tbuckley/cabot-search huggingface dataset:
Critical role for CD8+FoxP3+ regulatory T cells in colon cancer immune response in humans
Authors: I. Sobhani, S. Le Gouvello
Journal: Gut (2009)

Colorectal cancer (CRC) immunosurveillance is based on innate and adaptive immune effector cells, and various cytokines and chemokines are involved in the identification and destruction of cancer cells. Survival of patients depends on the density and function of these cells. Very recent studies highlighted the particular role of tumour cells themselves in initiating the antitumoural immune response.

Pronounced lymphocytic infiltration of colon or rectal tumour tissues is linked with longer patient survival, and immune suppression enhances the chance of appearance of cancer in human and animal models. The phenotypes of these cells (ie, CD8+ T cells (central and effector memory CD8+ T cells) and CD4+ T cells (CD4+ T helper cells of types 1, 2 and 17) and regulatory/suppressive CD4+CD25+high T cells (Treg cells)) predict prognosis.1 Interest in the antitumour immune response reached its peak with the results of a French clinical cohort study2 which showed for the first time that the presence of markers for TH1, cytotoxic polarisation and the memory T cells within tumour samples were better predictors of patient survival than the histopathological pTNM (tumour, node, metastases). Several mechanisms interfere with the efficiency of the host’s antitumour immune response in vivo: impairment or loss of the human leucocyte antigen class I-mediated antigen presentation, tumour expression of Fas ligand or B7H1 and B7H4, and altered dendritic cell functions and tumour-derived immunosuppressant molecules (transforming growth factor β (TGFβ), interleukin 10 (IL10), colony-stimulating factor-1 (CSF-1) and vascular endothelial factor (VEGF)).3

T4reg cells represent a heterogeneous group of T cells expressing various cell surface markers and cytokines, which are defined on the basis of their ability to control the activation and function of antigen-reactive T cells, thereby preventing self-reactivity. However, this activity can also …
IL-18 with IL-2 protects against <i>Strongyloides venezuelensis</i> infection by activating mucosal mast cell–dependent type 2 innate immunity
Authors: Yuki Sasaki, Tomohiro Yoshimoto, Haruhiko Maruyama, Tatsuya Tegoshi, Nobuo Ohta, Naoki Arizono, Kenji Nakanishi
Journal: The Journal of Experimental Medicine (2005)

C57BL/6 (B6) and B6 background STAT6−/− mice pretreated with IL-18 plus IL-2 showed prominent intestinal mastocytosis and rapidly expelled implanted adult worms of the gastrointestinal nematode Strongyloides venezuelensis. In contrast, identically pretreated mast cell–deficient W/Wv mice failed to do so. Thus, activated mucosal mast cells (MMC) are crucial for parasite expulsion. B6 mice infected with S. venezuelensis third-stage larvae (L3) completed parasite expulsion by day 12 after infection, whereas IL-18−/− or IL-18Rα−/− B6 mice exhibited marked impairment in parasite expulsion, suggesting a substantial contribution of IL-18–dependent MMC activation to parasite expulsion. Compared with IL-18−/− or IL-18Rα−/− mice, S. venezuelensis L3–infected STAT6−/− mice have poorly activated MMC and sustained infection; although their IL-18 production is normal. Neutralization of IL-18 and IL-2 further reduces expulsion in infected STAT6−/− mice. These results suggest that collaboration between IL-18–dependent and Th2 cell–dependent mastocytosis is important for prompt parasite expulsion.
Control of arterial branching morphogenesis in embryogenesis: go with the flow
Authors: F LENOBLE, V FLEURY, A PRIES, P CORVOL, A EICHMANN, R RENEMAN
Journal: Cardiovascular Research (2004)

Formation of a properly branched vascular system during embryogenesis is crucial for embryo survival. Here we review the regulation of the morphogenesis of the arterial and venous system during embryogenesis. We show that in addition to deterministic patterning mechanisms and plasticity of endothelial cells, arterial-venous differentiation and branching morphogenesis involves a prominent role for blood flow. Based on in vivo observations of developing arteries, we identified a novel morphological event crucial for the morphogenesis of the arterial tree, disconnection of small side branches. This disconnection of side branches occurs exactly at the point of bifurcation. The rate of disconnection of side branches depends on flow velocity and branching angle. The balance between disconnection and maintenance of arterial side branches determines the number of side branches connected to a large artery. Based on these observations, we postulate that the number of pre-existing collaterals connected to a large artery is a function of the disconnection process and can be regulated by hemodynamics. We furthermore show that embryonic arteries already adapt their lumen diameter to the amount of flow carried. Taken together, we suggest that hemodynamics plays a pivotal role in shaping the arterial system. We suggest that flow-evoked remodeling processes determine the number of preexisting collaterals during critical periods of embryo–fetal development. Insight into these basic principles of arterial growth and branching during embryogenesis may aid to understanding the observed variability in the capacity to establish a collateral circulation in patients with ischemic diseases and finding new strategies for therapeutic arteriogenesis.
An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers
Authors: Theresa R. Bomfim, Leticia Forny-Germano, Luciana B. Sathler, Jordano Brito-Moreira, Jean-Christophe Houzel, Helena Decker, Michael A. Silverman, Hala Kazi, Helen M. Melo, Paula L. McClean, Christian Holscher, Steven E. Arnold, Konrad Talbot, William L. Klein, Douglas P. Munoz, Sergio T. Ferreira, Fernanda G. De Felice
Journal: Journal of Clinical Investigation (2012)

Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.
Real-world behavior as a constraint on the cognitive architecture: Comparing ACT-R and DAC in the Newell Test
Authors: Paul F. M. J. Verschure
Journal: Behavioral and Brain Sciences (2003)

The Newell Test is an important step in advancing our understanding of cognition. One critical constraint is missing from this test: A cognitive architecture must be self-contained. ACT-R and connectionism fail on this account. I present an alternative proposal, called Distributed Adaptive Control (DAC), and expose it to the Newell Test with the goal of achieving a clearer specification of the different constraints and their relationships, as proposed by Anderson &amp; Lebiere (A&amp;L).
Hyper Immunoglobulin E Response in Mice with Monoclonal Populations of B and T Lymphocytes<b>✪ </b>
Authors: Maria A. Curotto de Lafaille, Stephanie Muriglan, Mary-Jean Sunshine, Ying Lei, Nino Kutchukhidze, Gláucia C. Furtado, Allen K. Wensky, Danyvid Olivares-Villagómez, Juan J. Lafaille
Journal: The Journal of Experimental Medicine (2001)

A key event in the pathogenesis of allergies is the production of antibodies of the immunoglobulin (Ig)E class. In normal individuals the levels of IgE are tightly regulated, as illustrated by the low serum IgE concentration. In addition, multiple immunizations are usually required to generate detectable IgE responses in normal experimental animals. To define the parameters that regulate IgE production in vivo, we generated mice bearing monoclonal populations of B and T lymphocytes specific for influenza virus hemagglutinin (HA) and chicken ovalbumin (OVA), respectively. A single immunization of the monoclonal mice with the cross-linked OVA-HA antigen led to serum IgE levels that reached 30-200 microg/ml. This unusually high IgE response was prevented by the infusion of regulatory alpha/beta CD4(+) T cells belonging to both CD25(+) and CD25(-) subpopulations. The regulation by the infused T cells impeded the development of fully competent OVA-specific effector/memory Th2 lymphocytes without inhibiting the initial proliferative response of T cells or promoting activation-induced cell death. Our results indicate that hyper IgE responses do not occur in normal individuals due to the presence of regulatory T cells, and imply that the induction of regulatory CD4(+) T cells could be used for the prevention of atopy.
Differential Roles of CD36 and αvβ5 Integrin in Photoreceptor Phagocytosis by the Retinal Pigment Epithelium
Authors: Silvia C. Finnemann, Roy L. Silverstein
Journal: The Journal of Experimental Medicine (2001)

Retinal pigment epithelial (RPE) cells employ αvβ5 integrin and CD36 receptors to phagocytose photoreceptor outer segment fragments (OS). We explored special properties of RPE phagocytosis to identify the contribution of CD36 to RPE phagocytosis measuring effects of CD36 antibodies on OS binding and internalization kinetics. Early, CD36 antibodies had no effect on OS binding or internalization. Both control and CD36 antibody treated RPE initiated internalization approximately 2 hours after OS challenge. Later, bivalent CD36 IgG accelerated OS engulfment while monovalent Fab fragments inhibited engulfment. Cross-linking Fab fragments restored the accelerating activity of intact IgG. Strikingly, antibodies were effective even if added to OS already bound by RPE. αvβ5 blocking antibody reduced OS binding equally well in the presence of CD36 antibodies but CD36 antibodies accelerated internalization of remaining bound OS. Furthermore, CD36 ligation at either apical or basal RPE surface partially substituted for soluble factors that are required for internalization but not for binding of OS at the RPE apical surface. Our results demonstrate that CD36 ligation is necessary and sufficient to activate the OS internalization mechanism of RPE. They suggest that CD36 acts as a signaling molecule in postbinding steps of RPE phagocytosis independently of the OS binding receptor αvβ5 integrin.
The effect of chronic hypotonic volume expansion on the renal regulation of acid-base equilibrium
Authors: David C. Lowance, Howard B. Garfinkel, William D. Mattern, William B. Schwartz
Journal: Journal of Clinical Investigation (1972)

Balance studies have been carried out to evaluate the influence of vasopressin-induced volume expansion on acid-base equilibrium in normal dogs and in dogs with steady-state metabolic acidosis induced by the administration of 5-7 mmoles/kg per day of hydrochloric acid.Hypotonic expansion in dogs with metabolic acidosis (mean plasma bicarbonate concentration 14 mEq/liter) produced a marked increase in renal acid excretion that restored plasma bicarbonate concentration to normal (20-21 mEq/liter) despite continued ingestion of acid. When water was restricted during the vasopressin period, and fluid retention thus prevented, no increase in acid excretion or plasma bicarbonate concentration occurred. From these findings we conclude that hypotonic expansion is a potent stimulus to renal hydrogen ion secretion and greatly facilitates the renal removal of an acid load. Normal dogs subjected to expansion demonstrated no change in net acid excretion or in plasma bicarbonate concentration even in the face of a marked diuresis of sodium and chloride and a reduction in plasma sodium concentration to approximately 110 mEq/liter. The animals did, however, regularly lose potassium, a finding that clearly indicates an acceleration of distal sodiumcation exchange. On the basis of these observations, and the findings in the expanded acidotic dogs, we suggest that in the expanded normal dogs acceleration of sodium-hydrogen exchange was responsible for preventing a bicarbonate diuresis and for stabilizing plasma bicarbonate concentration. These studies clearly demonstrate that chronic hypotonic expansion exerts a major influence on the renal regulation of acid-base equilibrium. The exact nature of the mechanism responsible for the increase in sodium-hydrogen exchange during hypotonic expansion remains to be determined.
Innovation in hip arthroscopy: is hip arthritis preventable in the athlete?
Authors: Henry B Ellis, Karen K Briggs, Marc J Philippon
Journal: British Journal of Sports Medicine (2011)

The hip is the second most common area for injury in collegiate athletes and may account for 2-5% of all sports injuries. Hip and groin pain in the athlete has long been associated with structural abnormalities of the femoral neck, acetabulum and labral pathology.The relationship between osteoarthritis and femoroacetabular impingement (FAI) is well established now with clinical studies, radiographic studies and computer simulations.The successful treatment of the athlete with FAI and subsequent labral and chondral damage has been well documented. New techniques, such as labral reconstruction, are being developed to address the more complex injuries seen in athletes, while helping to protect the joint surfaces and decrease the risk of early onsite osteoarthritis.The athlete's painful hip, which is becoming an increasingly more common complaint, is being identified and treated with greater chances of returning to play without compromising long-term hip function and the progression of hip osteoarthritis.
Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation
Authors: Jaerak Chang, Seongju Lee, Craig Blackstone
Journal: Journal of Clinical Investigation (2014)

Autophagy allows cells to adapt to changes in their environment by coordinating the degradation and recycling of cellular components and organelles to maintain homeostasis. Lysosomes are organelles critical for terminating autophagy via their fusion with mature autophagosomes to generate autolysosomes that degrade autophagic materials; therefore, maintenance of the lysosomal population is essential for autophagy-dependent cellular clearance. Here, we have demonstrated that the two most common autosomal recessive hereditary spastic paraplegia gene products, the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR), a pathway that generates new lysosomes. Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate. Loss of spastizin or spatacsin resulted in depletion of free lysosomes, which are competent to fuse with autophagosomes, and an accumulation of autolysosomes, reflecting a failure in ALR. Moreover, spastizin and spatacsin were essential components for the initiation of lysosomal tubulation. Together, these results link dysfunction of the autophagy/lysosomal biogenesis machinery to neurodegeneration.
PEDF induces p53-mediated apoptosis through PPAR gamma signaling in human umbilical vein endothelial cells
Authors: T HO, S CHEN, Y YANG, C LIAO, H CHENG, Y TSAO
Journal: Cardiovascular Research (2007)

Objective Pigment epithelial-derived factor (PEDF) is a potent anti-angiogenic factor whose effects are partially mediated through the induction of endothelial cell apoptosis. The pathway mediating endothelial cell apoptosis has not been fully established. Here we investigated the participation of peroxisome proliferator-activated receptor δ (PPARδ) and p53 in the apoptosis of human umbilical vein endothelial cells (HUVECs). Methods and results HUVECs pretreated with either PPARδ antagonist or PPARδ small interfering RNA (siRNA) suppressed PEDF-induced apoptosis as determined by TUNEL assay, annexin V-FITC/PI staining, and cleavage of procaspase-8, -9, -3. PEDF sequentially induced PPARδ and p53 expression as observed in immunoblotting and immunofluoresence assays. PEDF also increased the transcriptional activity of PPARδ as evident from electromobility shift assays, and p53 as determined by the phosphorylation and acetylation of p53 and the induction of Bax. The induction of p53 by PEDF was abolished by either PPARδ antagonist or PPARδ siRNA. PEDF-mediated HUVEC apoptosis and cleavage of procaspases were significantly attenuated by p53 siRNA. Conclusions Our observations indicate that PEDF induces HUVECs apoptosis through the sequential induction of PPARδ and p53 overexpression. With the growing interest in anti-angiogenesis as a novel approach to cancer therapy, defining the mechanism of PEDF-mediated HUVEC apoptosis may facilitate the development of new therapeutics.
A phase I study of AMD473 and docetaxel given once every 3 weeks in patients with advanced refractory cancer: a National Cancer Institute of Canada-Clinical Trials Group trial, IND 131
Authors: K.A. Gelmon, D. Stewart, K.N. Chi, S. Chia, C. Cripps, S. Huan, S. Janke, D. Ayers, D. Fry, J.A. Shabbits, W. Walsh, L. McIntosh, L.K. Seymour
Journal: Annals of Oncology (2004)
Effects of Imatinib on Monocyte-Derived Dendritic Cells Are Mediated by Inhibition of Nuclear Factor-κB and Akt Signaling Pathways
Authors: Silke Appel, Anette Rupf, Markus M. Weck, Oliver Schoor, Tim H. Brümmendorf, Toni Weinschenk, Frank Grünebach, Peter Brossart
Journal: Clinical Cancer Research (2005)

Abstract Dendritic cells are the most powerful antigen-presenting cells playing a decisive role for the initiation and maintenance of primary immune responses. However, signaling pathways involved in the differentiation of these cells have not been fully determined. Imatinib is a novel tyrosine kinase inhibitor effective against Abl kinases, c-Kit, and platelet-derived growth factor receptor. Using this compound, we show that human monocyte-derived dendritic cells generated in the presence of therapeutic concentrations of imatinib show a reduced expression of CD1a, MHC class I and II, and costimulatory molecules as well as decreased secretion of chemokines and cytokines resulting in an impaired capacity of dendritic cells to elicit primary T-cell responses. Using Western blot analyses, we found that these effects are mediated by inhibition of phosphatidylinositol 3-kinase/Akt pathways and a pronounced down-regulation of nuclear localized protein levels of nuclear factor-κB family members. Importantly, using blocking antibodies and tyrosine kinase inhibitors, we show that the inhibitory effects of imatinib on dendritic cell differentiation are not mediated via platelet-derived growth factor receptor and c-Kit. Taken together, our study reveals that imatinib inhibits dendritic cell differentiation and function via Akt and nuclear factor-κB signal transduction. Importantly, we show that imatinib can inhibit the function of normal, nonmalignant cells that may result in immunosuppression of these patients.
Deletions Affecting Codons 557-558 of the <i>c</i>-<i>KIT</i> Gene Indicate a Poor Prognosis in Patients With Completely Resected Gastrointestinal Stromal Tumors: A Study by the Spanish Group for Sarcoma Research (GEIS)
Authors: Javier Martín, Andrés Poveda, Antonio Llombart-Bosch, Rafael Ramos, José A. López-Guerrero, Javier García del Muro, Joan Maurel, Silvia Calabuig, Antonio Gutierrez, José L. González de Sande, Javier Martínez, Ana De Juan, Nuria Laínez, Ferrán Losa, Valentín Alija, Pilar Escudero, Antonio Casado, Pilar García, Remei Blanco, José M. Buesa
Journal: Journal of Clinical Oncology (2005)

To explore the prognostic value of mutations in c-KIT and PDGFR-alpha genes with respect to relapse-free survival (RFS) in patients with gastrointestinal stromal tumors (GIST). We have investigated the prognostic relevance of the type and position of the mutations, in addition to other clinicopathologic factors, in a large series of patients with GIST.For this study, 162 patients were selected according to the following criteria: completely resected tumors with negative margins attended between 1994 and 2001; no metastasis at diagnosis; tumor larger than 2 cm, c-KIT-positive immunostaining; and no other primary tumors.The median follow-up was 42 months for patients free of recurrence. Mutations were detected in 96 tumors (60%): 82 cases involving c-KIT and 14 cases involving PDFGR-alpha. Univariate analysis demonstrated the following as poor prognostic factors for RFS: tumors larger than 10 cm (P < .0001); mitotic count higher than 10 mitoses per 50 high-power fields (P < .0001); high risk index (P < .0001); intestinal GIST location (P = .0041); high cellularity (P < .0001); tumor necrosis (P < .0001); deletions affecting exon 11 (P = .0007); and deletions affecting codons 557 to 558 (P < .0001). After the multivariate analysis, only the high risk index (relative risk [RR], 12.36), high cellularity (RR, 3.97), and deletions affecting codons 557 to 558 of c-KIT (RR, 2.57) corresponded to independent prognostic factors for RFS in GIST patients.Deletions affecting codons 557 to 558 are relevant for the prognosis of RFS in GIST patients. This critical genetic alteration should be considered to be a new prognostic stratification variable for randomized trials exploring imatinib mesylate in the adjuvant setting in GIST patients.
Thrombin Stimulates Smooth Muscle Cell Differentiation From Peripheral Blood Mononuclear Cells via Protease-Activated Receptor-1, RhoA, and Myocardin
Authors: Kenneth Martin, Sharon Weiss, Pat Metharom, Jeffrey Schmeckpeper, Brian Hynes, John O'Sullivan, Noel Caplice
Journal: Circulation Research (2009)

Smooth muscle precursor cells have previously been reported to reside in bone marrow and in the circulation, but little is currently known regarding the proximate stimuli for smooth muscle cell differentiation of these putative progenitors.Because local thrombin generation occurs as an initial response to vascular injury, we hypothesized that thrombin may influence the differentiation of circulating smooth muscle progenitor cells.Peripheral blood mononuclear cells were cultured on type I collagen using a protocol optimized to stimulate smooth muscle cell outgrowth. Thrombin-stimulated upregulation of the transcription factor myocardin and smooth muscle myosin heavy chain, and both were inhibited by hirudin or the RhoA inhibitor Y27632. After 10 days of culture, smooth muscle outgrowth colonies formed, which stained positive for alpha-smooth muscle actin, smooth muscle myosin heavy chain, and calponin, in addition to having a contractile response to 100 nmol/L angiotensin II. Coincubation of peripheral blood mononuclear cells with thrombin, 10 micromol/L protease-activated receptor-1, but not protease-activated receptor-4 activating peptide significantly increased the number of smooth muscle outgrowth colonies formed. Thrombin-induced enhancement of smooth muscle outgrowth colony formation was inhibited by hirudin, Y27632, and an antibody against protease-activated receptor-1.These data illustrate a novel thrombin-induced pathway for smooth muscle differentiation from putative smooth muscle progenitors in peripheral blood.