tbuckley/cabot-search huggingface dataset:
Proarrhythmic Consequences of a KCNQ1 AKAP-Binding Domain Mutation
Authors: Jeffrey J. Saucerman, Sarah N. Healy, Mary E. Belik, Jose L. Puglisi, Andrew D. McCulloch
Journal: Circulation Research (2004)

The KCNQ1-G589D gene mutation, associated with a long-QT syndrome, has been shown to disrupt yotiao-mediated targeting of protein kinase A and protein phosphatase-1 to the I(Ks) channel. To investigate how this defect may lead to ventricular arrhythmia during sympathetic stimulation, we use integrative computational models of beta-adrenergic signaling, myocyte excitation-contraction coupling, and action potential propagation in a rabbit ventricular wedge. Paradoxically, we find that the KCNQ1-G589D mutation alone does not prolong the QT interval. But when coupled with beta-adrenergic stimulation in a whole-cell model, the KCNQ1-G589D mutation induced QT prolongation and transient afterdepolarizations, known cellular mechanisms for arrhythmogenesis. These cellular mechanisms amplified tissue heterogeneities in a three-dimensional rabbit ventricular wedge model, elevating transmural dispersion of repolarization and creating other T-wave abnormalities on simulated electrocardiograms. Increasing heart rate protected both single myocyte and the coupled myocardium models from arrhythmic consequences. These findings suggest that the KCNQ1-G589D mutation disrupts a critical link between beta-adrenergic signaling and myocyte electrophysiology, creating both triggers of cardiac arrhythmia and a myocardial substrate vulnerable to such electrical disturbances.
Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR
Authors: David W. Schoppy, Ryan L. Ragland, Oren Gilad, Nishita Shastri, Ashley A. Peters, Matilde Murga, Oscar Fernandez-Capetillo, J. Alan Diehl, Eric J. Brown
Journal: Journal of Clinical Investigation (2011)

Oncogenic Ras and p53 loss-of-function mutations are common in many advanced sporadic malignancies and together predict a limited responsiveness to conventional chemotherapy. Notably, studies in cultured cells have indicated that each of these genetic alterations creates a selective sensitivity to ataxia telangiectasia and Rad3-related (ATR) pathway inhibition. Here, we describe a genetic system to conditionally reduce ATR expression to 10% of normal levels in adult mice to compare the impact of this suppression on normal tissues and cancers in vivo. Hypomorphic suppression of ATR minimally affected normal bone marrow and intestinal homeostasis, indicating that this level of ATR expression was sufficient for highly proliferative adult tissues. In contrast, hypomorphic ATR reduction potently inhibited the growth of both p53-deficient fibrosarcomas expressing H-rasG12V and acute myeloid leukemias (AMLs) driven by MLL-ENL and N-rasG12D. Notably, DNA damage increased in a greater-than-additive fashion upon combining ATR suppression with oncogenic stress (H-rasG12V, K-rasG12D, or c-Myc overexpression), indicating that this cooperative genome-destabilizing interaction may contribute to tumor selectivity in vivo. This toxic interaction between ATR suppression and oncogenic stress occurred without regard to p53 status. These studies define a level of ATR pathway inhibition in which the growth of malignancies harboring oncogenic mutations can be suppressed with minimal impact on normal tissue homeostasis, highlighting ATR inhibition as a promising therapeutic strategy.
Plasma prednisolone levels and adrenocortical responsiveness after administration of prednisolone-21-phosphate as a retention enema.
Authors: D A Lee, G M Taylor, V H James, G Walker
Journal: Gut (1979)

Plasma prednisolone levels have been measured by radioimmunoassay after oral and rectal administration to healthy volunteers and to patients with idiopathic proctocolitis. The amount of prednisolone absorbed from a 20 mg retention enema given to patients with proctocolitis was about 44% of that absorbed from the same dose orally administered. Adrenocortical response to synthetic ACTH in patients receiving prolonged rectal therapy was either normal, or only slightly impaired, and this may be related to the pattern of steroid absorption rather than to the total amount absorbed.
Novel Action of Paclitaxel against Cancer Cells: Bystander Effect Mediated by Reactive Oxygen Species
Authors: Jérôme Alexandre, Yumin Hu, Weiqin Lu, Helene Pelicano, Peng Huang
Journal: Cancer Research (2007)

Abstract Generation of reactive oxygen species (ROS) has been observed in cancer cells treated with paclitaxel, but the underlying mechanisms and therapeutic implications remain unclear. In the present study, we showed that paclitaxel promoted ROS generation through enhancing the activity of NADPH oxidase (NOX) associated with plasma membranes. Treatment of breast cancer cells caused an increased translocation of Rac1, a positive regulatory protein of NOX, to the membrane fraction. The paclitaxel-induced ROS generation occurred rapidly within several hours of drug exposure, with O2− and H2O2 accumulation mainly outside the cells while the intracellular ROS remained unchanged. Importantly, the increase in extracellular ROS caused lethal damage to the bystander cancer cells not exposed to paclitaxel, as shown by two different methods using coculture systems where the bystander cells were differentiated from the paclitaxel-treated cells by fluorescent or radioactive labeling. This cytotoxic bystander effect was also observed with other microtubule-targeted agents vincristine and taxotere but not with 5-fluorouracil or doxorubicin. This toxic bystander effect was enhanced by CuZnSOD that converts O2− to H2O2 and was abolished by a catalase that eliminates H2O2. Furthermore, paclitaxel was able to induce an almost complete inhibition of proliferation of the bystander cells in the coculture system. Our study revealed a novel mechanism by which paclitaxel induces toxic bystander effect through generation of extracellular H2O2 from the membrane-associated NOX. This may contribute to the potent anticancer activity of paclitaxel and provide a novel basis to improve the clinical use of this important drug. [Cancer Res 2007;67(8):3512–7]
Polymorphisms in FcγRIIIA (CD16) Receptor Expression Are Associated With Clinical Response to Rituximab in Waldenström’s Macroglobulinemia
Authors: Steven P. Treon, Mark Hansen, Andrew R. Branagan, Sigitas Verselis, Christos Emmanouilides, Eva Kimby, Stanley R. Frankel, Nikolaos Touroutoglou, Barry Turnbull, Kenneth C. Anderson, David G. Maloney, Edward A. Fox
Journal: Journal of Clinical Oncology (2005)

Rituximab is an important therapeutic for Waldenstrom's macroglobulinemia (WM). Polymorphisms in FcgammaRIIIA (CD16) receptor expression modulate human immunoglobulin G1 binding and antibody-dependent cell-mediated cytotoxicity, and may therefore influence responses to rituximab.Sequence analysis of the entire coding region of FcgammaRIIIA was undertaken in 58 patients with WM whose outcomes after rituximab were known.Variations in five codons of FcgammaRIIIA were identified. Two were commonly observed (FcgammaRIIIA-48 and FcgammaRIIIA-158) and predicted for amino acid polymorphisms at FcgammaRIIIA-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). Polymorphisms at FcgammaRIIIA-158 were phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V), and valine/valine (V/V). A clear linkage between these polymorphisms was detected and all patients with FcgammaRIIIA-158F/F were always FcgammaRIIIA-48L/L, and patients with either FcgammaRIIIA-L/R or -L/H always expressed at least one valine at FcgammaRIIIA-158 (P < or = .001). The response trend was higher for patients with FcgammaRIIIA-48L/H (38.5%) versus -48L/R (25.0%) and LL (22.0%), and was significantly higher for patients with FcgammaRIIIA-158V/V (40.0%) and -V/F (35%) versus -158F/F (9.0%; P = .030). Responses for patients with FcgammaRIIIA-48L/L were higher when at least one valine was present at FcgammaRIIIA-158 (P = .057), thereby supporting a primary role for FcgammaRIIIA-158 polymorphisms in predicting rituximab responses. With a median follow-up of 13 months, no significant differences in the median time to progression and progression-free survival were observed when patients were grouped according to their FcgammaRIIIA-48 and -158 polymorphisms.The results of these studies therefore support a predictive role for FcgammaRIIIA-158 polymorphisms and responses to rituximab in WM.
Integrating phenotypic and expression profiles to map arsenic-response networks
Authors: Astrid C Haugen, Ryan Kelley, Jennifer B Collins, Charles J Tucker, Changchun Deng, Cynthia A Afshari, J Martin Brown, Trey Ideker, Bennett Van Houten
Journal: Genome biology (2004)

Abstract Background Arsenic is a nonmutagenic carcinogen affecting millions of people. The cellular impact of this metalloid in Saccharomyces cerevisiae was determined by profiling global gene expression and sensitivity phenotypes. These data were then mapped to a metabolic network composed of all known biochemical reactions in yeast, as well as the yeast network of 20,985 protein-protein/protein-DNA interactions. Results While the expression data unveiled no significant nodes in the metabolic network, the regulatory network revealed several important nodes as centers of arsenic-induced activity. The highest-scoring proteins included Fhl1, Msn2, Msn4, Yap1, Cad1 (Yap2), Pre1, Hsf1 and Met31. Contrary to the gene-expression analyses, the phenotypic-profiling data mapped to the metabolic network. The two significant metabolic networks unveiled were shikimate, and serine, threonine and glutamate biosynthesis. We also carried out transcriptional profiling of specific deletion strains, confirming that the transcription factors Yap1, Arr1 (Yap8), and Rpn4 strongly mediate the cell's adaptation to arsenic-induced stress but that Cad1 has negligible impact. Conclusions By integrating phenotypic and transcriptional profiling and mapping the data onto the metabolic and regulatory networks, we have shown that arsenic is likely to channel sulfur into glutathione for detoxification, leads to indirect oxidative stress by depleting glutathione pools, and alters protein turnover via arsenation of sulfhydryl groups on proteins. Furthermore, we show that phenotypically sensitive pathways are upstream of differentially expressed ones, indicating that transcriptional and phenotypic profiling implicate distinct, but related, pathways.
Notch signalling pathways mediate synovial angiogenesis in response to vascular endothelial growth factor and angiopoietin 2
Authors: Wei Gao, Catherine Sweeney, Ceara Walsh, Peadar Rooney, Jennifer McCormick, Douglas J Veale, Ursula Fearon
Journal: Annals of the Rheumatic Diseases (2012)

Objective Notch signalling pathways are critical for angiogenesis and endothelial cell (EC) fate; however the mechanisms regulating these processes in the inflamed joint remain to be elucidated. Here, we examine whether Notch signalling mediates vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2)-induced vascular function. Methods Notch-1 intracellular domain (Notch-1 IC), Notch-4 IC, Delta-like-ligand 4, Hes-related transcriptional repressors-1 and 2 ( Hrt-1 , Hrt-2 ) mRNA and/or protein expression was measured by Real-time PCR and/or western blot. VEGF/Ang2 induced EC function was assessed using transwell invasion chambers, matrigel tube formation assays and wound repair scratch assays ± Notch-1 siRNA or an γ-secretase inhibitor N-(N-(3,5-Difluorophenacetyl-L-alanly))-S-phenylglycine-t-Butyl Ester (DAPT) in RA synovial explants or human microvascular EC. Interleukin (IL)-6 and IL-8 were measured by ELISA and MMP2 and 9 by gelatine zymography. Results Notch-1 IC and Notch-4 IC protein expressions were demonstrated in RA and psoriatic arthritis synovial biopsies, with minimal expression observed in Osteoarthritis (OA). VEGF and Ang2 induced Notch-1 IC/ Notch-4 IC protein expression in synovial explant cultures and human microvascular EC levels were further potentiated by VEGF/Ang2 stimulation in combination. Notch-1, Delta-like-ligand 4, and Hrt-2 mRNA expression were significantly induced by VEGF and Ang2 alone and in combination. Furthermore VEGF/Ang2-induced EC invasion, angiogenesis and migration were inhibited by Notch-1 siRNA or DAPT. Conditioned media from VEGF/Ang2 stimulated RA synovial explants induced EC tube formation, an effect that was inhibited by DAPT. Finally, DAPT significantly decreased VEGF/Ang2 induced IL-6, IL-8, MMP2 and 9 expressions in RA synovial explants. Conclusions Notch-1 mediates VEGF/Ang2-induced angiogenesis and EC invasion in inflammatory arthritis.
HL-A in psoriasis vulgaris and in pustular psoriasis–population and family studies
Authors: A. SVEJGAARD, L. STAUB NIELSEN, E. SVEJGAARD, F. KISSMEYER NIELSEN, A. HJORTSHOJ, H. ZACHARIAE
Journal: British Journal of Dermatology (1974)

A collaborative study of HL‐A typing was done on 156 unrelated patients with psoriasis vulgaris and thirty‐one patients with pustular psoriasis. Highly significant increases of HL‐A13 and HL‐A17 were found in psoriasis vulgaris: about half of the patients carried either of these antigens as compared to about 12% of the controls. The effect of HL‐A13 and 17 is confined almost exclusively to psoriasis with onset before the age of 35 years. In contrast, none of these antigens was increased in pustular psoriasis, indicating that pustular and common psoriasis are different aetiological entities. Family studies in psoriasis vulgaris showed that psoriasis can develop in relatives lacking the HL‐A haplotype following psoriasis in the other family members. Hence, it seems most likely that HL‐A represents only part of the genetic basis of psoriasis vulgaris. This disease is probably of a polygenic threshold character, and HL‐A13 and 17 decreases the threshold making the expression of psoriasis more likely in individuals carrying these determinants in addition to other probably non‐HL‐A linked psoriasis determinants. This concept is supported by the observation of a higher incidence of a positive family history in HL‐A13 and/or 17 positive patients than in patients lacking these antigens. Studies of antistreptolysin O and antistreptococcal hyaluronidase titres and of triggering streptococcal infections yielded no clue as to the pathogenetic effect of HL‐A. The frequencies of HL‐A13 and 17 were not significantly increased in twenty‐one patients with psoriatic arthritis, but HL‐A27 may be increased in these patients. This study shows the importance of HL‐A in the subdivision of diseases and stresses the importance of family studies for clarifying the associations between HL‐A and disease.
Response to Letter Regarding Article, “Acute Kidney Injury and Cardiovascular Outcomes in Acute Severe Hypertension”
Authors: Lynda A. Szczech, Christopher B. Granger, Jason N. Katz, Joseph F. Dasta, Alpesh Amin, W. Frank Peacock, Peter A. McCullough, John W. Devlin, Matthew R. Weir, Allison Wyman, Frederick A. Anderson, Joseph Varon
Journal: Circulation (2011)

We thank Dr Lin and colleagues for their questions regarding the analysis from the Studying the Treatment of Acute Hypertension Registry (STAT) registry exploring the relationship between both acute and chronic kidney disease in patients with acute hypertension. 1There are two different aspects of their questions that can be addressed.First, on the mathematical or statistical level, Lin et al suggest different ways in which the data can be analyzed.The inclusion of various parameters of blood pressure (including mean arterial pressure) as well as the analysis of change in kidney function using different methods were conducted within STAT.The results and conclusions were not significantly different from those presented in the published article, so they were not included owing to space constraints.More importantly, though, Lin et al emphasize that these data are counterintuitive to what would be expected based on studies that have been conducted in settings other than acute severe hypertension.As they have noted, patients receiving chronic dialysis have mortality rates that are significantly higher than those with chronic kidney disease or the general population, and race and the presence of diabetes mellitus are both significantly associated with worse outcomes.These findings are consistent over multiple studies in the chronic outpatient care setting.However, few studies have examined these relationships during the event of hospitalization owing to acute severe hypertension.Regardless of whether the greater mortality risk associated with acute kidney injury than end stage renal disease in acute severe hypertension reflects differences in diagnosis or pathophysiology of the acute event between the two groups, the clinical message is an important one that should draw clinical as well as research attention to this previously under-recognized high-risk group of patients with acute kidney injury.We agree that the differences in relationships between these clinical and demographic parameters in the acute as compared with the chronic setting are intriguing.They represent a clear need to further study the associations with acute kidney injury in acute severe hypertension and to develop treatments to mitigate the risk.
Inflammation and Endothelial Function
Authors: Brian R. Clapp, Gideon M. Hirschfield, Clare Storry, J. Ruth Gallimore, Ray P. Stidwill, Mervyn Singer, John E. Deanfield, Raymond J. MacAllister, Mark B. Pepys, Patrick Vallance, Aroon D. Hingorani
Journal: Circulation (2005)

Circulating concentrations of the sensitive inflammatory marker C-reactive protein (CRP) predict future cardiovascular events, and CRP is elevated during sepsis and inflammation, when vascular reactivity may be modulated. We therefore investigated the direct effect of CRP on vascular reactivity.The effects of isolated, pure human CRP on vasoreactivity and protein expression were studied in vascular rings and cells in vitro, and effects on blood pressure were studied in rats in vivo. The temporal relationship between changes in CRP concentration and brachial flow-mediated dilation was also studied in humans after vaccination with Salmonella typhi capsular polysaccharide, a model of inflammatory endothelial dysfunction. In contrast to some previous reports, highly purified and well-characterized human CRP specifically induced hyporeactivity to phenylephrine in rings of human internal mammary artery and rat aorta that was mediated through physiological antagonism by nitric oxide (NO). CRP did not alter endothelial NO synthase protein expression but increased protein expression of GTP cyclohydrolase-1, the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, the NO synthase cofactor. In the vaccine model of inflammatory endothelial dysfunction in humans, increased CRP concentration coincided with the resolution rather than the development of endothelial dysfunction, consistent with the vitro findings; however, administration of human CRP to rats had no effect on blood pressure.Pure human CRP has specific, direct effects on vascular function in vitro via increased NO production; however, further clarification of the effect, if any, of CRP on vascular reactivity in humans in vivo will require clinical studies using specific inhibitors of CRP.
TGF-α Mediates Genetic Susceptibility to Chronic Kidney Disease
Authors: Denise Laouari, Martine Burtin, Aurélie Phelep, Carla Martino, Evangeline Pillebout, Xavier Montagutelli, Gérard Friedlander, Fabiola Terzi
Journal: Journal of the American Society of Nephrology (2010)

The mechanisms of progression of chronic kidney disease (CKD) are poorly understood. Epidemiologic studies suggest a strong genetic component, but the genes that contribute to the onset and progression of CKD are largely unknown. Here, we applied an experimental model of CKD (75% excision of total renal mass) to six different strains of mice and found that only the FVB/N strain developed renal lesions. We performed a genome-scan analysis in mice generated by back-crossing resistant and sensitive strains; we identified a major susceptibility locus (Ckdp1) on chromosome 6, which corresponds to regions on human chromosome 2 and 3 that link with CKD progression. In silico analysis revealed that the locus includes the gene encoding the EGF receptor (EGFR) ligand TGF-α. TGF-α protein levels markedly increased after nephron reduction exclusively in FVB/N mice, and this increase preceded the development of renal lesions. Furthermore, pharmacologic inhibition of EGFR prevented the development of renal lesions in the sensitive FVB/N strain. These data suggest that variable TGF-α expression may explain, in part, the genetic susceptibility to CKD progression. EGFR inhibition may be a therapeutic strategy to counteract the genetic predisposition to CKD.
Plasma insulin in pancreatic disease
Authors: M. F. Anderson, S. H. H. Davison, A. P. Dick, C. N. Hales, J. Owens
Journal: Gut (1970)

Pancreatic exocrine function tests and plasma insulin curves after a glucose load have been performed in 74 patients, 32 with no significant pancreatic disease, 31 with various disorders of the pancreas, and 11 with postmature diabetes mellitus. Exocrine function was impaired in all patients with chronic pancreatitis and chronic relapsing pancreatitis, whereas insulin production was defective in seven of 10 of those with chronic pancreatitis, and in one of seven with chronic relapsing pancreatitis. The findings in other examples of pancreatic disease are mentioned. Two out of four patients presenting with diabetes mellitus, who were found to have a flat plasma insulin curve, proved on investigation to have chronic pancreatitis. The results of plasma insulin response curves in this series are discussed in relation to pancreatic disease and their possible value in diagnosis.
Improving the Transparency of Prognosis Research: The Role of Reporting, Data Sharing, Registration, and Protocols
Authors: George Peat, Richard D. Riley, Peter Croft, Katherine I. Morley, Panayiotis A. Kyzas, Karel G. M. Moons, Pablo Perel, Ewout W. Steyerberg, Sara Schroter, Douglas G. Altman, Harry Hemingway
Journal: PLoS Medicine (2014)

George Peat and colleagues review and discuss current approaches to transparency and published debates and concerns about efforts to standardize prognosis research practice, and make five recommendations. Please see later in the article for the Editors' Summary.
A switch in RND3-RHOA signaling is critical for melanoma cell invasion following mutant-BRAF inhibition
Authors: R Matthew Klein, Paul J Higgins
Journal: Molecular Cancer (2011)

The initial use of BRAF targeted therapeutics in clinical trials has demonstrated encouraging responses in melanoma patients, although a rise in drug-resistant cells capable of advancing malignant disease has been described. The current study uses BRAFV600E expressing WM793 melanoma cells to derive data aimed at investigating the molecular determinant of cell invasion following treatment with clinical BRAF inhibitors. Small-molecule inhibitors targeting BRAF reduced MEK1/2-ERK1/2 pathway activation and cell survival; yet, viable cell subpopulations persisted. The residual cells exhibited an elongated cell shape, prominent actin stress fibers and retained the ability to invade 3-D dermal-like microenvironments. BRAF inhibitor treatments were associated with reduced expression of RND3, an antagonist of RHOA activation, and elevated RHOA-dependent signaling. Restoration of RND3 expression or RHOA knockdown attenuated the migratory ability of residual cells without affecting overall cell survival. The invasive ability of BRAF inhibitor treated cells embedded in collagen gels was diminished following RND3 re-expression or RHOA depletion. Conversely, melanoma cell movement in the absence of BRAF inhibition was unaffected by RND3 expression or RHOA depletion. These data reveal a novel switch in the requirement for RND3 and RHOA in coordinating the movement of residual WM793 cells that are initially refractive to BRAF inhibitor therapy. These results have important clinical implications because they suggest that combining BRAF inhibitors with therapies that target the invasion of drug-resistant cells could aid in controlling disease relapse.