tbuckley/cabot-search huggingface dataset:
Immunonutrition in Surgery and Critical Care
Authors: Kenneth A. Kudsk
Journal: Annual Review of Nutrition (2006)

The benefits of specialty supplemented enteral diets administered to critically ill and critically injured patients and those undergoing major surgical procedures have been documented in a number of randomized prospective studies. It is unclear which nutrient or combination of nutrients causes the beneficial effects, but there are significant reductions in infectious complications depending upon the patient populations studied. It is imperative that the data be interpreted in the context of individual patient risk since specialty formulas appear most beneficial in patients at risk of subsequent complications or in those with significant pre-existing malnutrition. Although controversy exists regarding the use of specialty supplemented enteral diets in critically ill patients, they have been administered safely with minimal risk of adverse outcome in malnourished patients and in the critically ill and critically injured.
Gelsolin and Cardiac Myocyte Apoptosis
Authors: Ryosuke Nishio, Akira Matsumori
Journal: Circulation Research (2009)

C ardiac remodeling is among the most important prob- lems in patients with heart failure. 1,2Ventricular remodeling involves numerous processes, involving molecular alterations, myocardial changes, and the abnormal geometry of the chamber.As a consequence of myocardial infarction (MI), ventricular remodeling occurs immediately as an adaptive response to maintain cardiac output. 3However, ventricular function and prognosis deteriorate with ongoing remodeling.MI triggers an inflammatory response, including cytokine activation, a cascade of intracellular signaling, and neurohormonal activation 4,5 These processes result in scar formation and myocyte loss through necrosis, apoptosis, and autophagy. 6An MI has been shown to be a prominent inducer of cardiomyocyte apoptosis, which, in turn, may contribute to progressive postinfarction remodeling, as demonstrated by recently reported animal and human studies. 7Yet, the pathophysiological mechanisms of apoptosis in cardiac myocytes remain unclear.The elucidation of the mechanisms of cardiomyocyte apoptosis may lead to an improved understanding of postinfarction remodeling and thereby possibly improve patient care.Cardiomyocytic apoptosis post-MI is induced by angiotensin II and ␤1-adrenergic stimulation, reactive oxygen species, overstretch, and nitric oxide. 8Apoptotic programmed cell death is characterized by DNA fragmentation attributable to the activation of an endogenous endonuclease.This endonuclease-mediated breakdown of DNA in apoptosis is activated through "caspase-dependent" pathways or "caspase-independent" pathways (Figure ). 9 Caspase-dependent pathways in apoptosis have 3 major cascades.One, the endoplasmic reticulum stress induced by extracellular or intracellular death signals activates caspase-12.Two, the mitochondrial stress induced by death signals stimulates the release of cytochrome c, resulting in the activation of caspase-9.Three, the death ligand binding induces death receptors to recruit FADD (Fas-associated death domain) and/or TRADD (tumor necrosis factor receptor-I-associated death domain), and caspase-8 is activated.These 3 cascades induce caspase-3 activation, leading to the cleavage of downstream targets of caspase-3, including the ICAD (inhibitor of CAD [caspase-3-activated DNase]) and PARP (poly[ADP-ribose] polymerase).Finally, endonuclease is activated, which induces DNA fragmentation.Caspase-independent pathways include the p38 mitogenactivated protein kinase signaling cascade and apoptosisinducing factor. 10Apoptosis is also regulated by a number of factors.Bax and Bid stimulate apoptogenic release, whereas activation of the pathway is prevented by the antiapoptotic proteins, including Bcl-2 and Akt.
Patient-reported outcomes of psoriasis improvement with etanercept therapy: results of a randomized phase III trial
Authors: G.G. Krueger, R.G. Langley, A.Y. Finlay, C.E.M. Griffiths, J.M. Woolley, D. Lalla, A. Jahreis
Journal: British Journal of Dermatology (2005)

Etanercept, a soluble tumour necrosis factor receptor, lessens the severity of psoriasis as measured by physician-reported clinical outcomes. Equally important is the patient perspective on the effect of etanercept therapy on daily life.To assess patient-reported outcomes (PROs) in patients with psoriasis receiving etanercept therapy.In this multinational, randomized, phase III trial, patients with psoriasis received placebo (n = 193), etanercept 50 mg per week (n = 196) or etanercept 50 mg twice weekly (n = 194) during the initial 12-week, double-blind period. Thereafter, all patients received open-label etanercept (50 mg per week). The following PROs were assessed: Dermatology Life Quality Index (DLQI), Short Form-36 Health Survey (SF-36), patient rating of pruritus, and patient global assessment of psoriasis.At week 12, DLQI total score improved by 65-70% in patients receiving etanercept compared with 6% in patients receiving placebo (P < 0.0001), and improvement in DLQI was clinically meaningful (> or = 5-point improvement or 0 score) for 72-77% of patients receiving etanercept therapy. All DLQI and SF-36 subscales and the SF-36 physical and mental component summary scores demonstrated significantly greater improvement with etanercept therapy than with placebo, illustrating that etanercept benefits patients with psoriasis across multiple domains that contribute to health-related quality of life. With etanercept therapy, distributions of patient ratings of pruritus and global assessment of disease shifted from moderate to severe (baseline) to minimal to good (week 12). Etanercept-induced benefits of PROs were maintained for patients who reduced their dose after 12 weeks.Etanercept therapy improves PROs in patients with psoriasis and makes a meaningful difference to their lives. These results support the efficacy profile of physician-reported clinical measures while providing a more complete understanding of the benefits experienced by patients with psoriasis treated with etanercept.
The expression of p38, ERK1 and Bax proteins has increased during the treatment of newly diagnosed acute promyelocytic leukemia with arsenic trioxide
Authors: A. Mandegary, R. Hosseini, S.H. Ghaffari, K. Alimoghaddam, S. Rostami, A. Ghavamzadeh, M.H. Ghahremani
Journal: Annals of Oncology (2010)
* IS Triticum monococcum a coeliac-safe wheat? A phase II, single blind, cross-over study on the effect of acute administration on intestinal permeability
Authors: B. Zanini, B. Petroboni, T. Not, N. Pogna, A. Lanzini
Journal: Gut (2011)

<h3>Introduction</h3> Atoxic, widely available, unexpensive cereals retaining dough properties for production of palatable baked goods for gluten free diet (GFD) of CD patients are actively researched. <i>Triticum monococcum</i> ssp monococcum (Tm) is an ancient wheat with virtually absent toxicity in vitro1 and ex vivo.2 The aim of our study was to investigate the ‘in vivo’ effect of a single dose of gluten of Tm (cultivar Monlis), in patients with CD on GFD. <h3>Methods</h3> We performed a phase II, single blind, cross-over study in CD patients on GFD for at least 12 months. Patient were randomly assigned to receive at day 0, 14 and 28 a single 2.5 g dose of rice, Tm and <i>Triticum aestivum</i> (Ta) flour mixed with gluten-free pudding. The primary end-point of the study was the change in intestinal permeability as assessed by changes of urinary lactulose/rhamnose ratio (L/R ratio) measured by HPLC. We also assessed the occurrence of adverse events graded for intensity and duration (WHO scale). Variables expressed as mean ± SEM; paired t test and χ<sup>2</sup> test used as appropriate. <h3>Results</h3> 12 CD patients were enrolled in the study. The urinary L/R ratio was 0.058 ± 0.03 with rice flour, 0.048 ± 0.02 with Tm and 0.063 ± 0.015 with Ta. Differences did not reach statistical level of significance. Gastrointestinal adverse events were 11, 8 and 31 with rice, Tm and Ta, respectively. Eight gastrointestinal events occurred during Tm administration, a value similar to that observed with rice (n = 11). In all cases events were graded as ‘mild’ or ‘moderate’. By contrast 31 adverse events were reported during Ta administration, a value significantly higher than that observed with Tm and with rice (table 1). In four cases events during Ta administration were graded ‘severe’ or ‘disabling’. Among extraintestinal adverse events, headache was reported in 13 cases and malaise in 3 cases, equally distributed among the 3 flours. <h3>Conclusion</h3> Administration of a single 2.5 g dose of Tm to CD patients did not cause changes in urinary L/R ratio relative to that observed following administration of rice, the non toxic reference flour. Tm was well tolerated by all patients thus providing the rationale for further investigation on the safety of this cereal for CD patients. By contrast Ta caused a significant number of gastrointestinal side effects that in four cases were severe, but did not alter significantly urinary L/R ratio indicating that this method is not sensitive enough for acute toxicity studies.
Medical thoracoscopy: hormone receptor content in pleural metastases due to breast cancer
Authors: C. Schwarz
Journal: European Respiratory Journal (2004)

Pleural metastases are common in the course of breast cancer, but, to date, the role of oestrogen receptor (OR) and progesterone receptor (PgR) content in metastatic tissue has been poorly evaluated. A series of 50 consecutive patients with a history of breast cancer (median age 64 yrs, range 40-86 yrs), which presented with pleural effusion and therefore underwent medical thoracoscopy, was analysed. Metastatic pleural involvement was histologically confirmed in all patients. The hormone receptor status of the pleural metastases was investigated using the immunohistochemical method in 49 and the biochemical method in 31 cases. The immunohistochemical test was performed using monoclonal antibodies. Biochemical analysis was performed on specimens quick-frozen in liquid nitrogen. OR and PgR were measured with the dextran-coated charcoal assay and Scatchard analysis. Immunohistochemical analysis yielded 29 OR-positive and 25 PgR-positive cases and biochemical analysis yielded 16 OR-positive and four PgR-positive cases, sometimes discrepant to hormone status of the primary breast cancer. Using a semiquantitative immunoreactive score, there was a significant association between receptor positivity and survival, but only for PgR positivity. Immunohistochemical and biochemical detection of hormone receptors (oestrogen and progesterone) in pleural metastases of breast cancer is feasible based on medical thoracoscopy as the method of choice, by which sufficient specimens may be obtained. The receptor status may enable a decision on antihormonal treatment. Whether a positive receptor status in pleural metastatic tissue is associated with a better prognosis remains to be confirmed.
Breast Cancer Antiestrogen Resistance-3 Expression Regulates Breast Cancer Cell Migration through Promotion of p130Cas Membrane Localization and Membrane Ruffling
Authors: Randy S. Schrecengost, Rebecca B. Riggins, Keena S. Thomas, Michael S. Guerrero, Amy H. Bouton
Journal: Cancer Research (2007)

Abstract Antiestrogens such as tamoxifen are widely used in the clinic to treat estrogen receptor–positive breast tumors. Resistance to tamoxifen can occur either de novo or develop over time in a large proportion of these tumors. Additionally, resistance is associated with enhanced motility and invasiveness in vitro. One molecule that has been implicated in tamoxifen resistance, breast cancer antiestrogen resistance-3 (BCAR3), has also been shown to regulate migration of fibroblasts. In this study, we investigated the role of BCAR3 in breast cancer cell migration and invasion. We found that BCAR3 was highly expressed in multiple breast cancer cell lines, where it associated with another protein, p130Cas (also known as breast cancer antiestrogen resistance-1; BCAR1), that plays a role in both tamoxifen resistance and cell motility. In cells with relatively low migratory potential, BCAR3 overexpression resulted in enhanced migration and colocalization with p130Cas at the cell membrane. Conversely, BCAR3 depletion from more aggressive breast cancer cell lines inhibited migration and invasion. This coincided with a relocalization of p130Cas away from the cell membrane and an attenuated response to epidermal growth factor stimulation that was characterized by a loss of membrane ruffles, decreased migration toward EGF, and disruption of p130Cas/Crk complexes. Based on these data, we propose that the spatial and temporal regulation of BCAR3/p130Cas interactions within the cell is important for controlling breast cancer cell motility. [Cancer Res 2007;67(13):6174–82]
Blockade of Wnt Signaling Inhibits Angiogenesis and Tumor Growth in Hepatocellular Carcinoma
Authors: Jie Hu, Aiwen Dong, Veronica Fernandez-Ruiz, Juanjuan Shan, Milosz Kawa, Eduardo Martínez-Ansó, Jesus Prieto, Cheng Qian
Journal: Cancer Research (2009)

Aberrant activation of Wnt signaling plays an important role in hepatocarcinogenesis. In addition to direct effects on tumor cells, Wnt signaling might be involved in the organization of tumor microenvironment. In this study, we have explored whether Wnt signaling blockade by exogenous expression of Wnt antagonists could inhibit tumor angiogenesis and control tumor growth. Human Wnt inhibitory factor 1 (WIF1) and secreted frizzled-related protein 1 (sFRP1) were each fused with Fc fragment of human IgG1 to construct fusion proteins WIF1-Fc and sFRP1-Fc. The recombinant adenoviral vectors carrying WIF1-Fc and sFRP1-Fc driven by cytomegalovirus promoter were constructed. Ad-WIF1-Fc or Ad-sFRP1-Fc induced the expression and correct conformation of WIF1-Fc and sFRP1-Fc fusion proteins. These molecules caused down-regulation of E2F1, cyclin D1, and c-myc and promoted cell apoptosis in hepatocellular carcinoma cells. Treatment of established hepatocellular carcinoma tumors with Ad-WIF1-Fc and/or Ad-sFRP1-Fc resulted in significant inhibition of tumor growth and prolonged animal survival. The antineoplastic effect was associated with increased apoptosis of tumor cells, reduced microvessel density, and decreased expression of vascular endothelial growth factor and stromal cell-derived factor-1. Tube formation and migration of human microvascular endothelial cells and mouse endothelial progenitor cells (EPC) were significantly inhibited by both WIF1-Fc and sFRP1-Fc. In addition, these molecules blocked EPC differentiation and caused EPC apoptosis. Our data indicate that Wnt antagonists WIF1-Fc and sFRP1-Fc inhibit Wnt signaling and exert potent antitumor activity by increasing the apoptosis rate in tumor cells and by impairing tumor vascularization.
Patterns of Relapse in Patients With Clinical Stage I Testicular Cancer Managed With Active Surveillance
Authors: Christian Kollmannsberger, Torgrim Tandstad, Philippe L. Bedard, Gabriella Cohn-Cedermark, Peter W. Chung, Michael A. Jewett, Tom Powles, Padraig R. Warde, Siamak Daneshmand, Andrew Protheroe, Scott Tyldesley, Peter C. Black, Kim Chi, Alan I. So, Malcom J. Moore, Craig R. Nichols
Journal: Journal of Clinical Oncology (2014)

To evaluate the performance of active surveillance as a management strategy in broad populations and to inform the development of surveillance schedules by individual patient data regarding timing and type of relapse.Retrospective study including data from 2,483 clinical stage I (CSI) patients, 1,139 CSI nonseminoma and 1,344 CSI seminoma managed with active surveillance, with the majority treated between 1998 and 2010. Clinical outcomes including relapse and death, time distribution, extent of relapse and method of relapse detection observed on active surveillance were recorded.Relapse occurred in 221 (19%) CSI-nonseminoma and 173 (13%) CSI-seminoma patients. Median time to relapse was 4 months (range, 2-61 months), 8 months (range, 2-77 months) and 14 months (range, 2-84 months) for lymphovascular invasion-positive CSI nonseminoma, lymphovascular invasion-negative CSI nonseminoma and CSI seminoma. Most relapses were observed within the first 2 years/3 years after orchiectomy for CSI nonseminoma (90%)/CSI seminoma (92%). Relapses were detected by computed tomography scan/tumor-markers in 87%/3% of seminoma recurrences, in 48%/38% of lymphovascular invasion-negative and 41%/61% of lymphovascular invasion-positive patients, respectively. 90% of CSI-nonseminoma and 99% of CSI-seminoma relapses exhibited International Germ Cell Collaborative Group good-risk features. Three patients with CSI nonseminoma died of disease (0.3%). One patient with CSI seminoma and two patients with CSI nonseminoma died because of treatment-related events. Overall, advanced disease was seen in both early- and late-relapse patients. All late recurrences were cured with standard therapy. Five-year disease-specific survival was 99.7% (95% CI, 99.24% to 99.93%).Active surveillance for CSI testis cancer leads to excellent outcomes. The vast majority of relapses occur within 2 years of orchiectomy for CSI nonseminoma and within 3 years for CSI seminoma. Late and advanced stage relapse are rarely seen. These data may inform further refinement of rationally designed surveillance schedules.
Marginal dietary zinc deficiency in vivo induces vascular smooth muscle cell apoptosis in large arteries
Authors: Keith Allen-Redpath, Ou Ou, John H. Beattie, In-Sook Kwun, Jorg Feldmann, Graeme F. Nixon
Journal: Cardiovascular Research (2013)

Dietary zinc deficiency has been associated with the development of atherosclerosis although the effects on vascular smooth muscle cells (VSMCs), important in maintaining atherosclerotic plaque integrity, are unknown. The main aim of this study was to elucidate the effect of a zinc-deficient environment on VSMCs using an in vivo model. Rats were maintained for 2 weeks on a marginally zinc-deficient diet which resulted in a significant reduction in plasma zinc levels. Large arteries from zinc-deficient rats had significantly increased apoptosis within the VSMC layers compared with arteries from rats on a zinc-adequate diet. This apoptosis occurred in parallel with a known apoptotic pathway, namely dephosphorylation of the pro-apoptotic protein Bcl-2-associated death promoter protein (BAD). Activation of extracellular signal-regulated kinase (ERK)1/2, which maintains BAD phosphorylation as a pro-survival mechanism, was decreased in arteries from zinc-deficient rats. The mechanisms of this in vivo effect were investigated in vitro. Cultured rat VSMCs incubated with plasma from zinc-deficient rats similarly resulted in increased apoptosis in parallel with BAD dephosphorylation and decreased ERK1/2 activation. Further related apoptotic mechanisms induced by plasma from zinc-deficient rats involved a prolonged rise in [Ca2+]i leading to subsequent activation of the phosphatase calcineurin. Calcineurin activation was required to dephosphorylate BAD. In addition, an increase in oxidative stress contributed to the apoptotic effect induced by plasma from zinc-deficient rats. In conclusion, a marginally zinc-deficient diet is pro-apoptotic for VSMCs and this may contribute to cardiovascular disease.
The thymic medulla: a unique microenvironment for intercellular self-antigen transfer
Authors: Christian Koble, Bruno Kyewski
Journal: The Journal of Experimental Medicine (2009)

Central tolerance is shaped by the array of self-antigens expressed and presented by various types of thymic antigen-presenting cells (APCs). Depending on the overall signal quality and/or quantity delivered in these interactions, self-reactive thymocytes either apoptose or commit to the T regulatory cell lineage. The cellular and molecular complexity underlying these events has only recently been appreciated. We analyzed the ex vivo presentation of ubiquitous or tissue-restricted self-antigens by medullary thymic epithelial cells (mTECs) and thymic dendritic cells (DCs), the two major APC types present in the medulla. We found that the ubiquitously expressed nuclear neo-self-antigen ovalbumin (OVA) was efficiently presented via major histocompatibility complex class II by mTECs and thymic DCs. However, presentation by DCs was highly dependent on antigen expression by TECs, and hemopoietic cells did not substitute for this antigen source. Accordingly, efficient deletion of OVA-specific T cells correlated with OVA expression by TECs. Notably, OVA was only presented by thymic but not peripheral DCs. We further demonstrate that thymic DCs are constitutively provided in situ with cytosolic as well as membrane-bound mTEC-derived proteins. The subset of DCs displaying transferred proteins was enriched in activated DCs, with these cells being most efficient in presenting TEC-derived antigens. These data provide evidence for a unique, constitutive, and unidirectional transfer of self-antigens within the thymic microenvironment, thus broadening the cellular base for tolerance induction toward promiscuously expressed tissue antigens.
High Perfusion Pressure Accelerates Renal Injury in Salt-Sensitive Hypertension
Authors: Takefumi Mori, Aaron Polichnowski, Padden Glocka, Mary Kaldunski, Yusuke Ohsaki, Mingyu Liang, Allen W. Cowley
Journal: Journal of the American Society of Nephrology (2008)

Renal injury in the Dahl salt-sensitive rat mimics human salt-sensitive forms of hypertension that are particularly prevalent in black individuals, but the mechanisms that lead to the development of this injury are incompletely understood. We studied the impact of renal perfusion pressure (RPP) on the development of renal injury in this model. During the development of salt-induced hypertension over 2 wk, the RPP to the left kidney was maintained at control levels (125 +/- 2 mmHg) by continuous servocontrol inflation of an aortic balloon implanted between the renal arteries; during the same period, the RPP to the right kidney rose to 164 +/- 8 mmHg. After 2 wk of a 4% salt diet, DNA microarray and real-time PCR identified genes related to fibrosis and epithelial-to-mesenchymal transition in the kidneys exposed to hypertension. The increased RPP to the right kidney accounted for differences in renal injury between the two kidneys, measured by percentage of injured cortical and juxtamedullary glomeruli, quantified proteinaceous casts, number of ED-1-positive cells per glomerular tuft area, and interstitial fibrosis. Interlobular arteriolar injury was not increased in the kidney exposed to elevated pressure but was reduced in the control kidney. We conclude that elevations of RPP contribute significantly to the fibrosis and epithelial-to-mesenchymal transition found in the early phases of hypertension in the salt-sensitive rat.