tbuckley/cabot-search huggingface dataset:
Protein Kinase C ε–Src Modules Direct Signal Transduction in Nitric Oxide–Induced Cardioprotection
Authors: Thomas M. Vondriska, Jun Zhang, Changxu Song, Xian-Liang Tang, Xinan Cao, Christopher P. Baines, Jason M. Pass, Shaoshan Wang, Roberto Bolli, Peipei Ping
Journal: Circulation Research (2001)

An essential role for protein kinase C epsilon (PKCepsilon) has been shown in multiple forms of cardioprotection; however, there is a distinct paucity of information concerning the signaling architecture that is responsible for the manifestation of a protective phenotype. We and others have recently shown that signal transduction may proceed via the formation of signaling complexes (Circ Res. 2001;88:59-62). In order to understand if the assembly of multiprotein complexes is the manner by which signaling is conducted in cardioprotection, we designed a series of experiments to characterize the associations of Src tyrosine kinase with PKCepsilon in a conscious rabbit model of nitric oxide (NO)-induced late preconditioning. Our data demonstrate that PKCepsilon and Src can form functional signaling modules in vitro: PKCepsilon interacts with Src; the association with PKCepsilon activates Src; and adult cardiac cells receiving recombinant adenoviruses encoding PKCepsilon exhibit increased Src activity. Furthermore, our results show that NO-induced late preconditioning involved PKCepsilon-Src module formation and enhanced the enzymatic activity of PKCepsilon-associated Src. Inhibition of PKC blocked cardioprotection, module formation, and PKCepsilon-associated Src activity, providing direct evidence for a functional role of the PKCepsilon-Src module in the orchestration of NO-induced cardioprotection in conscious rabbits.
Further evidence that a cartilage-pannus junction synovitis predilection is not a specific feature of rheumatoid arthritis
Authors: L A Rhodes
Journal: Annals of the Rheumatic Diseases (2005)

Qualitative differences in synovitis between the cartilage-pannus junction (CPJ) region and the adjoining suprapatellar pouch (SPP) have been reported in rheumatoid arthritis and the spondyloarthropathies.To determine if the distribution of synovitis is the same in osteoarthritis (OA) using sensitive measures of inflammation derived from dynamic, contrast enhanced magnetic resonance imaging (DEMRI).20 subjects with established OA of the knee were recruited. Conventional MR images together with the DEMRI measurements were obtained. Areas of synovitis at the CPJ region and at a distant site in the SPP were calculated; differences in CPJ and SPP synovitis were determined using DEMRI parameters: the initial rate of contrast enhancement (IRE) and maximal enhancement (ME).The area of synovitis was significantly greater adjacent to the CPJ than in the SPP. IRE and ME measures were greater at the CPJ than the SPP.The magnitude of synovitis at the CPJ is not disease-specific and applies across the spectrum of degenerative disease as well as inflammatory diseases.
SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma
Authors: Stephanie M. Robert, Susan C. Buckingham, Susan L. Campbell, Stefanie Robel, Kenneth T. Holt, Toyin Ogunrinu-Babarinde, Paula P. Warren, David M. White, Meredith A. Reid, Jenny M. Eschbacher, Michael E. Berens, Adrienne C. Lahti, Louis B. Nabors, Harald Sontheimer
Journal: Science Translational Medicine (2015)

SLC7A11, the catalytic subunit of the cystine/glutamate antiporter, System x c − (SXC), is up-regulated in a subpopulation of patient gliomas, where it is responsible for excitotoxic glutamate release, accelerated tumor growth, and tumor-associated seizures.
Analysis of p53 and BAX mutations, loss of heterozygosity, p53 and BCL2 expression and apoptosis in basal cell carcinoma in Korean patients
Authors: S. Cho, J-H. Hahm, Y-S. Hong
Journal: British Journal of Dermatology (2001)

Apart from some Japanese studies, there are few data on the gene mutations involved in the development of basal cell carcinomas (BCC) in Koreans or other Asians. Objective To gain insight into the molecular pathogenesis of BCC in Koreans.A collection of 33 cases of BCC were screened for mutations of p53 and BAX genes, p53 and BCL2 expression, loss of heterozygosity (LOH) and apoptosis.Mutations of p53, found in 9% (three of 33) of the cases, were all mis-sense mutations (G-->C transversions) at codon 246 on exon 7. In 6% (two of 33), BAX gene showed frameshift mutations resulting from deletions in the poly(G) tract. LOH on chromosome 9q was seen in 58% (14 of 24), and p53 mutations developed only among the 9q LOH+ cases; LOH on chromosome 18q, where BCL2 gene is located, was found in 13% (four of 30). Immunohistochemical expression of p53 was seen in 27% (nine of 33), and its expression did not coincide with p53 mutations. BCL2 expression was seen in 39% (13 of 33). Apoptosis was revealed in 21%. In BCC, 9q LOH and p53 mutations seem to be closely related; the immunoreactivity of p53 and its mutations were not directly related; and p53 and BCL2 expression were negatively correlated. Frameshift mutations of the BAX gene in BCC are documented for the first time.Various molecular mechanisms operate with redundant complexity in the pathogenesis of BCC. The LOH on chromosome 9q is the most frequent genetic alteration, as in other races; however, p53 mutations are much less frequent in Koreans than in Caucasians and suggest aetiologies other than ultraviolet radiation.
Glioblastoma multiforme after stereotactic radiotherapy for acoustic neuroma: Case report and review of the literature
Authors: Anandh Balasubramaniam, Patrick Shannon, Mojgan Hodaie, Normand Laperriere, Howard Michaels, Abhijit Guha
Journal: Neuro-Oncology (2007)

Indications for the use of radiotherapy in the management of a variety of benign intracranial neoplastic and nonneoplastic pathologies are increasing. Although the short-term risks are minimal, the long-term risks of radiation-induced de novo secondary neoplasms or malignant progression of the primary benign tumor need to be considered. There are currently 19 reported cases of tumors linked with stereotactic radiotherapy/radiosurgery, to which we add our second institutional experience of a patient who succumbed to a glioblastoma multiforme (GBM) after stereotactic radiotherapy for an acoustic neuroma (AN). Review of these 20 cases revealed 10 de novo secondary tumors, of which eight were malignant, with six being malignant gliomas. The majority of the cases (14 of 20) involved AN, with most being in patients with neurofibromatosis-2 (NF2; 8 of 14), reflecting the large numbers and long-term use of radiotherapy for AN. Accelerated growth of the primary benign AN, some 2 to 6 years after focused radiotherapy, was found in six of eight NF2 patients, with pathological verification of a malignant nerve sheath tumor documented in most. The exact carcinogenic risk after radiotherapy is unknown but likely extremely low. However, the risk is not zero and requires discussion with the patient, with specific consideration in young patients and those with a cancer predisposition.
Partial cell fusion: A newly recognized type of communication between dedifferentiating cardiomyocytes and fibroblasts
Authors: R DRIESEN, G DISPERSYN, F VERHEYEN, S VANDENEIJNDE, L HOFSTRA, F THONE, P DIJKSTRA, W DEBIE, M BORGERS, F RAMAEKERS
Journal: Cardiovascular Research (2005)

Fibroblasts have been shown to couple to neonatal cardiomyocytes in heterocellular cultures through functional gap junctions. Our objective was to provide evidence for an additional type of heterocellular communication between fibroblasts and adult cardiomyocytes in vitro and in vivo.The contact areas in heterocellular co-cultures were evaluated by specific labeling and the intercellular communication was studied using preloading of fibroblasts with tracer molecules. Heterocellular fibroblast-cardiomyocyte contacts present in the in vitro setting and in the border zone of a rabbit myocardial infarction in vivo were further examined by electron microscopy.Addition of fibroblasts preloaded with the fluorescent low molecular weight tracer calcein-AM to cultured myocytes indicated early dye transfer via connexin 43 functional gap junctions. At a later time-period after co-culturing, dye transfer of fibroblasts preloaded with the high molecular weight tracer dextran 10,000 suggested partial cell fusion. The membrane continuity giving rise to this partial cell fusion was confirmed by electron microscopy, clearly showing areas of intercytoplasmic contacts between fibroblasts and phenotypically adapted (dedifferentiated) cardiomyocytes. Fluorescein-labeled annexin V affinity studies revealed transient exposure of phosphatidylserine at the contact sites, suggesting that phosphatidylserine mediates the fusion process. Close contacts between cardiac fibroblasts and dedifferentiated cardiomyocytes accompanied by disruption of the basal lamina were observed in the border zone of a rabbit myocardial infarction in vivo.Our results suggest that the partial cell fusion-type of heterocellular communication in our co-culture model and the contacts observed in vivo may lead to new insights in cardiovascular disease.
Development of Inhalational Agents for Oncologic Use
Authors: Sunil Sharma, Dorothy White, Anthony R. Imondi, Michael E. Placke, David M. Vail, Mark G. Kris
Journal: Journal of Clinical Oncology (2001)

ABSTRACT: Because regional chemotherapy has been useful in treatment and palliation of many cancer types, the concept of delivering drugs by inhalation for the treatment of cancers in the lung is attractive. Much higher local drug exposure can be achieved with total doses considerably lower than those required for systemic administration, resulting in lower exposure of nonrespiratory tract tissues to potentially toxic drugs. Regional delivery of chemotherapy to the respiratory tract has been shown to have activity in preclinical and clinical studies. Technical improvements in delivery methods have now made it possible to conduct trials of inhalational agents, both to treat cancers affecting the respiratory tract and to deliver other drugs used in cancer patients. This review discusses the rationale of drug delivery by the inhalational route, its technical challenges, preclinical and clinical experiences, limitations, and promise.
Failure of renal dopamine response to salt loading in chronic renal disease.
Authors: I F Casson, M R Lee, A M Brownjohn, F M Parsons, A M Davison, E J Will, A D Clayden
Journal: BMJ (1983)

Eight patients with chronic glomerulonephritis and five age-matched normal volunteers were given additional sodium chloride by mouth under conditions of metabolic balance. Whereas in the normal volunteers plasma renin activity was suppressed and urinary excretion of free dopamine increased, in the patients dopamine was not mobilised and plasma renin activity was not completely suppressed. Abnormal retention of sodium and water in glomerulonephritis may be due partly to a failure to mobilise dopamine in the kidney. Specific renal dopamine agonists may be natriuretic and hypotensive in chronic glomerulonephritis.
Novel Cell Type–Specific Antiviral Mechanism of Interferon γ Action in Macrophages
Authors: Rachel M. Presti, Daniel L. Popkin, Megan Connick, Susanne Paetzold, Herbert W. Virgin
Journal: The Journal of Experimental Medicine (2001)

Interferon (IFN)-gamma and macrophages (Mphi) play key roles in acute, persistent, and latent murine cytomegalovirus (MCMV) infection. IFN-gamma mechanisms were compared in embryonic fibroblasts (MEFs) and bone marrow Mphi (BMMphi). IFN-gamma inhibited MCMV replication in a signal transducer and activator of transcription (STAT)-1alpha-dependent manner much more effectively in BMMphi (approximately 100-fold) than MEF (5-10-fold). Although initial STAT-1alpha activation by IFN-gamma was equivalent in MEF and BMMphi, microarray analysis demonstrated that IFN-gamma regulates different sets of genes in BMMphi compared with MEFs. IFN-gamma inhibition of MCMV growth was independent of known mechanisms involving IFN-alpha/beta, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase RNA activated (PKR), RNaseL, and Mx1, and did not involve IFN-gamma-induced soluble mediators. To characterize this novel mechanism, we identified the viral targets of IFN-gamma action, which differed in MEF and BMMphi. In BMMphi, IFN-gamma reduced immediate early 1 (IE1) mRNA during the first 3 h of infection, and significantly reduced IE1 protein expression for 96 h. Effects of IFN-gamma on IE1 protein expression were independent of RNaseL and PKR. In contrast, IFN-gamma had no significant effects on IE1 protein or mRNA expression in MEFs, but did decrease late gene mRNA expression. These studies in primary cells define a novel mechanism of IFN-gamma action restricted to Mphi, a cell type key for MCMV pathogenesis and latency.
Negative Feedback and Adaptive Resistance to the Targeted Therapy of Cancer
Authors: Sarat Chandarlapaty
Journal: Cancer Discovery (2012)

Mutational activation of growth factor signaling pathways is commonly observed and often necessary for oncogenic transformation. Under physiologic conditions, these pathways are subject to tight regulation through negative feedback, which limits the extent and duration of signaling events after physiologic stimulation. Until recently, the role of these negative feedback pathways in oncogene-driven cancers has been poorly understood. In this review, I discuss the evidence for the existence and relevance of negative feedback pathways within oncogenic signaling networks, the selective advantages such feedback pathways may confer, and the effects such feedback might have on therapies aimed at inhibiting oncogenic signaling.Negative feedback pathways are ubiquitous features of growth factor signaling networks. Because growth factor signaling networks play essential roles in the majority of cancers, their therapeutic targeting has become a major emphasis of clinical oncology. Drugs targeting these networks are predicted to inhibit the pathway but also to relieve the negative feedback. This loss of negative feedback can itself promote oncogenic signals and cancer cell survival. Drug-induced relief of feedback may be viewed as one of the major consequences of targeted therapy and a key contributor to therapeutic resistance.
Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report
Authors: S.A. Grimm, J.S. Pulido, K. Jahnke, D. Schiff, A.J. Hall, T.N. Shenkier, T. Siegal, N.D. Doolittle, T. Batchelor, U. Herrlinger, E.A. Neuwelt, N. Laperriere, M.C. Chamberlain, J.Y. Blay, A.J.M. Ferreri, A.M.P. Omuro, E. Thiel, L.E. Abrey
Journal: Annals of Oncology (2007)
Abdominal volume contribution to tidal volume as an early indicator of respiratory impairment in Duchenne muscular dystrophy
Authors: A. Lo Mauro, M. G. D'Angelo, M. Romei, F. Motta, D. Colombo, G. P. Comi, A. Pedotti, E. Marchi, A. C. Turconi, N. Bresolin, A. Aliverti
Journal: European Respiratory Journal (2009)

Duchenne muscular dystrophy (DMD) is characterised by progressive loss of muscular strength that leads to an increasingly restrictive pulmonary syndrome. However, it is still not clear whether this determines alterations in the breathing pattern. We studied: 66 DMD patients at different stages of the disease (mean± sem age 12.6±0.6 yrs, range 5–22 yrs of age), subdivided into four groups according to age; and 21 age-matched healthy male controls. Spirometry, lung volumes and nocturnal oxygen saturation were measured in all DMD patients. Ventilatory pattern and chest wall volume variations were assessed by optoelectronic plethysmography during spontaneous breathing both in seated and supine positions. Whilst in a seated position, no significant differences were found between patients and controls or between different age groups. In the supine position, the average contribution of abdominal volume change (Δ V AB ) to tidal volume progressively decreased with age (p&lt;0.001). The patients who showed nocturnal hypoxaemia showed significantly lower Δ V AB . In conclusion, chest wall motion during spontaneous breathing in awake conditions and in supine position is an important indicator of the degree of respiratory muscle impairment in DMD. Δ V AB is not only an important marker of the progression of the disease but is also an early indicator of nocturnal hypoxaemia.
Pan-European early switch/early discharge opportunities exist for hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections
Authors: D. Nathwani, C. Eckmann, W. Lawson, J.M. Stephens, C. Macahilig, C.T. Solem, D. Simoneau, R. Chambers, J.Z. Li, S. Haider
Journal: Clinical Microbiology and Infection (2014)

The objective of this study was to document pan-European real-world treatment patterns and healthcare resource use and estimate opportunities for early switch (ES) from intravenous (IV) to oral antibiotics and early discharge (ED) in hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft tissue infections (cSSTIs). This retrospective observational medical chart review study enrolled 342 physicians across 12 European countries who collected data from 1542 patients with documented MRSA cSSTI who were hospitalized (July 2010 to June 2011) and discharged alive (by July 2011). Data included clinical characteristics and outcomes, hospital length of stay (LOS), MRSA-targeted IV and oral antibiotic use, and ES and ED eligibility according to literature-based and expert-validated criteria. The most frequent initial MRSA-active antibiotics were vancomycin (50.2%), linezolid (15.1%), clindamycin (10.8%), and teicoplanin (10.4%). Patients discharged with MRSA-active antibiotics (n = 480) were most frequently prescribed linezolid (42.1%) and clindamycin (19.8%). IV treatment duration (9.3 ± 6.5 vs. 14.6 ± 9.9 days; p <0.001) and hospital LOS (19.1 ± 12.9 vs. 21.0 ± 18.2 days; p 0.162) tended to be shorter for patients switched from IV to oral treatment than for patients who received IV treatment only. Of the patients, 33.6% met ES criteria and could have discontinued IV treatment 6.0 ± 5.5 days earlier, and 37.9% met ED criteria and could have been discharged 6.2 ± 8.2 days earlier. More than one-third of European patients hospitalized for MRSA cSSTI could be eligible for ES and ED, resulting in substantial reductions in IV days and bed-days, with potential savings of €2000 per ED-eligible patient.
Impact of a spirometry expert system on general practitioners' decision making
Authors: P. J. P. Poels, T. R. J. Schermer, D. P. A. Schellekens, R. P. Akkermans, P. F. de Vries Robbé, A. Kaplan, B. J. A. M. Bottema, C. van Weel
Journal: European Respiratory Journal (2007)

The present study assessed the impact of computerised spirometry interpretation expert support on the diagnostic achievements of general practitioners (GPs), and on GPs' decision making in diagnosing chronic respiratory disease. A cluster-randomised controlled trial was performed in 78 GPs who each completed 10 standardised paper case descriptions. Intervention consisted of support for GPs' spirometry interpretation either by an expert system (expert support group) or by sham information (control group). Agreement of GPs' diagnoses was compared with an expert panel judgement, which served as the primary outcome. Secondary outcomes were: additional diagnostic test rates; width of differential diagnosis; certainty of diagnosis; estimated severity of disease; referral rate; and medication or nonmedication changes. Effects were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). There were no differences between the expert support and control groups in the agreement between GPs and expert panel diagnosis of chronic obstructive pulmonary disease (OR (95% CI) 1.08 (0.70–1.66)), asthma (1.13 (0.70–1.80)), and absence of respiratory disease (1.32 (0.61–2.86)). A higher rate of additional diagnostic tests was observed in the expert support group (2.5 (1.17–5.35)). Computerised spirometry expert support had no detectable benefit on general practitioners' diagnostic achievements and the decision-making process when diagnosing chronic respiratory disease.
Activating Transcription Factor 2 and c-Jun–Mediated Induction of FoxP3 for Experimental Therapy of Mammary Tumor in the Mouse
Authors: Yan Liu, Yin Wang, Weiquan Li, Pan Zheng, Yang Liu
Journal: Cancer Research (2009)

FOXP3 is inactivated in breast cancer cells by a number of mechanisms, including somatic mutations, deletion, and epigenetic silencing. Because the mutation and deletion are usually heterozygous in the cancer samples, it is of interest to determine whether the gene can be induced for the purpose of cancer therapy. Here, we report that anisomycin, a potent activator of activating transcription factor (ATF) 2, and c-Jun-NH(2)-kinase, induces expression of FoxP3 in both normal and malignant mammary epithelial cells. The induction is mediated by ATF2 and c-Jun. Targeted mutation of ATF2 abrogates both constitutive and inducible expression of FoxP3 in normal epithelial cells. Both ATF2 and c-Jun interact with a novel enhancer in the intron 1 of the FoxP3 locus. Moreover, shRNA silencing of ATF2 and FoxP3 reveals an important role of ATF2-FoxP3 pathway in the anisomycin-induced apoptosis of breast cancer cells. A low dose of anisomycin was also remarkably effective in treating established mammary tumor in the mice. Our data showed that FoxP3 can be reactivated for cancer therapy.
Retrospective cohort study of 205 cases with congenital dyserythropoietic anemia type II: Definition of clinical and molecular spectrum and identification of new diagnostic scores
Authors: Roberta Russo, Antonella Gambale, Concetta Langella, Immacolata Andolfo, Sule Unal, Achille Iolascon
Journal: American Journal of Hematology (2014)

Congenital Dyserythropoietic Anemia II (CDA II) is a rare hyporegenerative anemia of variable degree, whose causative gene is SEC23B . More than 60 causative mutations in 142 independent pedigrees have been described so far. However, the prevalence of the CDA II is probably underestimated, since its clinical spectrum was not yet well‐defined and thus it is often misdiagnosed with more frequent clinically‐related anemias. This study represents the first meta‐analysis on clinical and molecular spectrum of CDA II from the largest cohort of cases ever described. We characterized 41 new cases and 18 mutations not yet associated to CDA II, thus expanding the global series to 205 cases (172 unrelated) and the total number of causative variants to 84. The 68.3% of patients are included in our International Registry of CDA II (Napoli, Italy). A genotype–phenotype correlation in three genotypic groups of patients was assessed. To quantify the degree of severity in each patient, a method based on ranking score was performed. We introduced a clinical index to easily discriminate patients with a well‐compensated hemolytic anemia from those with ineffective erythropoiesis. Finally, the worldwide geographical distribution of SEC23B alleles highlighted the presence of multiple founder effects in different areas of the world. Am. J. Hematol. 89:E169–E175, 2014. © 2014 Wiley Periodicals, Inc.