tbuckley/cabot-search huggingface dataset:
GATA2, a novel therapeutic target for RAS-oncogene-addicted NSCLC?
Authors: Richard Lee
Journal: Thorax (2012)

GATA2, a novel therapeutic target for RAS-oncogene-addicted NSCLC?Targeted cancer therapy with Epidermal Growth Factor Receptor (EGFR)-tyrosine kinase inhibitors (TKI), such as Gefitinib and Erlotinib, is revolutionising treatment of non-small cell lung cancer (NSCLC) in patients with activating mutations in EGFR.Another proto-oncogene, KRAS, is mutually exclusive to EGFR mutations and predicts poor response to TKIs, therefore offering an attractive therapeutic target to circumvent intrinsic EGFR-TKI resistance.However, despite a wealth of data on the RAS signalling pathway, currently there is no effective therapeutic inhibitor.Signalling pathways downstream of RAS, which may be more susceptible to inhibition, are, therefore, an area of great interest.Kumar et al consider the role of the GATA2 transcriptional network in RAS-oncogene-addicted NSCLC.Using gene expression and genome occupancy analysis, the investigators demonstrate that NSCLC cell lines with mutations in KRAS and related RTK/RAS oncogenes depend upon GATA2 for survival through regulation of the proteasome, Interleukin 1 (IL1)/Nuclear Factor Kappa Beta (NFKB) and the Rho-signalling cascade.In vivo, GATA2 loss prevented tumour development and induced tumour regression in established tumours in a KRAS-driven NSCLC murine model.Similar regression was seen with the study of pharmacological inhibitors of downstream pathways.This work remains to be validated in clinical trials but is an appealing approach: several of the nodes of the GATA2 signalling pathway are amenable to existing approved clinical agents, facilitating translation to clinical therapies.This interesting study describes a new means by which KRAS-mutant NSCLC could be tackled, and offers another step forward in the development of personalised approaches to treating lung cancer.
Increased Ca2+ signaling after alpha-adrenoceptor activation in vascular hypertrophy.
Authors: P Papageorgiou, K G Morgan
Journal: Circulation Research (1991)

In an effort to explain the increased sensitivity to agonists of hypertrophic vascular muscle, intracellular Ca2+ concentration ([Ca2+]i)-signaling mechanisms were studied in normal and hypertrophic rat aortas from normotensive and coarctation-hypertensive rats. Based on both fura 2 fluorescence and aequorin luminescence measurements, qualitatively different patterns of Ca2+ mobilization occur in normal and hypertrophic rat aortic muscle. Normal rat aortic muscle contracts to phenylephrine with little or no increase in [Ca2+]i, whereas the angiotensin II-induced contraction is accompanied by a marked [Ca2+]i transient. In contrast, hypertrophic rat aortic muscle shows a dramatic increase in Ca2+ signaling after phenylephrine stimulation. Moreover, both the amplitude of the angiotensin-induced [Ca2+]i transient and the contractile sensitivity to this agonist are decreased in the hypertrophic muscle. Our results strongly suggest that the amplitude of the [Ca2+]i transient after agonist stimulation determines the contractile sensitivity and that there is an altered coupling of the alpha-adrenoceptor in the hypertrophic vascular muscle.
Prospective Multicentric Randomized Phase III Study of Imatinib in Patients With Advanced Gastrointestinal Stromal Tumors Comparing Interruption Versus Continuation of Treatment Beyond 1 Year: The French Sarcoma Group
Authors: Jean-Yves Blay, Axel Le Cesne, Isabelle Ray-Coquard, Binh Bui, Florence Duffaud, Catherine Delbaldo, Antoine Adenis, Patrice Viens, Maria Rios, Emmanuelle Bompas, Didier Cupissol, Cecile Guillemet, Pierre Kerbrat, Jérome Fayette, Sylvie Chabaud, Patrice Berthaud, David Perol
Journal: Journal of Clinical Oncology (2007)

Imatinib is the standard treatment of advanced GI stromal tumors (GISTs). It is not known whether imatinib may be stopped in patients in whom disease is controlled.This prospective, randomized, multicentric phase III study was designed to compare continuous (CONT) compared with interrupted (INT) imatinib beyond 1 year of treatment in patients with advanced GIST. The primary end point was progression-free survival. Secondary end points included overall survival, response rate after reinitiation of imatinib, and quality of life. Early stopping rules in cases of rapid progression of disease were defined, with preplanned interim analyses.Between May 2002 and April 2004, 182 patients with advanced GIST were enrolled. Between May 2003 and April 2004, 98 patients in response or stable disease under imatinib reached more than 1 year of follow-up. Forty were not eligible for randomization, and 58 patients were randomly assigned, 32 and 26 patients in the INT and CONT arms, respectively. As of October 15, 2005, eight of 26 patients in the CONT group and 26 of 32 patients in the INT group had documented disease progression (P < .0001). Twenty-four of 26 patients with documented progression in the INT arm responded to imatinib reintroduction. No differences in overall survival or imatinib resistance were observed between the two arms. Quality of life evaluated 6 months after random assignment using the 30-item Quality of Life Questionnaire was not significantly different between the two groups of randomly assigned patients.Imatinib interruption results in rapid progression in most patients with advanced GIST, and cannot be recommended in routine practice unless patient experience significant toxicity
Idiopathic pulmonary fibrosis: treatment options in pursuit of evidence-based approaches
Authors: G. Raghu
Journal: European Respiratory Journal (2006)

The long-standing need to determine an effective medical treatment regimen with clinically significant and relevant end-points to improve outcome for patients with idiopathic pulmonary fibrosis (IPF) is being pursued by investigators in several phase I, II and III clinical trials. Patients confronted with IPF are understandably frustrated and vulnerable to hearsay and are desperate to try any medication in the hope of easing their suffering and increasing the likelihood of enhanced survival. This is particularly so when such medicines are available for clinical use either by prescription and/or over the counter. Caring physicians, also frustrated with the lack of evidence for an effective IPF treatment regimen, may find themselves reaching out for anecdotal reports and reacting to signals generated by post hoc exploratory and subgroup analyses derived from clinical studies, wanting to try some treatment regimen for their patients. In this regard, the joint American Thoracic Society/European Respiratory Society international consensus statement on IPF provided a guideline pending documentation of an effective treatment regimen 1. Acknowledging the limitations of the then-existing skeletal data, low-dose prednisone plus azathioprine or cyclophosphamide was suggested as a treatment regimen for patients with IPF, and an apparent “standard of care” for treatment of IPF with prednisone and azathioprine has evolved worldwide. The statement contained the disclaimer that its recommendation was based on the consensus of opinion of the expert panel, and the approach needs to be revisited as there was no grade-A evidence to support the treatment guidelines.

The widely acknowledged notion that the currently available treatment regimen is ineffective is largely based on individual physicians’ experience. While this may be appropriate for treatment with lone corticosteroid therapy 2, colchicine 3, 4, cyclophosphamide 5, 6 and d-penicillamine 7, care should be taken in generalising the notion to treatment with …
TNF- down-regulates sarcoplasmic reticulum Ca2+ ATPase expression and leads to left ventricular diastolic dysfunction through binding of NF- B to promoter response element
Authors: C.-T. Tsai, C.-K. Wu, J.-K. Lee, S.-N. Chang, Y.-M. Kuo, Y.-C. Wang, L.-P. Lai, F.-T. Chiang, J.-J. Hwang, J.-L. Lin
Journal: Cardiovascular Research (2015)

AimsTNF-alpha (TNF-α) causes left ventricular diastolic dysfunction. Down-regulation of sarcoplasmic reticulum Ca2+-ATPase 2a protein (SERCA2a) expression is one of the major mechanisms underlying diastolic dysfunction. We investigated whether TNF-α modulates SERCA2a expression and alters cardiac diastolic function, and its detailed signalling pathway.
CyberKnife® enhanced conventionally fractionated chemoradiation for high grade glioma in close proximity to critical structures
Authors: Eric Oermann, Brian T Collins, Kelly T Erickson, Xia Yu, Sue Lei, Simeng Suy, Heather N Hanscom, Joy Kim, Hyeon U Park, Andrew Eldabh, Christopher Kalhorn, Kevin McGrail, Deepa Subramaniam, Walter C Jean, Sean P Collins
Journal: Journal of Hematology & Oncology (2010)

With conventional radiation technique alone, it is difficult to deliver radical treatment (>or= 60 Gy) to gliomas that are close to critical structures without incurring the risk of late radiation induced complications. Temozolomide-related improvements in high-grade glioma survival have placed a higher premium on optimal radiation therapy delivery. We investigated the safety and efficacy of utilizing highly conformal and precise CyberKnife radiotherapy to enhance conventional radiotherapy in the treatment of high grade glioma.Between January 2002 and January 2009, 24 patients with good performance status and high-grade gliomas in close proximity to critical structures (i.e. eyes, optic nerves, optic chiasm and brainstem) were treated with the CyberKnife. All patients received conventional radiation therapy following tumor resection, with a median dose of 50 Gy (range: 40 - 50.4 Gy). Subsequently, an additional dose of 10 Gy was delivered in 5 successive 2 Gy daily fractions utilizing the CyberKnife image-guided radiosurgical system. The majority of patients (88%) received concurrent and/or adjuvant Temozolmide.During CyberKnife treatments, the mean number of radiation beams utilized was 173 and the mean number of verification images was 58. Among the 24 patients, the mean clinical treatment volume was 174 cc, the mean prescription isodose line was 73% and the mean percent target coverage was 94%. At a median follow-up of 23 months for the glioblastoma multiforme cohort, the median survival was 18 months and the two-year survival rate was 37%. At a median follow-up of 63 months for the anaplastic glioma cohort, the median survival has not been reached and the 4-year survival rate was 71%. There have been no severe late complications referable to this radiation regimen in these patients.We utilized fractionated CyberKnife radiotherapy as an adjunct to conventional radiation to improve the targeting accuracy of high-grade glioma radiation treatment. This technique was safe, effective and allowed for optimal dose-delivery in our patients. The value of image-guided radiation therapy for the treatment of high-grade gliomas deserves further study.
Mucosal involvement in bullous and cicatricial pemphigoid. A clinical and immunopathological study
Authors: V.A. VENNING, P.A. FRITH, A.J. BRON, P.R. MILLARD, F. WOJNAROWSKA
Journal: British Journal of Dermatology (1988)

Thirty-six patients with bullous pemphigoid (BP) and 15 with cicatricial pemphigoid (CP) were studied for evidence of mucosal involvement both clinically and by direct immunofluorescence. Twenty-one patients with BP and all those with CP had lesions of the mucous membranes. Eighteen patients with BP and 14 patients with CP had involvement of the oral mucosa. Lesions of the eyes, nose, pharynx, vulva and urethra also occurred in both groups. The lesions tended to be more widespread in CP patients. Twenty-one patients with BP and 14 with CP were examined by an ophthalmologist. Fine scarring of the tarsal conjunctiva was found in both groups, but also in elderly controls. However, symblepharon occurred in one patient with BP as well as in three patients with CP, but was not seen in a group of 20 controls. Direct immunofluorescence (IF) studies showed linear deposition of IgG or C3 or both in the basement membrane zone of the skin, oral mucosa and conjunctival mucosa in both groups. The frequency of positive immunofluorescence was higher in the conjunctiva than in the lip mucosa or skin in both BP and CP patients. The significance of these findings and the relationship between BP and CP is discussed.
Dynamic and static conditioning pressures evoke equivalent rapid resetting in rat aortic baroreceptors.
Authors: M C Andresen, M Y Yang
Journal: Circulation Research (1990)

A recent study suggested that exposure of carotid sinus baroreceptors to pulsatile pressures for a period of minutes can decrease the static threshold pressure at which they begin to discharge; that is, the exposure can sensitize baroreceptors. Another study found that the rapid resetting of carotid sinus baroreceptors to elevated conditioning pressures was reduced or eliminated by pulsatile conditioning. In the present study, we tested the responses of aortic baroreceptors in an in vitro preparation to a range of static and dynamic conditioning pressures lasting 15 minutes. Slow test ramps of increasing pressure were used to assess static discharge properties (threshold and gain). To be accepted for analysis (n = 12), each baroreceptor had to successfully complete static and dynamic test sequences for at least three different conditioning mean arterial pressure levels. We measured aortic diameter simultaneously with pressure and baroreceptor discharge. Generally, we found no significant difference between the static pressure threshold measured before and after dynamic conditioning. The static pressure threshold was linearly related to the mean level of the conditioning pressure, and no differences in the slopes of these relations (a measure of the ability of a baroreceptor to rapidly reset) were found between static and dynamic conditioning. After dynamic conditioning, discharge rates returned to near control levels in all cases within a few seconds of the return to static conditioning. Two baroreceptors exposed to the vasodilator nitroprusside throughout the experiment showed similar results. Diameter measurements indicated no role of vessel diameter changes during dynamic or static conditioning. In conclusion, we found no evidence of a long-lasting sensitization of aortic baroreceptors by dynamic pressure inputs.(ABSTRACT TRUNCATED AT 250 WORDS)
Identification of iGb3 and iGb4 in melanoma B16F10-Nex2 cells and the iNKT cell-mediated antitumor effect of dendritic cells primed with iGb3
Authors: Bianca R Dias, Elaine G Rodrigues, Leonardo Nimrichter, Ernesto S Nakayasu, Igor C Almeida, Luiz R Travassos
Journal: Molecular Cancer (2009)

Abstract Background CD1d-restricted iNKT cells are protective against murine melanoma B16F10-Nex2 growing subcutaneously in syngeneic C57Bl/6 mice as inferred from the fast tumor development in CD1d-KO in comparison with wild type animals. CD1d glycoproteins are related to the class I MHC molecules, and are involved in the presentation, particularly by dentritic cells (DC), of lipid antigens to iNKT cells. In the present work we attempted to identify the endogenous lipid mediator expressed in melanoma cells inducing such immunesurveillance response and study the possibility of protecting animals challenged with tumor cells with lipid-primed DC. Results Crude cytosolic and membrane fractions from in vivo growing melanoma contained iNKT-stimulating substances. Lipids were then extracted from these cells and one of the fractions (i.e. F3A) was shown to prime bone marrow-derived dendritic cells (BMDC) to stimulate iNKT murine hybridoma (DN32D3) cells to produce IL-2. The active fraction was analyzed by electrospray ionization-mass spectrometry (ESI-LIT-MS) and both iGb3 and iGb4 were identified along with GM3. When iGb3 was incubated with BMDC and tested with DN32D3 cells, IL-2 was equally produced indicating iNKT cell activation. GM3 consistently inhibited this response. To assess the antitumor response-induced by iGb3, a cytotoxicity assay in vitro was used with [ 3 H]-thymidine labeled B16F10-Nex2 cells. At target/effector (iGb3-activated iNKT) cell ratio of 100 -1 -100 -4 tumor cell lysis was shown. The antitumor activity in vivo was tested in mice challenged i.v. with B16F10-Nex2 cells and treated with iGb3- or α-galactosylceramide-primed DCs. A 4-fold lower tumor load in the lungs was observed with either treatment. Conclusion Our results show the expression of globo and isoglobohexosylceramides in murine melanoma B16F10-Nex2. The expression of iGb3 and its precursor, iGb4, on tumor cells may prime an effective iNKT cell-dependent antitumor response, modulated negatively by GM3 which is also produced in these cells. iGb3-primed BMDC exerted a significant iNKT cell-mediated anti-tumor activity in mice challenged with melanoma cells.
Effect of sleeping alone on sleep quality in female bed partners of snorers
Authors: M. Blumen, M. A. Quera Salva, M-P. d'Ortho, K. Leroux, P. Audibert, C. Fermanian, F. Chabolle, F. Lofaso
Journal: European Respiratory Journal (2009)

The aim of the present study was to objectively measure the effect of sleeping alone for one night on sleep quality in female bed partners of male snorers. Females complaining of poor sleep due to snoring by their bed partner and having no known hearing loss or snoring were included in a prospective multicentre cross-sectional study. 23 females underwent one polysomnography recording while sleeping with their bed partner and another while sleeping alone. Their sleep parameters were compared between the two nights. We excluded seven couples because the female partner snored for &gt;10% of the sleep time (n = 6) or had obstructive sleep apnoea syndrome (n = 1). In the remaining 16 females, sleep time, sleep efficiency, arousal index and percentages of deep sleep (stages 3–4) and rapid eye movement (REM) sleep were not significantly different between the two nights. Percentages of light sleep (non-REM stage 2) and awakening index were lower when sleeping alone (p = 0.023 and p = 0.046, respectively). Sleep quality was decreased and sleep fragmentation increased in females sleeping with male snorers. Some females had unrecognised snoring. However, our data do not suggest that objective sleep quality improves substantially in the female nonsnoring partner when she sleeps alone for one night.
Reversal of Glomerular Lesions Involves Coordinated Restructuring of Glomerular Microvasculature
Authors: Marcin Adamczak, Marie-Luise Gross, Kerstin Amann, Eberhard Ritz
Journal: Journal of the American Society of Nephrology (2004)

There is increasing evidence from both human and experimental studies that at least partial reversal of glomerulosclerosis can be achieved by glomerular remodeling. This requires substantial changes in glomerular architecture, specifically of glomerular capillaries. It was the purpose of the present study to characterize the stereologic and topologic characteristics of glomerular capillaries when partial reversal of glomerular lesions is achieved by high-dose angiotensin-converting enzyme inhibitor treatment. Sham-operated male Sprague-Dawley rats were compared with subtotally nephrectomized (SNX) rats. The latter were kept untreated for 8 wk and subsequently randomly divided into one group that was continued without treatment and another group that was treated with enalapril (48 mg/kg body wt per d administered in the drinking fluid for 4 wk). Renal morphology was evaluated after 8 or 12 wk, respectively, by stereologic techniques after pressure-controlled perfusion fixation. In SNX rats at 8 and particularly at 12 wk, the glomerulosclerosis index was significantly higher than in sham-operated rats. At 12 wk, it was lower in rats that had been treated for 4 wk with enalapril compared with untreated SNX rats, suggesting partial reversal of glomerular lesions. This was associated with a decrease in mean glomerular volume and mean glomerular tuft volume, a reduced number of capillaries per glomerulus, and reduced total length of capillaries per glomerulus but without any significant change in the length of individual capillaries. The numerical capillary density (Euler number density) as an index of topologic complexity did not change. The total capillary surface area per glomerulus was strikingly increased after subtotal nephrectomy and partially reversed after enalapril. This was accounted for primarily by fewer capillaries without any change in diameter. In parallel, the number of endothelial cells per glomerulus was strikingly increased after subtotal nephrectomy and decreased with enalapril treatment, but endothelial cell volume remained elevated. The study shows harmonious coordinate remodeling of the entire glomerulus during regression of glomerular lesions after subtotal nephrectomy. Proportionate reduction of glomerular volume and capillary number without change of individual capillary length were found. The numerical capillary density of the tuft therefore remained unchanged.
Activation of the fibrinolytic system in patients with fulminant liver failure
Authors: Ricardo J.B. Pernambuco, Peter G. Langley, Robin D. Hughes, Satoru Izumi, Roger Williams
Journal: Hepatology (1993)

Abnormalities of blood coagulation and fibrinolysis are a major part of fulminant liver failure. In this study, the key components of the fibrinolytic system were determined in 42 patients with this condition. Admission levels of plasma plasminogen activity were low (9.1% of normal), as to a lesser extent were the activities of its inhibitors alpha 2-antiplasmin (20.5% of normal) and C1 inhibitor (64% of normal). Tissue plasminogen activator activity was found at normal levels, whereas the level of its fast inhibitor, plasminogen activator inhibitor-1, was greatly increased compared with that of controls (24.3 U/ml and 7.4 U/ml, respectively), indicating a shift toward inhibition of fibrinolysis in these patients. Thrombin-antithrombin complex levels in plasma were significantly increased in fulminant liver failure compared with those in controls (33.5 micrograms/L vs. 2.5 micrograms/L, p < 0.001), indicating activation of coagulation in these patients. High plasma levels of D-dimer, a fragment of cross-linked fibrin, were also found (1,510 micrograms/L vs. 33 micrograms/L in controls, p < 0.001); this finding correlated with the increased level of thrombin-antithrombin complex (r = 0.61, p < 0.001), consistent with activation of fibrinolysis resulting from intravascular coagulation. In conclusion, there are gross abnormalities of the fibrinolytic system in fulminant liver failure, but because inhibitory activity appears to be present in adequate quantities, this limits the incidence of bleeding due to fibrinolysis.