tbuckley/cabot-search huggingface dataset:
Mechanisms of signal transduction during alpha 2-adrenergic receptor-mediated contraction of vascular smooth muscle.
Authors: T K Aburto, C Lajoie, K G Morgan
Journal: Circulation Research (1993)

Little is known about the signaling pathways involved in alpha 2-adrenergic receptor-mediated contraction of vascular smooth muscle. In the present study, we measured intracellular Ca2+ ([Ca2+]i), myosin light chain (MLC) phosphorylation, and myofilament Ca2+ sensitivity during stimulation with the relatively selective alpha 2-agonist UK 14304. These effects were compared and contrasted with corresponding changes during depolarization by elevation of the [K+] in the bathing medium. These studies were performed using spiral strips of the rabbit saphenous vein, a tissue with a relatively high density of postsynaptic alpha 2-receptors. UK 14304 (10(-5) M) caused parallel changes in [Ca2+]i, MLC phosphorylation, and force consisting of an initial phasic, followed by a sustained steady-state response. The steady-state increase in [Ca2+]i, MLC phosphorylation, and force caused by UK 14304 in the presence of 2.5 mM extracellular Ca2+ were indistinguishable from those during 51 mM K+ depolarization. However, when extracellular Ca2+ was removed in the presence of UK 14304, [Ca2+]i and MLC phosphorylation fell to resting levels, but force remained significantly elevated above basal levels. UK 14304 caused no change in the steady-state [Ca2+]i-MLC phosphorylation relation. Thus, the [Ca2+]i sensitization of force was not caused by a sensitization of MLC phosphorylation. These results indicate that in a 2.5-mM Ca2+ bathing medium, the dominant mechanism by which alpha 2-adrenergic receptor stimulation causes an increase in vascular tone is through a relatively large increase in [Ca2+]i and MLC phosphorylation. However, in Ca(2+)-free bathing medium, a second mechanism is unmasked which appears to involve an increased Ca2+ sensitivity and is independent of myosin phosphorylation.
An alternate route toward a science of mind
Authors: David A. Schwartz
Journal: Behavioral and Brain Sciences (2001)

Shepard has challenged psychologists to identify nonarbitrary principles of mind upon which to build a more explanatory and general cognitive science. I suggest that such nonarbitrary principles may fruitfully be sought not only in the laws of physics and mathematics, but also in the logical entailments of different categories of representation. In the example offered here, conceptualizing mental events as indexical with respect to the events they represent enables one to account parsimoniously for a wide range of empirical psychological phenomena. [Shepard]
Conditional Loss of ErbB3 Delays Mammary Gland Hyperplasia Induced by Mutant <i>PIK3CA</i> without Affecting Mammary Tumor Latency, Gene Expression, or Signaling
Authors: Christian D. Young, Adam D. Pfefferle, Philip Owens, María G. Kuba, Brent N. Rexer, Justin M. Balko, Violeta Sánchez, Hailing Cheng, Charles M. Perou, Jean J. Zhao, Rebecca S. Cook, Carlos L. Arteaga
Journal: Cancer Research (2013)

Abstract Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), have been shown to transform mammary epithelial cells (MEC). Studies suggest this transforming activity requires binding of mutant p110α via p85 to phosphorylated YXXM motifs in activated receptor tyrosine kinases (RTK) or adaptors. Using transgenic mice, we examined if ErbB3, a potent activator of PI3K, is required for mutant PIK3CA-mediated transformation of MECs. Conditional loss of ErbB3 in mammary epithelium resulted in a delay of PIK3CAH1047R-dependent mammary gland hyperplasia, but tumor latency, gene expression, and PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with several tyrosyl phosphoproteins, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Similarly, inhibition of ErbB RTKs with lapatinib did not affect PI3K signaling in PIK3CAH1047R-expressing tumors. However, the p110α-specific inhibitor BYL719 in combination with lapatinib impaired mammary tumor growth and PI3K signaling more potently than BYL719 alone. Furthermore, coinhibition of p110α and ErbB3 potently suppressed proliferation and PI3K signaling in human breast cancer cells harboring PIK3CAH1047R. These data suggest that PIK3CAH1047R-driven tumor growth and PI3K signaling can occur independently of ErbB RTKs. However, simultaneous blockade of p110α and ErbB RTKs results in superior inhibition of PI3K and mammary tumor growth, suggesting a rational therapeutic combination against breast cancers harboring PIK3CA activating mutations. Cancer Res; 73(13); 4075–85. ©2013 AACR.
Long-Term Outcome of Cirrhotic Patients With Early Hepatocellular Carcinoma Treated With Ultrasound-Guided Percutaneous Laser Ablation: A Retrospective Analysis
Authors: Claudio Maurizio Pacella, Giampiero Francica, Francesca Marta Lilja Di Lascio, Vincenzo Arienti, Ettore Antico, Bruno Caspani, Fabrizio Magnolfi, Angelo Salomone Megna, Stefano Pretolani, Renato Regine, Massimo Sponza, Roberto Stasi
Journal: Journal of Clinical Oncology (2009)

Percutaneous laser ablation (PLA) has been proposed as an active treatment in patients with hepatocellular carcinoma (HCC). However, large multicenter studies using this technique have not been reported.We retrospectively analyzed treatment and survival parameters of 432 cirrhotic patients with nonsurgical early HCC (single nodule < or = 4 cm or three nodules < or = 3 cm each) who had received PLA in nine Italian centers.Single tumors were seen in 344 (80%) of 432 patients, and two to three nodules were seen in 88 patients (20%), for a total of 548 tumors. An initial complete response after PLA was observed in 338 patients (78%). Median overall survival time was 47 months (95% CI, 41 to 53 months). The 3- and 5-year cumulative survival rates were 61% and 34%, respectively. In multivariate analysis, independent predictors of survival were serum albumin levels more than 3.5 g/dL (P = .002; risk ratio [RR] = 0.580; 95% CI, 0.409 to 0.821), the achievement of a complete tumor ablation (P = .001; RR = 0.517; 95% CI, 0.346 to 0.771), and age less than 73 years (P < .001; RR = 0.466; 95% CI, 0.320 to 0.681). Child-Turcotte-Pugh class A patients had a 5-year cumulative survival rate of 41%; this figure increased up to 60% with a median survival time of 63 months (95% CI, 48 to 78 months) in patients with tumors < or = 2.0 cm.This analysis confirms that a complete tumor ablation results in improved survival in patients with nonsurgical HCC. Ideal candidates for PLA are younger patients with normal serum albumin levels and tumor size < or = 2 cm.
Mortality in Colorectal Cancer and Use of Statins
Authors: Deniz Tural, Saadettin Kilickap
Journal: Journal of Clinical Oncology (2015)

ation. In the study Cardwell et al, 1 there was not a reduction in the rate of cancer-specific mortality in aspirin users but rather in statin nonusers after adjustment for confounders (hazard ratio, 1.06; 95% CI, 0.90 to 1.27; Appendix Table A3 of report). Furthermore, in those aspirin nonusers (but statin users after adjustment for confounders), there was a 30% reduction in the rate of cancer-specific mortality (hazard ratio, 0.70; 95% CI, 0.57 to 0.86). There was methodologic bias in this study, because in a recent study, Cuzick et al 2 suggested that a minimum of 3 years of aspirin use seemed to be necessary to see any benefit, at least 5 years of use were needed to see reduction in death resulting from cancer, and 10 years were likely needed for full benefit. In this study, Cuzick et al demonstrated that a low-dose aspirin taken every day for a decade could reduce colorectal cancer by approximately 35% and deaths resulting from these cancers by 40%. However, the Cardwell et al study did not take into account the length of time of aspirin use; their analysis had only aspirin user and nonuser as variables, which may have had a bias effect on the study outcome. Another point that requires careful consideration is that information about use of nonaspirin nonsteroidal anti-inflammatory drugs was not included in the evaluation. It is well known that such drugs significantly reduce the risk of colorectal cancer, the same as aspirin. 3 Also, in the study by Cardwell et al, 1 lifestyle and dietary habit were not included in the evaluation. Yang et al 4 suggested that higher total calcium and milk intake after colorectal cancer diagnosis are associated with lower risk of mortality in patients with nonmetastatic colorectal cancer. In another recent study, Wen at al 5 demonstrated that patients who exercised and ran at low speed had an overall 30% lower adjusted risk of all-cause mortality. Conversely, in the Cardwell et al study, patients who used statins had a higher proportion of comorbid diseases, which may have affected the outcome of the trial. These patients may have visited health care professionals more frequently for health problems other than cancer; this may have affected the time of cancer diagnosis, because cancer may have been discovered when patients were seen for some other medical problem. In conclusion, we suggest that other confounders may have interfered with the results of this study.
Infliximab in active early rheumatoid arthritis
Authors: F C Breedveld, P Emery, E Keystone, K Patel, D E Furst, J R Kalden, E W St Clair, M Weisman, J Smolen, P E Lipsky, R N Maini
Journal: Annals of the Rheumatic Diseases (2004)

To examine the impact of the combination of infliximab plus methotrexate (MTX) on the progression of structural damage in patients with early rheumatoid arthritis (RA).Subanalyses were carried out on data for patients with early RA in the Anti-TNF Therapy in RA with Concomitant Therapy (ATTRACT) study, in which 428 patients with active RA despite MTX therapy received placebo with MTX (MTX-only) or infliximab 3 mg/kg or 10 mg/kg every (q) 4 or 8 weeks with MTX (infliximab plus MTX) for 102 weeks. Early RA was defined as disease duration of 3 years or less; 82 of the 428 patients (19%) met this definition. Structural damage was assessed with the modified van der Heijde-Sharp score. The changes from baseline to week 102 in total modified van der Heijde-Sharp score were compared between the infliximab plus MTX groups and the MTX-only group.The erosion and joint space narrowing scores from baseline to week 102 in the cohort of patients with early RA decreased significantly in each infliximab dose regimen compared with the MTX-only regimen. Consistent benefit was seen in the joints of both hands and feet.Infliximab combined with MTX inhibited the progression of structural damage in patients with early RA during the 2 year period of treatment. Early intervention with infliximab in patients with active RA despite MTX therapy may provide long term benefits by preventing radiographic progression and preserving joint integrity.
Bedside B-Type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction
Authors: Alan S Maisel, James McCord, Richard M Nowak, Judd E Hollander, Alan H B Wu, Philippe Duc, Torbjørn Omland, Alan B Storrow, Padma Krishnaswamy, William T Abraham, Paul Clopton, Gabriel Steg, Marie Claude Aumont, Arne Westheim, Cathrine Wold Knudsen, Alberto Perez, Richard Kamin, Radmila Kazanegra, Howard C Herrmann, Peter A McCullough
Journal: Journal of the American College of Cardiology (2003)
Heterocellular Contact at the Myoendothelial Junction Influences Gap Junction Organization
Authors: Brant E. Isakson, Brian R. Duling
Journal: Circulation Research (2005)

Heterocellular communication between vascular smooth muscle cells (VSMC) and endothelial cells (EC) at the myoendothelial junction (MEJ) is a critical part of control of the arteriolar wall. We have developed an in vitro model of the MEJ composed of primary cultures of murine EC and VSMC. Immunoctytochemistry and immunoblots demonstrated Cx37 and Cx43 in both cell types, whereas Cx40 was found only in EC. Cx37 was excluded from the MEJ in both EC and VSMC. Connexin composition as well as functionality of the gap junctions at the MEJ was assessed by measuring diffusional transfer of biocytin and Cy3. Using connexin-specific blockers and manipulations of expression of individual connexin proteins, we confirmed that Cx37 is not a part of EC–VSMC coupling, and we demonstrated that heterotypic gap junctions are functional at the MEJ. We speculate that specific gap junction organization may be a vital component of EC–VSMC contact at the MEJ.
Collagen accumulation after myocardial infarction: effects of ETA receptor blockade and implications for early remodeling: Presented in part at the 72nd Scientific Session of the American Heart Association, Atlanta, GA, USA, November 7-10, 1999, and published in abstract form (Circulation 1999;100(Suppl. 1):562)
Authors: D. Fraccarollo, P. Galuppo, J. Bauersachs, G. Ertl
Journal: Cardiovascular Research (2002)

Objectives: Endothelin A (ETA) receptor blockade started early after myocardial infarction (MI) promotes adverse left ventricular (LV) dilatation. We tested the hypothesis that inhibition of ETA receptors during the early phase of healing affects collagen synthesis and accumulation, and induces expansion of infarcted myocardium. Methods: Starting 3 h after coronary ligation, female Wistar rats were treated with the selective ETA receptor antagonist LU 135252 (30 mg/kg body wt/day) or placebo. A period of 7 days after MI, hemodynamic, morphometric and biochemical studies were performed. Results: ETA receptor blockade enhanced infarct expansion index and decreased LV systolic function. Infarct scar of LU 135252-treated rats displayed decreased gene expression of fibrillar type I/III collagens and of transforming growth factor-β1 (TGF-β1). Collagen content in the infarct scar and border regions was lower after ETA inhibition. In addition, Western blot analysis revealed, after ETA receptor blockade, enhanced matrix metalloproteinases MMP-13, and MMP-2 expression in the infarcted LV myocardium. Conclusions: These data demonstrate that endothelin stimulates collagen accumulation at the site of infarction. Decreased collagen and TGF-β1 gene expression, associated with enhanced infarct expansion and MMP up-regulation likely contributes to ETA receptor blockade–mediated deleterious effects on ventricular remodeling after infarction.
A comparative study of apoptosis and proliferation in germinoma and glioblastoma
Authors: Masahiro Mizoguchi, Takanori Inamura, Tadahisa Shono, Kiyonobu Ikezaki, Satoshi Inoha, Shoichiro Ohgami, Masashi Fukui
Journal: Neuro-Oncology (2000)

Intracranial germinoma has a relatively good prognosis when treated with radiotherapy and chemotherapy, whereas glioblastoma has a poor prognosis irrespective of these treatments.Cell proliferation and cell death are opposing processes in tumor growth, with tumor progression re ecting the balance between proliferating and apoptotic cells.We investigated cell proliferation and cell death using MIB-1 staining and nick-end labeling in 13 germinomas in comparison with 11 glioblastomas.Expression of BAX and Bcl-2, which regulate apoptosis, were studied by immunohistochemistry.Although germinomas showed strong MIB-1 immunostaining similar to that seen in glioblastomas, germinomas included signi cantly more apoptotic cells.The ratio of apoptotic ratio to MIB-1 labeling index for germinomas was 72.9 ± 36.9 (mean ± SD), a higher, statistically signi cant ratio as compared with glioblastomas (14.5 ± 11.2; P < 0.01).Furthermore, germinomas showed greater expression of BAX than did glioblastomas, while the expression of Bcl-2 was weak in both tumor types.A comparison of these apoptotic-related proteins showed that immunoreactivity for BAX was relatively higher in germinomas than in glioblastomas (P < 0.01), corresponding well to numerous apoptotic cells identi ed in germinoma tissues.These ndings may account for the prognostic difference between germinoma and glioblastoma in the face of a similar proliferation potential according to MIB-1 immunostaining.The balance between cell proliferation and death should be considered when predicting outcomes in patients with intracranial tumors.
Androgen receptors in human skin cytosol: physiological and pathological variations
Authors: IRENE MOWSZOWICZ, FRANCOISE WRIGHT, MARTINE GIACOMINI, MOHAMED RIAHI
Journal: British Journal of Dermatology (1982)

The androgen binding capacity has been measured in thé cytosol of genital and pubic skin of normal men and women and patients with disorders of androgen sensitivity. The binding capacity was highest in genital skin, but no differences were observed with age or sex. This, and the presence of a normal binding capacity in some patients with patent clinical insensitivity, suggests that the androgen receptor in human skin cytosol is not regulated by androgens.
Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target
Authors: F Spinale
Journal: Cardiovascular Research (2000)

A fundamental structural event in the progression of heart failure due to dilated cardiomyopathy is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) are an endogenous family of enzymes which contribute to matrix remodeling in several disease states. The goal of this report is to summarize recent findings regarding the myocardial MMP system and the relation to matrix remodeling in the failing heart. In both experimental and clinical forms of dilated cardiomyopathy (DCM), increased expression of certain species of myocardial MMPs have been demonstrated. Specifically, increased myocardial levels of the gelatinase, MMP-9 has been identified in both ischemic and non-ischemic forms of human DCM. In addition, stromelysin or MMP-3 increased by over four-fold in DCM. The increased levels of MMP-3 in DCM may have particular importance since this MMP degrades a wide range of extracellular proteins and can activate other MMPs. In normal human LV myocardium, the membrane type 1 MMP (MT1-MMP) was detected. These MT-MMPs may provide important sites for local MMP activation within the myocardium. In a pacing model of LV failure, MMP expression and activity increased early and were temporally associated with LV myocardial matrix remodeling. Using a broad-spectrum pharmacological MMP inhibitor in this pacing model, the degree of LV dilation was attenuated and associated with an improvement in LV pump function. Thus, increased LV myocardial MMP expression and activity are contributory factors in the LV remodeling process in cardiomyopathic disease states. Regulation of myocardial MMP expression and activity may be an important therapeutic target for controlling myocardial matrix remodeling in the setting of developing heart failure.
Home Sample Collection Tests for HIV Infection
Authors: B M Branson
Journal: JAMA (1998)

Home sample collection (HSC) tests allow persons to test themselves for human immunodeficiency virus (HIV) infection at home without medical supervision. Characterizing the use of such tests can help assess their potential effect on public health efforts to prevent and control HIV.To describe use of HIV HSC tests.Retrospective descriptive analysis from data collected by test manufacturers during 1996 and 1997.United States.Volunteer sample of consumers who used either of 2 HSC tests.Demographic and behavioral aspects of users.During the first year of availability, 174316 HIV HSC tests were submitted to the manufacturers for analysis; 0.9% of the results were positive for HIV, and 97% of all users called to learn test results. Survey responses from 70620 HIV-negative and 865 HIV-positive users revealed that most were men, white, and aged 25 to 34 years; HIV prevalence was highest among nonwhites, aged 35 to 44 years, men who have sex with men, and injection drug users. Bisexual men accounted for a large proportion of HIV-positive users. Nearly 60% of all users and 49% of those who tested HIV positive had never been tested before. Telephone counselors found that 23% of HIV-positive users already had a source of follow-up care, 65% accepted referrals, and 12% had tested themselves to evaluate the effects of antiretroviral therapy.Home sample collection tests for HIV were used by persons who were at risk for HIV and by persons who did not use other testing. Most HIV-positive users either had a source of medical care or received referrals.
Effects of serotonin on intracellular pH and contraction in vascular smooth muscle.
Authors: A M Kahn, M Bishara, E J Cragoe, J C Allen, C L Seidel, S S Navran, R G O'Neil, N A McCarty, H Shelat
Journal: Circulation Research (1992)

Serotonin (5-HT) and other contractile agonists stimulate Na(+)-H+ exchange in vascular smooth muscle. Since intracellular alkalinization, per se, stimulates contraction, we tested whether 5-HT-induced contraction was associated with an increased pHi. In HCO3(-)-free buffer (pHo 7.4), 5-HT (10(-5) M) increased pHi, as measured by 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein fluorescence, from 7.10 +/- 0.03 to 7.34 +/- 0.03 (p &lt; 0.01) in primary cultures of canine femoral artery vascular smooth muscle cells grown to confluence in the presence of 10% fetal calf serum. In HCO3- buffer (24 mM, pHo 7.4), resting pHi was 7.26 +/- 0.04 (p &lt; 0.01 versus HCO3(-)-free buffer) but was not altered by 5-HT. In both types of buffer, 5-HT stimulated 5-(N-ethyl-N-isopropyl)amiloride-sensitive 22Na+ uptake (Na(+)-H+ exchange). In HCO3- buffer and in Na(+)- and HCO3(-)-free buffer, 5-HT increased 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid-sensitive 36Cl- uptake, suggesting that 5-HT stimulated Na(+)-independent Cl(-)-HCO3- and Cl(-)-Cl- exchange activities, respectively. Individual vascular smooth muscle cells were then cultured on rat tail tendon collagen gels in the presence of 0.5% fetal calf serum, and cell length and pHi were measured by video and epifluorescence microscopy. 5-HT contracted cells in a dose-dependent, reversible, and ketanserin-inhibitable manner. These cells, like cells grown in 10% fetal calf serum, exhibited Na(+)-H+ and Na(+)-independent Cl(-)-HCO3- exchange. In HCO3- buffer, 5-HT contracted cells without an associated change in pHi. We concluded the following: 1) 5-HT stimulated both Na(+)-H+ and Na(+)-independent Cl(-)-HCO3- exchange activities in cultured vascular smooth muscle cells in parallel. 2) As a result of enhanced H+ and HCO3- efflux, pHi was not altered. 3) In the presence of HCO3-, 5-HT-induced contraction was not associated with a change in pHi.
Asthma--contrasts in care.
Authors: C Fletcher
Journal: Thorax (1978)

Asthma-contrasts in care Sir,-I congratulate you on the new appearance and new plans for Thorax.I look forward both to signed leaders and to signed correspondence.I have one criticism to make of the otherwise admirable and important leader that you wrote on "Asthma-contrasts in care" (February 1978).You refer to "epidemiologists, who have successfully publicised the dubious toxicity of our most useful remedies without pointing out the therapeutic alter- natives."This is a serious accusation to make of professional colleagues and you should be more explicit, with a reference to the "publicising" of which you consider them guilty, and with your reasons for asking epidemiologists to make therapeutic recommendations.I presume that you must be referring to the account given by Speizer and Doll of the epidemic of asthma deaths in the 1960s, which were attributed to the overuse of strong isoprenaline aerosols.They carried out no publicity but only described their findings and suggested a possible cause.The Department of Health subsequently sent out the warning note to doctors that was followed by an immediate drop in asthma deaths.Has any clinician saved as many lives of asthmatics in his whole career as were saved by this simple public health measure?Have you any other explanation of the rise and fall of asthmatic deaths in the 1960?If not, I consider it most improper to attribute doctors' resistance to prescribing newer, safer aerosols to a factual account of an epidemic and an explanation