tbuckley/cabot-search huggingface dataset:
Upregulation of Rac GTPase-Activating Protein 1 Is Significantly Associated with the Early Recurrence of Human Hepatocellular Carcinoma
Authors: Suk Mei Wang, London Lucien P.J. Ooi, Kam M. Hui
Journal: Clinical Cancer Research (2011)

Abstract Purpose: To assess the significance of Rac GTPase-activating protein 1 (RACGAP1) expression in identifying HBV-positive human hepatocellular carcinoma (HCC) patients who are at high risk for recurrent disease. Experimental Design: The prognostic significance of RACGAP1 was compared with clinicopathologic parameters available at diagnosis using multivariate and log-rank test. RACGAP1 expression and outcome in recurrence was compared between 35 patients with recurrence and 41 patients without recurrence using Kaplan–Meier analysis. RACGAP1-targeted molecules and pathways were identified and characterized by inhibition with siRNA duplexes. Results: Kaplan–Meier analysis showed that the level of RACGAP1 expression is sufficient to predict the early recurrence of HCC: high RACGAP1 expression correlates with high risk of postresection recurrent HCC (P &amp;lt; 0.0005). Silencing of RACGAP1 in Hep3B and MHCC97-H HCC cells with high endogenous RACGAP1 expression inhibited cell migration and invasion. Using Ingenuity Pathway Analysis, the target molecules silenced in the RACGAP1 interactome were mostly genes related to the mitotic roles of the polo-like kinases. These included PRC1, AURKB, CDC2, ECT2, KIF23, PAK1, and PPP2R5E. In providing clinical corroboration of these results, when expression of these transcripts was analyzed in an expression database that we have established previously for HBV-positive HCC patients, these genes was mostly upregulated in patients who exhibited early recurrent disease and hence provided important corroboration of these results. Conclusions: siRNA-silencing RACGAP1 mainly targeted genes in an interactome clinically relevant to early HCC recurrence. Besides being an independent informative prognostic biomarker, RACGAP1 could also be a potential molecular target for designing therapeutic strategies for HCC. Clin Cancer Res; 17(18); 6040–51. ©2011 AACR.
MAP2K4/MKK4 Expression in Pancreatic Cancer
Authors: Wei Xin, Ki J. Yun, Francesca Ricci, Marianna Zahurak, Wanglong Qiu, Gloria H. Su, Charles J. Yeo, Ralph H. Hruban, Scott E. Kern, Christine A. Iacobuzio-Donahue
Journal: Clinical Cancer Research (2004)

MKK4 (MAP2K4/SEK1) is a member of the mitogen-activated protein kinase family, originally identified as a kinase involved in the stress-activated protein kinase pathway by directly phosphorylating c-Jun NH2-terminal kinase. MKK4 genetic inactivation has been observed in a subset of pancreatic carcinomas, implicating deregulation of the stress-activated protein kinase pathway in pancreatic carcinogenesis. We evaluated Mkk4 protein expression patterns by immunohistochemical labeling in a series of 60 resected primary infiltrating pancreatic adenocarcinomas (24 cases with known MKK4 genetic status), and 14 different tissue arrays representing the primary carcinoma and all of the gross metastases from 26 patients that died of metastatic pancreatic cancer. Among the surgically resected carcinomas, focal or diffuse-positive immunolabeling for Mkk4 protein was found in 52 of 60 cases (86.7%). Among the eight carcinomas with negative Mkk4 immunolabeling, three harbored a homozygous deletion or intragenic mutation of the MKK4 gene, in contrast to none of the 52 cases with positive Mkk4 immunolabeling (P < 0.01). Loss of Mkk4 immunolabeling showed a trend toward shorter survival, with Mkk4-positive carcinomas having half the risk of death than Mkk4-negative carcinomas (P = 0.09). Mkk4 immunolabeling patterns were also evaluated among unresectable primary and metastatic cancer tissues from autopsy specimens, indicating intact Mkk4 immunolabeling in 88.8% of the unresectable primary carcinomas as compared with 63.3% of distant metastases (P < 0.001). Our data indicate that the loss of Mkk4 protein expression in pancreatic carcinomas may be more frequent than suggested by the rates of genetic inactivation alone and that MKK4 loss may contribute to disease progression. The correlation of MKK4 genetic status with immunolabeling patterns validate this approach for the evaluation of MKK4 status in routine histologic sections and may provide useful information regarding patient prognosis.
The minimal important difference of the tricuspid annular plane systolic excursion in pulmonary arterial hypertension
Authors: Rubina Khair, Neal Chaisson, Rachel Damico, Todd Kolb, Ryan Tedford, Paul Hassoun, Stephen Mathai
Journal: European Respiratory Journal (2014)

Treatment of pulmonary arterial hypertension (PAH), a disease of the pulmonary vessels causing right ventricular (RV) failure and death, has evolved. No validated methods for assessing response to PAH therapies beyond impact on survival exist; thus there is a need to identify surrogate endpoints for PAH. Studies have shown tricuspid annular plane of systolic excursion (TAPSE) as a marker of RV function correlating with survival. Clinically-relevant changes in TAPSE in response to PAH therapy have yet to be described.  Consecutive treatment naive patients with PAH diagnosed by right heart catheterization were included. For each patient, a transthoracic echocardiogram (TTE), six-minute walk test (6MWT), N-terminal pro-BNP, and Medical Outcomes Short Form-36 survey (SF-36) was obtained at baseline and 3 months. Several estimates of the minimal important difference (MID) of TAPSE will be made by both distribution- and anchor-based methods regressing change in TAPSE with treatment against change in 6MWT and SF-36. A consensus estimate will be defined using triangulation methodology.  25 subjects were enrolled; 11 have completed at least 3 months of PAH therapy. Mean TAPSE improved by 0.2 cm (SD 0.4 cm). Additionally, the 6MWT improved by a mean of 81.9 m (SD 87.4 m). The MID will be determined when all subjects have completed study protocol.  These preliminary data indicate TAPSE may be responsive to PAH-specific therapy in patients with PAH. With completion of the study protocol, the MID for TAPSE will be determined using multiple methods. Defining the MID for TAPSE will offer a clinically relevant, widely available metric to assess response to therapy in PAH.
RADIUM AND CANCER
Authors: A. C. Morson
Journal: BMJ (1914)

<h3>OBJECTIVE</h3> To describe the clinical, neurophysiological, and MRI findings in 10 patients with primary lateral sclerosis (PLS). <h3>RESULTS</h3> The course of the disease was very slowly progressive. Spasticity due to upper motor neuron dysfunction was the most prominent sign, but EMG showed slight lower motor neuron signs, such as a mixed pattern on maximal voluntary contraction and enlarged motor unit potentials. One patient had clinically mild lower motor neuron involvement. Central motor conduction times (CMCT) were more prolonged in PLS than is the case in ALS. Minor sensory signs were found on neurophysiological examination, comparable with those in ALS. In four patients serum creatine kinase activity was raised. On MRI cortical atrophy was seen, most pronounced in the precentral gyrus and expanding into the parietal-occipital region. <h3>CONCLUSIONS</h3> PLS is a distinct clinical syndrome, part of the range of motor neuron diseases. Besides pronounced upper motor neuron symptoms, mild lower motor neuron symptoms can also be found, as well as (subclinical) sensory symptoms. PLS can be distinguished from ALS by its slow clinical course, a severely prolonged MEP, and a more extensive focal cortical atrophy.
Long leg arthropathy.
Authors: A S Dixon, S Campbell-Smith
Journal: Annals of the Rheumatic Diseases (1969)

There arenow abundant examples oftheway in whichmechanical factors concerned withtheuseof a limbinfluence thepattern andseverity ofsubsequentjoint disease irrespective ofdiagnosis, bothin inflammatory arthritis andnon-inflammatory arthrosis. Forexample, Jacqueline (1953) notedthat, inhemiplegic patients whosubsequently developed rheumatoid arthritis, theparalysed sidedidnot develop theclinical or radiological changesof rheumatoid arthritis, although biopsy (Thompson andBywaters, 1963)showedthesynovium tobe affected. Similarly, disuse ofa limbbecause ofa lowermotorneurone lesion suchas poliomyelitis will also protect against thesubsequent development ofrheumatoid arthritis (Secondo, Barboso, and Mellini, 1967).Kamermann(1966) showedthat disuse duetoprevious traumawillhavethesame effect. Courtright andKuzell (1965) confirmed this sparing effect ofdisuse inanother patient andalso inexperimental adjuvant arthritis inrats.Conversely, increased use ofa joint increases thefrequencyandseverity ofarthritis. Thus,byusing careful gradingsystems,RotesQueroland Roig-Escofet (1968) showedthatthere isusually a more severearthritis inthejoints oftheright than oftheleft hand.VanDam (1964) andSoila (1963) published similar findings withregard toradiological erosions ofarticular boneinrheumatoid arthritis. Castillo, ElSallab, andScott(1965) notedthat manualworkersdeveloped larger, more cystic erosions comparedwithnon-manualworkers affected byrheumatoid arthritis. We haveobserved that, whenpatients develop ulnardeviation ofthe fingers, itmore frequently affects theright hand before theleft.Lindsay (1913) foundinvolvement ofthesmall joints ofthehandtobemore frequent on theright thanon theleft sideingout. Inarthrosis similar observations havebeenmade. ThusCosteandForestier (1935) showedthathemiplegia protected against thedevelopment ofHeberden'snodesandGlyn,Sutherland, Walker, and Young(1966) thatthejoints oftheparalysed limb inpoliomyelitis hadless tendency toarthrosis than thenon-paralysed joints. Similarly over-useofa joint witharthrosis increases thesize ofosteophytic outgrowths. This paperdescribes acommon mechanical alterationintheuse ofthekneewhichpredisposes this joint tomore severedisease. Thisdisordered gait occurswhena patient walksfora numberofyears withan uncorrected inequality ofleglength and results inselective damagetothekneeofthelonger leg.We haveobserved this whether theinequality ofleglength isapparent (duetohipcontracture) or real(duetoa truereduction inleglength) and whether itisduetodamagetoonehipfromprevious infection, arthritis, congenital dysplasia, or trauma. Whatever thepredisposing cause,thekneeinthe seemingly longer legisthenusedabnormally. This brings about more severearthritis ofthekneeifthe patient isaffected byrheumatoid arthritis, or more precocious arthrosis ofthekneeifthepatient is affected by osteoarthrosis. We referto thisas longlegarthropathy.
Selective upregulation of platelet-derived growth factor alpha receptors by transforming growth factor beta in scleroderma fibroblasts.
Authors: A Yamakage, K Kikuchi, E A Smith, E C LeRoy, M Trojanowska
Journal: The Journal of Experimental Medicine (1992)

Transforming growth factor beta (TGF-beta), a multifunctional cytokine, is an indirect mitogen for human fibroblasts through platelet-derived growth factor (PDGF), particularly the A ligand-alpha receptor arm of that system. TGF-beta effects on PDGF alpha receptor expression were studied in vitro using ligand binding techniques in three human dermal fibroblast strains: newborn foreskin, adult skin, and scleroderma (systemic sclerosis, SSc). Each cell strain responded differently to TGF-beta. In newborn foreskin fibroblasts, PDGF alpha receptor number decreased in a dose-dependent manner after exposure to low concentrations of TGF-beta (0.1-1 ng/ml). Responses of normal skin fibroblasts were varied, and mean net receptor number was unchanged. Increases in PDGF alpha receptor number by TGF-beta occurred consistently with SSc fibroblasts and low concentrations of TGF-beta (0.1-1 ng/ml) were particularly stimulatory. Increased surface expression of alpha receptor subunit by TGF-beta in SSc fibroblasts correlated with increased new PDGF alpha receptor synthesis as demonstrated by radioimmunoprecipitation analysis of metabolically labeled cells and with increased steady-state levels of corresponding mRNAs. In normal adult skin fibroblasts, TGF-beta had no effect on either synthesis or mRNA expression of alpha receptor subunits. Proliferative responses to PDGF-AA after pretreatment with TGF-beta correlated positively with effects of TGF-beta on expression of alpha receptor subunit. Decreased mitogenic responses to PDGF-AA were observed in foreskin fibroblasts, small changes in responses in adult fibroblasts, and significant increases in SSc fibroblasts. Thus, costimulation with PDGF-AA and TGF-beta selectively enhanced proliferation of fibroblasts with the SSc phenotype. Immunohistochemical examination of SSc and control skin biopsies revealed the presence of PDGF-AA in SSc skin. Data obtained by ligand binding, immunoprecipitation, mRNA, and mitogenic techniques are consistent with the hypothesis that activation of the PDGF-AA ligand/alpha receptor pathway is a characteristic of the SSc fibroblast and may contribute to the expansion of fibroblasts in SSc.
An essential role for gp39, the ligand for CD40, in thymic selection.
Authors: T M Foy, D M Page, T J Waldschmidt, A Schoneveld, J D Laman, S R Masters, L Tygrett, J A Ledbetter, A Aruffo, E Claassen, J C Xu, R A Flavell, S Oehen, S M Hedrick, R J Noelle
Journal: The Journal of Experimental Medicine (1995)

The interactions between CD40 on B cells and its ligand gp39 on activated T helper cells are known to be essential for the development of thymus-dependent humoral immunity. However, CD40 is also functionally expressed on thymic epithelial cells and dendritic cells, suggesting that gp39-CD40 interactions may also play a role in thymic education, the process by which self-reactive cells are deleted from the T cell repertoire. Six systems of negative selection were studied for their reliance on gp39-CD40 interactions to mediate negative selection. In all cases, when the antigen/superantigen was endogenously expressed (in contrast to exogenously administered), negative selection was blocked by loss of gp39 function. Specifically, blockade of gp39-CD40 interactions prevented the deletion of thymocytes expressing V beta 3, V beta 11, and V beta 12, specificities normally deleted in BALB/c mice because of the endogenous expression of minor lymphocyte-stimulating determinants. Independent verification of a role of gp39 in negative selection was provided by studies in gp39-deficient mice where alterations in T cell receptor (TCR) V beta expression were also observed. Studies were also performed in the AND TCR transgenic (Tg) mice, which bear the V alpha 11, V beta 3 TCR and recognize both pigeon cytochrome c (PCC)/IEk and H-2As. Neonatal administration of anti-gp39 to AND TCR Tg mice that endogenously express H-2As or endogenously produce PCC prevented the deletion of TCR Tg T cells. In contrast, deletion mediated by high-dose PCC peptide antigen (administered exogenously) in AND TCR mice was unaltered by administration of anti-gp39. In addition, deletion by Staphylococcus enterotoxin B in conventional mice was also unaffected by anti-gp39 administration. gp39 expression was induced on thymocytes by mitogens or by antigen on TCR Tg thymocytes. Immunohistochemical analysis of B7-2 expression in the thymus indicated that, in the absence of gp39, B7-2 expression was substantially reduced. Taken together, these data suggest that gp39 may influence negative selection through the regulation of costimulatory molecule expression. Moreover, the data support the hypothesis that, for negative selection to some endogenously produced antigens, negative selection may be dependent on TCR engagement and costimulation.
alpha-Adrenergic reduction of cyclic adenosine monophosphate concentrations in rat myocardium.
Authors: A M Watanabe, D R Hathaway, H R Besch, B B Farmer, R A Harris
Journal: Circulation Research (1977)

We determined the effect of alpha-adrenergic receptor stimulation on cyclic adenosine monophosphate (cyclic AMP) concentrations in isolated myocytes derived from adult rat hearts and in isolated perfused rat hearts. Activation of alpha-adrenergic receptors with either phenylephrine (10(-8) M to 10(-6) M) or epinephrine (10(-8) M to 10(-6) M) plus propranolol (10(-6) M) resulted in a reduction in cyclic AMP levels in isolated myocytes. The action of phenylephrine was antagonized by phentolamine (10(-6) M). Phenylephrine (10(-5)M attenuated cyclic AMP generation in response to isoproterenol (10(-8) M and 10(-5) M). However, this effect of phenylephrine was not antagonized by phentolamine. Elevation of cyclic AMP concentrations produced by glucagon and by theophylline in isolated myocytes was attenuated by phenylephrine and by epinephrine plus propranolol and the attenuation was antagonized by phentolamine. In isolated perfused rat hearts epinephrine (10(-6) M), when given with propranolol, diminished the rate of development of tension and also reduced tissue levels of cyclic AMP. Epinephrine alone, as well as isoproterenol, increased contractility and myocardial cyclic AMP concentrations as expected. These results indicate that catecholamines may increase or decrease cyclic AMP levels in rat myocardium, depending on the intensity of stimulation of receptor types. Increases are mediated by beta-adrenergic receptors, whereas decreases appear to by mediated by alpha-adrenergic receptors.
Quantitative Immunofluorescence Reveals the Signature of Active B-cell Receptor Signaling in Diffuse Large B-cell Lymphoma
Authors: Agata M. Bogusz, Richard H.G. Baxter, Treeve Currie, Papiya Sinha, Aliyah R. Sohani, Jeffery L. Kutok, Scott J. Rodig
Journal: Clinical Cancer Research (2012)

Abstract Purpose: B-cell receptor (BCR)–mediated signaling is important in the pathogenesis of a subset of diffuse large B-cell lymphomas (DLBCL) and the BCR-associated kinases SYK and BTK have recently emerged as potential therapeutic targets. We sought to identify a signature of activated BCR signaling in DLBCL to aid the identification of tumors that may be most likely to respond to BCR-pathway inhibition. Experimental Design: We applied quantitative immunofluorescence (qIF) using antibodies to phosphorylated forms of proximal BCR signaling kinases LYN, SYK, and BTK and antibody to BCR-associated transcription factor FOXO1 on BCR-cross-linked formalin-fixed paraffin-embedded (FFPE) DLBCL cell lines as a model system and on two clinical cohorts of FFPE DLBCL specimens (n = 154). Results: A robust signature of active BCR signaling was identified and validated in BCR-cross-linked DLBCL cell lines and in 71/154 (46%) of the primary DLBCL patient specimens. Further analysis of the primary biopsy samples revealed increased nuclear exclusion of FOXO1 among DLBCL with qIF evidence of active BCR signaling compared with those without (P = 0.004). Nuclear exclusion of FOXO1 was also detected in a subset of DLBCL without evidence of proximal BCR signaling suggesting that alternative mechanisms for PI3K/AKT activation may mediate FOXO1 subcellular localization in these cases. Conclusion: This study establishes the feasibility of detecting BCR activation in primary FFPE biopsy specimens of DLBCL. It lays a foundation for future dissection of signal transduction networks in DLBCL and provides a potential platform for evaluating individual tumors in patients receiving novel therapies targeting the BCR pathway. Clin Cancer Res; 18(22); 6122–35. ©2012 AACR.
Paracetamol reduces influenza-induced immunopathology in a mouse model of infection without compromising virus clearance or the generation of protective immunity
Authors: S. N. Lauder, P. R. Taylor, S. R. Clark, R. L. Evans, J. P. Hindley, K. Smart, H. Leach, E. J. Kidd, K. J. Broadley, S. A. Jones, M. P. Wise, A. J. Godkin, V. O'Donnell, A. M. Gallimore
Journal: Thorax (2011)

<h3>Background</h3> Seasonal influenza A infection affects a significant cohort of the global population annually, resulting in considerable morbidity and mortality. Therapeutic strategies are of limited efficacy, and during a pandemic outbreak would only be available to a minority of the global population. Over-the-counter medicines are routinely taken by individuals suffering from influenza, but few studies have been conducted to determine their effectiveness in reducing pulmonary immunopathology or the influence they exert upon the generation of protective immunity. <h3>Methods</h3> A mouse model of influenza infection was utilised to assess the efficacy of paracetamol (acetaminophen) in reducing influenza-induced pathology and to examine whether paracetamol affects generation of protective immunity. <h3>Results</h3> Administration (intraperitoneal) of paracetamol significantly decreased the infiltration of inflammatory cells into the airway spaces, reduced pulmonary immunopathology associated with acute infection and improved the overall lung function of mice, without adversely affecting the induction of virus-specific adaptive responses. Mice treated with paracetamol exhibited an ability to resist a second infection with heterologous virus comparable with that of untreated mice. <h3>Conclusions</h3> Our results demonstrate that paracetamol dramatically reduces the morbidity associated with influenza but does not compromise the development of adaptive immune responses. Overall, these data support the utility of paracetamol for reducing the clinical symptoms associated with influenza virus infection.
The costs and consequences of assisted reproductive technology: an economic perspective
Authors: M. P. Connolly, S. Hoorens, G. M. Chambers
Journal: Human Reproduction Update (2010)

Despite the growing use of assisted reproductive technologies (ART) worldwide, there is only a limited understanding of the economics of ART to inform policy about effective, safe and equitable financing of ART treatment. A review was undertaken of key studies regarding the costs and consequences of ART treatment, specifically examining the direct and indirect costs of treatment, economic drivers of utilization and clinical practice and broader economic consequences of ART-conceived children. The direct costs of ART treatment vary substantially between countries, with the USA standing out as the most expensive. The direct costs generally reflect the costliness of the underlying healthcare system. If unsubsidized, direct costs represent a significant economic burden to patients. The level of affordability of ART treatment is an important driver of utilization, treatment choices, embryo transfer practices and ultimately multiple birth rates. The costs associated with caring for multiple-birth ART infants and their mothers are substantial, reflecting the underlying morbidity associated with such pregnancies. Investment analysis of ART treatment and ART-conceived children indicates that appropriate funding of ART services appears to represent sound fiscal policy. The complex interaction between the cost of ART treatment and how treatments are subsidized in different healthcare settings and for different patient groups has far-reaching consequences for ART utilization, clinical practice and infant outcomes. A greater understanding of the economics of ART is needed to inform policy decisions and to ensure the best possible outcomes from ART treatment.