); past users ceasing use <1 year ago (1.42, 1.08 to 1.86; 63/1758 recalled), 1-4 years ago (1.23, 1.04 to 1.46; 176/5910 recalled), and ≥5 years ago (1.07, 0.85 to 1.34; 92/3800 recalled)). Results are plotted according to the median number of years since last use of hormone replacement therapy in each of these categories



From June 1996 to March 1998, 87 967 postmenopausal women aged 50-64 invited to routine …
Screening for Asymptomatic Carotid Artery Stenosis: A Systematic Review and Meta-analysis for the U.S. Preventive Services Task Force
Authors: Daniel E. Jonas, Cynthia Feltner, Halle R. Amick, Stacey Sheridan, Zhi-Jie Zheng, Daniel J. Watford, Jamie L. Carter, Cassandra J. Rowe, Russell Harris
Journal: Annals of Internal Medicine (2014)

Approximately 10% of ischemic strokes are caused by carotid artery stenosis (CAS). Estimated prevalence of asymptomatic CAS is 1%.To evaluate evidence on screening and treating asymptomatic adults for CAS.MEDLINE, the Cochrane Library, EMBASE, and trial registries through September 2013; MEDLINE through March 2014 for trials.Good- or fair-quality trials of screening, carotid endarterectomy (CEA), or stenting compared with medical therapy or of intensification of medical therapy; systematic reviews; multi-institution studies reporting harms; and externally validated risk-stratification tools.Dual extraction and quality assessment.No trials compared screening with no screening or stenting with medical therapy or assessed intensification of medical therapy, and no externally validated, reliable risk-stratification tools were found. Given the specificity of ultrasonography (range, 88% to 94% for CAS ≥ 50% to ≥ 70%), its use in low-prevalence populations would yield many false-positive results. Absolute reduction of nonperioperative strokes was 5.5% (95% CI, 3.9% to 7.0%; 3 trials; 5223 participants) over approximately 5 years for CEA compared with medical therapy. The 30-day rates of stroke or death after CEA in trials and cohort studies were 2.4% (CI, 1.7% to 3.1%; 6 trials; 3435 participants) and 3.3% (CI, 2.7% to 3.9%; 7 studies; 17474 participants), respectively. Other harms of interventions included myocardial infarction, nerve injury, and hematoma.Trials may have overestimated benefits and used highly selected surgeons. Medical therapy used in trials was outdated, and stroke rates have declined in recent decades. Harms may have been underreported.Current evidence does not establish incremental overall benefit of CEA, stenting, or intensification of medical therapy. Potential for overall benefit is limited by low prevalence and harms.Agency for Healthcare Research and Quality.
CD62L as a Therapeutic Target in Chronic Lymphocytic Leukemia
Authors: Melinda Burgess, Devinder Gill, Richa Singhania, Catherine Cheung, Lynne Chambers, Brent A. Renyolds, Louise Smith, Peter Mollee, Nicholas Saunders, Nigel AJ McMillan
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Despite advances in the treatment of chronic lymphocytic leukemia (CLL), the disease remains incurable with standard therapies and relapse is inevitable. A growing body of evidence indicates that alterations in the adhesion properties of neoplastic cells play a pivotal role in the development and progression of CLL. Experimental Design: The expression of 71 cell surface molecules was examined on CLL peripheral blood mononuclear cells (PBMCs) over 3 weeks in culture. The most highly upregulated marker, CD62L, was examined further for expression on CD5+/CD19+ CLL cells in vitro and in lymph node and bone marrow biopsies. The prosurvival role of CD62L was examined using a functional blocking antibody and therapeutic potential evaluated by comparison with current chemotherapy agents. Results: Blocking CD62L resulted in apoptosis of CLL cells but not PBMCs from healthy donors suggesting a novel role for CD62L in CLL cell survival. The beneficial effect of coculturing CLL cells with bone marrow stromal cells or endothelial cells does not protect CLL cells from anti-CD62L–related toxicity. Moreover, combining fludarabine or mafosfamide with the anti-CD62L in vitro produced an additive effect both with and without stromal cells. Conclusion: This is the first reported data showing that blocking the activation and homing marker, CD62L, regulates CLL cell survival in vitro. These data also suggest that therapeutic antibodies against CD62L may provide additional clinical benefit to patients with CLL receiving current standard chemotherapy protocols. Clin Cancer Res; 19(20); 5675–85. ©2013 AACR.
A Prospective Study of Self-Reported Sleep Duration and Incident Diabetes in Women
Authors: Najib T. Ayas, David P. White, Wael K. Al-Delaimy, JoAnn E. Manson, Meir J. Stampfer, Frank E. Speizer, Sanjay Patel, Frank B. Hu
Journal: Diabetes Care (2003)

Short-term sleep restriction results in impaired glucose tolerance. To test whether habitually short sleep duration increases the risk of developing diabetes, we studied a cohort of 70,026 women enrolled in the Nurses Health Study, without diabetes at baseline, and who responded to a question about daily sleep duration in 1986. Subjects were followed until 1996 for the diagnosis of diabetes (1,969 cases). Long and short sleep durations were associated with an increased risk of diabetes diagnosis. The relative risks (RRs) for short (slept ≤5 h per day) and long (slept ≥9 h per day) sleepers were 1.57 (95% CI 1.28–1.92) and 1.47 (1.19–1.80), respectively. After adjustment for BMI and a variety of confounders, the RR was not significantly increased for short sleepers (1.18 [0.96–1.44]) but remained modestly increased for long sleepers (1.29 [1.05–1.59]). We then performed a similar analysis using only symptomatic cases (n = 1,187). Adjusted RRs for symptomatic diabetes were modestly elevated in both short (1.34 [1.04–1.72]) and long (1.35 [1.04–1.75]) sleepers. Our data suggest that the association between a reduced self-reported sleep duration and diabetes diagnosis could be due to confounding by BMI, or sleep restriction may mediate its effects on diabetes through weight gain. Sleep restriction may be an independent risk factor for developing symptomatic diabetes.
Role of NO pathway, calcium and potassium channels in the peripheral pulmonary vascular tone in dogs
Authors: F. Chabot, F. Schrijen, C. Saunier
Journal: European Respiratory Journal (2001)

Because hypoxic pulmonary vasoconstriction occurs mainly in the small pulmonary arteries, the authors investigated the effects of drugs acting on the nitric oxide (NO) pathway and the calcium and potassium channels in the peripheral pulmonary circulation, without interference with the overall pulmonary or systemic circulation. Mixed venous blood was infused in wedged areas to study the pressure/flow relationship and to compute peripheral pulmonary vascular resistance (PPVR). The authors studied the effects of N ω -nitro-l-arginine methyl ester (l‐NAME), an NO synthase inhibitor, sodium nitroprusside (SNP, an NO donor), the calcium channel blockers verapamil, nifedipine and nicardipine, and the potassium channel opener levcromakalim, during normoxia and acute mild normocapnic hypoxia. In the peripheral pulmonary circulation, l‐NAME caused an increase in PPVR during normoxia (+95%; p&lt;0.001) and hypoxia (+60%; p&lt;0.01). Following the increase by l‐NAME, SNP decreased PPVR during normoxia (−24%; p&lt;0.05) and hypoxia (−23%; p&lt;0.05). Verapamil, nifedipine and nicardipine did not modify PPVR during normoxia but during hypoxia they decreased PPVR (−28%, nonsignificant; −27%, p&lt;0.01 and −33%, p&lt;0.05, respectively). Levcromakalim did not modify PPVR during normoxia or hypoxia. In conclusion, the nitric oxide pathway and voltage-dependent calcium channels, and not adenosine triphosphate sensitive potassium channels, play an important role in the control of peripheral pulmonary circulation in dogs.
Effects of Renal Arterial Infusion of Sodium and Potassium on Renin Secretion in the Dog
Authors: ROBERT E. SHADE, JAMES O. DAVIS, J. Alan JOHNSON, ROBERT T. WITTY
Journal: Circulation Research (1972)

The nonfiltering kidney model was used to determine whether sodium or potassium inhibits renin secretion in the absence of a functional macula densa in dogs with thoracic inferior vena caval constriction. The control rate of renin secretion was high, and decreases were readily recognized. After control observations, hypertonic sodium chloride or hypertonic potassium chloride was infused into the renal artery for 1 hour, and renin secretion was measured at 15-minute intervals. An increase in renal venous plasma sodium concentration from 141 to 154-158 mEq/liter caused no change in renin secretion for the first 45 minutes of infusion in dogs with a nonfiltering kidney. In contrast, dogs with thoracic caval constriction but with a filtering kidney showed a striking decrease in renin secretion during intrarenal sodium infusion (3,097 to 1,061 ng angiotensin/min, P &lt;0.02). An increase in renal venous plasma potassium concentration from 3.9 to 6.1 mEq/liter in one group of dogs and from 4.9 to 8.3 mEq/liter in a second group also caused no change in renin secretion in the nonfiltering kidney of dogs with thoracic caval constriction. However, in dogs with thoracic caval constriction and a filtering kidney, potassium infusion decreased renin secretion (1,952 to 984 ng angiotensin/min, P &lt;0.05). In all experiments, infusion of sodium chloride or potassium chloride failed to produce a significant change in renal blood flow, arterial blood pressure, or inferior vena caval pressure. Therefore, no evidence was obtained for a vascular action or a direct effect of sodium or potassium on the juxtaglomerular cells, and the data are consistent with an action mediated by the renal tubular system.
EXHALED ACETONE AS A NEW BIOMARKER OF HEART FAILURE SEVERITY
Authors: Fabiana G. Marcondes-Braga, Fernando Bacal, Guilherme L. Batista, Paulo Saldiva, Silvia M. Ayub-Ferreira, Victor Issa, Sandrigo Mangini, Edimar A. Bocchi, Ivano G.R. Gutz
Journal: Journal of the American College of Cardiology (2011)
Molecular Pathways: Regulation of Metabolism by RB
Authors: Brian F. Clem, Jason Chesney
Journal: Clinical Cancer Research (2012)

Abstract The discovery of the retinoblastoma (RB-1) gene as a tumor suppressor that is disrupted in a majority of human cancers either via direct or indirect genetic alterations has resulted in increased interest in its functions and downstream effectors. Although the canonical pathway that links this tumor suppressor to human cancers details its interaction with the E2F transcription factors and cell-cycle progression, recent studies have shown an essential role for RB-1 in the suppression of glycolytic and glutaminolytic metabolism. Characterization of the precise metabolic transporters and enzymes suppressed by the RB-E2F axis should enable the identification of small molecule antagonists that have selective and potent antitumor properties. Clin Cancer Res; 18(22); 6096–100. ©2012 AACR.
A role for IL-25 and IL-33–driven type-2 innate lymphoid cells in atopic dermatitis
Authors: Maryam Salimi, Jillian L. Barlow, Sean P. Saunders, Luzheng Xue, Danuta Gutowska-Owsiak, Xinwen Wang, Li-Chieh Huang, David Johnson, Seth T. Scanlon, Andrew N.J. McKenzie, Padraic G. Fallon, Graham S. Ogg
Journal: The Journal of Experimental Medicine (2013)

Type 2 innate lymphoid cells (ILC2s, nuocytes, NHC) require RORA and GATA3 for their development. We show that human ILC2s express skin homing receptors and infiltrate the skin after allergen challenge, where they produce the type 2 cytokines IL-5 and IL-13. Skin-derived ILC2s express the IL-33 receptor ST2, which is up-regulated during activation, and are enriched in lesional skin biopsies from atopic patients. Signaling via IL-33 induces type 2 cytokine and amphiregulin expression, and increases ILC2 migration. Furthermore, we demonstrate that E-cadherin ligation on human ILC2 dramatically inhibits IL-5 and IL-13 production. Interestingly, down-regulation of E-cadherin is characteristic of filaggrin insufficiency, a cardinal feature of atopic dermatitis (AD). ILC2 may contribute to increases in type 2 cytokine production in the absence of the suppressive E-cadherin ligation through this novel mechanism of barrier sensing. Using Rag1−/− and RORα-deficient mice, we confirm that ILC2s are present in mouse skin and promote AD-like inflammation. IL-25 and IL-33 are the predominant ILC2-inducing cytokines in this model. The presence of ILC2s in skin, and their production of type 2 cytokines in response to IL-33, identifies a role for ILC2s in the pathogenesis of cutaneous atopic disease.