tbuckley/cabot-search huggingface dataset:
Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer
Authors: Helena Linardou, Issa J Dahabreh, Dimitra Kanaloupiti, Fotios Siannis, Dimitrios Bafaloukos, Paris Kosmidis, Christos A Papadimitriou, Samuel Murray
Journal: The Lancet Oncology (2008)
Chronic Inhibition of Mammalian Target of Rapamycin Signaling Downregulates Insulin Receptor Substrates 1 and 2 and AKT Activation
Authors: Salvatore Di Paolo, Annalisa Teutonico, Domenica Leogrande, Carmen Capobianco, Paolo F. Schena
Journal: Journal of the American Society of Nephrology (2006)

Overactivation of the mammalian target of rapamycin (mTOR) branch downstream of the phosphatidylinositol 3-kinase-AKT pathway critically modulates insulin and growth factor signaling by insulin receptor substrates (IRS). On the basis of in vitro studies, the mTOR inhibitor rapamycin has been reported to lead to enhanced activation of AKT by relieving this feedback inhibition on IRS function. In view of the critical role of AKT in insulin signaling and tumorigenesis, the in vivo expression and activation of this kinase and of IRS-1 and IRS-2 were explored in PBMC of 30 patients who were treated long term with rapamycin. A marked decrease of basal and insulin-stimulated AKT phosphorylation, which correlated with the increase of patients' insulin resistance, and a significant increase of IRS total protein expression, together with a lower (IRS-2) or absent (IRS-1) increase of insulin-induced tyrosine phosphorylation, were found. Therefore, contrary to the expectations, long-term exposure to rapamycin caused the impairment of IRS signaling and AKT activation, and this would help to explain the antiproliferative effect and the possible deterioration of glucose metabolism that are observed in rapamycin-treated patients. These findings may form a novel basis for improved understanding of the role of mTOR inhibition in human diseases, such as diabetes and cancer.
PTU-098 A Survey to Investigate GP Knowledge, Practice and Support Requirements Regarding the Clinical Management of Liver Disease in Primary Care
Authors: B Williams, G Abouda
Journal: Gut (2013)

<h3>Introduction</h3> The management of liver disease in primary care often lacks consistency and clearly defined care pathways. We aimed to explore GP perspectives on the management of liver disease in the Hull and East Riding of Yorkshire region. <h3>Methods</h3> A 9 question survey was sent to 321 GPs in Hull and East Riding of Yorkshire focusing on knowledge, practise and support requirements of liver disease management in primary care. 105 GPs (33%) responded: 26% from NHS Hull and 39% from NHS East Riding <h3>Results</h3> GPs saw patients with a variety of liver diseases. Most common were lifestyle-related. <i>Graph 1</i> – Liver diseases seen by GPs very often, often or sometimes GPs graded the importance of a range of liver investigations in primary care. <i>Graph 2</i> – The degree to which GPs felt liver investigations were important in the clinical management of liver disease in primary care. For investigations that GPs graded as ‘Very Important and Essential’ many were not, in ‘real-life’ primary care practise, documented in patient records (Williams et. al. 2012). <i>Graph 3</i> – The degree to which potential barriers might influence GP capacity to manage liver disease in primary care. Only 6% of GPs stated they had a ‘special interest’ in liver disease and no GP stated that someone else in the practise took the lead on liver disease. <i>Graph 4</i> – Reasons for GPs not having a ‘special interest’ in liver disease However, as ’generalists’, 83% of GPs felt they needed more educational support via protected learning sessions, improved national guidelines and joint specialist-GP clinics. <h3>Conclusion</h3> This survey revealed that many GPs, despite not having a ‘special interest’ in liver disease, would welcome greater educational support from specialists and improved national guidelines. The barriers most cited as influencing GP capacity to manage liver disease are surmountable and should be the focal point for new integrated care pathways. <h3>Disclosure of Interest</h3> None Declared
Glimepiride Improves Both First and Second Phases of Insulin Secretion in Type 2 Diabetes
Authors: Mary Korytkowski, Abraham Thomas, Lynn Reid, Mary Beth Tedesco, William E. Gooding, John Gerich
Journal: Diabetes Care (2002)

OBJECTIVE—The purpose of this study was to assess the effect of glimepiride on insulin sensitivity and secretion in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS—After a 2-week washout from prior sulfonylurea therapy, 11 obese subjects with type 2 diabetes underwent euglycemic and hyperglycemic clamp studies before and during glimepiride therapy. RESULTS—Glimepiride resulted in a 2.4-mmol/l decrease in fasting plasma glucose (P = 0.04) that was correlated with reductions in postabsorptive endogenous glucose production (EGP) (16.4 ± 0.6 vs. 13.5 ± 0.5 μmol · kg−1 · min−1, P = 0.01) (r = 0.21, P = 0.01). Postabsorptive EGP on glimepiride was similar to that of control subjects (12.8 ± 0.9 μmol · kg−1 · min−1, NS). Fasting plasma insulin (66 ± 18 vs. 84 ± 48 pmol/l, P = 0.05), and first-phase (19 ± 8 vs. 32 ± 11 pmol/l, P = 0.04) and second-phase incremental insulin responses to glucose (48 ± 23 vs. 72 ± 32 pmol/l, P = 0.02) improved with glimepiride therapy. Insulin sensitivity did not change with treatment (4.6 ± 0.7 vs. 4.3 ± 0.7 μmol · kg−1 · min−1 · pmol−1) and remained below that of control subjects (8.1 ± 1.8 μmol · kg−1 · min−1 · pmol−1, P = 0.04). CONCLUSIONS—The current study demonstrates that glimepiride improves both first and second phases of insulin secretion, but not insulin sensitivity, in individuals with type 2 diabetes.
Preferential Replication of Systemically Delivered Oncolytic Vaccinia Virus in Focally Irradiated Glioma Xenografts
Authors: Sunil J. Advani, Lisa Buckel, Nanhai G. Chen, Daniel J. Scanderbeg, Ulrike Geissinger, Qian Zhang, Yong A. Yu, Richard J. Aguilar, Arno J. Mundt, Aladar A. Szalay
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Radiotherapy is part of the standard of care in high-grade gliomas but its outcomes remain poor. Integrating oncolytic viruses with standard anticancer therapies is an area of active investigation. The aim of this study was to determine how tumor-targeted ionizing radiation (IR) could be combined with systemically delivered oncolytic vaccinia virus. Experimental Design: U-87 glioma xenografts were grown subcutaneously or orthotopically. Oncolytic vaccinia viruses GLV-1h68 and LIVP 1.1.1 were injected systemically and IR was given focally to glioma xenografts. In a bilateral tumor model, glioma xenografts were grown in both flanks, oncolytic vaccinia was injected systemically and radiation was delivered specifically to the right flank tumor, whereas the left flank tumor was shielded. Viral replication and tumor regression, after systemic injection, was analyzed and compared in irradiated and nonirradiated glioma xenografts. Results: Systemically administered oncolytic vaccinia virus replicated to higher titers in preirradiated U-87 xenografts than in nonirradiated glioma xenografts. This increased oncolytic viral replication correlated with increased tumor xenograft regression and mouse survival in subcutaneous and orthotopic U-87 glioma models compared with monotherapies. The ability of focal IR to mediate selective replication of oncolytic vaccinia was shown in a bilateral glioma model in which systemically administered oncolytic vaccinia replicated preferentially in the irradiated tumor compared with the nonirradiated tumor in the same mouse. Conclusion: These findings show a potential clinical role of focal IR in sensitizing irradiated tumor sites for preferential vaccinia virus–mediated oncolysis. Clin Cancer Res; 18(9); 2579–90. ©2012 AACR.
Strategic Targeting of Advance Care Planning Interventions
Authors: J. Andrew Billings, Rachelle Bernacki
Journal: JAMA Internal Medicine (2014)

Strategically selecting patients for discussions and documentation about limiting life-sustaining treatments-choosing the right time along the end-of-life trajectory for such an intervention and identifying patients at high risk of facing end-of-life decisions-can have a profound impact on the value of advance care planning (ACP) efforts. Timing is important because the completion of an advance directive (AD) too far from or too close to the time of death can lead to end-of-life decisions that do not optimally reflect the patient's values, goals, and preferences: a poorly chosen target patient population that is unlikely to need an AD in the near future may lead to patients making unrealistic, hypothetical choices, while assessing preferences in the emergency department or hospital in the face of a calamity is notoriously inadequate. Because much of the currently studied ACP efforts have led to a disappointingly small proportion of patients eventually benefitting from an AD, careful targeting of the intervention should also improve the efficacy of such projects. A key to optimal timing and strategic selection of target patients for an ACP program is prognostication, and we briefly highlight prognostication tools and studies that may point us toward high-value AD interventions.
Steroid use in acute liver failure
Authors: Jamuna Karkhanis, Elizabeth C. Verna, Matthew S. Chang, Todd R. Stravitz, Michael Schilsky, William M. Lee, Robert S. Brown
Journal: Hepatology (2013)

Drug-induced and indeterminate acute liver failure (ALF) might be due to an autoimmune-like hepatitis that is responsive to corticosteroid therapy. The aim of this study was to evaluate whether corticosteroids improve survival in fulminant autoimmune hepatitis, drug-induced, or indeterminate ALF, and whether this benefit varies according to the severity of illness. We conducted a retrospective analysis of autoimmune, indeterminate, and drug-induced ALF patients in the Acute Liver Failure Study Group from 1998–2007. The primary endpoints were overall and spontaneous survival (SS, survival without transplant). In all, 361 ALF patients were studied, 66 with autoimmune (25 steroids, 41 no steroids), 164 with indeterminate (21 steroids, 143 no steroids), and 131 with drug-induced (16 steroids, 115 no steroids) ALF. Steroid use was not associated with improved overall survival (61% versus 66%, P = 0.41), nor with improved survival in any diagnosis category. Steroid use was associated with diminished survival in certain subgroups of patients, including those with the highest quartile of the Model for Endstage Liver Disease (MELD) (&gt;40, survival 30% versus 57%, P = 0.03). In multivariate analysis controlling for steroid use and diagnosis, age (odds ratio [OR] 1.37 per decade), coma grade (OR 2.02 grade 2, 2.65 grade 3, 5.29 grade 4), MELD (OR 1.07), and pH &lt; 7.4 (OR 3.09) were significantly associated with mortality. Although steroid use was associated with a marginal benefit in SS overall (35% versus 23%, P = 0.047), this benefit did not persistent in multivariate analysis; mechanical ventilation (OR 0.24), MELD (OR 0.93), and alanine aminotransferase (1.02) were the only significant predictors of SS. Conclusion : Corticosteroids did not improve overall survival or SS in drug-induced, indeterminate, or autoimmune ALF and were associated with lower survival in patients with the highest MELD scores. (Hepatology 2014;59:612–621)
STREPTOCOCCAL M ANTIGEN LOCATION AND SYNTHESIS, STUDIED BY IMMUNOFLUORESCENCE
Authors: Jerome J. Hahn, Roger M. Cole
Journal: The Journal of Experimental Medicine (1963)

Streptococcal M protein has been studied directly in the intact streptococcal cell by specific immunofluorescence. By this method, it can be seen to be concentrated in or on the cell wall, but cannot be detected in the capsule. The lack of type-specific (but not group-specific) immunofluorescence after trypsinization; and the inhibition of group-specific immunofluorescence by unlabeled type-specific antibody, are observations most compatible with a location of the M antigen determinants on the cell surface superficial to the group antigen. M antigen is not "resynthesized" after trypsinization of living cells, but appears anew only at sites of new cell wall growth. A limited amount of such growth, leading sometimes to detectable amounts of M in the gross, can take place in deficient media without detectable increases in optical density of the cell population.
Bosentan for the Treatment of Human Immunodeficiency Virus–associated Pulmonary Arterial Hypertension
Authors: Olivier Sitbon, Virginie Gressin, Rudolf Speich, Peter S. Macdonald, Milos Opravil, David A. Cooper, Thierry Fourme, Marc Humbert, Jean-François Delfraissy, Gérald Simonneau
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Clinical studies have shown the importance of endothelin as a pathogenic mediator in pulmonary arterial hypertension (PAH). We describe the effects of bosentan, an oral dual endothelin receptor antagonist, in patients with PAH associated with human immunodeficiency virus (HIV) infection. In this prospective study, 16 patients with PAH associated with HIV infection in stable condition received bosentan for 16 weeks. Efficacy endpoints included exercise capacity, cardiopulmonary hemodynamics, Doppler echocardiography, New York Heart Association functional class, and quality of life (SF-36 and EQ-5D). Safety was assessed by laboratory tests, vital signs, and adverse events. Improvements were observed from baseline to Week 16 in all efficacy parameters: 6-minute walk distance (+91 +/- 60 m, p < 0.001), New York Heart Association class (14 patients improved), hemodynamics (cardiac index: +0.9 +/- 0.7 L/minute/m(2), p < 0.001), Doppler echocardiographic variables, and quality of life. During the study, no patient died and none required epoprostenol treatment. Hepatic tolerability was similar to that reported in patients with PAH. Bosentan had no negative impact on control of HIV infection. Although limited by uncontrolled design, small sample size and short duration, this study suggests that bosentan may benefit patients with PAH associated with HIV infection, and that endothelin is an important pathogenic mediator in this disease.
HUNDRED DAY LEUKEMIA: PREFERENTIAL INDUCTION IN RAT BY PULSE-DOSES OF 7,8,12-TRIMETHYLBENZ(A)ANTHRACENE
Authors: Charles Huggins, Lorraine Grand, Hisao Oka
Journal: The Journal of Experimental Medicine (1970)

A series of pulse-doses of 7, 8, 12-trimethylbenz(a)anthracene-induced leukemia rapidly and consistently in very high yield in rats of Long-Evans (L-E) strain. The predominant type was a diffuse hepatic leukemia of erythroblastic stem cells. Progressive hypothermia and a decline in pituitary function are newly recognized signs of advanced leukemia in rat.
Protective effects of Fc-fused PD-L1 on two different animal models of colitis
Authors: Mi-Young Song, Chun-Pyo Hong, Seong Jeong Park, Jung-Hwan Kim, Bo-Gie Yang, Yunji Park, Sae Won Kim, Kwang Soon Kim, Ji Yeung Lee, Seung-Woo Lee, Myoung Ho Jang, Young-Chul Sung
Journal: Gut (2014)

Programmed death-ligand 1 (PD-L1) has been shown to negatively regulate immune responses via its interaction with PD-1 receptor. In this study, we investigated the effects of PD-L1-Fc treatment on intestinal inflammation using two murine models of inflammatory colitis induced by dextran sulfate sodium (DSS) and T-cell transfer.The anti-colitis effect of adenovirus expressing Fc-conjugated PD-L1 (Ad/PD-L1-Fc) and recombinant PD-L1-Fc protein was evaluated in DSS-treated wild-type and Rag-1 knockout (KO) mice. We examined differentiation of T-helper cells, frequency of innate immune cells, and cytokine production by dendritic cells (DCs) in the colon from DSS-treated mice after PD-L1-Fc administration. In Rag-1 KO mice reconstituted with CD4 CD45RB(high) T cells, we assessed the treatment effect of PD-L1-Fc protein on the development of colitis.Administration of Ad/PD-L1-Fc significantly ameliorated DSS-induced colitis, which was accompanied by diminished frequency of interleukin (IL)-17A-producing CD4 T cells and increased interferon-γ-producing CD4 T cells in the colon of DSS-fed mice. The anti-colitic effect of PD-L1-Fc treatment was also observed in DSS-treated Rag-1 KO mice, indicating lymphoid cell independency. PD-L1-Fc modulated cytokine production by colonic DCs and the effect was dependent on PD-1 expression. Furthermore, PD-L1-Fc protein could significantly reduce the severity of colitis in CD4 CD45RB(high) T-cell-transferred Rag-1 KO mice.Based on the protective effect of PD-L1-Fc against DSS-induced and T-cell-induced colitis, our results suggest that PD-1-mediated inhibitory signals have a crucial role in limiting the development of colonic inflammation. This implicates that PD-L1-Fc may provide a novel therapeutic approach to treat inflammatory bowel disease.
Effect of temperature on handgrip holding time.
Authors: T. J. Barter, P. C. Freer
Journal: British Journal of Sports Medicine (1984)

The effect of intramuscular temperature upon the holding time of 70% MVC handgrip contraction was studied in 12 college-age men. The intramuscular temperature was regulated by 30 minutes immersion of the forearm and hand in a waterbath at 18 degrees C, 35 degrees C, or 45 degrees C. Elevating intramuscular temperature significantly reduced the holding time duration, (25.7 +/- 6.2 vis 38.3 +/- 8.1, P less than 0.01), while reducing the temperature had no significant effect (37.5 +/- 9.4 vis 38.3 +/- 8.1, N.S.).
Watching Synaptogenesis in the Adult Brain
Authors: Wolfgang Kelsch, Shuyin Sim, Carlos Lois
Journal: Annual Review of Neuroscience (2010)

Although the lifelong addition of new neurons to the olfactory bulb and dentate gyrus of mammalian brains is by now an accepted fact, the function of adult-generated neurons still largely remains a mystery. The ability of new neurons to form synapses with preexisting neurons without disrupting circuit function is central to the hypothesized role of adult neurogenesis as a substrate for learning and memory. With the development of several new genetic labeling and imaging techniques, the study of synapse development and integration of these new neurons into mature circuits both in vitro and in vivo is rapidly advancing our insight into their structural plasticity. Investigators' observation of synaptogenesis occurring in the adult brain is beginning to shed light on the flexibility that adult neurogenesis offers to mature circuits and the potential contribution of the transient plasticity that new neurons provide toward circuit refinement and adaptation to changing environmental demands.
EZH2 Is Essential for Glioblastoma Cancer Stem Cell Maintenance
Authors: Mario-Luca Suvà, Nicolò Riggi, Michalina Janiszewska, Ivan Radovanovic, Paolo Provero, Jean-Christophe Stehle, Karine Baumer, Marie-Aude Le Bitoux, Denis Marino, Luisa Cironi, Victor E. Marquez, Virginie Clément, Ivan Stamenkovic
Journal: Cancer Research (2009)

Abstract Overexpression of the polycomb group protein enhancer of zeste homologue 2 (EZH2) occurs in diverse malignancies, including prostate cancer, breast cancer, and glioblastoma multiforme (GBM). Based on its ability to modulate transcription of key genes implicated in cell cycle control, DNA repair, and cell differentiation, EZH2 is believed to play a crucial role in tissue-specific stem cell maintenance and tumor development. Here, we show that targeted pharmacologic disruption of EZH2 by the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep), or its specific downregulation by short hairpin RNA (shRNA), strongly impairs GBM cancer stem cell (CSC) self-renewal in vitro and tumor-initiating capacity in vivo. Using genome-wide expression analysis of DZNep-treated GBM CSCs, we found the expression of c-myc, recently reported to be essential for GBM CSCs, to be strongly repressed upon EZH2 depletion. Specific shRNA-mediated downregulation of EZH2 in combination with chromatin immunoprecipitation experiments revealed that c-myc is a direct target of EZH2 in GBM CSCs. Taken together, our observations provide evidence that direct transcriptional regulation of c-myc by EZH2 may constitute a novel mechanism underlying GBM CSC maintenance and suggest that EZH2 may be a valuable new therapeutic target for GBM management. [Cancer Res 2009;69(24):9211–8]
Cardiolipin-protein complexes and initiation of complement activation after coronary artery occlusion.
Authors: R D Rossen, L H Michael, H K Hawkins, K Youker, W J Dreyer, R E Baughn, M L Entman
Journal: Circulation Research (1994)

Specific rabbit anti-cardiolipin (anti-CL) antibodies were used to investigate the hypothesis that cardiolipin, associated with mitochondrial membrane proteins, binds C1 and facilitates activation of the complement cascade following reperfusion of ischemic myocardium. By immunoelectron microscopy, anti-CL localized to subsarcolemmal mitochondria, emerging through breaks in membranes of damaged cardiac myocytes. Anti-CL reacted with > 15 mitochondrial constituents, most of which comigrated with the proteins that bind C1q in transblots of subsarcolemmal mitochondria, fractionated by polyacrylamide gel electrophoresis under reducing conditions in the presence of sodium dodecyl sulfate. A subset of the C1q-binding proteins > 24 to 37 kDa served as stable sites for assembly of C3, C5, and C9. Cardiac lymph, collected during the first hour after reperfusion of ischemic myocardium, contained proteins of diverse size that reacted with both anti-CL and C1q. Cardiac lymph, collected before occlusion and 4 to 5 hours after reperfusion, in comparison, had few if any C1q or anti-CL reactive proteins. Treatment with phospholipase suppressed the C1q-binding activity and anti-CL reactivity of the proteins in reperfusion lymph and those with similar properties in mitochondrial extracts. Our data suggest that during ischemia, mitochondria, extruded through breaks in the sarcolemma, unfold and release membrane fragments in which cardiolipin and protein are intimately associated. By binding C1 and supplying sites for the assembly of later-acting complement components, these fragments provide the means to disseminate the complement-mediated inflammatory response to ischemic injury.