tbuckley/cabot-search huggingface dataset:
Sensitization of Hepatic Lipocytes by High–Fat Diet to Stimulatory Effects of Kupffer Cell–Derived Factors: Implication in Alcoholic Liver Fibrogenesis
Authors: Masaki Matsuoka, Martin Y. Zhang, Hidekazu Tsukamoto
Journal: Hepatology (1990)

A high-fat diet has previously been shown to be a key factor for induction of alcoholic liver fibrosis in a rat model of intragastric ethanol infusion. To explore a possible mechanism by which the high-fat diet facilitated such an effect, the present study examined how the high-fat diet with or without ethanol affected proliferation and collagen formation of hepatic lipocytes, perisinusoidal cells that have been suggested to be involved in liver fibrogenesis. We also evaluated effects of the high-fat diet on the sensitivity of lipocytes to stimulatory effects of Kupffer cell-derived factors. Intragastric infusion of ethanol and the high-fat diet for 9 to 10 wk resulted in induction of a varying degree of perivenular fibrosis in 75% of animals. Lipocytes isolated from these animals (A) had significantly higher basal rates of proliferation (three to four times) and collagen formation (1.5 times) than those isolated from control animals, which were isocalorically infused with the high-fat diet (H) or the low-fat diet (L), or those that were fed chow ad libitum (C). Lipocytes from the H group exhibited significantly higher relative production of collagen than those from the L group, but their net collagen production was not enhanced. The dialyzed Kupffer cell-conditioned medium from the A group markedly stimulated proliferation and collagen formation of lipocytes from the groups given the high-fat diet (A and H) but had minimal effects on those from the L and C groups, establishing the order of decreasing lipocyte sensitivity from the A, H, L to C group. Similarly, lipocytes from the H and A groups exhibited a more profound responsiveness to the stimulatory effect of transforming growth factor beta 1 on collagen formation. These results demonstrate (a) that lipocytes isolated from the rats given the high-fat diet and ethanol are markedly proliferative and produce more collagen; and (b) that the Kupffer cells derived from these animals release factors that stimulate proliferation and collagen formation of lipocytes and (c) that the high-fat diet sensitizes lipocytes for stimulatory effects of the Kupffer cell-derived factors and transforming growth factor beta 1.
Final Results of the 94–01 French Head and Neck Oncology and Radiotherapy Group Randomized Trial Comparing Radiotherapy Alone With Concomitant Radiochemotherapy in Advanced-Stage Oropharynx Carcinoma
Authors: Fabrice Denis, Pascal Garaud, Etienne Bardet, Marc Alfonsi, Christian Sire, Thierry Germain, Philippe Bergerot, Beatrix Rhein, Jacques Tortochaux, Gilles Calais
Journal: Journal of Clinical Oncology (2003)

We report the 5-year survival and late toxicity results of a randomized clinical trial, which showed a 3-year improvement in overall survival and locoregional control of stage III or IV oropharynx carcinoma, using concomitant radiochemotherapy (arm B), compared with standard radiotherapy (arm A).A total of 226 patients were entered onto a phase III multicenter randomized trial comparing radiotherapy alone (70 Gy in 35 fractions; arm A) with concomitant radiochemotherapy (70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and fluorouracil; arm B). Prognostic factors were evaluated by univariate and multivariate analysis. Five-year late toxicity was evaluated using National Cancer Institute Common Toxicity Criteria for neurological toxicity, hearing, taste, mandibula, and teeth damage, and Radiation Therapy Oncology Group toxicity criteria for skin, salivary gland, and mucosa.Five-year overall survival, specific disease-free survival, and locoregional control rates were 22% and 16% (log-rank P =.05), 27% and 15% (P =.01), and 48% and 25% (P =.002), in arm B and arm A, respectively. Stage IV, hemoglobin level lower than 125 g/L, and standard treatment were independent prognostic factors of short survival and locoregional failure by univariate and multivariate analysis. One or more grade 3 to 4 complications occurred in 56% of the patients in arm B, compared with 30% in arm A (P was not significant).Concomitant radiochemotherapy improved overall survival and locoregional control rates and does not statistically increase severe late morbidity. Anemia was the most important prognostic factor for survival in both arms.
Role of biological therapy for inflammatory bowel disease in developing countries
Authors: Naila Arebi
Journal: Gut (2012)

I would like to comment on the interesting manuscript by Rogler et al .1 The authors highlight the rising incidence of Inflammatory Bowel Disease (IBD) in the developing world and express concern how such countries might finance the escalation of Biological therapy. They describe the barriers to access of these drugs, namely lack of infrastructure for financing and monitoring drug treatment. In their discussion, they explore how best to treat severe IBD in this context and argue that transfer of experience of anti-tumour necrosis factor agents from experts in the West to developing countries offers a means of increasing access to …
Hemodynamic and microvascular responses in the hindquarters during the development of renal hypertension in rats. Evidence for the involvement of an autoregulatory component.
Authors: G A Meininger, V M Lubrano, H J Granger
Journal: Circulation Research (1984)

Microvascular responses in the cremaster muscle were compared with changes in mean arterial pressure and hindquarters vascular resistance during the development (initial 3 hours) of two-kidney one-clip renal hypertension in rats, to examine the possibility that an autoregulatory mechanism may contribute to the development of hypertension. Rats were anesthetized with urethane and chloralose and implanted with Doppler flow probes on the renal artery and abdominal aorta. Acute hypertension was produced by inflation of a balloon occluder on the renal artery to reduce renal flow by 50%. The cremaster muscle was isolated with intact innervation and circulation for measurement of microvessel diameters. To determine whether increased pressure contributed to the changes in hindquarters vascular resistance or in microvascular diameters during acute hypertension, arterial pressure was prevented from increasing in the hindquarters region after renal artery stenosis by servo-controlled inflation of a balloon occluder around the sacral aorta to maintain hindquarters pressure at normotensive levels. In hypertensive rats with unprotected hindquarters, mean arterial pressure and hindquarters vascular resistance increased 26% and 20%, respectively, after renal artery stenosis. In comparison, hypertensive rats with protected hindquarters exhibited a similar increase in mean arterial pressure, but hindquarters vascular resistance was significantly reduced compared to that in hypertensive rats with unprotected hindquarters. In the cremaster microcirculation, vasoconstriction was observed only in the small third- (mean +/- SEM: 29 +/- 4 micron) and fourth- (12 +/- 2 micron) order arterioles in rats with unprotected hindquarters. In general, microvessel diameters in rats with protected hindquarters that had lower hindquarters vascular resistance than those with unprotected hindquarters were larger for the second- (82 +/- 5 micron), third-, and fourth-order arterioles, suggesting less vasoconstrictor tone. Our data indicate that the increase in hindquarters resistance during the development of renal hypertension is, in part, dependent on the presence of a pressure-dependent autoregulatory process.
T<scp>HE</scp> E<scp>XTRACELLULAR</scp> Ca<sup>2+</sup>-S<scp>ENSING</scp> R<scp>ECEPTOR</scp>: Central Mediator of Systemic Calcium Homeostasis
Authors: Edward M. Brown
Journal: Annual Review of Nutrition (2000)

▪ Abstract The cloning of the G protein-coupled, extracellular calcium (Ca 2+ o )-sensing receptor (CaR) has identified a central mediator of the mechanism governing systemic Ca 2+ o homeostasis. This system enables organisms to adapt successfully to wide variations in dietary Ca 2+ o intake while maintaining near constancy of Ca 2+ o . Whereas discussions of Ca 2+ o homeostasis have generally focused on the key role of Ca 2+ o -elicited changes in parathyroid hormone secretion, the presence of the CaRs in effector tissues of this system enables direct regulation of processes (e.g. renal tubular Ca 2+ reabsorption and possibly bone formation and resorption) that add additional layers of homeostatic control. As we understand more about how the CaR regulates these tissues, we may find that it participates in other processes relevant to mineral ion homeostasis, including the control of the 1-hydroxylation and activation of vitamin D 3 or reabsorption of phosphate in the renal proximal tubule. Regardless, the remarkable sensitivity of the CaR to small changes in Ca 2+ o allows adjustments in the response of the Ca 2+ o homeostatic system to increases or decreases in the intake of dietary Ca 2+ , for instance, that cause barely detectable alterations in Ca 2+ o . Furthermore, the CaR likely participates in coordinating interactions among several different homeostatic control systems (including those for water, Mg 2+ o , Na + , extracellular volume, and/or blood pressure), despite the fact that these systems are often considered to function largely independently of mineral ion metabolism.
Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions
Authors: E Choy, N Sattar
Journal: Annals of the Rheumatic Diseases (2009)

In severe untreated rheumatoid arthritis (RA), reductions in high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol and total cholesterol have been noted; this is in line with findings in other pathologies/conditions associated with inflammation or infection, such as sepsis, cancer, trauma or the postoperative period. Although the precise mechanisms remain to be established, cytokine-induced activation of the reticuloendothelial system is potentially critical to such changes. Consequently, dampening of inflammation in severe RA—as occurs with several biologics—may lead to increases, not only in high-density lipoprotein-cholesterol, but also with other lipid moieties, including total and low-density lipoprotein-cholesterol and, perhaps, triglycerides. This concept is consistent with findings following antitumour necrosis factor treatment and interleukin-6 receptor inhibition in patients with RA. At the same time, it is increasingly apparent that potent dampening of inflammation, however achieved, broadly reduces the risk of cardiovascular disease in RA. Therefore, changes in lipid profiles, particularly increases in cholesterol and triglycerides that occur with treatments for severe inflammation, may not represent increased cardiovascular risk as in the usual understanding of lipid-level elevations in individuals without significant inflammation. Rather, changes in lipid levels, in part or largely, may represent a predictable response to attenuation of inflammation. These observations are increasingly important clinically and should aid in the understanding and interpretation of lipid changes under inflammatory conditions, as well as in the context of potent anti-inflammatory interventions.
Interdependency of β-Adrenergic Receptors and CFTR in Regulation of Alveolar Active Na <sup>+</sup> Transport
Authors: Gökhan M. Mutlu, Yochai Adir, Mohammed Jameel, Alexander T. Akhmedov, Lynn Welch, Vidas Dumasius, Fan Jing Meng, Joseph Zabner, Craig Koenig, Erin Rachel Lewis, Rajesh Balagani, Geri Traver, Jacob I. Sznajder, Phillip Factor
Journal: Circulation Research (2005)

β-Adrenergic receptors (βAR) regulate active Na + transport in the alveolar epithelium and accelerate clearance of excess airspace fluid. Accumulating data indicates that the cystic fibrosis transmembrane conductance regulator (CFTR) is important for upregulation of the active ion transport that is needed to maintain alveolar fluid homeostasis during pulmonary edema. We hypothesized that βAR regulation of alveolar active transport may be mediated via a CFTR dependent pathway. To test this hypothesis we used a recombinant adenovirus that expresses a human CFTR cDNA (adCFTR) to increase CFTR function in the alveolar epithelium of normal rats and mice. Alveolar fluid clearance (AFC), an index of alveolar active Na + transport, was 92% greater in CFTR overexpressing lungs than controls. Addition of the Cl − channel blockers NPPB, glibenclamide, or bumetanide and experiments using Cl − free alveolar instillate solutions indicate that the accelerated AFC in this model is due to increased Cl − channel function. Conversely, CFTR overexpression in mice with no β 1 - or β 2 -adrenergic receptors had no effect on AFC. Overexpression of a human β 2 AR in the alveolar epithelium significantly increased AFC in normal mice but had no effect in mice with a non-functional human CFTR gene (Δφ508 mutation). These studies indicate that upregulation of alveolar CFTR function speeds clearance of excess fluid from the airspace and that CFTRs effect on active Na + transport requires the βAR. These studies reveal a previously undetected interdependency between CFTR and βAR that is essential for upregulation of active Na + transport and fluid clearance in the alveolus.
A preoperative diagnostic test that distinguishes benign from malignant thyroid carcinoma based on gene expression
Authors: Janete M. Cerutti, Rosana Delcelo, Marcelo João Amadei, Claudia Nakabashi, Rui M.B. Maciel, Bercedis Peterson, Jennifer Shoemaker, Gregory J. Riggins
Journal: Journal of Clinical Investigation (2004)

Accurate diagnosis of thyroid tumors is challenging. A particular problem is distinguishing between follicular thyroid carcinoma (FTC) and benign follicular thyroid adenoma (FTA), where histology of fine-needle aspirates is not conclusive. It is often necessary to remove healthy thyroid to rule out carcinoma. In order to find markers to improve diagnosis, we quantified gene transcript expression from FTC, FTA, and normal thyroid, revealing 73 differentially expressed transcripts (P ≤ 0.0001). Using an independent set of 23 FTCs, FTAs, and matched normal thyroids, 17 genes with large expression differences were tested by real-time RT-PCR. Four genes (DDIT3, ARG2, ITM1, and C1orf24) differed between the two classes FTC and FTA, and a linear combination of expression levels distinguished FTC from FTA with an estimated predictive accuracy of 0.83. Furthermore, immunohistochemistry for DDIT3 and ARG2 showed consistent staining for carcinoma in an independent set 59 follicular tumors (estimated concordance, 0.76; 95% confidence interval, [0.59, 0.93]). A simple test based on a combination of these markers might improve preoperative diagnosis of thyroid nodules, allowing better treatment decisions and reducing long-term health costs.
Selective and strain-specific NFAT4 activation by the <i>Toxoplasma gondii</i> polymorphic dense granule protein GRA6
Authors: Ji Su Ma, Miwa Sasai, Jun Ohshima, Youngae Lee, Hironori Bando, Kiyoshi Takeda, Masahiro Yamamoto
Journal: The Journal of Experimental Medicine (2014)

Toxoplasma gondii infection results in co-option and subversion of host cellular signaling pathways. This process involves discharge of T. gondii effector molecules from parasite secretory organelles such as rhoptries and dense granules. We report that the T. gondii polymorphic dense granule protein GRA6 regulates activation of the host transcription factor nuclear factor of activated T cells 4 (NFAT4). GRA6 overexpression robustly and selectively activated NFAT4 via calcium modulating ligand (CAMLG). Infection with wild-type (WT) but not GRA6-deficient parasites induced NFAT4 activation. Moreover, GRA6-deficient parasites failed to exhibit full virulence in local infection, and the treatment of WT mice with an NFAT inhibitor mitigated virulence of WT parasites. Notably, NFAT4-deficient mice displayed prolonged survival, decreased recruitment of CD11b+ Ly6G+ cells to the site of infection, and impaired expression of chemokines such as Cxcl2 and Ccl2. In addition, infection with type I parasites culminated in significantly higher NFAT4 activation than type II parasites due to a polymorphism in the C terminus of GRA6. Collectively, our data suggest that GRA6-dependent NFAT4 activation is required for T. gondii manipulation of host immune responses to maximize the parasite virulence in a strain-dependent manner.
Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells
Authors: Chenggang Li, Po-Shun Lee, Yang Sun, Xiaoxiao Gu, Erik Zhang, Yanan Guo, Chin-Lee Wu, Neil Auricchio, Carmen Priolo, Jing Li, Alfredo Csibi, Andrey Parkhitko, Tasha Morrison, Anna Planaguma, Shamsah Kazani, Elliot Israel, Kai-Feng Xu, Elizabeth Petri Henske, John Blenis, Bruce D. Levy, David Kwiatkowski, Jane J. Yu
Journal: The Journal of Experimental Medicine (2014)

Lymphangioleiomyomatosis (LAM) is a progressive neoplastic disorder that leads to lung destruction and respiratory failure primarily in women. LAM is typically caused by tuberous sclerosis complex 2 (TSC2) mutations resulting in mTORC1 activation in proliferative smooth muscle–like cells in the lung. The female predominance of LAM suggests that estradiol contributes to disease development. Metabolomic profiling identified an estradiol-enhanced prostaglandin biosynthesis signature in Tsc2-deficient (TSC−) cells, both in vitro and in vivo. Estradiol increased the expression of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostaglandin biosynthesis, which was also increased at baseline in TSC-deficient cells and was not affected by rapamycin treatment. However, both Torin 1 treatment and Rictor knockdown led to reduced COX-2 expression and phospho-Akt-S473. Prostaglandin production was also increased in TSC-deficient cells. In preclinical models, both Celecoxib and aspirin reduced tumor development. LAM patients had significantly higher serum prostaglandin levels than healthy women. 15-epi-lipoxin-A4 was identified in exhaled breath condensate from LAM subjects and was increased by aspirin treatment, indicative of functional COX-2 expression in the LAM airway. In vitro, 15-epi-lipoxin-A4 reduced the proliferation of LAM patient–derived cells in a dose-dependent manner. Targeting COX-2 and prostaglandin pathways may have therapeutic value in LAM and TSC-related diseases, and possibly in other conditions associated with mTOR hyperactivation.
Do statins reduce the risk of myocardial infarction in patients with heart failure? A pooled individual‐level reanalysis of CORONA and GISSI‐HF
Authors: Matthew J. Feinstein, Pardeep Jhund, Joseph Kang, Hongyan Ning, Aldo Maggioni, John Wikstrand, John Kjekshus, Luigi Tavazzi, John McMurray, Donald M. Lloyd‐Jones
Journal: European Journal of Heart Failure (2015)
Incidence and predictive factors of lower respiratory tract infections among the very elderly in the general population. The Leiden 85-plus Study
Authors: A Sliedrecht, W P J den Elzen, T J M Verheij, R G J Westendorp, J Gussekloo
Journal: Thorax (2008)

To target preventive strategies in old age, which of the very elderly are predisposed to developing lower respiratory tract infections was investigated.Prospective observational follow-up study.General population.Unselected cohort of 587 participants aged 85 years in Leiden, The Netherlands.As reported in the literature, predictive factors were selected and assessed at baseline. During a 5 year follow-up period, information on the development of lower respiratory tract infections was obtained from general practitioners or nursing home physicians. Associations between predictive factors were analysed with Cox regression, and population attributable risks were calculated.The incidence of lower respiratory tract infections among persons aged 85-90 years was 94 (95% CI 80-108) per 1000 person years. After multivariate analysis, history of chronic obstructive pulmonary disease (COPD), smoking, oral glucocorticosteroid use, severe cognitive impairment, history of stroke and declined functional status remained independently associated with the occurrence of lower respiratory tract infections. Smoking was the greatest contributor with a population attributable risk of 32%.In the very old, smoking, COPD, stroke and declined functional status were associated with the occurrence of lower respiratory tract infections and provide a means of targeting patients at risk of severe health complications.
Sequence Determinants of Quaternary Structure in Lumazine Synthase
Authors: María Silvina Fornasari, Diego A. Laplagne, Nicolás Frankel, Ana A. Cauerhff, Fernando A. Goldbaum, Julián Echave
Journal: Molecular Biology and Evolution (2004)

Riboflavin, an essential cofactor for all organisms, is biosynthesized in plants, fungi and microorganisms. The penultimate step in the pathway is catalyzed by the enzyme lumazine synthase. One of the most distinctive characteristics of this enzyme is that it is found in different species in two different quaternary structures, pentameric and icosahedral, built from practically the same structural monomeric unit. In fact, the icosahedral structure is best described as a capsid of twelve pentamers. Despite this noticeable difference, the active sites are virtually identical in all structurally studied members. Furthermore, the main regions involved in the catalysis are located at the interface between adjacent subunits in the pentamer. Thus, the two quaternary forms of the enzyme must meet similar structural requirements to achieve their function, but, at the same time, they should differ in the sequence traits responsible for the different quaternary structures observed.
Arginine methylation of the B cell antigen receptor promotes differentiation
Authors: Simona Infantino, Beate Benz, Tanja Waldmann, Manfred Jung, Robert Schneider, Michael Reth
Journal: The Journal of Experimental Medicine (2010)

Signals processed through the B cell antigen receptor (BCR) control both the proliferation and differentiation of B lymphocytes. How these different signaling modes are established at the BCR is poorly understood. We show that a conserved arginine in the tail sequence of the Igα subunit of the BCR is methylated by the protein arginine methyltransferase 1. This modification negatively regulates the calcium and PI-3 kinase pathways of the BCR while promoting signals leading to B cell differentiation. Thus, Igα arginine methylation can play an important role in specifying the outcome of BCR signaling.