tbuckley/cabot-search huggingface dataset:
Importance of interaction between nerve growth factor and 9 1 integrin in glial tumor angiogenesis
Authors: E. M. Walsh, R. Kim, L. Del Valle, M. Weaver, J. Sheffield, P. Lazarovici, C. Marcinkiewicz
Journal: Neuro-Oncology (2012)

NGF is a growth factor for which the role in the promotion of angiogenesis is still not completely understood. We found that NGF promotes the pathological neovascularization process in glioma through a direct interaction with α9β1 integrin, which is up-regulated on microvascular endothelial cells in cancer tissue. We propagated gHMVEC primary cells using a new method of immune-selection, and these cells demonstrated α9β1 integrin-dependent binding of NGF in a cell adhesion assay. Moreover, NGF induced gHMVEC proliferation and chemotaxis inhibited by specific blockers of α9β1 integrin, such as MLD-disintegrins and monoclonal antibody Y9A2. A Matrigel tube formation assay revealed that NGF significantly increased capillary-like growth from gHMVEC to a level comparable to treatment with VEGF. The snake venom disintegrin, VLO5, inhibited the agonistic effect of both growth factors, whereas the effect of Y9A2 was not statistically significant. Angiogenesis exogenously induced by NGF was also α9β1-integrin dependent in an embryonic quail CAM system. However, angiogenesis pathologically induced by developing glioma in this system was only sensitive for inhibition with MLD-disintegrin, suggesting a more complex effect of cancer cells on the neovascularization process. The anti-angiogenic effect of MLD-disintegrins is probably related to their pro-apoptotic ability induced in activated tumoral endothelial cells. Therefore, the molecular basis of these disintegrins may be useful for developing new angiostatic pharmaceuticals for application in cancer therapy.
The leukocyte activation antigen CD69 limits allergic asthma and skin contact hypersensitivity
Authors: Pilar Martín, Manuel Gómez, Amalia Lamana, Adela Matesanz Marín, José R. Cortés, Marta Ramírez-Huesca, Olga Barreiro, Pedro López-Romero, Cristina Gutiérrez-Vázquez, Hortensia de la Fuente, Aránzazu Cruz-Adalia, Francisco Sánchez-Madrid
Journal: Journal of Allergy and Clinical Immunology (2010)
COOH-Terminal Src Kinase–Mediated c-Jun Phosphorylation Promotes c-Jun Degradation and Inhibits Cell Transformation
Authors: Feng Zhu, Bu Young Choi, Wei-Ya Ma, Zhongliang Zhao, Yiguo Zhang, Yong Yeon Cho, Hong Seok Choi, Akira Imamoto, Ann M. Bode, Zigang Dong
Journal: Cancer Research (2006)

Abstract The oncoprotein c-Jun is a component of the activator protein-1 transcription factor complex, which is involved in cellular proliferation, transformation, and death. The stabilization of c-Jun is critically important for its function. The phosphorylation of c-Jun by c-Jun NH2-terminal kinase 1 and extracellular signal-regulated protein kinases reduces c-Jun ubiquitination resulting in increased stabilization of c-Jun. In this report, we showed that COOH-terminal Src kinase (CSK) binds with and phosphorylates c-Jun at Y26 and Y170. Phosphorylation of c-Jun by CSK, in opposition to c-Jun NH2-terminal kinase 1 and extracellular signal-regulated protein kinases, promoted c-Jun degradation and reduced stability. By promoting c-Jun degradation, CSK helps to maintain a low steady-state level of c-Jun, thereby inhibiting activator protein-1 activity and cell transformation caused by c-Jun. These results indicated that this function of CSK controls cell proliferation under normal growth conditions and may have implications for CSK loss of function in carcinogenesis. (Cancer Res 2006; 66(11): 5729-36)
Effect of naloxone on met-enkephalin-induced gastric acid secretion and serum gastrin in man.
Authors: P S Olsen, P Kirkegaard, B Petersen, J Christiansen
Journal: Gut (1982)

It has previously been demonstrated that met-enkephalin, and endogenous opiate, stimulates gastric acid secretion in man, while naloxone inhibits meal-stimulated acid secretion. In seven healthy subjects the opiate receptor antagonist naloxone was infused in a dose of 10 microgram/kg/h during stimulation of gastric acid secretion with pentagastrin 100 ng/kg/h and met-enkephalin 0.1 microgram/kg/h. Naloxone had no effect on pentagastrin-induced acid secretion, whereas met-enkephalin-induced acid secretion was completely abolished in both studies without affecting serum gastrin levels, suggesting that the acid inhibitory effect of naloxone is specifically directed towards met-enkephalin-induced acid secretion. The results support the assumption that met-enkephalin participates in the physiological stimulation of gastric acid secretion.
Staged bilateral lobectomy for synchronous bilateral squamous cell carcinoma of lung.
Authors: A Soorae
Journal: Thorax (1978)

The history, diagnosis, and treatment by staged bilateral lobectomy of synchronous bilateral squamous cell carcinoma of the lung occurring in a 61-year-old man is presented. Histological diagnosis of pulmonary lesions suspected of being carcinomas should always be obtained, and extrathoracic metastasis should be excluded by all available means before planning treatment. The side showing evidence of greater malignancy on histology, or the one with the larger carcinoma, should be operated on first. Conservative, staged, bilateral resection is recommended.
Pseudoleukemia following the use of G‐CSF
Authors: Sigrun Reykdal, Ronald Sham, Pradyumna Phatak, Peter Kouides
Journal: American Journal of Hematology (1995)

To the Edi/ort Dr. Parikh and colleagues comment that case 1 was given cytosine arabinoside and daunorubicin, which they believed caused the massive cell lysis.We consider this unlikely.The patient had an LDH of 13,000 and other evidence of massive cell lysis prior to the administration of these agents.Secondly, these agents were administered for 1 day only, which is only a small dose in the context of leukemia therapy.The authors also suggest that there was evidence of disease resistant to all-trans retinoic acid.In fact, in case 1 the patient had "intermediate cells," which have been described by Warrell and colleagues as an indicator of response [I].In the second case the patient developed very rapid deterioration and assessment of resistance to all-trans retinoic acid therapy is very difficult because of this.Therefore, we continue to believe that the use of hydroxyurea in the setting of acute promyelocytic leukemia being treated with all-trans retinoic acid should be approached cautiously.
Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia
Authors: John J.P. Kastelein, Fatima Akdim, Erik S.G. Stroes, Aeilko H. Zwinderman, Michiel L. Bots, Anton F.H. Stalenhoef, Frank L.J. Visseren, Eric J.G. Sijbrands, Mieke D. Trip, Evan A. Stein, Daniel Gaudet, Raphael Duivenvoorden, Enrico P. Veltri, A. David Marais, Eric de Groot
Journal: New England Journal of Medicine (2008)

Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown.We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries.The primary outcome, the mean (+/-SE) change in the carotid-artery intima-media thickness, was 0.0058+/-0.0037 mm in the simvastatin-only group and 0.0111+/-0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P=0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (+/-SD) LDL cholesterol level was 192.7+/-60.3 mg per deciliter (4.98+/-1.56 mmol per liter) in the simvastatin group and 141.3+/-52.6 mg per deciliter (3.65+/-1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups.In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097 [ClinicalTrials.gov].).
Randomized phase II adjuvant factorial study of dose-dense temozolomide alone and in combination with isotretinoin, celecoxib, and/or thalidomide for glioblastoma
Authors: Marta Penas-Prado, Kenneth R. Hess, Michael J. Fisch, Lore W. Lagrone, Morris D. Groves, Victor A. Levin, John F. De Groot, Vinay K. Puduvalli, Howard Colman, Gena Volas-Redd, Pierre Giglio, Charles A. Conrad, Michael E. Salacz, Justin D. Floyd, Monica E. Loghin, Sigmund H. Hsu, Javier Gonzalez, Eric L. Chang, Shiao Y. Woo, Anita Mahajan, Kenneth D. Aldape, W. K. Alfred Yung, Mark R. Gilbert
Journal: Neuro-Oncology (2014)

Chemoradiation, followed by adjuvant temozolomide, is the standard treatment for newly diagnosed glioblastoma. Adding other active agents may enhance treatment efficacy. The primary objective of this factorial phase II study was to determine if one of 3 potential chemotherapy agents added to dose-dense temozolomide (ddTMZ) improves progression-free survival (PFS) for patients with newly diagnosed glioblastoma. A prior phase I trial established the safety of combining ddTMZ with isotretinoin, celecoxib, and/or thalidomide. Adults with good performance status and no evidence of progression post chemoradiation were randomized into 8 arms: ddTMZ alone (7 days on/7 days off) or doublet, triplet, and quadruplet combinations with isotretinoin, celecoxib, and thalidomide. The study enrolled 155 participants with a median age of 53 years (range, 18-84 y). None of the agents demonstrated improved PFS when compared with arms not containing that specific agent. There was no difference in PFS for triplet compared with doublet regimens, although a trend for improved overall survival (OS) was seen (20.1 vs 17.0 months, P = .15). Compared with ddTMZ, the ddTMZ + isotretinoin doublet had worse PFS (10.5 vs 6.5 months, P = .043) and OS (21.2 vs 11.7 months, P = .037). Trends were also seen for worse outcomes with isotretinoin-containing regimens, but there was no impact with celecoxib or thalidomide combinations. Treatment was well tolerated with expected high rates of lymphopenia. The results do not establish a benefit for these combinations but indicate that adding isotretinoin to ddTMZ may be detrimental. This study demonstrated the feasibility and utility of the factorial design in efficiently testing drug combinations in newly diagnosed glioblastoma. NCT00112502.
Conjugated Equine Estrogen Influence on Mammographic Density in Postmenopausal Women in a Substudy of the Women's Health Initiative Randomized Trial
Authors: Anne McTiernan, Rowan T. Chlebowski, Christopher Martin, Jennifer David Peck, Aaron Aragaki, Etta D. Pisano, C.Y. Wang, Karen C. Johnson, JoAnn E. Manson, Robert B. Wallace, Mara Z. Vitolins, Gerardo Heiss
Journal: Journal of Clinical Oncology (2009)

Purpose Increased mammographic density is associated with increased breast cancer risk and reduced sensitivity of screening mammography and is related to hormone exposure. However, the effects of conjugated equine estrogens (CEEs) alone on mammographic density in diverse racial/ethnic populations are not established. We examined the effect of CEE alone on mammographic density in a subsample of the Women's Health Initiative (WHI) clinical trial participants. Patients and Methods In the WHI trial, women were randomly assigned to daily CEE 0.625 mg or placebo. The effect of CEE on mammographic percent density was determined over 1 and 2 years in a stratified random sample of 435 racially and ethnically diverse participants from 15 of 40 WHI clinics. Results Use of CEE resulted in mean increase in mammographic percent density of 1.6 percentage points (95% CI, 0.8 to 2.4) at year 1 compared with a mean decrease of 1.0 percentage point (95% CI, −1.7 to −0.4) in the placebo group (P &lt; .001). The effect persisted for 2 years, with a mean increase of 1.7 percentage points (95% CI, 0.7 to 2.7) versus a mean decrease of 1.2 percentage points (95% CI, −1.8 to −0.5; P &lt; .001) in the hormone and placebo groups, respectively. These effects were greater in women age 60 to 79 years (P = .03 for interaction across age). Conclusion Use of CEE results in a modest but statistically significant increase in mammographic density that is sustained over at least a 2-year period. The clinical significance of the CEE effect on mammographic density remains to be determined.
P336Exome sequencing of multiple affected individuals from an Irish family with Brugada Syndrome uncovers a novel locus for the disorder
Authors: J G Barc, RF Marsman, RF Marsman, S Le Scouarnec, S Le Scouarnec, Y Mizusawa, Y Mizusawa, P Lindenbaum, P Lindenbaum, N Carter, N Carter, R Redon, R Redon, AAM Wilde, AAM Wilde, P Mckeown, P Mckeown, CR Bezzina, CR Bezzina
Journal: Cardiovascular Research (2014)

Introduction: Brugada Syndrome (BrS) is a disorder associated with an increased risk of sudden cardiac death and specific ECG features consisting of ST-segment elevation in the right precordial leads. Loss-of-function mutations in SCN5A underlie the disorder in ∼25% of patients. While other genes have been implicated, these account for <1% of subjects. Thus the genetic basis of BrS remains unknown in the majority of cases. We here set out to identify the genetic defect underlying BrS in a 3 generation family from Ireland with a case of spontaneous type 1 ECG who died suddenly at 24 years old.
Strenuous Resistive Breathing Induces Plasma Cytokines
Authors: Theodoros Vassilakopoulos, Paraskevi Katsaounou, Maria-Helena Karatza, Androniki Kollintza, Spyros Zakynthinos, Charis Roussos
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Inspiratory resistive breathing increases plasma cytokines, yet the stimulus (or stimuli) and source(s) remain unknown. We tested the role of reactive oxygen species as stimuli and of monocytes as sources of resistive breathing-induced cytokines. Six healthy subjects performed two resistive breathing sessions at 75% of maximum inspiratory pressure before and after a combination of antioxidants (vitamin E 200 mg, vitamin A 50,000 IU, and vitamin C 1,000 mg per day for 60 days, allopurinol 600 mg/day for 15 days, and N-acetylcysteine 2 g/day for 3 days before the second session). Blood was drawn before, at the end, and at 30 and 120 minutes after resistive breathing. Before antioxidants, plasma cytokine levels (determined by enzyme-linked immunosorbent assay) increased secondary to resistive breathing (tumor necrosis factor-α and interleukin [IL]-6 by twofold and IL-1β by threefold). After antioxidants, plasma IL-1β became undetectable. The tumor necrosis factor-α response to resistive breathing was abolished, and the IL-6 response was significantly blunted. Intracellular cytokine detection (by flow cytometry) showed no change in either the percentage of monocytes producing the cytokines or their mean fluorescence intensity both before and after antioxidants. We conclude that oxidative stress is a major stimulus for the resistive breathing–induced cytokine production and that monocytes play no role in this process.
The Development and Course of Bipolar Spectrum Disorders: An Integrated Reward and Circadian Rhythm Dysregulation Model
Authors: Lauren B. Alloy, Robin Nusslock, Elaine M. Boland
Journal: Annual Review of Clinical Psychology (2015)

In this article, we present and review the evidence for two major biopsychosocial theories of the onset and course of bipolar spectrum disorders (BSDs) that integrate behavioral, environmental, and neurobiological mechanisms: the reward hypersensitivity and the social/circadian rhythm disruption models. We describe the clinical features, spectrum, age of onset, and course of BSDs. We then discuss research designs relevant to demonstrating whether a hypothesized mechanism represents a correlate, vulnerability, or predictor of the course of BSDs, as well as important methodological issues. We next present the reward hypersensitivity model of BSD, followed by the social/circadian rhythm disruption model of BSD. For each model, we review evidence regarding whether the proposed underlying mechanism is associated with BSDs, provides vulnerability to the onset of BSDs, and predicts the course of BSDs. We then present a new integrated reward/circadian rhythm (RCR) dysregulation model of BSD and discuss how the RCR model explains the symptoms, onset, and course of BSDs. We end with recommendations for future research directions.
Erythropoietin is a JAK2 and ERK1/2 effector that can promote renal tumor cell proliferation under hypoxic conditions
Authors: Makito Miyake, Steve Goodison, Adrienne Lawton, Ge Zhang, Evan Gomes-Giacoia, Charles J Rosser
Journal: Journal of Hematology & Oncology (2013)

Abstract Background Erythropoietin (EPO) provides an alternative to transfusion for increasing red blood cell mass and treating anemia in cancer patients. However, recent studies have reported increased adverse events and/or reduced survival in patients receiving both EPO and chemotherapy, potentially related to EPO-induced cancer progression. Additional preclinical studies that elucidate the possible mechanism underlying EPO cellular growth stimulation are needed. Methods Using commercial tissue microarray (TMA) of a variety of cancers and benign tissues, EPO and EPO receptor immunohistochemical staining was performed. Furthermore using a panel of human renal cells (Caki-1, 786-O, 769-P, RPTEC), in vitro and in vivo experiments were performed with the addition of EPO in normoxic and hypoxic states to note phenotypic and genotypic changes. Results EPO expression score was significantly elevated in lung cancer and lymphoma (compared to benign tissues), while EPOR expression score was significantly elevated in lymphoma, thyroid, uterine, lung and prostate cancers (compared to benign tissues). EPO and EPOR expression scores in RCC and benign renal tissue were not significantly different. Experimentally, we show that exposure of human renal cells to recombinant EPO (rhEPO) induces cellular proliferation, which we report for the first time, is further enhanced in a hypoxic state. Mechanistic investigations revealed that EPO stimulates the expression of cyclin D1 while inhibiting the expression of p21 cip1 and p27 kip1 through the phosphorylation of JAK2 and ERK1/2, leading to a more rapid progression through the cell cycle. We also demonstrate an increase in the growth of renal cell carcinoma xenograft tumors when systemic rhEPO is administered. Conclusions In summary, we elucidated a previously unidentified mechanism by which EPO administration regulates progression through the cell cycle, and show that EPO effects are significantly enhanced under hypoxic conditions.
Doctors' leaders question accuracy of rating general practices
Authors: A. O'Dowd
Journal: BMJ (2009)

Doctors’ leaders have claimed that the new ratings for general practices that were launched in England this week will not paint an accurate picture of the quality of services provided.

The Department of Health launched a comparison service on 14 October that deals with general practices, on the NHS’s main information website, NHS Choices.

Patients in England will be able to add comments about their experience of a particular surgery as well as read other people’s comments on the website, under its “Find and choose services” section.

The department is keen that patients see information about practices before choosing the one …
Phase II Clinical and Pharmacokinetic Study of Aflibercept in Patients with Previously Treated Metastatic Colorectal Cancer
Authors: Patricia A. Tang, Steven J. Cohen, Christian Kollmannsberger, Georg Bjarnason, Kiran Virik, Mary J. MacKenzie, Lillian Lourenco, Lisa Wang, Alice Chen, Malcolm J. Moore
Journal: Clinical Cancer Research (2012)

Aflibercept is a recombinant fusion protein of the VEGF receptor (VEGFR) 1 and VEGFR2 extracellular domains. We assessed the safety and efficacy of aflibercept in patients with metastatic colorectal cancer (MCRC) who had received at least one prior palliative regimen.Seventy-five patients were enrolled onto this two-stage phase II trial in two cohorts, bevacizumab naïve (n = 24) and prior bevacizumab (n = 51). Aflibercept was administered at 4 mg/kg i.v. in two-week cycles. The primary endpoint was a combination of objective response rate and 16-week progression-free survival (PFS).In the bevacizumab-naïve cohort (n = 24), the best response was stable disease for 16 weeks or more in five of 24 patients. In the prior bevacizumab cohort (n = 50), one patient achieved a partial response and six patients had stable disease for 16 weeks or more. The median PFS in the bevacizumab-naïve and prior bevacizumab cohorts was two months [95% confidence interval (CI): 1.7-8.6 months] and 2.4 months (95% CI: 1.9-3.7 months), respectively. Median overall survival (OS) was 10.4 months (95% CI: 7.6-15.5) and 8.5 months (95% CI: 6.2-10.6), respectively. The most common grade 3 or higher treatment-related adverse events were hypertension, proteinuria, fatigue, and headache. Ten patients discontinued study treatment due to toxicity. Mean free to VEGF-bound aflibercept ratio was 1.82, suggesting that free aflibercept was present in sufficient amount to bind endogenous VEGF.Aflibercept showed limited single-agent activity in patients with pretreated MCRC with moderate toxicity. Further study of aflibercept with chemotherapy is ongoing.
Clonal analysis of CD4+/CD8+ T cells in a patient with aplastic anemia.
Authors: U Moebius, F Herrmann, T Hercend, S C Meuer
Journal: Journal of Clinical Investigation (1991)

T cell clones were established from peripheral blood of a patient with severe aplastic anemia. 8 of 18 individual clonal T cell populations stably coexpressed CD4 and CD8 molecules, a phenotype characteristic for thymocytes and a minor subpopulation of circulating T lymphocytes. Analysis of T cell receptor genes revealed identical rearrangements of T cell receptor beta chain genes, suggesting clonality of these T cells. CD4+/CD8+ T cells clones were found to be efficiently cytotoxic towards autologous lymphoblasts. Autocytotoxicity could be blocked by a CD3 MAb, a MAb specific for monomorphic MHC class II determinants, and particularly, by an MHC-DP-specific MAb, suggesting specificity for autologous DP molecules. Perhaps more important, CD4+/CD8+ T cell clones inhibited differentiation of autologous progenitor enriched bone marrow cells in vitro by a direct cell-mediated mechanism. These data suggest that circulating cytotoxic CD4+/CD8+ T cell clones specific for autologous MHC-DP determinants may be involved in hematopoietic failure in some cases of aplastic anemia.