tbuckley/cabot-search huggingface dataset:
Mitoxantrone Inhibits HIF-1α Expression in a Topoisomerase II–Independent Pathway
Authors: Yng-Miin Toh, Tsai-Kun Li
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Solid tumors encounter a growth-limiting hypoxic microenvironment as they develop. Hypoxia-inducible factors (HIF) play important roles in hypoxia-associated tumor development and therapeutic resistance. Targeting the HIF pathway (especially HIF-1α) represents a promising cancer treatment strategy. Here, we report a novel class of HIF-1α inhibitors and the possible molecular basis of inhibition. Experimental Design: We analyzed the inhibitory effects of clinically used topoisomerase II (TOP2)–targeting drugs on HIF-1α expression with a primary focus on mitoxantrone. The potential role of TOP2 in mitoxantrone-inhibited HIF-1α expression was studied using pharmacologic inhibition, a knockdown approach, and TOP2 mutant cells. Moreover, involvement of mitoxantrone in proteasome-mediated degradation, transcription, and translation of HIF-1α was examined. Results: The TOP2-targeting mitoxantrone, but neither doxorubicin nor etoposide (VP-16), strongly inhibited HIF-1α expression under hypoxic conditions in a dose- and time-dependent manner. Surprisingly, the mitoxantrone-mediated inhibition of HIF-1α expression was largely independent of two TOP2 isozymes, proteasomal degradation, and transcription. Furthermore, mitoxantrone inhibited HIF-1α expression and function in a similar fashion as cycloheximide, suggesting that mitoxantrone might inhibit HIF-1α via a blockage at its translation step. In vitro translation experiments using HIF-1α mRNA further confirmed inhibition of HIF-1α translation by mitoxantrone. Interestingly, levels of the polysome-bound HIF-1α and VEGF-A mRNA were elevated and decreased after mitoxantrone treatment, respectively. Conclusions: We have identified the TOP2-targeting compound, mitoxantrone, as an HIF-1α inhibitor possibly through a translation inhibition mechanism, suggesting the possibility of an additional anticancer activity for mitoxantrone. Clin Cancer Res; 17(15); 5026–37. ©2011 AACR.
Constitutive co-stimulation by B cells is sufficient to trigger T cell-driven autoimmune disease
Authors: G Franco Salinas, T Cantaert, M Nolte, E Bettelli, V K Kuchroo, P P Tak, R A Van Lier, D L Baeten
Journal: Annals of the Rheumatic Diseases (2010)

At least two distinct signals are required for classical T cell activation: (1) the cognate antigen presented in the context of MHC class II molecules and (2) co-stimulation. Using myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) as a prototypical model of T cell-driven autoimmune disease, the authors and others demonstrated previously that autoimmune B cells are crucial in T cell activation by acting as potent antigen-presenting cells. Although the importance of …
HDL Particle Size Is a Critical Determinant of ABCA1-Mediated Macrophage Cellular Cholesterol Export
Authors: Xian-Ming Du, Mi-Jurng Kim, Liming Hou, Wilfried Le Goff, M. John Chapman, Miranda Van Eck, Linda K. Curtiss, John R. Burnett, Sian P. Cartland, Carmel M. Quinn, Maaike Kockx, Anatol Kontush, Kerry-Anne Rye, Leonard Kritharides, Wendy Jessup
Journal: Circulation Research (2015)

Rationale: High-density lipoprotein (HDL) is a heterogeneous population of particles. Differences in the capacities of HDL subfractions to remove cellular cholesterol may explain variable correlations between HDL-cholesterol and cardiovascular risk and inform future targets for HDL-related therapies. The ATP binding cassette transporter A1 (ABCA1) facilitates cholesterol efflux to lipid-free apolipoprotein A-I, but the majority of apolipoprotein A-I in the circulation is transported in a lipidated state and ABCA1-dependent efflux to individual HDL subfractions has not been systematically studied. Objective: Our aims were to determine which HDL particle subfractions are most efficient in mediating cellular cholesterol efflux from foam cell macrophages and to identify the cellular cholesterol transporters involved in this process. Methods and Results: We used reconstituted HDL particles of defined size and composition, isolated subfractions of human plasma HDL, cell lines stably expressing ABCA1 or ABCG1, and both mouse and human macrophages in which ABCA1 or ABCG1 expression was deleted. We show that ABCA1 is the major mediator of macrophage cholesterol efflux to HDL, demonstrating most marked efficiency with small, dense HDL subfractions (HDL3b and HDL3c). ABCG1 has a lesser role in cholesterol efflux and a negligible role in efflux to HDL3b and HDL3c subfractions. Conclusions: Small, dense HDL subfractions are the most efficient mediators of cholesterol efflux, and ABCA1 mediates cholesterol efflux to small dense HDL and to lipid-free apolipoprotein A-I. HDL-directed therapies should target increasing the concentrations or the cholesterol efflux capacity of small, dense HDL species in vivo.
RNA Helicase DDX5 Is a p53-Independent Target of ARF That Participates in Ribosome Biogenesis
Authors: Anthony J. Saporita, Hsiang-Chun Chang, Crystal L. Winkeler, Anthony J. Apicelli, Raleigh D. Kladney, Jianbo Wang, R. Reid Townsend, Loren S. Michel, Jason D. Weber
Journal: Cancer Research (2011)

Abstract The p19ARF tumor suppressor limits ribosome biogenesis and responds to hyperproliferative signals to activate the p53 checkpoint response. Although its activation of p53 has been well characterized, the role of ARF in restraining nucleolar ribosome production is poorly understood. Here we report the use of a mass spectroscopic analysis to identify protein changes within the nucleoli of Arf-deficient mouse cells. Through this approach, we discovered that ARF limited the nucleolar localization of the RNA helicase DDX5, which promotes the synthesis and maturation of rRNA, ultimately increasing ribosome output and proliferation. ARF inhibited the interaction between DDX5 and nucleophosmin (NPM), preventing association of DDX5 with the rDNA promoter and nuclear pre-ribosomes. In addition, Arf-deficient cells transformed by oncogenic RasV12 were addicted to DDX5, because reduction of DDX5 was sufficient to impair RasV12-driven colony formation in soft agar and tumor growth in mice. Taken together, our findings indicate that DDX5 is a key p53-independent target of the ARF tumor suppressor and is a novel non-oncogene participant in ribosome biogenesis. Cancer Res; 71(21); 6708–17. ©2011 AACR.
<i>In vitro</i>Peptide Immunization of Target Tax Protein Human T-Cell Leukemia Virus Type 1–Specific CD4+ Helper T Lymphocytes
Authors: Hiroya Kobayashi, Toshihiro Ngato, Keisuke Sato, Naoko Aoki, Shoji Kimura, Yuetsu Tanaka, Hitoshi Aizawa, Masatoshi Tateno, Esteban Celis
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Adult T-cell leukemia/lymphoma induced by human T-cell leukemia virus type 1 (HTLV-1) is usually a fatal lymphoproliferative malignant disease. HTLV-1 Tax protein plays a critical role in HTLV-1-associated leukemogenesis and is an attractive target for vaccine development. Although HTLV-1 Tax is the most dominant antigen for HTLV-1-specific CD8+ CTLs in HTLV-1-infected individuals, few epitopes recognized by CD4+ helper T lymphocytes in HTLV-1 Tax protein have been described. The aim of the present study was to study T-helper-cell responses to HTLV-1 Tax and to identify naturally processed MHC class II–restricted epitopes that could be used for vaccine development. Experimental Design: An MHC class II binding peptide algorithm was used to predict potential T-helper cell epitope peptides from HTLV-1 Tax. We assessed the ability of the corresponding peptides to elicit helper T-cell responses by in vitro vaccination of purified CD4+ T lymphocytes. Results: Peptides Tax191-205 and Tax305-319 were effective in inducing T-helper-cell responses. Although Tax191-205 was restricted by the HLA-DR1 and DR9 alleles, responses to Tax305-319 were restricted by either DR15 or DQ9. Both these epitopes were found to be naturally processed by HTLV-1+ T-cell lymphoma cells and by autologous antigen-presenting cells that were pulsed with HTLV-1 Tax+ tumor lysates. Notably, the two newly identified helper T-cell epitopes are found to lie proximal to known CTL epitopes, which will facilitate the development of prophylactic peptide–based vaccine capable of inducing simultaneous CTL and T-helper responses. Conclusion: Our data suggest that HTLV-1 Tax protein could serve as tumor-associated antigen for CD4+ helper T cells and that the present epitopes might be used for T-cell-based immunotherapy against tumors expressing HTLV-1.
Biphasic effects of prostaglandin E2 on the human fat cell adenylate cyclase.
Authors: H Kather, B Simon
Journal: Journal of Clinical Investigation (1979)

Adenylate cyclase of human fat cell ghosts shows a biphasic response towards prostaglandin E2 with inhibition occurring at nanomolar concentrations of the hormone and stimulation at concentrations beyond 10(-6) mol/liter. The expression of the inhibitory effect is critically dependent on GTP. Under the conditions employed (1 mmol/liter ATP, 5 mmol/liter Mg2+, 30 degrees C) the inhibitory component of prostaglandin E2 became apparent at GTP concentrations exceeding 10(-6) mol/liter. The prostaglandin E2-induced inhibition displayed characteristic features of prostaglandin action in intact fat cells with respect to the effective concentrations and degree of inhibition. It is concluded that prostaglandin E2 is capable of inducing antagonistic effects upon lipolysis via interaction with the membrane-bound adenylate cyclase.
VHZ is a novel centrosomal phosphatase associated with cell growth and human primary cancers
Authors: Jing Ping Tang, Cheng Peow Tan, Jie Li, Md Monowarul Siddique, Ke Guo, Siew Wee Chan, Jung Eun Park, Wan Ngee Tay, Zhi Yuan Huang, Wen Cai Li, Jian Chen, Qi Zeng
Journal: Molecular Cancer (2010)

Abstract Background VHZ is a VH1-like (member Z) dual specific protein phosphatase encoded by DUSP23 gene. Some of the dual specific protein phosphatases (DSPs) play an important role in cell cycle control and have shown to be associated with carcinogenesis. Here, the expression of VHZ associated with cell growth and human cancers was investigated. Results We generated a mouse monoclonal antibody (mAb clone#209) and rabbit polyclonal antibodies (rAb) against VHZ. We performed cell proliferation assay to learn how VHZ is associated with cell cycle by retroviral transduction to express VHZ, VHZ(C95S), and control vector in MCF-7 cells. Overexpression of VHZ [but not VHZ(C95S)] in MCF-7 cells promoted cell proliferation compared to control cells. shRNA-mediated knockdown of VHZ in MCF-7 cells showed that reduction of VHZ resulted in increased G1 but decreased S phase cell populations. Using indirect immunofluorescence, we showed that both exogenous and endogenous VHZ protein was localized at the centrosome in addition to its cytoplasmic distribution. Furthermore, using immunohistochemistry, we revealed that VHZ protein was overexpressed either in enlarged centrosomes (VHZ-centrosomal-stain) of some invasive ductal carcinomas (IDC) Stage I (8/65 cases) or in entire cytoplasm (VHZ-cytosol-stain) of invasive epithelia of some IDC Stage II/III (11/47 cases) of breast cancers examined. More importantly, upregulation of VHZ protein is also associated with numerous types of human cancer, in particular breast cancer. VHZ mAb may be useful as a reagent in clinical diagnosis for assessing VHZ positive tumors. Conclusions We generated a VHZ-specific mAb to reveal that VHZ has a novel subcellular localization, namely the centrosome. VHZ is able to facilitate G1/S cell cycle transition in a PTP activity-dependent manner. The upregulation of its protein levels in primary human cancers supports the clinical relevance of the protein in cancers.
Na+/K+-ATPase activity in vascular smooth muscle from streptozotocin diabetic rat
Authors: J Smith
Journal: Cardiovascular Research (1997)

Objectives: Insulin-deficient diabetes impairs carbohydrate metabolism in a variety of tissues. Vascular smooth muscle may be susceptible to the diabetes-induced disturbance in glycolysis since Na+/K+-ATPase in this tissue preferentially utilizes ATP generated by glycolysis. The purpose of this study was to determine if chronic exposure to the metabolic alterations associated with insulin-deficient diabetes directly inhibited Na+/K+-ATPase activity, or its regulation, in vascular smooth muscle. Methods: Diabetes was induced by intravenous administration of streptozotocin (60 mg/kg). After 12 weeks, Na+/K+-ATPase activity in aorta and superior mesenteric artery was evaluated under a variety of conditions. Na+/K+-ATPase was estimated by measuring the influx of rubidium-86 (86Rb) in the presence or absence of the Na+/K+-ATPase inhibitor, ouabain. The metabolism of [3H]glucose and [14C]glucose was used to estimate glycolysis or glucose oxidation, respectively. Results: Glycolysis and glucose oxidation were decreased in aortic smooth muscle (27 and 34%, respectively). An intact endothelium was associated with a marked decrease in ouabain-sensitive (pump-mediated) 86Rb uptake in diabetic aorta. However, ouabain-sensitive 86Rb uptake was similar in de-endothelialized aorta and superior mesenteric artery from diabetic and non-diabetic rats under both unstimulated conditions and during maximal stimulation. Removal of glucose or oxygen reduced ouabain-sensitive 86Rb uptake to a similar extent in both groups. In contrast, the receptor-mediated stimulation of ouabain-sensitive 86Rb uptake by insulin was decreased. Conclusions: These results suggest that intrinsic Na+/K+-ATPase activity is not diminished in diabetic vascular smooth muscle under physiological conditions and that the impairment of cellular metabolism in diabetic blood vessels does not limit stimulation of Na+/K+-ATPase activity. However, modulation of Na+/K+-ATPase activity by endothelial factors or insulin appears to be altered in aorta from diabetic rats.
Expression of the alpha 1-proteinase inhibitor gene family during evolution of the genus Mus
Authors: R L Goodwin, K W Barbour, F G Berger
Journal: Molecular Biology and Evolution (1997)

alpha 1-Proteinase inhibitors (alpha 1-PIs) are members of the serpin superfamily of proteinase inhibitors, and are important in the maintenance of homeostasis in a wide variety of animal taxa. Previous studies have shown that in mice (genus Mus), evolution of alpha 1-PIs is characterized by gene amplification, region-specific concerted evolution, and rapid accumulation of amino acid substitutions. The latter occurs primarily in the reactive center, which is the region of the alpha 1-PI molecule that determines the inhibitor's specificity for target proteinases. The P1 residue within the reactive center, which is methionine in so-called orthodox alpha 1-PIs and an amino acid other than methionine in unorthodox alpha 1-PIs, is a primary determinant of inhibitor specificity. In the present study, we find that the expression of mRNAs encoding unorthodox alpha 1-PIs is polymorphic within Mus species, i.e., among individuals or inbred strains. This is in striking contrast to mRNAs that encode orthodox alpha 1-PIs, whose concentrations are relatively invariant. The intraspecies variations in mRNA expression represent polymorphisms in the structure of the alpha 1-PI gene family. The results, taken together with previously described aspects of alpha 1-PI evolution, indicate that the dissimilar levels of polymorphism exhibited by orthodox and unorthodox alpha 1-PIs, which likely have distinct physiological functions, may reflect different levels of selective constraint. The significance of this finding to the evolution of gene families is discussed.
Immune interferon produced to high levels by antigenic stimulation of human lymphocytes with influenza virus.
Authors: F A Ennis, A Meager
Journal: The Journal of Experimental Medicine (1981)

Influenza virus stimulation of human lymphocytes induced high levels of immune interferon in lymphocyte cultures. The lymphocytes of normal adults produced approximately 1,000 U/10(6) cells, which was in large part gamma interferon. The lymphocytes of individuals recently vaccinated yielded very high levels (10-50,000 U/10(6) cells) of interferon. The interferon was pH 2 labile, and was not neutralized by antisera to alpha or beta interferon. It did not bind to a monoclonal antibody to alpha interferon, and after partial purification it had characteristics identical to human gamma interferon induced by phytohemagglutinin. The highest yields were produced by treatment of stimulator cells with live virus. Stimulation by whole inactivated virus resulted in lower levels of interferon, and purified hemagglutinin did not induce interferon. The antigen responsible for stimulating the lymphocyte response and interferon induction is a cross-reactive determinant present on all human and non-human influenza viruses tested.
Differential recognition of double-stranded RNA by RIG-I–like receptors in antiviral immunity
Authors: Takeshi Saito, Michael Gale
Journal: The Journal of Experimental Medicine (2008)

Retinoic acid–inducible gene (RIG)-I–like receptors (RLRs) are cytosolic RNA helicases that sense viral RNA and trigger signaling pathways that induce the production of type I interferons (IFNs) and proinflammatory cytokines. RLRs recognize distinct and overlapping sets of viruses, but the mechanisms that dictate this specificity were unknown. A new study now provides evidence for size-based discrimination of double-stranded RNA (dsRNA) by RLRs and suggests how host cells recognize a variety of RNA viruses.
Barriers to physical activity promotion by general practitioners and practice nurses.
Authors: J McKenna, P J Naylor, N McDowell
Journal: British Journal of Sports Medicine (1998)

OBJECTIVE: To examine the promotion of physical activity by general practitioners (GPs) and practice nurses (PNs). METHODS: A questionnaire that examined the types of barriers and the levels of their influence as well as stage of change for activity promotion and for personal behaviour was mailed to 846 subjects. RESULTS: The return rate exceeded 70% in each group with a high proportion (69%) of GPs and PNs reporting that they regularly promote physical activity with their patients. GPs were less likely to regularly promote physical activity with their patients if they indicated lack of time as a barrier (odds ratio (OR) = 0.73, 95% confidence interval (CI) 0.58 to 0.93) or lack of incentives (OR = 0.74, 95% CI 0.59 to 0.94), and more likely to promote exercise if they themselves were regular exercisers (OR = 3.19, 95% CI 1.96 to 5.18). However, for PNs longer consultation times (by 1.5 to 2 minutes) had a higher likelihood of producing regular promotion of activity (OR = 1.61, 95% CI 1.02 to 1.62). For PNs personal physical activity stage was the strongest significant predictor of promotion level, but with a stronger effect (OR = 4.77, 95% CI 1.48 to 15.35) than in the GPs. CONCLUSION: The main finding is that GPs in the action or maintenance stage of changing their own physical activity are three times more likely to regularly promote the same behaviour in their patients than those in the other stages; for PNs the same difference quadruples the likelihood of them promoting physical activity. Professional readiness to change is influenced by known system barriers in GPs, and not in PNs, but is more strongly predicted by personal physical activity behaviour in both groups.
EST FOLLOWING A SELF-INFLICTED SKULL AND DURAL LESION
Authors: JULIAN W. SELIG
Journal: American Journal of Psychiatry (1964)

A case is reported in which EST is successfully given in spite of a recent head wound resulting in absence of a small portion of the skull in the frontal lesion, laceration of the dura, but no actual brain tissue damage. It is urged that successful treatments along with physical complications be reported. However, this is not to say that EST should be given indiscriminately. Also, non-successful treatments should be reported.
Objective Cancer-Related Variables Are Not Associated With Depressive Symptoms in Women Treated for Early-Stage Breast Cancer
Authors: Wayne A. Bardwell, Loki Natarajan, Joel E. Dimsdale, Cheryl L. Rock, Joanne E. Mortimer, Kathy Hollenbach, John P. Pierce
Journal: Journal of Clinical Oncology (2006)

Women with breast cancer are thought to be vulnerable to depression for reasons associated with impact of diagnosis, treatment, and metabolic/endocrine changes. While the literature shows that most of these women do not become clinically depressed, 15% to 30% report elevated depressive symptoms that may be clinically important. The purpose was to identify and determine the relative importance of predictors of depressive symptoms in women treated for early-stage breast cancer.A total of 2,595 women (< or = 4 years following completion of initial treatment for early-stage breast cancer) provided data on cancer-related variables, personal characteristics, health behaviors, physical functioning/symptoms, and psychosocial variables. Participants were divided into high or low depressive groups using the Center for Epidemiologic Studies Depression Scale screening form.Results of the binary logistic regression analysis were significant (overall R2 = 32.4%). Before entry of psychosocial variables, younger age, being unmarried, poorer physical functioning, and more vasomotor and gastrointestinal symptoms were significant risk factors for elevated depressive symptoms (R2 = 16.1%), but objective cancer-related variables were not. After inclusion of psychosocial variables in the model (DeltaR2 = 16.3%), none of the preceding variables remained significant. Greater risk for depressive symptoms was associated with stressful life events, less optimism, ambivalence over expressing negative emotions, sleep disturbance, and poorer social functioning.Depressive symptoms in women treated for early-stage breast cancer are not associated with objective cancer-related factors. Rather, they are most strongly linked with many subjective psychosocial variables.
Inhibition of Breast Cancer Cell Growth <i>In vitro</i> and <i>In vivo</i>: Effect of Restoration of Wwox Expression
Authors: Dimitrios Iliopoulos, Muller Fabbri, Teresa Druck, Haiyan R. Qin, Shuang-Yin Han, Kay Huebner
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The WWOX gene is down-regulated in breast cancer and loss of Wwox expression correlates with important clinical features of breast cancer. Thus, we have examined the effect of restoration of Wwox expression in breast cancer-derived cells. Experimental Design: Wwox protein expression was restored by the following: (a) infection with a recombinant adenovirus carrying WWOX cDNA (Ad-WWOX) or (b) treatment with the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, to activate the endogenous WWOX gene, in breast cancer-derived cells in vitro and in vivo. Results: Restoration of Wwox expression led to suppression of growth of Wwox-deficient breast cancer-derived cells, through activation of the intrinsic caspase pathway, but did not affect growth of Wwox-sufficient MCF7 cells. Intratumoral Wwox restoration, through Ad-WWOX infection or endogenous Wwox reactivation by 5-aza-2′-deoxycytidine injection, suppressed tumor growth in nude mice by inducing apoptosis. Alteration of global methylation levels was not observed. Conclusions: The results confirm that overexpression of exogenous Wwox inhibits breast cancer cell growth in vitro and in vivo and, perhaps more importantly, shows that restoration of endogenous Wwox expression, and likely other proteins, by treatment with a de novo methyltransferase inhibitor, also inhibits breast cancer cell growth and reverses breast cancer xenograft growth.