tbuckley/cabot-search huggingface dataset:
Suppression of Acute and Chronic Rejection by Hepatocyte Growth Factor in a Murine Model of Cardiac Transplantation
Authors: Kazuhiro Yamaura, Ken-ichi Ito, Katsuaki Tsukioka, Yuko Wada, Akiko Makiuchi, Masayuki Sakaguchi, Tomohiro Akashima, Minoru Fujimori, Yoshiki Sawa, Ryuichi Morishita, Kunio Matsumoto, Toshikazu Nakamura, Jun-ichi Suzuki, Jun Amano, Mitsuaki Isobe
Journal: Circulation (2004)

Although treatment with immunosuppressive agents has contributed to overcoming acute rejection and improving the midterm survival of transplanted hearts, cardiac allograft vasculopathy (CAV) has remained the main cause of primary graft failure. Recent approaches have shown that hepatocyte growth factor (HGF) exhibits cardiotrophic functions. We therefore addressed whether HGF would regulate acute and chronic rejection in cardiac transplantation.We used a murine heterotopic cardiac transplantation model between fully incompatible strains and administered 500 microg x kg(-1) x d(-1) HGF during the initial 14 days after transplantation. The HGF-treated allografts showed significantly prolonged survival (42.3+/-4.1 days, P<0.001) compared with the controls (11.1+/-0.6 days), with tolerance induction in 47.4%. Histopathologically, the number of infiltrating cells was significantly decreased and myocardial necrosis was less prominent with a reduction of apoptosis in the allografts by HGF treatment during acute rejection. In the long-term surviving allografts, HGF significantly inhibited the development of CAV and interstitial fibrosis. With respect to intragraft cytokine mRNA expression, HGF treatment reduced the early expression of interferon-gamma and enhanced the expression of transforming growth factor-beta1 during the acute phase and of interleukin-10 continuously through the acute phase to the chronic phase.Our findings demonstrate that HGF can prolong the survival of allografts by its cardioprotective and immunomodulative potencies. Thus, HGF administration may constitute a new therapeutic approach to preventing cardiac graft failure that has not been overcome by conventional immunosuppressive agents.
Nonopsonic antibodies in cystic fibrosis. Pseudomonas aeruginosa lipopolysaccharide-specific immunoglobulin G antibodies from infected patient sera inhibit neutrophil oxidative responses.
Authors: I Eichler, L Joris, Y P Hsu, J Van Wye, R Bram, R Moss
Journal: Journal of Clinical Investigation (1989)

Antibody opsonins from cystic fibrosis (CF) patients were investigated using nonmucoid and mucoid lipopolysaccharide (LPS) immunotype 1 Pseudomonas aeruginosa as bacterial ligands and PMN phagocytes. CF sera were compared to normal sera, polyvalent PA LPS hyperimmune globulin, and isotype switch variant monoclonal antibodies (MAbs) specific for type 1 PA LPS. Sera from PA-infected CF patients (CF PA+) had elevated levels of PA LPS and alginate IgG antibodies and promoted significantly greater antibody-dependent PMN chemiluminescence responses than sera from uninfected CF patients (CF PA-) or normal human sera (NHS). After adjustment for autologous IgG PA LPS antibody content, however, CF PA+ sera had less antibody-dependent opsonic activity than sera from CF PA- patients (P less than 0.025) or NHS (P less than 0.0025), suggesting qualitative opsonic defects of IgG PA LPS antibodies in CF PA+ sera. Antigen-specific immunoprecipitation of PA LPS antibodies enhanced opsonization by 40% of CF PA+ sera while uniformly reducing that from CF PA- sera (P less than 0.01), indicating LPS-specific nonopsonic antibodies in some CF PA+ sera. Alginate antibodies were not critical opsonins in most uninfected CF patient sera. PA LPS IgG antibodies isolated by immunoaffinity chromatography from NHS, hyperimmune globulin, and CF PA- sources were opsonic and had greater activity at equal antigen-binding concentration than identical antibodies isolated from infected CF patients (P less than 0.01-0.05); the majority of isolates from CF PA+ sera did not promote PMN oxidative responses above nonopsonic baseline. A potential isotypic basis for these findings was supported by differences in PMN responses to PA opsonized with MAbs of identical specificity but differing isotypes. PA LPS-specific IgG antibodies inhibiting PMN oxidative responses in infected patient sera demonstrate antigen-specific immunomodulation of host responses by chronic bacterial parasitism in CF, which may play a role in the pathophysiology of lung disease.
TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer
Authors: Neil E. Bhola, Justin M. Balko, Teresa C. Dugger, María Gabriela Kuba, Violeta Sánchez, Melinda Sanders, Jamie Stanford, Rebecca S. Cook, Carlos L. Arteaga
Journal: Journal of Clinical Investigation (2013)

After an initial response to chemotherapy, many patients with triple-negative breast cancer (TNBC) have recurrence of drug-resistant metastatic disease. Studies with TNBC cells suggest that chemotherapy-resistant populations of cancer stem-like cells (CSCs) with self-renewing and tumor-initiating capacities are responsible for these relapses. TGF-β has been shown to increase stem-like properties in human breast cancer cells. We analyzed RNA expression in matched pairs of primary breast cancer biopsies before and after chemotherapy. Biopsies after chemotherapy displayed increased RNA transcripts of genes associated with CSCs and TGF-β signaling. In TNBC cell lines and mouse xenografts, the chemotherapeutic drug paclitaxel increased autocrine TGF-β signaling and IL-8 expression and enriched for CSCs, as indicated by mammosphere formation and CSC markers. The TGF-β type I receptor kinase inhibitor LY2157299, a neutralizing TGF-β type II receptor antibody, and SMAD4 siRNA all blocked paclitaxel-induced IL8 transcription and CSC expansion. Moreover, treatment of TNBC xenografts with LY2157299 prevented reestablishment of tumors after paclitaxel treatment. These data suggest that chemotherapy-induced TGF-β signaling enhances tumor recurrence through IL-8–dependent expansion of CSCs and that TGF-β pathway inhibitors prevent the development of drug-resistant CSCs. These findings support testing a combination of TGF-β inhibitors and anticancer chemotherapy in patients with TNBC.
De Novo Expression of Killer Immunoglobulin-Like Receptors and Signaling Proteins Regulates the Cytotoxic Function of CD4 T Cells in Acute Coronary Syndromes
Authors: Takako Nakajima, Ömer Goek, Xiaoyu Zhang, Stephen L. Kopecky, Robert L. Frye, Jörg J. Goronzy, Cornelia M. Weyand
Journal: Circulation Research (2003)

The inflammatory infiltrate in atherosclerotic plaque is composed of T cells and macrophages. CD4 + T cells with a unique phenotype, CD4 + CD28 null , are preferentially recruited into culprit lesions. These T cells are distinct from classic CD4 + CD28 + T cells in gene expression and function, including their ability to mediate cytolysis. In this study, we have investigated the regulation of CD4 + CD28 null T-cell cytolytic function. In patients with acute coronary syndromes (ACS), CD4 + CD28 null T cells express killer immunoglobulin-like receptors (KIRs). KIRs encompass a polymorphic family of receptors that recognize HLA class I molecules and have been implicated in self-tolerance. CD4 + CD28 null T-cell clones from patients with ACS and age-matched controls were compared for their KIR-expression profile. T-cell clones derived from the patients expressed a broader spectrum of KIRs ( P &lt;0.001) with preference for the stimulatory variant, CD158j. Additionally, CD4 + T-cell clones from patients but not those from controls acquired de novo expression of the DAP12 molecule, an adapter chain that transmits CD158j-derived signals. Cumulative expression of CD158j and DAP12 endowed cytolytic competence on CD4 + CD28 null T cells, allowing them to kill in the absence of T-cell receptor triggering. Our data demonstrate that CD4 + CD28 null T cells in ACS are characterized by a unique gene expression profile. Consequently, these T cells acquire cytolytic capability that can bypass the need for T-cell receptor triggering and, thus, impose a threat to self-tolerance.
Interleukin 10 Increases CCR5 Expression and HIV Infection in Human Monocytes
Authors: Silvano Sozzani, Silvia Ghezzi, Gioacchino Iannolo, Walter Luini, Alessandro Borsatti, Nadia Polentarutti, Antonio Sica, Massimo Locati, Charles Mackay, Timothy N.C. Wells, Priscilla Biswas, Elisa Vicenzi, Guido Poli, Alberto Mantovani
Journal: The Journal of Experimental Medicine (1998)

The immunosuppressive and antiinflammatory cytokine interleukin (IL) 10 selectively upregulates the expression of the CC chemokine receptors CCR5, 2, and 1 in human monocytes by prolonging their mRNA half-life. IL-10–stimulated monocytes display an increased number of cell surface receptors for, and better chemotactic responsiveness to, relevant agonists than do control cells. In addition, IL-10–stimulated monocytes are more efficiently infected by HIV BaL. This effect was associated to the enhancement of viral entry through CCR5. These data add support to an emerging paradigm in which pro- and antiinflammatory molecules exert reciprocal and opposing influence on chemokine agonist production and receptor expression.
Accessory cell-T lymphocyte interactions. Antigen-dependent and -independent clustering.
Authors: K Inaba, R M Steinman
Journal: The Journal of Experimental Medicine (1986)

Previous work documented the capacity of dendritic cells (DC) to stimulate primary immune responses and to physically cluster with the responding lymphocytes. Rapid cell-cell aggregation assays were used here to study the interaction of DC and other types of APC with T lymphocytes. Graded doses of APC were sedimented with T cells that had been primed to alloantigens, soluble proteins, or lectin, and then labeled with carboxyfluorescein diacetate. The number of clustered T cells was measured after 10 min at 4 or 37 degrees C. At 4 degrees, binding was antigen-dependent and included greater than 50% of the added T cells. Clustering was mediated by all types of APC tested, including DC, macrophages, B lymphocytes, and fresh Langerhans cells, although DC were the most effective. Specificity was evident in the findings that alloreactive T lymphoblasts bound to allogeneic but not syngeneic APC; KLH- and OVA-reactive T cells bound to syngeneic APC in the presence of specific protein: and Con A blasts needed lectin to cluster. A 30 min pretreatment with chloroquine, a drug known to inhibit APC activity, markedly blocked the specific binding of alloreactive and protein-specific T blasts at 4 degrees C. Since Lyt-2- alloreactive blasts should specifically recognize Ia, presentation of Ia seems to be altered by chloroquine. Binding assays at 37 degrees C gave similar results to those performed at 4 degrees C, with one exception. When DC were used as APC, striking antigen-independent clustering occurred. DC could efficiently cluster primed T cells in the absence of alloantigen, soluble protein, or lectin. We suggest that antigen-independent binding contributes to the distinctive capacity of DC to prime T cells in the afferent limb of the immune response, whereas antigen-dependent binding between other APC and sensitized lymphocytes is critical in the efferent limb.
The role of H-2-linked genes in helper T-cell function. I. In vitro expression in B cells of immune response genes controlling helper T-cell activity
Authors: JW Kappler, P Marrack
Journal: The Journal of Experimental Medicine (1977)

The ability of murine helper T cells primed to the antigen, sheep erythrocytes (SRBC) to cross-react with burro erythrocytes (BRBC) in the in vitro anti-trinitrophenol (TNP) response to TNP-RBC was shown to be under genetic control. Although non-H-2 genes were shown to influence the absolute level of helper activity assayed after SRBC priming, the extent of cross-reaction of SRBC-primed helpers with BRBC was shown to be controlled by an H-2-1inked Ir gene(s). H-2 haplotypes were identified which determined high, intermediate, or low response to the cross- reacting determinants and the gene(s) controlling the cross-reaction tentatively mapped to the K through I-E end of the H-2 complex. Helpers primed in F(1) mice of high x intermediate or high x low responder parents were tested for cross-reaction using B cells and macrophages (Mφ) of parental haplotypes. In each case the extent of cross-reaction was predicted by the H-2 haplotype of the B cells and Mφ, establishing the expression of the Ir gene(s) in B cells and/or Mφ a t least, but not ruling out its expression in T cells as well. The low cross-reaction seen when T cells from F(1) mice of high × low responder parents were tested on low responder B cells and Mφ was not increased by the presence of high responder Mφ, indicating the Ir gene(s) is expressed in the B cell a t least although it may be expressed in Mφ as well. These and our previously reported experiments are consistent with the hypothesis that helper T cells recognize antigen bound to the surface of B cells and Mφ in association with the product(s) of Ir gene(s) expressed on the B cell and Mφ.
RECURRENT MILD TRAUMATIC BRAIN INJURY AMONGST A COHORT OF RUGBY UNION PLAYERS
Authors: S Hollis, G Heller, M Stevenson, P Schofield
Journal: British Journal of Sports Medicine (2014)

Background Community, or non-professional, rugby has a high incidence of mild traumatic brain injury (mTBI). Risk of further mTBI, or long term consequences of repeat mTBI, is an emerging public health issue. Objective To identify the time to recurrent mTBI and key predictors for time to recurrent mTBI among community rugby players. Design Prospective cohort study. Setting Rugby union players from Sydney, Australia playing in grade, suburban and school-level community competitions. Participants A cohort of 3 207 male players was recruited pre-season and followed between one and three playing seasons. Demographic information, player characteristics and concussion history was collected. Players sustaining an mTBI were recorded and information pertaining to the injury, recovery and return-to-play was collected over three months. Risk factor assessment Loss of consciousness and post-traumatic amnesia. Main outcome measurements Time to mTBI, namely, the number of hours of game exposure played up to the time the player sustained a first and repeat mTBI. Results Players were more likely to sustain a second mTBI if they experienced loss of consciousness (LOC) or post-traumatic amnesia (PTA) with their first mTBI. Players who experienced LOC with their first mTBI were three times more likely to sustain a second mTBI compared to those who did not experience LOC (P=.037). Players who experienced PTA with their first mTBI were 2.5 times more likely to sustain a second mTBI compared to those who did not experience PTA (P=.059). Conclusions Community rugby players are three times more likely to sustain a subsequent mTBI if they experienced a LOC with their first mTBI, and 2.5 times more likely if they experienced PTA. It is recommended that coaches and support staff identify players who experience LOC or PTA with their mTBI in order to prevent or delay subsequent mTBIs from being sustained by the player.
Myocardial blood flow and mechanics in volume overload-induced left ventricular hypertrophy in dogs
Authors: P. B HULTGREN, A. A BOVE
Journal: Cardiovascular Research (1981)

Chronic volume overload and subsequent left ventricular hypertrophy (LVH) were produced by a surgical shunt between the left subclavian artery and the left atrial appendage in eight dogs. A sham operation was performed on six control dogs. Analysis of biplane ventriculograms showed no significant differences in ejection fraction, mean wall stress, tension-time index, or stress-time index. A significant increase was found in stroke work per gram of left ventricle (P < 0.005). Myocardial blood flow (MBF) was measured using 9 μm, radioactive microspheres at rest, at a constant treadmill workload (CWL) of 2 mph, 2% grade, and at a constant heart rate (CHR) of 175 beats·min−1. Total LVMBF (cm3·min−1) in the shunt dogs was increased at rest (P <0.05) with CWL (P <0.05) and at CHR (P <0.05). However, no differences were found between the groups in the LVMBF·g−1 of myocardium (cm3·g−1·min−1) at rest or during exercise, or in the endocardial to epicardial blood flow ratio. Volume overload hypertrophy, without the presence of heart failure, is associated with normal haemodynamic and mechanical function at rest, normal LVMBF·g−1 of myocardium and normal flow distribution at rest and during exercise.
How Genetically Engineered Mouse Tumor Models Provide Insights Into Human Cancers
Authors: Katerina Politi, William Pao
Journal: Journal of Clinical Oncology (2011)

Genetically engineered mouse models (GEMMs) of human cancer were first created nearly 30 years ago. These early transgenic models demonstrated that mouse cells could be transformed in vivo by expression of an oncogene. A new field emerged, dedicated to generating and using mouse models of human cancer to address a wide variety of questions in cancer biology. The aim of this review is to highlight the contributions of mouse models to the diagnosis and treatment of human cancers. Because of the breadth of the topic, we have selected representative examples of how GEMMs are clinically relevant rather than provided an exhaustive list of experiments. Today, as detailed here, sophisticated mouse models are being created to study many aspects of cancer biology, including but not limited to mechanisms of sensitivity and resistance to drug treatment, oncogene cooperation, early detection, and metastasis. Alternatives to GEMMs, such as chemically induced or spontaneous tumor models, are not discussed in this review.
Competitive Performance of Carbon “Quantum” Dots in Optical Bioimaging
Authors: Li Cao, Sheng-Tao Yang, Xin Wang, Pengju G. Luo, Jia-Hui Liu, Sushant Sahu, Yamin Liu, Ya-Ping Sun
Journal: Theranostics (2012)

Carbon-based "quantum" dots or carbon dots are surface-functionalized small carbon nanoparticles. For bright fluorescence emissions, the carbon nanoparticles may be surface-doped with an inorganic salt and then the same organic functionalization. In this study, carbon dots without and with the ZnS doping were prepared, followed by gel-column fractionation to harvest dots of 40% and 60% in fluorescence quantum yields, respectively. These highly fluorescent carbon dots were evaluated for optical imaging in mice, from which bright fluorescence images were obtained. Of particular interest was the observed competitive performance of the carbon dots in vivo to that of the well-established CdSe/ZnS QDs. The results suggest that carbon dots may be further developed into a new class of high-performance yet nontoxic contrast agents for optical bioimaging.
Glucocorticoid Regulation of Cardiac K <sup>+</sup> Currents and L-Type Ca <sup>2+</sup> Current in Neonatal Mice
Authors: Li Wang, Zhong-Ping Feng, Henry J. Duff
Journal: Circulation Research (1999)

Previous studies have reported that dexamethasone (Dex) prolongs cardiac action potential repolarization in mice and rats. However, the cellular mechanisms of this effect have not been addressed. Because action potential duration is influenced by a complex interplay of both inward and outward currents, this study evaluated the role of K+ currents and the L-type Ca2+ current in response to chronic in vivo Dex treatment. Accordingly, neonatal mice were randomly allocated to treatment with Dex (1 mg/kg per day) or placebo (saline) given subcutaneously for 5 days. At 14 to 15 days of age, the L-type Ca2+ current and K+ currents were recorded in ventricular myocytes using whole-cell patch-clamp techniques. The density of peak outward K+ currents was significantly decreased in the chronic Dex-treated group, but the current measured at the end of a 1-second depolarization pulse was similar in both groups. We further measured the magnitudes of the fast-inactivating (I(to)) and the slowly inactivating (I(slow)) currents that contribute to the peak outward K+ currents. I(to) was reduced from 17.5+/-3.0 pA/pF (control) to 10.6+/-2.5 pA/pF (Dex) at +50 mV (P<0.05), but I(slow) was not significantly different. These data suggest that downregulation of I(to) is responsible for the reduced peak outward current. Time courses of the onset and offset of in vivo Dex effects were also assessed. A period of 3 days of treatment was required to observe the Dex effect on peak outward K(+) currents, whereas a 7-day period after discontinuation of Dex was required to recover the baseline current density. Acute in vitro treatment with Dex (1 micromol/L) had no effect on K+ current densities. In addition, chronic Dex treatment significantly increased the density of the L-type Ca2+ current (I(Ca-L)) from -7.2+/-0.5 pA/pF of control to -8.9+/-0.6 pA/pF of Dex at +10 mV, P<0.05. In conclusion, chronic in vivo Dex treatment decreases I(to) and increases I(Ca-L) in neonatal mouse ventricular myocytes, both of which contribute to the prolongation of cardiac action potential repolarization induced by glucocorticoids.
The Multilevel Compliance Challenge: Recommendations for a Call to Action
Authors: Nancy Houston Miller, Martha Hill, Thomas Kottke, Ira S. Ockene
Journal: Circulation (1997)

Despite the universally accepted importance of compliance, strategies known for more than two decades to be effective are not routinely incorporated into clinical practice. For the benefits of primary and secondary prevention to be realized in diverse population groups and settings, emphasis must be placed on implementing strategies at the patient, provider, and organization levels. Current knowledge of compliance strategies, if integrated into a multilevel approach, offers enormous promise for decreasing risk and improving patient outcomes.
Immunocytochemical Detection of Disseminated Tumor Cells in the Bone Marrow of Patients With Esophageal Carcinoma
Authors: S. Thorban, J. D. Roder, H. Nekarda, A. Funk, J. R. Siewert, K. Pantel
Journal: JNCI Journal of the National Cancer Institute (1996)

Background:Approximately half of the patients diagnosed with localized esophageal cancer die of metastatic disease within the first 2 years following tumor resection. The development of monoclonal antibodies (MAbs) directed against epithelial cell-associated and tumor antigens has enabled the detection of single disseminated tumor cells in secondary organs.