tbuckley/cabot-search huggingface dataset:
Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11βHSD2-dependent mechanism
Authors: Vivi M. Heine, David H. Rowitch
Journal: Journal of Clinical Investigation (2009)

Glucocorticoids (GCs) are administered to human fetuses at risk of premature delivery and to infants with life-threatening respiratory and cardiac conditions. However, there are ongoing concerns about adverse effects of GC treatment on the developing human brain, although the precise molecular mechanisms underlying GC-induced brain injury are unclear. Here, we identified what we believe to be novel cross-antagonistic interactions of Sonic hedgehog (Shh) and GC signaling in proliferating mouse cerebellar granule neuron precursors (CGNPs). Chronic GC treatment (from P0 through P7) in mouse pups inhibited Shh-induced proliferation and upregulation of expression of N-myc, Gli1, and D-type cyclin protein in CGNPs. Conversely, acute GC treatment (on P7 only) caused transient apoptosis. Shh signaling antagonized these effects of GCs, in part by induction of 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2). Importantly, 11betaHSD2 antagonized the effects of the GCs corticosterone, hydrocortisone, and prednisolone, but not the synthetic GC dexamethasone. Our findings indicate that Shh signaling is protective in the setting of GC-induced mouse neonatal brain injury. Furthermore, they led us to propose that 11betaHSD2-sensitive GCs (e.g., hydrocortisone) should be used in preference to dexamethasone in neonatal human infants because of the potential for reduced neurotoxicity.
Contact sensitizer 2,4‐dinitrochlorobenzene is a highly potent human <scp>TRPA</scp>1 agonist
Authors: M. Saarnilehto, H. Chapman, T. Savinko, K. Lindstedt, A. I. Lauerma, A. Koivisto
Journal: Allergy (2014)

2,4-Dinitrochlorobenzene (DNCB) is widely used in human clinical studies and in experimental animal studies to evoke allergic contact dermatitis. 2,4-Dinitrochlorobenzene is a potent immunogen capable of inducing contact sensitization in all humans exposed. However, the mechanism by which DNCB evokes such symptoms is presently unknown. TRPA1 is a nonselective cation channel that is expressed in peptidergic sensory neurons and fibroblasts. TRPA1 activation was recently implicated in the pathophysiology of atopic dermatitis especially in transducing cutaneous itch signals. Here, we test the hypothesis that DNCB acts as a TRPA1 agonist and thereby evokes allergic symptoms. We found that DNCB activates human TRPA1 dose dependently in FLIPR experiments with an EC50 of 167 nM, an effect that was fully blocked by selective TRPA1 antagonists Chembridge-5861528 and A-967079. Similarly, DNCB activated nonselective TRPA1 current in patch clamp studies. Neutralization of 3 critical cysteines in TRPA1 resulted in a loss of DNCB agonism.
The Kaposi sarcoma-associated herpesvirus (KSHV) is present as an intact latent genome in KS tissue but replicates in the peripheral blood mononuclear cells of KS patients.
Authors: L L Decker, P Shankar, G Khan, R B Freeman, B J Dezube, J Lieberman, D A Thorley-Lawson
Journal: The Journal of Experimental Medicine (1996)

Short DNA sequences have been identified, originally in association with Kaposi's sarcoma (KS) biopsies, that are highly homologous to oncogenic, lymphotropic herpesviruses. Recently a virus, Kaposi sarcoma associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8), bearing these sequences has been identified in a cell line derived from a body cavity-based lymphoma. In this report, we show that the same sequences are present in KS biopsies as DNA molecules of a form and size characteristic of latent herpesviruses-large, covalently closed, circular episomes. The genomes migrate with an apparent size larger than the herpesvirus Epstein-Barr virus (172 kb). This form of the viral genome was found in four of four biopsies and three of five peripheral blood samples from KS patients. Linear forms of the viral genome, characteristic of viral replication, were not detected in the biopsies, but were present in the peripheral blood of three out of five patients. The sequences for KSHV/HHV-8 were also detected in the blood of four of five allograft patients and three of five healthy donors without KS suggesting that the virus is widespread throughout the human population.
A Phase I, Dose-Escalation Study of the Multitargeted Receptor Tyrosine Kinase Inhibitor, Golvatinib, in Patients with Advanced Solid Tumors
Authors: L. Rhoda Molife, Emma Jane Dean, Montserrat Blanco-Codesido, Matthew G. Krebs, Andre T. Brunetto, Alastair Peter Greystoke, Gennaro Daniele, Lucy Lee, Galina Kuznetsov, Khin Than Myint, Karen Wood, Begoña de las Heras, Malcolm Richard Ranson
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Receptor tyrosine kinases c-Met and Ron transduce signals regulating cell migration and matrix invasion. This phase I dose-escalation trial tested golvatinib, a highly potent, small-molecule, ATP-competitive inhibitor of c-Met and multiple members of the Eph receptor family plus c-Kit and Ron. Experimental Design: Patients with advanced solid tumors received golvatinib orally, once daily, continuously. Using a “3+3” design, dosing started at 100 mg once daily, escalating to the maximum tolerated dose (MTD) defined by dose-limiting toxicities. Pharmacokinetic, pharmacodynamic, and preliminary antitumor activity was assessed during dose escalation and in a MTD expansion cohort. Results: Thirty-four patients were treated at six dose levels. The MTD was determined as 400 mg once daily. Three dose-limiting toxicities were observed: grade 3 increased γ-glutamyltransferase and alkaline phosphatase (200 mg), repeated grade 2 fatigue, and grade 3 fatigue (50.0%). Frequent treatment-related adverse events (with incidence &amp;gt;10%) included diarrhea (58.8%), nausea (50%), vomiting (44.1%), fatigue (41.2%), decreased appetite (32.4%), elevated alanine aminotransferase (32.4%), elevated aspartate aminotransferase (20.6%), dry skin (11.8%), and dysgeusia (11.8%). Best overall response was stable disease (median duration 85 days, range 85–237). Pharmacokinetics demonstrated high variability, although maximum plasma concentration and area under the plasma concentration–time curve increased with dose. Soluble urokinase-type plasminogen activator receptor, VEGFR2, c-Met, and angiopoietin-2 levels increased after dose. Posttreatment decrease in either p-c-Met or p-ERK was observed in 3 of 4 paired biopsies at MTD. Conclusions: Golvatinib at the MTD of 400 mg once daily was well tolerated with pharmacodynamic evidence of c-Met target modulation. Clin Cancer Res; 20(24); 6284–94. ©2014 AACR.
A1C Is Associated With Intima-Media Thickness in Individuals With Normal Glucose Tolerance
Authors: Thomas Bobbert, Knut Mai, Antje Fischer-Rosinský, Andreas F.H. Pfeiffer, Joachim Spranger
Journal: Diabetes Care (2009)

OBJECTIVE One-hour glucose during an oral glucose tolerance test (OGTT) was recently proposed as a valuable marker to identify individuals with normal glucose tolerance (NGT) and increased intima-media thickness (IMT). However, central markers of glycemic control were not considered. The aim of this study was to identify which marker of glycemic control is most informative with respect to the variation of IMT in individuals with NGT. RESEARCH DESIGN AND METHODS Cardiovascular risk factors, glucose metabolism (OGTT), and IMT were determined in 1,219 nondiabetic individuals (851 women, 368 men; 558 with NGT). RESULTS One-hour glucose and A1C levels were significantly correlated to carotid IMT in individuals with NGT, whereas fasting and 2-h glucose levels were not informative. Only A1C was associated with IMT independent of other confounders, whereas 1-h glucose was not informative. Comparable results were found in the total cohort, including individuals with IFG and IGT. CONCLUSIONS A1C was the most informative glycemic marker with respect to IMT in individuals with NGT.
Elevated expression of IL-3Rα in acute myelogenous leukemia is associated with enhanced blast proliferation, increased cellularity, and poor prognosis
Authors: Ugo Testa, Roberta Riccioni, Stefania Militi, Eliana Coccia, Emilia Stellacci, Paola Samoggia, Roberto Latagliata, Gualtiero Mariani, Annalisa Rossini, Angela Battistini, Francesco Lo-Coco, Cesare Peschle
Journal: Blood (2002)
Ophthalmological findings in elite amateur Turkish boxers
Authors: M Hazar, M Beyleroglu, M Subasi, M Or
Journal: British Journal of Sports Medicine (2002)

To evaluate the nature and incidence of pathological ocular conditions in boxing.A group of 20 active, elite, amateur, asymptomatic Turkish boxers were examined and compared with a control group composed of 20 age matched sportsmen who were not boxers. The boxers had been actively boxing for 5-20 years (mean 9.65), were aged 16-34 (mean 22.25), and weighed 51-91 kg (mean 73.07). They had been involved in 67-500 fights (mean 143.8), with 5-40 losses (mean 17.75). All were championship title holders at the national, European, Olympic, or World level.An atrophic retinal hole was found in one boxer, which was treated with laser prophylaxis. In this series, the incidence of traumatic eye injuries was much lower than in the literature. Possible reasons are their young age, their division being mainly lightweight or middleweight, few fight losses, being elite boxers, their fighting distance being near or distant, protective methods, and racial factors.Boxing does not appear to be as hazardous to the eyes as previously reported, but prospective, longitudinal studies need to be carried out, including boxers of all divisions, ages, boxing experience, and level, and using various methods of fighting and protection. It should be made mandatory for all boxers to have a complete ophthalmological examination at the beginning of their careers and periodically thereafter.
Statistical Issues in Interpretation of Chronic Bioassay Tests for Carcinogenicity
Authors: J J Gart, K C Chu, R E Tarone
Journal: JNCI Journal of the National Cancer Institute (1979)

The interpretation of chronic bioassay tests for carcinogenicity requires that the data be appropriately recorded. A “case history” for each animal links the pathology data for each organ of each animal to the length of its life. This information can be used in interpretation of the tumor incidence in light of the survival information. The role of historical controls was discussed, and the use of significance tests in a multidisciplinary approach to the assessment of the pattern of tumor response was suggested. Multiple comparison methods valid for the interpretation of continuous (or measurement) data do not apply to the discrete data analyses used in these studies. The ideas and methods of these studies were appliedd to an animal study of chloroform.
The Expression of Functional Chemokine Receptor CXCR4 Is Associated with the Metastatic Potential of Human Nasopharyngeal Carcinoma
Authors: Jinyue Hu, Xiyun Deng, Xiuwu Bian, Guancheng Li, Yongqing Tong, Yuehui Li, Qingliang Wang, Rong Xin, Xiaojuan He, Guohua Zhou, Pingli Xie, Yanwen Li, Ji Ming Wang, Ya Cao
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Chemokine receptors are implicated in metastasis of several malignant tumors. This study was done to evaluate the contribution of chemokine receptors CXCR4 and CCR7 to metastasis of human nasopharyngeal carcinoma. Experimental Design: Reverse transcription-PCR, immunohistochemistry, and flow cytometry were used to evaluate mRNA and protein expression of CXCR4 and CCR7 in nasopharyngeal carcinoma tumor tissues and cell lines. Chemotaxis assays were used to evaluate the function of CXCR4 in nasopharyngeal carcinoma cells. Antisense CXCR4 was used to inhibit receptor expression and to block metastasis of human nasopharyngeal carcinoma cells in vivo in athymic mice. Results: CXCR4 protein was detected in tumor cells in 31 of 40 primary human nasopharyngeal carcinoma and in 13 of 15 lymph node metastases. CXCR4 transcripts were detected in eight CXCR4 protein–positive primary nasopharyngeal carcinoma tissues and seven nasopharyngeal carcinoma cell lines tested. On the other hand, the transcripts for CCR7 were detected only in four primary nasopharyngeal carcinoma tissues and in none of the nasopharyngeal carcinoma cell lines. In functional experiments, metastatic nasopharyngeal carcinoma cell lines that expressed high levels of CXCR4 were found to migrate in response to the CXCR4 ligand SDF-1α. Transfection of antisense CXCR4 in metastatic nasopharyngeal carcinoma cells inhibited the expression of CXCR4 and SDF-1α-induced cell migration in vitro and reduced the capacity of the tumor cells to form metastasis in the lungs and lymph nodes when injected in athymic mice. Conclusion: The expression of functional CXCR4 but not CCR7 is correlated with the metastatic potential of human nasopharyngeal carcinoma cells. Therefore, CXCR4 may be considered as a potential target for the prevention of nasopharyngeal carcinoma metastasis.
PRELIMINARY REPORT ON THE FORCIBLE FEEDING OF SUFFRAGE PRISONERS
Authors: A. Savill, C. M. Moullin, V. Horsley
Journal: BMJ (1912)

rORCIBLE FEEDING.TEm Bans 5< production of all opium containing less than 9 per cent. of miorphine was opposed by Sir WILLIAM MIEYER on behalf of India, whose opium averages 71 per cent. of morphine.The proposal was supported by the United States dele- gates, who urged that opium should be restricted to purely medical purposes, and that since medicinal opium was opium which contained 10 per cent. of morphine, the Persian proposal was corollary to this end.
Diet and arterial hypertension: Is the sodium ion alone important?
Authors: Michele Buemi, Massimino Senatore, Francesco Corica, Carmela Aloisi, Adolfo Romeo, Domenico Tramontana, Nicola Frisina
Journal: Medicinal Research Reviews (2002)

Abstract Hypertension is a widespread phenomenon whose ultimate cause is still unknown. Many factors contribute to this disease, and partially for this reason, hypertension responds to different treatments in different individuals. It is difficult to generalize about therapies for general populations. In particular, the role of electrolytes in hypertension varies widely across individuals. This review focuses its attention on sodium, potassium, calcium, and magnesium ions in order to investigate whether these electrolytes play a role in the pathogenesis of arterial hypertension and its treatment. Some individuals are especially sensitive to sodium, and changing their intake of dietary sodium may lead to variations in the levels of the other electrolytes. These changes in electrolyte levels can complicate treatments for arterial hypertension in some patients. © 2002 Wiley Periodicals, Inc. Med Res Rev, 22, No. 4, 419–428, 2002; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/med.10013
Efficacy of vincristine and etoposide with escalating cyclophosphamide in poor-prognosis pediatric brain tumors1
Authors: David S. Ziegler, Richard J. Cohn, Geoffrey McCowage, Frank Alvaro, Cecilia Oswald, Robert Mrongovius, Les White
Journal: Neuro-Oncology (2006)

The objective of this study was to assess the efficacy of the VETOPEC regimen, a regimen of vincristine and etoposide with escalating doses of cyclophosphamide (CPA), in pediatric patients with high-risk brain tumors. Three consecutive studies by the Australia and New Zealand Children's Cancer Study Group—VETOPEC I, Baby Brain 91, and VETOPEC II—have used a specific chemotherapy regimen of vincristine (VCR), etoposide (VP-16) and escalating CPA in patients with relapsed, refractory, or high-risk solid tumors. Patients in the VETOPEC II cohort were treated with very high dose CPA with peripheral blood stem cell (PBSC) rescue. We analyzed the subset of patients with high-risk brain tumors treated with these intensive VETOPEC-based protocols to assess the response, toxicity, and survival. We also assessed whether the use of very high dose chemotherapy with stem cell rescue improved the response rate or affected toxicity. Seventy-one brain tumor patients were treated with VETOPEC-based protocols. Of the 54 patients evaluable for tumor response, 17 had a complete response (CR) and 20 a partial response (PR) to treatment, which yielded an overall response rate of 69%. The CR + PR was 83% (19/23) for medulloblastomas, 56% (5/9) for primitive neuroectodermal tumors, 55% (6/11) for grade 3 and 4 astrocytomas, and 80% (6/8) for ependymomas. At a median follow-up of 36 months, overall survival for the entire cohort of 71 patients was 32%, with event-free survival of 13%. There were no toxic deaths within the PBSC-supported VETOPEC II cohort, despite higher CPA doses, compared with 7% among the non-PBSC patients. This regimen produces high response rates in a variety of very poor prognosis pediatric brain tumors. The maximum tolerated dose of CPA was not reached. Higher escalation in doses of CPA did not deliver a further improvement in response. With PBSC rescue in the VETOPEC II study, hematologic toxicity was no longer a limiting factor. The response rates observed support further development of this chemotherapy regimen.
Long-term Outcome after TAVI and the Impact of New Left Bundle Branch Block or Need for Pacemaker Implantation on Survival
Authors: Ömer Aktug, Ralf Herpertz, Kathrin Brehmer, Rüdiger Autschbach, Nikolaus Marx, Shahram Lotfi, Rainer Hoffmann
Journal: Journal of the American College of Cardiology (2013)
PKCα Activates eNOS and Increases Arterial Blood Flow In Vivo
Authors: Chohreh Partovian, Zhenwu Zhuang, Karen Moodie, Michelle Lin, Noriyuki Ouchi, William C. Sessa, Kenneth Walsh, Michael Simons
Journal: Circulation Research (2005)

Endothelial nitric oxide synthase (eNOS) plays an important role in control of vascular tone and angiogenesis among other functions. Its regulation is complex and has not been fully established. Several studies have emphasized the importance of phosphorylation in the regulation of eNOS activity. Although it is commonly accepted that protein kinase C (PKC) signaling inhibits eNOS activity by phosphorylating Thr497 and dephosphorylating Ser1179, the distinct role of different PKC isoforms has not been studied so far. The PKC family comprises roughly 12 different isozymes that activate distinct downstream pathways. The present study was designed to investigate the role of PKCalpha isoform in regulation of eNOS activity. Overexpression of PKCalpha in primary endothelial cells was associated with increased eNOS-Ser1179 phosphorylation and increased NO production. Inhibition of PKCalpha activity either by siRNA transfection or by overexpression of a dominant negative mutant resulted in a marked decrease in FGF2-induced Ser1179 phosphorylation and NO production. In vivo, PKCalpha transduction in rat femoral arteries resulted in a significant increase in the resting blood flow that was suppressed by treatment with L-NAME, an eNOS inhibitor. In conclusion, these data demonstrate for the first time that PKCalpha stimulates NO production in endothelial cells and plays a role in regulation of blood flow in vivo.
Phenotypic expression in familial adenomatous polyposis: partial prediction by mutation analysis.
Authors: K P Nugent, R K Phillips, S V Hodgson, S Cottrell, J Smith-Ravin, K Pack, W F Bodmer
Journal: Gut (1994)

The phenotypic expression in familial adenomatous polyposis (FAP) is variable. This study compares the phenotype of 27 patients with an identical 5 base pair (bp) deletion at codon 1309 with a group of 61 matched patients with FAP where knowledge of specific mutations is not available and with seven other different mutations in 24 subjects. Patients with the codon 1309 deletion have significantly more colorectal polyps at the time of colectomy than age and sex matched FAP controls (p = 0.0001). The median number of polyps in colectomy specimens of patients with the deletion at codon 1309 was 4000 (interquartile (IQ) range 3000-4875), compared with 600 (IQ range 488-1400) in the matched controls. Mutations at codon 1323, 1407, and 233 were also associated with large numbers of polyps. Desmoid disease and extracolonic cancers were more common with the mutation at codon 1309 (p = 0.003). In conclusion, there may be a correlation between a specific germline mutation and the number of large bowel polyps. There is residual heterogeneity in phenotypic expression, however, and this may result from the influence of other genes, specific environmental factors or chance.
Survival and prognostic factors after initiation of treatment in Waldenstrom’s macroglobulinemia
Authors: M.A. Dimopoulos, G. Hamilos, K. Zervas, A. Symeonidis, G. Kouvatseas, P. Roussou, D. Gika, T. Karmiris, K. Bourantas, A. Zomas, C. Mitsouli, I. Xilouri, E. Vervessou, K. Matsis, N. Anagnostopoulos, T. Economopoulos
Journal: Annals of Oncology (2003)
Resistance to Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors
Authors: Ann W. Gramza, Christopher L. Corless, Michael C. Heinrich
Journal: Clinical Cancer Research (2009)

Abstract Gastrointestinal stromal tumors (GIST) are the most common type of sarcoma in the gastrointestinal tract. Surgery is the primary treatment modality, but many patients suffer disease recurrence or metastasis. Fortunately, the management of advanced GIST has been revolutionized by the use of small molecule kinase inhibitors that target the underlying pathogenetic mutant kinases found in the vast majority of cases. Approximately 85% of GISTs have oncogenic mutations in KIT, allowing for constitutive kinase activation that is responsible for cellular proliferation and survival. About 5 to 7% of GISTs have activating mutations of the homologous platelet-derived growth factor receptor alpha (PDGFRA) kinase. The progression-free and overall survival of patients with advanced disease is greatly improved by treatment with the kinase inhibitors imatinib and sunitinib. However, the emergence of drug-resistant tumor clones limits the long-term benefit of these drugs in most patients. Resistance to these kinase inhibitors is associated with distinctive clinical and molecular features, with the development of secondary mutations of the oncogenic kinase being the most common mechanism. We review the molecular basis of GIST response and/or resistance to TKIs, and discuss strategies to prevent and/or overcome drug resistance. These concepts are directly relevant to the development of targeted molecular therapy for other solid tumors. (Clin Cancer Res 2009;15(24):7510–8)
Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia.
Authors: R Gucalp, P Ritch, P H Wiernik, P R Sarma, A Keller, S P Richman, K Tauer, J Neidhart, L E Mallette, R Siegel
Journal: Journal of Clinical Oncology (1992)

This multicenter, double-blind, randomized trial was performed to determine the efficacy and safety of pamidronate disodium (APD) in comparison to etidronate disodium (EHDP) in the treatment of cancer-related hypercalcemia.Sixty-five male and female adult patients with cancer and corrected calcium levels of greater than or equal to 12.0 mg/dL after 24 hours of hydration were randomized to receive either 60 mg APD given as a single 24-hour infusion or 7.5 mg/kg EHDP given as a 2-hour infusion daily for 3 days.APD normalized corrected calcium levels in 70% (21 of 30) of patients, whereas EHDP did so in 41% (14 of 34) of patients (P = .026). The mean corrected serum calcium level decreased from 14.6 to 10.5 mg/dL in the APD-treated group and from 13.8 to 11.6 mg/dL in the EHDP-treated group within the first week of treatment. There was no difference in response to APD in patients without versus those with bone metastases (78% v 67%). Both drugs were well tolerated.This study demonstrated that a single 60-mg infusion of APD is safe and more effective than EHDP given at the dose of 7.5 mg/kg for 3 days in the treatment of cancer-related hypercalcemia.