tbuckley/cabot-search huggingface dataset:
Cyclophosphamide Creates a Receptive Microenvironment for Prostate Cancer Skeletal Metastasis
Authors: Serk In Park, Jinhui Liao, Janice E. Berry, Xin Li, Amy J. Koh, Megan E. Michalski, Matthew R. Eber, Fabiana N. Soki, David Sadler, Sudha Sud, Sandra Tisdelle, Stephanie D. Daignault, Jeffrey A. Nemeth, Linda A. Snyder, Thomas J. Wronski, Kenneth J. Pienta, Laurie K. McCauley
Journal: Cancer Research (2012)

Abstract A number of cancers predominantly metastasize to bone, due to its complex microenvironment and multiple types of constitutive cells. Prostate cancer especially has been shown to localize preferentially to bones with higher marrow cellularity. Using an experimental prostate cancer metastasis model, we investigated the effects of cyclophosphamide, a bone marrow–suppressive chemotherapeutic drug, on the development and growth of metastatic tumors in bone. Priming the murine host with cyclophosphamide before intracardiac tumor cell inoculation was found to significantly promote tumor localization and subsequent growth in bone. Shortly after cyclophosphamide treatment, there was an abrupt expansion of myeloid lineage cells in the bone marrow and the peripheral blood, associated with increases in cytokines with myelogenic potential such as C-C chemokine ligand (CCL)2, interleukin (IL)-6, and VEGF-A. More importantly, neutralizing host-derived murine CCL2, but not IL-6, in the premetastatic murine host significantly reduced the prometastatic effects of cyclophosphamide. Together, our findings suggest that bone marrow perturbation by cytotoxic chemotherapy can contribute to bone metastasis via a transient increase in bone marrow myeloid cells and myelogenic cytokines. These changes can be reversed by inhibition of CCL2. Cancer Res; 72(10); 2522–32. ©2012 AACR.
Individual Patient-Specific Immunity against High-Grade Glioma after Vaccination with Autologous Tumor Derived Peptides Bound to the 96 KD Chaperone Protein
Authors: Courtney A. Crane, Seunggu J. Han, Brian Ahn, Jessica Oehlke, Valerie Kivett, Anne Fedoroff, Nicholas Butowski, Susan M. Chang, Jennifer Clarke, Mitchel S. Berger, Michael W. McDermott, Michael D. Prados, Andrew T. Parsa
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Cancer immunotherapy offers hope of a highly specific nontoxic adjuvant treatment. Heat shock protein peptide complexes (HSPPCs) found in cancer cells carry tumor-specific antigenic proteins and can facilitate adaptive and innate immune responses. Here we show that peptides bound to a 96 kD chaperone protein (HSP-96) from brain tissue containing glioblastoma multiforme (GBM) can be used to safely immunize patients with recurrent GBM. Experimental Design: Multimodality immunomonitoring was completed on 12 patients with recurrent GBM before and after immunization with an autologous HSPPC vaccine derived from surgically resected tumor. Clinical endpoints included safety assessments and overall survival. Results: No adverse events attributable to the vaccine were found. Testing of peripheral blood leukocytes before and after vaccination revealed a significant peripheral immune response specific for the peptides bound to HSP-96, in 11 of the 12 patients treated. Brain biopsies of immune responders after vaccination revealed focal CD4, CD8, and CD56 IFNγ positive cell infiltrates, consistent with tumor site specific immune responses. Immune responders had a median survival of 47 weeks after surgery and vaccination, compared with 16 weeks for the single nonresponder. Conclusions: These data provide the first evidence in humans of individual patient-specific immune responses against autologous tumor derived peptides bound to HSP-96. Clin Cancer Res; 19(1); 205–14. ©2012 AACR.
Integrin αMβ2-Mediated Cell Migration to Fibrinogen and Its Recognition Peptides
Authors: Christopher B. Forsyth, Dmitry A. Solovjov, Tatiana P. Ugarova, Edward F. Plow
Journal: The Journal of Experimental Medicine (2001)

Leukocyte migration is the hallmark of inflammation, and integrin αMβ2 and its ligand fibrinogen (Fg) are key participants in this cellular response. Cells expressing wild-type or mutant αMβ2 and Fg or its derivatives have been used to dissect the molecular requirements for this receptor–ligand pair to mediate cell migration. The major conclusions are that (a) Fg, its D fragment, and its P1 and P2 αMβ2 recognition peptides support a chemotactic response; (b) when the I domain of αL was replaced with the I domain of αM, the chimeric receptor supported cell migration to Fg; however, the αM subunit, containing the I domain but lacking the β2 subunit, supported migration poorly, thus, the αMI domain is necessary but not sufficient to support chemotaxis, and efficient migration requires the β2 subunit and αMI domain; and (c) in addition to supporting cell migration, P2 enhanced αMβ2-mediated chemotaxis to Fg and the P1 peptide. This activation was associated with exposure of the activation-dependent epitope recognized by monoclonal antibody 7E3 and was observed also with human neutrophils. Taken together, these data define specific molecular requirements for αMβ2 to mediate cell migration to Fg derivatives and assign a novel proinflammatory activity to the P2 peptide.
Once-daily tazarotene gel versus twice-daily fluocinonide cream in the treatment of plaque psoriasis
Authors: M Lebwohl, E Ast, J P Callen, S I Cullen, S R Hong, C L Kulp-Shorten, N J Lowe, T J Phillips, T Rosen, D I Wolf, J M Quell, J Sefton, J C Lue, J R Gibson, R A Chandraratna
Journal: Journal of the American Academy of Dermatology (1998)
Statins Protect Human Aortic Smooth Muscle Cells From Inorganic Phosphate-Induced Calcification by Restoring Gas6-Axl Survival Pathway
Authors: Bo-Kyung Son, Koichi Kozaki, Katsuya Iijima, Masato Eto, Taro Kojima, Hidetaka Ota, Yuka Senda, Koji Maemura, Toru Nakano, Masahiro Akishita, Yasuyoshi Ouchi
Journal: Circulation Research (2006)

Vascular calcification is clinically important in the development of cardiovascular disease. It is reported that hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) inhibited vascular calcification in several clinical trials. However, the mechanism is poorly understood. Recently, it has been suggested that apoptosis is one of the important processes regulating vascular smooth muscle cell (VSMC) calcification. In this study, we investigated the effect of statins on VSMC calcification by testing their effect on apoptosis, focusing in particular on regulation of the survival pathway mediated by growth arrest-specific gene 6 (Gas6), a member of the vitamin K–dependent protein family, and its receptor, Axl. In human aortic smooth muscle cells (HASMC), statins significantly inhibited inorganic phosphate (Pi)-induced calcification in a concentration-dependent manner (reduced by 49% at 0.1 μmol/L atorvastatin). The inhibitory effect of statins was mediated by preventing apoptosis, which was increased by Pi in a concentration-dependent manner, and not by inhibiting sodium-dependent phosphate cotransporter (NPC) activity, another mechanism regulating HASMC calcification. Furthermore, the antiapoptotic effect of statins was dependent on restoration of Gas6, whose expression was downregulated by Pi. Restoration of Gas6 mRNA by statins was mediated by mRNA stabilization, and not by an increase in transcriptional activity. Suppression of Gas6 using small interfering RNA and the Axl-extracellular domain abolished the preventive effect of statins on Pi-induced apoptosis and calcification. These data demonstrate that statins protected HASMC from Pi-induced calcification by inhibiting apoptosis via restoration of the Gas6-Axl pathway.
Angiotensin II Increases Expression of α1C Subunit of L-Type Calcium Channel Through a Reactive Oxygen Species and cAMP Response Element–Binding Protein–Dependent Pathway in HL-1 Myocytes
Authors: Chia-Ti Tsai, Danny Ling Wang, Wen-Pin Chen, Juey-Jen Hwang, Chia-Shan Hsieh, Kuan-Lih Hsu, Chuen-Den Tseng, Ling-Ping Lai, Yung-Zu Tseng, Fu-Tien Chiang, Jiunn-Lee Lin
Journal: Circulation Research (2007)

Angiotensin II (Ang II) is involved in the pathogenesis of atrial fibrillation (AF). L-type calcium channel (LCC) expression is altered in AF remodeling. We investigated whether Ang II modulates LCC current through transcriptional regulation, by using murine atrial HL-1 cells, which have a spontaneous calcium transient, and an in vivo rat model. Ang II increased LCC alpha1C subunit mRNA and protein levels and LCC current density, which resulted in an augmented calcium transient in atrial myocytes. An approximately 2-kb promoter region of LCC alpha1C subunit gene was cloned to the pGL3 luciferase vector. Ang II significantly increased promoter activity in a concentration- and time-dependent manner. Truncation and mutational analysis of the LCC alpha1C subunit gene promoter showed that cAMP response element (CRE) (-1853 to -1845) was an important cis element in Ang II-induced LCC alpha1C subunit gene expression. Transfection of dominant-negative CRE binding protein (CREB) (pCMV-CREBS133A) abolished the Ang II effect. Ang II (1 micromol/L, 2 hours) induced serine 133 phosphorylation of CREB and binding of CREB to CRE and increased LCC alpha1C subunit gene promoter activity through a protein kinase C/NADPH oxidase/reactive oxygen species pathway, which was blocked by the Ang II type 1 receptor blocker losartan and the antioxidant simvastatin. In the rat model, Ang II infusion increased LCC alpha1C subunit expression and serine 133 phosphorylation of CREB, which were attenuated by oral losartan and simvastatin. In summary, Ang II induced LCC alpha1C subunit expression via a protein kinase C-, reactive oxygen species-, and CREB-dependent pathway and was blocked by losartan and simvastatin.
Physical Fitness and Subsequent Myocardial Infarction in Healthy Workers
Authors: Ruth K. Peters
Journal: JAMA (1983)

Physical work capacity (PWC), a measure of physical fitness, was assessed by bicycle ergometry on 2,779 healthy men younger than 55 years who were subsequently followed up for an average of 4.8 years for symptomatic myocardial infarction (MI). There were 36 MIs. The relative risk (RR) of MI for below median PWC, adjusted for conventional risk factors for heart disease, was 2.2 (95% confidence limits, 1.1 and 4.7). This increased risk appeared to be limited to men with certain other risk factors present simultaneously: above-median cholesterol level, smoking, above-median systolic BP, or a combination of these. Among men with at least two of these factors, the adjusted RR for below-median PWC was 6.6 (95% confidence limits, 2.3 and 27.8). Poor physical fitness may be an important risk factor for heart disease, especially when conventional risk factors are also present.
Treatment With All-<i>Trans</i> Retinoic Acid and Anthracycline Monochemotherapy for Children With Acute Promyelocytic Leukemia: A Multicenter Study by the PETHEMA Group
Authors: Juan J. Ortega, Luis Madero, Guillermo Martín, Amparo Verdeguer, Purificación García, Ricardo Parody, José Fuster, Antonio Molines, Andrés Novo, Guillermo Debén, Antonia Rodríguez, Eulogio Conde, Javier de la Serna, María J. Allegue, Francisco J. Capote, José D. González, Pascual Bolufer, Marcos González, Miguel A. Sanz
Journal: Journal of Clinical Oncology (2005)

To analyze the simultaneous combination of all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for children with acute promyelocytic leukemia (APL).Since November 1996, 66 children (younger than 18 years) with genetically proven APL received induction therapy with ATRA and idarubicin. Consolidation therapy consisted of three courses of anthracycline monochemotherapy. After November 1999, patients with intermediate and high risk of relapse received consolidation therapy with ATRA and slightly reinforced doses of idarubicin. Maintenance therapy consisted of ATRA and low-dose mercaptopurine and methotrexate.Thirty-nine girls (59%) and 27 boys (41%) were included in this study. The WBC count at presentation was more than 10 x 10(9)/L in 26 patients (39%). Sixty-one children (92%) achieved complete remission (CR). Early deaths from hemorrhage and retinoic acid syndrome occurred in three patients and two patients, respectively. Toxicity was manageable during consolidation and maintenance therapy. No deaths in CR, clinical cardiomyotoxicity, or secondary malignancy occurred. Two patients had molecular persistence at the end of consolidation. Three clinical relapses and two molecular relapses were also observed. Apart from one molecular relapse, all these events occurred among children with hyperleukocytosis. The 5-year cumulative incidence of relapse was 17%, whereas disease-free and overall survival rates were 82% and 87%, respectively.A high incidence of hyperleukocytosis in children with APL was confirmed. Besides low toxicity and a high degree of compliance, a risk-adapted therapy combining ATRA and anthracycline monochemotherapy showed an antileukemic efficacy comparable to those previously reported with other chemotherapy combinations in children.
Deletion of DOCK2, a regulator of the actin cytoskeleton in lymphocytes, suppresses cardiac allograft rejection
Authors: Hongsi Jiang, Fan Pan, Laurie M. Erickson, Mei-Shiang Jang, Terukazu Sanui, Yuya Kunisaki, Takehiko Sasazuki, Masakazu Kobayashi, Yoshinori Fukui
Journal: The Journal of Experimental Medicine (2005)

Allograft rejection is induced by graft tissue infiltration of alloreactive T cells that are activated mainly in secondary lymphoid organs of the host. DOCK2 plays a critical role in lymphocyte homing and immunological synapse formation by regulating the actin cytoskeleton, yet its role in the in vivo immune response remains unknown. We show here that DOCK2 deficiency enables long-term survival of cardiac allografts across a complete mismatch of the major histocompatibility complex molecules. In DOCK2-deficient mice, alloreactivity and allocytotoxicity were suppressed significantly even after in vivo priming with alloantigens, which resulted in reduced intragraft expression of effector molecules, such as interferon-γ, granzyme B, and perforin. This is mediated, at least in part, by preventing potentially alloreactive T cells from recruiting into secondary lymphoid organs. In addition, we found that DOCK2 is critical for CD28-mediated Rac activation and is required for the full activation of alloreactive T cells. Although DOCK2-deficient, alloreactive T cells were activated in vitro in the presence of exogenous interleukin-2, these T cells, when transferred adoptively, failed to infiltrate into the allografts that were transplanted into RAG1-deficient mice. Thus, DOCK2 deficiency attenuates allograft rejection by simultaneously suppressing multiple and key processes. We propose that DOCK2 could be a novel molecular target for controlling transplant rejection.
Nuclear accumulation of androgen receptor in gender difference of dilated cardiomyopathy due to lamin A/C mutations
Authors: Takuro Arimura, Kenji Onoue, Yumiko Takahashi-Tanaka, Taisuke Ishikawa, Masayoshi Kuwahara, Mitsutoshi Setou, Shuji Shigenobu, Katsushi Yamaguchi, Anne T. Bertrand, Noboru Machida, Kazumi Takayama, Masayuki Fukusato, Ryo Tanaka, Satoshi Somekawa, Tomoya Nakano, Yoshihisa Yamane, Keiji Kuba, Yumiko Imai, Yoshihiko Saito, Gisèle Bonne, Akinori Kimura
Journal: Cardiovascular Research (2013)

Dilated cardiomyopathy (DCM) is characterized by ventricular dilation associated with systolic dysfunction, which could be caused by mutations in lamina/C gene (LMNA). LMNA-linked DCM is severe in males in both human patients and a knock-in mouse model carrying a homozygous p.H222P mutation (LmnaH222P/H222P). The aim of this study was to investigate the molecular mechanisms underlying the gender difference of LMNA-linked DCM. A whole-exome analysis of a multiplex family with DCM exhibiting the gender difference revealed a DCM-linked LMNA mutation, p.R225X. Immunohistochemical analyses of neonatal rat cardiomyocytes expressing mutant LMNA constructs and heart samples from the LMNA-linked DCM patients and LmnaH222P/H222P mice demonstrated a nuclear accumulation of androgen receptor (AR) and its co-activators, serum response factor, and four-and-a-half LIM protein-2. Role of sex hormones in the gender difference was investigated in vivo using the LmnaH222P/H222P mice, where male and female mice were castrated and ovariectomized, respectively, or treated with testosterone or an antagonist of AR. Examination of the mice by echocardiography, followed by the analyses of histological changes and gene/protein expression profiles in the hearts, confirmed the involvement of testicular hormone in the disease progression and enhanced cardiac remodelling in the LmnaH222P/H222P mice. These observations indicated that nuclear accumulation of AR was associated with the gender difference in LMNA-linked DCM.
Insulin resistance and low-density apolipoprotein B-associated lipoviral particles in hepatitis C virus genotype 1 infection
Authors: S. H. Bridge, D. A. Sheridan, D. J. Felmlee, S. U. Nielsen, H. C. Thomas, S. D. Taylor-Robinson, R. D. G. Neely, G. L. Toms, M. F. Bassendine
Journal: Gut (2010)

<h3>Background</h3> The density of hepatitis C virus (HCV) in plasma is heterogeneous but the factors which influence this are poorly understood. Evidence from animal models and cell culture suggest that low-density apolipoprotein B (apoB)-associated HCV lipoviral particles (LVP) are more infectious than high-density HCV. <h3>Objective</h3> To measure LVP in patients with chronic hepatitis C genotype 1 (CHC-G1) and examine metabolic determinants of LVP load. <h3>Patients</h3> 51 patients with CHC-G1 infection. <h3>Methods</h3> Fasting lipid profiles and homeostasis model assessment of insulin resistance (HOMA-IR) were determined in 51 patients with CHC-G1. LVP and non-LVP viral load were measured by real-time PCR of plasma at density &lt;1.07 g/ml and &gt;1.07 g/ml, respectively, following iodixanol density gradient ultracentrifugation. The LVP ratio was calculated using the formula: LVP/(LVP + non-LVP). <h3>Results</h3> The mean LVP ratio was 0.241 but varied 25-fold (from 0.029 to 0.74). Univariate analysis showed that the LVP ratio correlated with HOMA-IR (p=0.004) and the triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio (p=0.004), but not with apoB. In multivariate analysis, HOMA-IR was the main determinant of LVP load (log<sub>10</sub>IU/ml) (R<sup>2</sup>=16.6%; p=0.037) but the TG/HDL-C ratio was the strongest predictor of the LVP ratio (R<sup>2</sup>=24.4%; p=0.019). Higher LVP ratios were associated with non-response to antiviral therapy (p=0.037) and with greater liver stiffness (p=0.001). <h3>Conclusion</h3> IR and associated dyslipidaemia are the major determinants of low-density apoB-associated LVP in fasting plasma. This provides a possible mechanism to explain why IR is associated with more rapidly progressive liver disease and poorer treatment outcomes.
Superior mesenteric embolectomy
Authors: G. L. Bohn, K. J. Carroll
Journal: Gut (1964)

This paper reports a successful superior mesenteric embolectomy. The possibility of successful surgical treatment makes its recognition particularly important. In any patient with a known history of cardiovascular disease who presents a sudden severe abdominal pain of obscure origin this diagnosis must be entertained. The pain at first is colicky because of the severe peristalsis which is induced but when ischaemia is marked it then becomes constant. With the crises of pain in the early stages the blood pressure falls and then recovers with the cessation of pain and this intermittent shock was a feature in the patient reported. A plain radiograph of the abdomen in the early stages is characterized by the absence or minimal presence of air in both the small and large bowel giving the film a very clear appearance. Prompt exploration is needed.
Striatal Dopaminergic D<sub>2</sub> Receptor Density Measured by [<sup>123</sup>I]Iodobenzamide SPECT in the Prediction of Treatment Outcome of Alcohol-Dependent Patients
Authors: J Guardia, A M Catafau, F Batlle, J C Martín, L Segura, B Gonzalvo, G Prat, I Carrió, M Casas
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: The authors’ goal was to study striatal dopaminergic dopamine 2 (D2) receptors as a biological marker of early relapse in detoxified alcoholic patients by using [123I]iodobenzamide ([123I]IBZM) single photon emission computed tomography (SPECT). METHOD: The authors performed [123I]IBZM SPECT on 21 alcohol-dependent inpatients during detoxification and on nine healthy volunteers, using the ratios of basal ganglia to occipital lobes for SPECT quantification. Depending on treatment outcome 3 months after hospital discharge, patients were determined to be relapsers or nonrelapsers. RESULTS: Alcohol-dependent subjects with early relapse (within 3 months after hospital discharge) showed a higher uptake of [123I]IBZM in the basal ganglia during detoxification (mean ratio=1.83, SD=0.9) than patients who did not have early relapse (mean ratio=1.69, SD=0.11). CONCLUSIONS: These results suggest that low levels of dopamine, or an increased density of free striatal dopaminergic D2 receptors, could be related to early relapse in alcohol-dependent patients. Therefore, [123I]IBZM SPECT could become a biological marker of vulnerability to relapse for alcoholic patients in recovery.
Recipes for Creating Animal Models of Diabetic Cardiovascular Disease
Authors: Willa Hsueh, E. Dale Abel, Jan L. Breslow, Nobuyo Maeda, Richard C. Davis, Edward A. Fisher, Hayes Dansky, Donald A. McClain, Richard McIndoe, Momtaz K. Wassef, Cristina Rabadán-Diehl, Ira J. Goldberg
Journal: Circulation Research (2007)

For more than 50 years, investigators have unsuccessfully tried to recreate in experimental animals the cardiovascular complications of diabetes seen in humans. In particular, accelerated atherosclerosis and dilated cardiomyopathy, the major causes of mortality in patients with diabetes, have been conspicuously absent in many mouse models of the disease. Under the auspices of the NIH, the Animal Models of Diabetic Complications Consortium has worked to address this issue. This effort has focused on the development of mouse models because of the high level of genomic information available and the many well-developed genetic manipulations that may be performed in mice. Importantly, the consortium has also worked to standardize many methods to assess metabolic and cardiovascular end points for measurement of the diabetic state and its macrovascular complications. Finally, for maximum benefits from these animal models in the study of atherosclerosis and of other diabetic complications, the consortium has created a system for sharing both the animal models and the accumulated phenotypic data with the greater scientific community.
Resistance to change, contrast, and intrinsic motivation
Authors: K. Geoffrey White, Judy Cameron
Journal: Behavioral and Brain Sciences (2000)

Many studies have demonstrated differential resistance to change in the context of negative behavioral contrast. That is, as a result of introducing a disruptor, response rates decrease to a greater extent when the maintaining reinforcement schedule is leaner. Resistance to change also applies to positive contrast, in that increases in response rate are greater in leaner schedules. The negative contrast effects seen in studies of intrinsically motivated behavior reflect an increase in resistance to change as a result of adding extrinsic reinforcers.