tbuckley/cabot-search huggingface dataset:
The Src Homology 2 Domain of Vav Is Required for Its Compartmentation to the Plasma Membrane and Activation of C-Jun Nh2-Terminal Kinase 1
Authors: Ramachandran Arudchandran, Martin J. Brown, Matthew J. Peirce, James S. Song, Juan Zhang, Reuben P. Siraganian, Ulrich Blank, Juan Rivera
Journal: The Journal of Experimental Medicine (2000)

Vav is a hematopoietic cell-specific guanine nucleotide exchange factor (GEF) whose activation is mediated by receptor engagement. The relationship of Vav localization to its function is presently unclear. We found that Vav redistributes to the plasma membrane in response to Fcin receptor I (FcinRI) engagement. The redistribution of Vav was mediated by its Src homology 2 (SH2) domain and required Syk activity. The FcinRI and Vav were found to colocalize and were recruited to glycosphingolipid-enriched microdomains (GEMs). The scaffold protein, linker for activation of T cells (LAT), and Rac1 (a target of Vav activity) were constitutively present in GEMs. Expression of an SH2 domain-containing COOH-terminal fragment of Vav inhibited Vav phosphorylation and movement to the GEMs but had no effect on the tyrosine phosphorylation of the adaptor protein, SLP-76 (SH2 domain-containing leukocyte protein of 76 kD), and LAT. However, assembly of the multiprotein complex containing these proteins was inhibited. In addition, FcinRI-dependent activation of c-Jun NH(2)-terminal kinase 1 (JNK1) was also inhibited. Thus, Vav localization to the plasma membrane is mediated by its SH2 domain and may serve to regulate downstream effectors like JNK1.
Heart-specific targeting of firefly luciferase by the myosin light chain-2 promoter and developmental regulation in transgenic mice.
Authors: W M Franz, D Breves, K Klingel, G Brem, P H Hofschneider, R Kandolf
Journal: Circulation Research (1993)

Based on hybridization studies indicating constitutive expression levels of the endogenous myosin light chain-2 (MLC-2) gene in embryonic, fetal, and adult myocardium, a model system for selective targeting of genes to the heart of transgenic mice has been developed. A 2.1-kb DNA fragment of the 5' flanking region of the rat cardiac MLC-2 gene was fused to the firefly luciferase reporter gene and introduced into fertilized mouse oocytes. In four independent transgenic mouse lines, the expression of the MLC-2-luciferase fusion gene was found exclusively in heart muscle. In contrast to the endogenous MLC-2 gene, no luciferase activity was detectable in slow-twitch skeletal muscle or any other tissue of transgenic mice. This result suggests that the 2.1-kb DNA fragment of the 5' flanking region of the cardiac MLC-2 gene contains the regulatory elements required for selective gene expression in cardiac myocytes in vivo. In contrast to the endogenous steady-state MLC-2 expression during development, transgenic luciferase activity was 10-fold higher during embryogenesis, when formation of the ventricular loop and septum takes place. The enhanced luciferase activity in early heart development may suggest a growth-dependent control mechanism, involving either transcriptional or posttranscriptional regulation. In conclusion, this model system with the 2.1-kb ventricle-specific MLC-2 promoter sequence should facilitate the overexpression of gene products in the developing and mature heart muscle and further elucidate molecular mechanisms of myocardial diseases such as cardiomyopathies.
Diagnostic Performance of Digital versus Film Mammography for Breast-Cancer Screening
Authors: Etta D. Pisano, Constantine Gatsonis, Edward Hendrick, Martin Yaffe, Janet K. Baum, Suddhasatta Acharyya, Emily F. Conant, Laurie L. Fajardo, Lawrence Bassett, Carl D'Orsi, Roberta Jong, Murray Rebner
Journal: New England Journal of Medicine (2005)

Film mammography has limited sensitivity for the detection of breast cancer in women with radiographically dense breasts. We assessed whether the use of digital mammography would avoid some of these limitations.
Influence of atmospheric nitric oxide concentration on the measurement of nitric oxide in exhaled air
Authors: M. Corradi, A. Pelizzoni, M. Majori, A. Cuomo, E. d. Munari, A. Pesci
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Measurement of nitric oxide (NO) in exhaled air shows promise as a non-invasive method of detecting lung inflammation. However, variable concentrations of NO are measured in environmental air. The aim of this study was to verify a possible relationship between exhaled NO and atmospheric NO values during high atmospheric NO days. <h3>METHOD</h3> Exhaled air from 78 healthy non-smokers of mean age 35.3 years was examined for the presence of NO using a chemiluminescence NO analyser and NO levels were expressed as part per billion (ppb). The exhaled air from all the subjects was collected into a single bag and into two sequential bags. Before each test atmospheric NO was measured. <h3>RESULTS</h3> The mean (SE) concentration of exhaled NO collected into the single bag was 17.1 (0.6) ppb while the mean values of exhaled NO in bags 1 and 2 were 16.7 (1.3) ppb and 13.8 (1.2) ppb, respectively. The atmospheric NO concentrations registered before each test varied from 0.4 to 71 ppb. There was a significant correlation between exhaled NO in the single bag and atmospheric NO (<i>r</i> = 0.38, p = 0.001). The atmospheric NO concentration also correlated with exhaled NO both in bag 1 (<i>r</i> = 0.44, p = 0.0001) and in bag 2 (<i>r</i> = 0.42, p = 0.0001). These correlations disappeared with atmospheric NO concentrations lower than 35 ppb. <h3>CONCLUSIONS</h3> These results indicate a relationship between atmospheric NO and NO levels measured in exhaled air, therefore exhaled NO should not be measured on very high atmospheric NO days.
Adrenal Cortex and Renal Pressor Function
Authors: HIROFUMI SOKABE, AKIRA MIKASA, HISAKAZU YASUDA, GEORGES M. C. MASSON
Journal: Circulation Research (1963)

The pressor response of the nephrectomized rat to the injection of kidney extracts and to a renal graft, was used as an index of the renal content and secretion of pressor substances during adrenal insufficiency or treatment with corticosteroids. Adrenalectomy caused an elevation of both content and secretion, which was best demonstrated after two to three weeks of maintenance therapy. Treatment with cortisone and cortisol decreased slightly but significantly the secretion of pressor substances without altering renal content. ACTH had no effect on either function. Sequential studies of content and secretion of pressor substances during treatment with DCA plus salt showed first a rapid disappearance of prossor activity from renal vein blood followed by a decrease in renal content to near zero levels; DCA without excess salt elicited the same effects but more gradually; administration of 1% saline alone decreased secretion without altering content. It is concluded that salt active corticosteroids specifically inhibit the formation and secretion of renal pressor substances and that determination of the index of secretion constitutes a more reliable and sensitive indicator of the renal pressor function than determination of the pressor activity in kidney extracts.
Adenoviral Gene Transfer of the Human Inducible Nitric Oxide Synthase Gene Enhances the Radiation Response of Human Colorectal Cancer Associated with Alterations in Tumor Vascularity
Authors: Zifa Wang, Tracy Cook, Sean Alber, Kaihong Liu, Imre Kovesdi, Simon K. Watkins, Yoram Vodovotz, Timothy R. Billiar, David Blumberg
Journal: Cancer Research (2004)

Abstract Nitric oxide is a potent radiosensitizer of tumors, but its use clinically is limited by serious side effects when administered systemically. We have demonstrated previously that gene transfer of the inducible nitric oxide synthase gene (iNOS) into colorectal cancer cells enhances radiation-induced apoptosis in vitro. The objectives of this study were to further characterize the effects of iNOS gene transfer on the radiosensitivity of human colorectal cancer cells in vitro and tumors grown in athymic nude mice. Adenoviral gene transfer of iNOS (AdiNOS) into human colorectal cancer cell lines (HCT-116 and SNU-1040 cells) significantly enhanced the effects of radiation with sensitizing enhancement ratios (0.1) of 1.65 and 1.6, respectively. The radiation enhancement induced by iNOS was associated with increased iNOS expression and nitric oxide production and prevented by L-NIO, an enzymatic inhibitor of iNOS. AdiNOS treatment of HCT-116 tumors combined with radiation (2 Gy × three fractions) led to a 3.4-fold greater (P &amp;lt; 0.005) tumor growth delay compared with radiation (RT) alone. AdiNOS plus RT also caused significant (P &amp;lt; 0.01) tumor regression with 63% of tumors regressing compared with only 6% of tumors treated with RT. AdiNOS plus RT significantly (P ≤ 0.001) increased the percentage of apoptotic cells (22 ± 4%) compared with either tumors treated with control vector plus RT (9 ± 1%), AdiNOS alone (9 ± 3%), or no treatment (2 ± 1%). These radiosensitizing effects of AdiNOS occurred at low infection efficiency (4% of tumor infected), indicating a significant bystander effect.
Endoscopic regression of Barrett's oesophagus during omeprazole treatment; a randomised double blind study
Authors: F T M Peters, S Ganesh, E J Kuipers, W J Sluiter, E C Klinkenberg-Knol, C B H W Lamers, J H Kleibeuker
Journal: Gut (1999)

<h3>BACKGROUND</h3> Barrett’s oesophagus, columnar metaplasia of the epithelium, is a premalignant condition with a 50–100-fold increased risk of cancer. The condition is caused by chronic gastro-oesophageal reflux. Regression of metaplasia may decrease the cancer risk. <h3>AIMS</h3> To determine whether elimination of acid gastro-oesophageal reflux induces a regression of metaplastic epithelium. <h3>METHODS</h3> Sixty eight patients with acid reflux and proven Barrett’s oesophagus were included in a prospective, randomised, double blind study with parallel groups, and were treated with profound acid secretion suppression with omeprazole 40 mg twice daily, or with mild acid secretion suppression with ranitidine 150 mg twice daily, for 24 months. Endoscopy was performed at 0, 3, 9, 15, and 24 months with measurement of length and surface area of Barrett’s oesophagus; pH-metry was performed at 0 and 3 months. Per protocol analysis was performed on 26 patients treated with omeprazole, and 27 patients treated with ranitidine. <h3>RESULTS</h3> Omeprazole reduced reflux to 0.1%, ranitidine to 9.4% per 24 hours. Symptoms were ameliorated in both groups. There was a small, but statistically significant regression of Barrett’s oesophagus in the omeprazole group, both in length and in area. No change was observed in the ranitidine group. The difference between the regression in the omeprazole and ranitidine group was statistically significant for the area of Barrett’s oesophagus (p=0.02), and showed a trend in the same direction for the length of Barrett’s oesophagus (p=0.06). <h3>CONCLUSIONS</h3> Profound suppression of acid secretion, leading to elimination of acid reflux, induces partial regression of Barrett’s oesophagus.
Reduction in Physician Reimbursement and Use of Hormone Therapy in Prostate Cancer
Authors: S. P. Elliott, S. L. Jarosek, T. J. Wilt, B. A. Virnig
Journal: JNCI Journal of the National Cancer Institute (2010)

BackgroundUse of androgen suppression therapy (AST) in prostate cancer increased more than threefold from 1991 to 1999. The 2003 Medicare Modernization Act reduced reimbursements for AST by 64% between 2004 and 2005, but the effect of this large reduction on use of AST is unknown.
Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer
Authors: Rolf Sauer, Heinz Becker, Werner Hohenberger, Claus Rödel, Christian Wittekind, Rainer Fietkau, Peter Martus, Jörg Tschmelitsch, Eva Hager, Clemens F. Hess, Johann-H. Karstens, Torsten Liersch, Heinz Schmidberger, Rudolf Raab
Journal: New England Journal of Medicine (2004)

Postoperative chemoradiotherapy is the recommended standard therapy for patients with locally advanced rectal cancer. In recent years, encouraging results with preoperative radiotherapy have been reported. We compared preoperative chemoradiotherapy with postoperative chemoradiotherapy for locally advanced rectal cancer.We randomly assigned patients with clinical stage T3 or T4 or node-positive disease to receive either preoperative or postoperative chemoradiotherapy. The preoperative treatment consisted of 5040 cGy delivered in fractions of 180 cGy per day, five days per week, and fluorouracil, given in a 120-hour continuous intravenous infusion at a dose of 1000 mg per square meter of body-surface area per day during the first and fifth weeks of radiotherapy. Surgery was performed six weeks after the completion of chemoradiotherapy. One month after surgery, four five-day cycles of fluorouracil (500 mg per square meter per day) were given. Chemoradiotherapy was identical in the postoperative-treatment group, except for the delivery of a boost of 540 cGy. The primary end point was overall survival.Four hundred twenty-one patients were randomly assigned to receive preoperative chemoradiotherapy and 402 patients to receive postoperative chemoradiotherapy. The overall five-year survival rates were 76 percent and 74 percent, respectively (P=0.80). The five-year cumulative incidence of local relapse was 6 percent for patients assigned to preoperative chemoradiotherapy and 13 percent in the postoperative-treatment group (P=0.006). Grade 3 or 4 acute toxic effects occurred in 27 percent of the patients in the preoperative-treatment group, as compared with 40 percent of the patients in the postoperative-treatment group (P=0.001); the corresponding rates of long-term toxic effects were 14 percent and 24 percent, respectively (P=0.01).Preoperative chemoradiotherapy, as compared with postoperative chemoradiotherapy, improved local control and was associated with reduced toxicity but did not improve overall survival.
Why Should Results From Metastatic Trials No Longer Matter for Early-Stage Disease?
Authors: Anne-Sophie Dieudonné, Diether Lambrechts, Hans Wildiers, Patrick Neven
Journal: Journal of Clinical Oncology (2013)

al 1 regarding our current knowledge about the importance of CYP2D6 status when prescribing tamoxifen concluded that results from ongoing prospective studies in the metastatic/neoadjuvant setting will not help to close the circle on this topic.We do agree with their conclusion that published retrospective studies-so far-do not provide sufficient evidence to determine whether or not CYP2D6 testing should be performed in daily practice.However, we believe that two registered, ongoing, prospective studies in the neoadjuvant/metastatic setting (the European CYPTAMBRUT-2 study [Study to Assess Response to Tamoxifen in (cT3)/Inoperable Locally Advanced/Metastatic Estrogen Receptor-Positive Breast Cancer by the "Tamoxifen Activity Score" Based on Drug Interaction and Polymorphisms in Genes Coding for Tamoxifen Metabolising Enzymes] and the study of the Eastern Cooperative Oncology Group E3108 [Tamoxifen Citrate in Treating Patients With Metastatic or Recurrent Breast Cancer]) will provide answers that are not available from retrospective studies and which are likely to be relevant in the adjuvant setting.Although metastatic breast cancer differs in many respects from early breast cancer, in which tamoxifen helps to eradicate subclinical disseminated disease, metabolic pathways of tamoxifen for efficacy are disease-stage independent.It is unlikely that endoxifen levels matter in the adjuvant setting if they do not matter in the metastatic setting.However, if endoxifen levels do matter in metastatic disease, it does probably but not necessarily follow that this applies in the adjuvant setting.As principal investigators of the European CYPTAMBRUT-2 study, we would like to stress that this study includes only patients in the first-line metastatic/neoadjuvant setting.Patients with hormoneinsensitive or aromatase inhibitor-refractory disease were excluded from this study, as were premenopausal women.The study has so far recruited 240 of 260 patients.
Prognostic Value of Tumor Size, Metastases, Extension into Bone, and Increased Tumor Marker in Children With Malignant Sacrococcygeal Germ Cell Tumors: A Prospective Evaluation of 71 Patients Treated in the German Cooperative Protocols Maligne Keimzelltumoren (MAKEI) 83/86 and MAKEI 89
Authors: G. Calaminus, D.T. Schneider, J.P.M. Bökkerink, H. Gadner, D. Harms, R. Willers, U. Göbel
Journal: Journal of Clinical Oncology (2003)

To evaluate the prognostic value of metastases, extension into bone, and alpha-fetoprotein (AFP) elevation in children with malignant sacrococcygeal germ cell tumors (GCTs) prospectively collected in two cooperative Maligne Keimzelltumoren (MAKEI) protocols (83/86 and 89).Between October 1983 and October 1995, 76 of 210 registered patients with sacrococcygeal primaries presented either with pure yolk sac tumor, embryonal carcinoma (EC), or yolk sac tumor and EC mixed with immature and mature teratoma elements. Stages T1 and T2 disease were diagnosed in 15 and 61 children, respectively, 41 patients had metastases, and 35 children presented with extension into bone. At diagnosis, 22 children had an AFP elevation of less than 10,000 ng/mL. Thirty-six children showed an AFP level between 10,000 and 100,000 ng/mL, and 12 patients had values of greater than 100,000 ng/mL. Five patients died of complication during treatment and were excluded from further evaluation. Seventy-one patients could be analyzed.The 5-year relapse-free survival rate (RFS, Kaplan-Meier) was 0.76 +/- 0.03 (54 of 71 patients; median observation time, 54 months after diagnosis). The RFS of patients with and without metastases was different, but not significantly so (0.71 v 0.82). The outcome of patients with extension into bone (n = 31) and without this extension (n = 40) was 0.71 versus 0.80 (RFS, 5 years). Above-normal AFP level had no prognostic significance (P =.52).In children with malignant sacrococcygeal GCTs treated with an intensive, short-interval, platinum-based regimen, the stage, extent of metastases, extension into bone, and AFP level had no prognostic significance.
Impact of surgical ventricular reconstruction on sphericity index in patients with ischaemic cardiomyopathy: follow‐up from the <scp>STICH</scp> trial
Authors: Jin‐Oh Choi, Richard C. Daly, Grace Lin, Brian D. Lahr, Heather J. Wiste, Thomas M. Beaver, Attilio Iacovoni, Marcin Malinowski, Ivar Friedrich, Jean L. Rouleau, Roberto R. Favaloro, George Sopko, Irene M. Lang, Harvey D. White, Carmelo A. Milano, Robert H. Jones, Kerry L. Lee, Eric J. Velazquez, Jae K. Oh
Journal: European Journal of Heart Failure (2015)
Inflammation Controls B Lymphopoiesis by Regulating Chemokine CXCL12 Expression
Authors: Yoshihiro Ueda, Kaiyong Yang, Sandra J. Foster, Motonari Kondo, Garnett Kelsoe
Journal: The Journal of Experimental Medicine (2004)

Inflammation removes developing and mature lymphocytes from the bone marrow (BM) and induces the appearance of developing B cells in the spleen. BM granulocyte numbers increase after lymphocyte reductions to support a reactive granulocytosis. Here, we demonstrate that inflammation, acting primarily through tumor necrosis factor alpha (TNFalpha), mobilizes BM lymphocytes. Mobilization reflects a reduced CXCL12 message and protein in BM and changes to the BM environment that prevents homing by cells from naive donors. The effects of TNFalpha are potentiated by interleukin 1 beta (IL-1beta), which acts primarily to expand the BM granulocyte compartment. Our observations indicate that inflammation induces lymphocyte mobilization by suppressing CXCL12 retention signals in BM, which, in turn, increases the ability of IL-1beta to expand the BM granulocyte compartment. Consistent with this idea, lymphocyte mobilization and a modest expansion of BM granulocyte numbers follow injections of pertussis toxin. We propose that TNFalpha and IL-1beta transiently specialize the BM to support acute granulocytic responses and consequently promote extramedullary lymphopoiesis.
The vanishing role of whole brain radiotherapy for primary central nervous system lymphoma
Authors: M. Weller
Journal: Neuro-Oncology (2014)

To estimate the value of whole brain radiotherapy (WBRT) in the treatment of primary CNS lymphoma (PCNSL), it is important to recall the goals of treatment when confronted with this disease. Presumably, our goals of PCNSL treatment are to improve neurological deficits, improve or maintain quality of life, delay neurological progression, prolong progression-free survival, prolong overall survival, and eventually achieve a cure. Very few of these goals are achieved with WBRT in the current landscape of improved systemic therapy options for PCNSL. Historically, it had been recognized that PCNSL is less sensitive to irradiation than lymphomas elsewhere in the body and might therefore potentially require higher doses to achieve local control. Accordingly, Radiation Therapy Oncology Group (RTOG) study 8315 explored whether treating the whole brain at 40 Gy and increasing the tumor dose to 60 Gy would result in improved outcome. In fact, median overall survival was only 11.6 months from the start of radiotherapy; 16 of 26 patients with posttreatment CT scans were considered to have had a complete response, a finding commonly cited to demonstrate the efficacy of RT in that disease. Importantly, however, these 16 patients represent a highly selected population because patients who progressed during radiotherapy were not included in that analysis. 1
Coronary Physiology Revisited
Authors: Morton J. Kern
Journal: Circulation (2000)

Various coronary physiological measurements can be made in the cardiac catheterization laboratory using sensor-tipped guidewires; they include the measurement of poststenotic absolute coronary flow reserve, the relative coronary flow reserve, and the pressure-derived fractional flow reserve of the myocardium. Ambiguity regarding abnormal microcirculation has been reduced or eliminated with measurements of relative coronary flow reserve and fractional flow reserve. The role of microvascular flow impairment can be separately determined with coronary flow velocity reserve measurements. In addition to lesion assessment before and after intervention, emerging applications of coronary physiology include the determination of physiological responses to new pharmacological agents, such as glycoprotein IIb/IIIa blockers, in patients with acute myocardial infarction. Measurements of coronary physiology in the catheterization laboratory provide objective data that complement angiography for clinical decision-making.