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Sample records for anemia pathway inhibitors

  1. A High-Throughput Screening Strategy to Identify Protein-Protein Interaction Inhibitors That Block the Fanconi Anemia DNA Repair Pathway.

    Science.gov (United States)

    Voter, Andrew F; Manthei, Kelly A; Keck, James L

    2016-07-01

    Induction of the Fanconi anemia (FA) DNA repair pathway is a common mechanism by which tumors evolve resistance to DNA crosslinking chemotherapies. Proper execution of the FA pathway requires interaction between the FA complementation group M protein (FANCM) and the RecQ-mediated genome instability protein (RMI) complex, and mutations that disrupt FANCM/RMI interactions sensitize cells to DNA crosslinking agents. Inhibitors that block FANCM/RMI complex formation could be useful therapeutics for resensitizing tumors that have acquired chemotherapeutic resistance. To identify such inhibitors, we have developed and validated high-throughput fluorescence polarization and proximity assays that are sensitive to inhibitors that disrupt interactions between the RMI complex and its binding site on FANCM (a peptide referred to as MM2). A pilot screen of 74,807 small molecules was performed using the fluorescence polarization assay. Hits from the primary screen were further tested using the proximity assay, and an orthogonal proximity assay was used to assess inhibitor selectivity. Direct physical interaction between the RMI complex and the most selective inhibitor identified through the screening process was measured by surface plasmon resonance and isothermal titration calorimetry. Observation of direct binding by this small molecule validates the screening protocol.

  2. Targeting the Fanconi Anemia Pathway to Identify Tailored Anticancer Therapeutics

    Directory of Open Access Journals (Sweden)

    Chelsea Jenkins

    2012-01-01

    Full Text Available The Fanconi Anemia (FA pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs. The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways. Selective killing of cancer cells with an intact FA pathway but deficient in certain other DNA repair pathways is an emerging approach to tailored cancer therapy. Inhibiting the FA pathway becomes selectively lethal when certain repair genes are defective, such as the checkpoint kinase ATM. Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

  3. Iron-deficiency anemia caused by a proton pump inhibitor.

    Science.gov (United States)

    Hashimoto, Rintaro; Matsuda, Tomoki; Chonan, Akimichi

    2014-01-01

    A 59-year-old man was orally administered rabeprazole, a proton pump inhibitor (PPI), for gastroesophageal reflux disease, after which he gradually developed iron-deficiency anemia. The anemia did not improve following the administration of ferrous fumarate, and endoscopic screening of the entire gastrointestinal tract, including the small intestine, did not reveal any findings indicating the cause of the anemia. The patient was then switched from rabeprazole to famotidine and the anemia was cured within three months. There is much debate as to whether the long-term use of PPIs causes iron-deficiency. However, this case strongly suggests that PPIs can induce iron-deficiency anemia.

  4. Anemia

    Science.gov (United States)

    ... Hemolytic anemia Idiopathic aplastic anemia Megaloblastic anemia Pernicious anemia Sickle cell anemia Thalassemia Causes Although many parts of the ... anemia Immune hemolytic anemia Iron deficiency anemia Pernicious anemia Sickle cell anemia Vitamin B12 deficiency anemia Review Date 2/ ...

  5. Tissue factor pathway inhibitor endocytosis.

    Science.gov (United States)

    Schwartz, A L; Broze, G J

    1997-10-01

    Tissue factor pathway inhibitor (TFPI), a 42 kD protein, provides the physiological inhibition of tissue factor initiated coagulation by inhibition of both factor Xa and factor VIIa/tissue factor. In plasma, most TFPI is lipoprotein bound with an additional "releasable" pool bound to the endothelial cell surface. TFPI clearance is via receptor mediated endocytosis into liver. Heparin sulfate proteoglycans and LRP (low density lipoprotein receptor-related protein), an extremely large (∼600 kD) cell surface protein, primarily mediate this clearance, although additional TFPI binding sites and endocytosis pathways exist. (Trends Cardiovasc Med 1997; 7:234-239). © 1997, Elsevier Science Inc.

  6. Non-specific chemical inhibition of the Fanconi anemia pathway sensitizes cancer cells to cisplatin

    Directory of Open Access Journals (Sweden)

    Jacquemont Céline

    2012-04-01

    Full Text Available Abstract Background Platinum compounds such as cisplatin and carboplatin are DNA crosslinking agents widely used for cancer chemotherapy. However, the effectiveness of platinum compounds is often tempered by the acquisition of cellular drug resistance. Until now, no pharmacological approach has successfully overcome cisplatin resistance in cancer treatment. Since the Fanconi anemia (FA pathway is a DNA damage response pathway required for cellular resistance to DNA interstrand crosslinking agents, identification of small molecules that inhibit the FA pathway may reveal classes of chemicals that sensitize cancer cells to cisplatin. Results Through a cell-based screening assay of over 16,000 chemicals, we identified 26 small molecules that inhibit ionizing radiation and cisplatin-induced FANCD2 foci formation, a marker of FA pathway activity, in multiple human cell lines. Most of these small molecules also compromised ionizing radiation-induced RAD51 foci formation and homologous recombination repair, indicating that they are not selective toward the regulation of FANCD2. These compounds include known inhibitors of the proteasome, cathepsin B, lysosome, CHK1, HSP90, CDK and PKC, and several uncharacterized chemicals including a novel proteasome inhibitor (Chembridge compound 5929407. Isobologram analyses demonstrated that half of the identified molecules sensitized ovarian cancer cells to cisplatin. Among them, 9 demonstrated increased efficiency toward FA pathway-proficient, cisplatin-resistant ovarian cancer cells. Six small molecules, including bortezomib (proteasome inhibitor, CA-074-Me (cathepsin B inhibitor and 17-AAG (HSP90 inhibitor, synergized with cisplatin specifically in FA-proficient ovarian cancer cells (2008 + FANCF, but not in FA-deficient isogenic cells (2008. In addition, geldanamycin (HSP90 inhibitor and two CHK1 inhibitors (UCN-01 and SB218078 exhibited a significantly stronger synergism with cisplatin in FA

  7. Anemias.

    Science.gov (United States)

    Broadway-Duren, Jacqueline B; Klaassen, Hillary

    2013-12-01

    Anemias continue to present a challenge to the health care profession. Anemia is defined as a reduction in one or more of the RBC indices. Patients presenting with a mild form of anemia may be asymptomatic; however, in more serious cases the anemia can become life threatening. In many cases the clinical presentation also reflects the underlying cause. Anemia may be attributed to various causes, whereas autoimmune RBC destruction may be attributed to intrinsic and extrinsic factors. Laboratory tests are essential in facilitating early detection and differentiation of anemia.

  8. Anemia

    Science.gov (United States)

    ... are affected. Low levels of red blood cells leads to anemia. With low levels of white blood cells, the ... foods they eat. Food fads and dieting can lead to anemia. Talk to your doctor about taking iron pills ( ...

  9. BRCA/Fanconi anemia pathway implicates chemoresistance to gemcitabine in biliary tract cancer.

    Science.gov (United States)

    Nakashima, Shinsuke; Kobayashi, Shogo; Nagano, Hiroaki; Tomokuni, Akira; Tomimaru, Yoshito; Asaoka, Tadafumi; Hama, Naoki; Wada, Hiroshi; Kawamoto, Koichi; Marubashi, Shigeru; Eguchi, Hidetoshi; Doki, Yuichiro; Mori, Masaki

    2015-05-01

    The BRCA/Fanconi anemia (FA) pathway plays a key role in the repair of DNA double strand breaks. We focused on this pathway to clarify chemoresistance mechanisms in biliary tract cancer (BTC). We also investigated changes in the CD24(+)/44(+) population that may be involved in chemoresistance, as this population likely includes cancer stem cells. We used three BTC cell lines to establish gemcitabine (GEM)-resistant (GR) cells and evaluated the expression of BRCA/FA pathway components, chemoresistance, and the effect of BRCA/FA pathway inhibition on the CD24(+)/44(+) population. FANCD2 and CD24 expression were evaluated in 108 resected BTC specimens. GR cells highly expressed the BRCA/FA components. The BRCA/FA pathway was upregulated by GEM and cisplatin (CDDP) exposure. Inhibition using siRNA and RAD51 inhibitor sensitized GR cells to GEM or CDDP. The CD24(+)/44(+) population was increased in GR and parent BTC cells treated with GEM or CDDP and highly expressed BRCA/FA genes. FANCD2 was related to CD24 expression in resected BTC specimens. Inhibition of the BRCA/FA pathway under GEM reduced the CD24(+)/44(+) population in MzChA1-GR cells. Thus, high expression of the BRCA/FA pathway is one mechanism of chemoresistance against GEM and/or CDDP and is related to the CD24(+)/44(+) population in BTC.

  10. Anemia

    Science.gov (United States)

    ... Physician October 01, 2002, http://www.aafp.org/afp/20021001/1217.html)Normocytic Anemia by JR Brill, ... Physician November 15, 2000, http://www.aafp.org/afp/20001115/2255.html) Last Updated: February 2014 This ...

  11. Ubiquitin-like protein UBL5 promotes the functional integrity of the Fanconi anemia pathway

    DEFF Research Database (Denmark)

    Oka, Yasuyoshi; Bekker-Jensen, Simon; Mailand, Niels

    2015-01-01

    in promoting the function of the Fanconi anemia (FA) pathway for repair of DNA interstrand crosslinks (ICLs), mediated by a specific interaction with the central FA pathway component FANCI. UBL5-deficient cells display spliceosome-independent reduction of FANCI protein stability, defective FANCI function...

  12. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors.

    NARCIS (Netherlands)

    Taniguchi, T; Tischkowitz, M; Ameziane, N.; Hodgson, SV; Mathew, C.G.; Joenje, H.; Mok, SC; Andrea, d' AD

    2003-01-01

    Ovarian tumor cells are often genomically unstable and hypersensitive to cisplatin. To understand the molecular basis for this phenotype, we examined the integrity of the Fanconi anemia-BRCA (FANC-BRCA) pathway in those cells. This pathway regulates cisplatin sensitivity and is governed by the coord

  13. Clinical implications of hedgehog signaling pathway inhibitors

    Institute of Scientific and Technical Information of China (English)

    Hailan Liu; Dongsheng Gu; Jingwu Xie

    2011-01-01

    Hedgehog was first described in Drosophila melanogaster by the Nobel laureates Eric Wieschaus and Christiane Nusslein-Volhard. The hedgehog (Hh) pathway is a major regulator of cell differentiation,proliferation, tissue polarity, stem cell maintenance, and carcinogenesis. The first link of Hh signaling to cancer was established through studies of a rare familial disease, Gorlin syndrome, in 1996. Follow-up studies revealed activation of this pathway in basal cell carcinoma, medulloblastoma and, leukemia as well as in gastrointestinal, lung, ovarian, breast, and prostate cancer. Targeted inhibition of Hh signaling is now believed to be effective in the treatment and prevention of human cancer. The discovery and synthesis of specific inhibitors for this pathway are even more exciting. In this review, we summarize major advances in the understanding of Hh signaling pathway activation in human cancer, mouse models for studying Hhmediated carcinogenesis, the roles of Hh signaling in tumor development and metastasis, antagonists for Hh signaling and their clinical implications.

  14. Signaling Pathways in Pathogenesis of Diamond Blackfan Anemia

    Science.gov (United States)

    2015-12-01

    erythroid differentiation. We hypothesize that RPS19 insufficiency mediates defects in erythropoiesis through upregulation of p53 and miR34a. To...formation, but also aberrant erythroid differentiation. We hypothesize that RPS19 insufficiency mediates defects in erythropoiesis through upregulation...that mediate RPS14-induced anemia in MDS. How were the results disseminated to communities of interest? The data were presented at UCLA during

  15. Structure of the FANCI-FANCD2 Complex: Insights into the Fanconi Anemia DNA Repair Pathway

    Energy Technology Data Exchange (ETDEWEB)

    Joo, Woo; Xu, Guozhou; Persky, Nicole S.; Smogorzewska, Agata; Rudge, Derek G.; Buzovetsky, Olga; Elledge, Stephen J.; Pavletich, Nikola P. (Harvard-Med); (Cornell); (MSKCC)

    2011-08-29

    Fanconi anemia is a cancer predisposition syndrome caused by defects in the repair of DNA interstrand cross-links (ICLs). Central to this pathway is the Fanconi anemia I-Fanconi anemia D2 (FANCI-FANCD2) (ID) complex, which is activated by DNA damage-induced phosphorylation and monoubiquitination. The 3.4 angstrom crystal structure of the {approx}300 kilodalton ID complex reveals that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting that they occur on monomeric proteins or an opened-up complex and that they may serve to stabilize I-D heterodimerization. The 7.8 angstrom electron-density map of FANCI-DNA crystals and in vitro data show that each protein has binding sites for both single- and double-stranded DNA, suggesting that the ID complex recognizes DNA structures that result from the encounter of replication forks with an ICL.

  16. Structure of the FANCI-FANCD2 Complex: Insights into the Fanconi Anemia DNA Repair Pathway

    Energy Technology Data Exchange (ETDEWEB)

    W Joo; G Xu; n Persky; A Smogorzewska; D Rudge; O Buzovetsky; S Elledge; N Pavletich

    2011-12-31

    Fanconi anemia is a cancer predisposition syndrome caused by defects in the repair of DNA interstrand cross-links (ICLs). Central to this pathway is the Fanconi anemia I-Fanconi anemia D2 (FANCI-FANCD2) (ID) complex, which is activated by DNA damage-induced phosphorylation and monoubiquitination. The 3.4 angstrom crystal structure of the {approx}300 kilodalton ID complex reveals that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting that they occur on monomeric proteins or an opened-up complex and that they may serve to stabilize I-D heterodimerization. The 7.8 angstrom electron-density map of FANCI-DNA crystals and in vitro data show that each protein has binding sites for both single- and double-stranded DNA, suggesting that the ID complex recognizes DNA structures that result from the encounter of replication forks with an ICL.

  17. Different Pathways Leading to Integrase Inhibitors Resistance

    Science.gov (United States)

    Thierry, Eloïse; Deprez, Eric; Delelis, Olivier

    2017-01-01

    Integrase strand-transfer inhibitors (INSTIs), such as raltegravir (RAL), elvitegravir, or dolutegravir (DTG), are efficient antiretroviral agents used in HIV treatment in order to inhibit retroviral integration. By contrast to RAL treatments leading to well-identified mutation resistance pathways at the integrase level, recent clinical studies report several cases of patients failing DTG treatment without clearly identified resistance mutation in the integrase gene raising questions for the mechanism behind the resistance. These compounds, by impairing the integration of HIV-1 viral DNA into the host DNA, lead to an accumulation of unintegrated circular viral DNA forms. This viral DNA could be at the origin of the INSTI resistance by two different ways. The first one, sustained by a recent report, involves 2-long terminal repeat circles integration and the second one involves expression of accumulated unintegrated viral DNA leading to a basal production of viral particles maintaining the viral information. PMID:28123383

  18. Formaldehyde catabolism is essential in cells deficient for the Fanconi anemia DNA-repair pathway.

    Science.gov (United States)

    Rosado, Ivan V; Langevin, Frédéric; Crossan, Gerry P; Takata, Minoru; Patel, Ketan J

    2011-11-13

    Metabolism is predicted to generate formaldehyde, a toxic, simple, reactive aldehyde that can damage DNA. Here we report a synthetic lethal interaction in avian cells between ADH5, encoding the main formaldehyde-detoxifying enzyme, and the Fanconi anemia (FA) DNA-repair pathway. These results define a fundamental role for the combined action of formaldehyde catabolism and DNA cross-link repair in vertebrate cell survival.

  19. How SUMOylation Fine-Tunes the Fanconi Anemia DNA Repair Pathway

    Directory of Open Access Journals (Sweden)

    Kate eColeman

    2016-04-01

    Full Text Available Fanconi Anemia (FA is a rare human genetic disorder characterized by developmental defects, bone marrow failure and cancer predisposition, primarily due to a deficiency in the repair of DNA interstrand crosslinks (ICLs. ICL repair through the FA DNA repair pathway is a complicated multi-step process, involving at least 19 FANC proteins and coordination of multiple DNA repair activities, including homologous recombination (HR, nucleotide excision repair (NER and translesion synthesis (TLS. SUMOylation is a critical regulator of several DNA repair pathways, however, the role of this modification in controlling the FA pathway is poorly understood. Here, we summarize recent advances in the fine-tuning of the FA pathway by SUMO-targeted ubiquitin ligases (STUbLs and other SUMO-related interactions, and discuss the implications of these findings in the design of novel therapeutics for alleviating FA-associated condition, including cancer.

  20. Clinical development of phosphatidylinositol-3 kinase pathway inhibitors.

    Science.gov (United States)

    Arteaga, Carlos L

    2010-01-01

    The PI3K pathway is the most commonly altered in human cancer. Several recent phase I studies with therapeutic inhibitors of this pathway have shown that pharmacological inhibition of PI3K in humans is feasible and overall well tolerated. Furthermore, there has already been clinical evidence of anti-tumor activity in patients with advanced cancer. The intensity and duration of PI3K inhibition required for an antitumor effect and the optimal pharmacodynamic biomarker(s) of pathway inactivation remain to be established. Preclinical and early clinical data support focusing on trials with PI3K inhibitors that are at a minimum enriched with patients with alterations in this signaling pathway. These inhibitors are likely to be more effective in combination with established and other novel molecular therapies.

  1. The Fanconi anemia pathway: Repairing the link between DNA damage and squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Romick-Rosendale, Lindsey E. [Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children' s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229 (United States); Lui, Vivian W.Y.; Grandis, Jennifer R. [Department of Otolaryngology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Wells, Susanne I., E-mail: Susanne.Wells@cchmc.org [Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children' s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229 (United States)

    2013-03-15

    Fanconi anemia (FA) is a rare inherited recessive disease caused by mutations in one of fifteen genes known to encode FA pathway components. In response to DNA damage, nuclear FA proteins associate into high molecular weight complexes through a cascade of post-translational modifications and physical interactions, followed by the repair of damaged DNA. Hematopoietic cells are particularly sensitive to the loss of these interactions, and bone marrow failure occurs almost universally in FA patients. FA as a disease is further characterized by cancer susceptibility, which highlights the importance of the FA pathway in tumor suppression, and will be the focus of this review. Acute myeloid leukemia is the most common cancer type, often subsequent to bone marrow failure. However, FA patients are also at an extreme risk of squamous cell carcinoma (SCC) of the head and neck and gynecological tract, with an even greater incidence in those individuals who have received a bone marrow transplant and recovered from hematopoietic disease. FA tumor suppression in hematopoietic versus epithelial compartments could be mechanistically similar or distinct. Definition of compartment specific FA activities is now critical to assess the effects of today's bone marrow failure treatments on tomorrow's solid tumor development. It is our hope that current therapies can then be optimized to decrease the risk of malignant transformation in both hematopoietic and epithelial cells. Here we review our current understanding of the mechanisms of action of the Fanconi anemia pathway as it contributes to stress responses, DNA repair and squamous cell carcinoma susceptibility.

  2. Inhibitors and pathways of hepatocytic protein degradation.

    Science.gov (United States)

    Seglen, P O; Gordon, P B; Grinde, B; Solheim, A; Kovács, A L; Poli, A

    1981-01-01

    On the basis of experiments using amino acids and various inhibitors (lysosomotropic amines, leupeptin, chymostatin, vanadate, vinblastine, anoxia, methylaminopurines), five different modes of endogenous protein degradation in isolated rat hepatocytes can be distinguished. The two non-lysosomal (amine-resistant) mechanisms preferentially degrade relatively labile (short-lived) proteins: one of these mechanisms is energy-dependent and chymostatin-sensitive, the other is not. Of the three lysosomal (amine-sensitive) mechanisms, one--quantitatively minor--is amino acid-resistant and preferentially degrades labile proteins. The two amino acid-sensitive mechanisms each seen account for about one-half of the degradation of relatively stable (long-lived) proteins; one of them is suppressed by leucine and apparently corresponds to the formation of electron microscopically visible autophagosomes; the other may represent a different type of autophagy, inhibited by asparagine and glutamine. A new class of inhibitors, the purine derivatives (methylated 6-aminopurines, and 6-mercaptopurines) appear to specifically suppress autophagic/lysosomal protein degradation, and may help to further elucidate the mechanisms of autophagy.

  3. Hedgehog pathway as a drug target: Smoothened inhibitors in development

    Directory of Open Access Journals (Sweden)

    Lin TL

    2012-03-01

    Full Text Available Tara L Lin1, William Matsui21Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas, Kansas City, MO, USA; 2Division of Hematologic Malignancies, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USAAbstract: Emerging laboratory and clinical investigations demonstrate that Hedgehog signaling (Hh represents a novel therapeutic target in various human cancers. This conserved signaling pathway precisely regulates self-renewal and terminal differentiation in embryonic development, but is typically silenced in adult tissues, with reactivation usually only during tissue repair. Aberrant Hh pathway signaling has been implicated in the pathogenesis, self-renewal, and chemotherapy resistance of a growing number of solid and hematologic malignancies. Major components of the Hh pathway include the Hh ligands (Sonic, Desert, and Indian, the transmembrane receptor Patched, the signal transducer Smoothened (Smo, and transcription factors Gli1–3 which regulate the transcription of Hh target genes. Mutations in Hh pathway genes, increased Hh signaling in tumor stroma, and Hh overexpression in self-renewing cells (cancer stem cells have been described, and these different modes of Hh signaling have implications for the design of Hh pathway inhibitors and their integration into conventional treatment regimens. Discovery of a naturally-occurring Smo inhibitor, cyclopamine, and the identification of Hh pathway mutations and over expression in cancer cells prompted the development of several cyclopamine derivatives. Encouraging laboratory and in vivo data has resulted in Phase I and II clinical trials of Smo inhibitors. In this review, we will discuss the current understanding of Hh pathway signaling in malignancy and Smo antagonists in development. Recent data with these agents shows that they are well-tolerated and may be effective for subsets of patients. Challenges remain

  4. The Fanconi anemia DNA damage repair pathway in the spotlight for germline predisposition to colorectal cancer

    Science.gov (United States)

    Esteban-Jurado, Clara; Franch-Expósito, Sebastià; Muñoz, Jenifer; Ocaña, Teresa; Carballal, Sabela; López-Cerón, Maria; Cuatrecasas, Miriam; Vila-Casadesús, Maria; Lozano, Juan José; Serra, Enric; Beltran, Sergi; Brea-Fernández, Alejandro; Ruiz-Ponte, Clara; Castells, Antoni; Bujanda, Luis; Garre, Pilar; Caldés, Trinidad; Cubiella, Joaquín; Balaguer, Francesc; Castellví-Bel, Sergi

    2016-01-01

    Colorectal cancer (CRC) is one of the most common neoplasms in the world. Fanconi anemia (FA) is a very rare genetic disease causing bone marrow failure, congenital growth abnormalities and cancer predisposition. The comprehensive FA DNA damage repair pathway requires the collaboration of 53 proteins and it is necessary to restore genome integrity by efficiently repairing damaged DNA. A link between FA genes in breast and ovarian cancer germline predisposition has been previously suggested. We selected 74 CRC patients from 40 unrelated Spanish families with strong CRC aggregation compatible with an autosomal dominant pattern of inheritance and without mutations in known hereditary CRC genes and performed germline DNA whole-exome sequencing with the aim of finding new candidate germline predisposition variants. After sequencing and data analysis, variant prioritization selected only those very rare alterations, producing a putative loss of function and located in genes with a role compatible with cancer. We detected an enrichment for variants in FA DNA damage repair pathway genes in our familial CRC cohort as 6 families carried heterozygous, rare, potentially pathogenic variants located in BRCA2/FANCD1, BRIP1/FANCJ, FANCC, FANCE and REV3L/POLZ. In conclusion, the FA DNA damage repair pathway may play an important role in the inherited predisposition to CRC. PMID:27165003

  5. The Fanconi Anemia Pathway Protects Genome Integrity from R-loops.

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    María L García-Rubio

    2015-11-01

    Full Text Available Co-transcriptional RNA-DNA hybrids (R loops cause genome instability. To prevent harmful R loop accumulation, cells have evolved specific eukaryotic factors, one being the BRCA2 double-strand break repair protein. As BRCA2 also protects stalled replication forks and is the FANCD1 member of the Fanconi Anemia (FA pathway, we investigated the FA role in R loop-dependent genome instability. Using human and murine cells defective in FANCD2 or FANCA and primary bone marrow cells from FANCD2 deficient mice, we show that the FA pathway removes R loops, and that many DNA breaks accumulated in FA cells are R loop-dependent. Importantly, FANCD2 foci in untreated and MMC-treated cells are largely R loop dependent, suggesting that the FA functions at R loop-containing sites. We conclude that co-transcriptional R loops and R loop-mediated DNA damage greatly contribute to genome instability and that one major function of the FA pathway is to protect cells from R loops.

  6. Developmental defects in zebrafish for classification of EGF pathway inhibitors

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    Pruvot, Benoist; Curé, Yoann; Djiotsa, Joachim; Voncken, Audrey; Muller, Marc, E-mail: m.muller@ulg.ac.be

    2014-01-15

    One of the major challenges when testing drug candidates targeted at a specific pathway in whole animals is the discrimination between specific effects and unwanted, off-target effects. Here we used the zebrafish to define several developmental defects caused by impairment of Egf signaling, a major pathway of interest in tumor biology. We inactivated Egf signaling by genetically blocking Egf expression or using specific inhibitors of the Egf receptor function. We show that the combined occurrence of defects in cartilage formation, disturbance of blood flow in the trunk and a decrease of myelin basic protein expression represent good indicators for impairment of Egf signaling. Finally, we present a classification of known tyrosine kinase inhibitors according to their specificity for the Egf pathway. In conclusion, we show that developmental indicators can help to discriminate between specific effects on the target pathway from off-target effects in molecularly targeted drug screening experiments in whole animal systems. - Highlights: • We analyze the functions of Egf signaling on zebrafish development. • Genetic blocking of Egf expression causes cartilage, myelin and circulatory defects. • Chemical inhibition of Egf receptor function causes similar defects. • Developmental defects can reveal the specificity of Egf pathway inhibitors.

  7. The Fanconi Anemia BRCA Pathway as a Predictor of Benefit from Bevacizumab in a Large Phase 3 Clinical Trial in Ovarian Cancer

    Science.gov (United States)

    2014-12-01

    1 AWARD NUMBER: W81XWH-13-1-0421 TITLE: The Fanconi Anemia BRCA Pathway as a Predictor of Benefit from Bevacizumab in a Large Phase III Clinical...DATES COVERED 30Sep2013 - 29Sep2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-13-1-0421 The Fanconi Anemia BRCA Pathway as a Predictor of...another upfront clinical trial GOG262. We found that germline or somatic mutations in the BRCA-Fanconi anemia pathway was significantly associated with

  8. The Fanconi anemia pathway and ICL repair: implications for cancer therapy.

    Science.gov (United States)

    Wang, Lily C; Gautier, Jean

    2010-10-01

    Fanconi anemia (FA) is an inherited disease caused by mutations in at least 13 genes and characterized by genomic instability. In addition to displaying strikingly heterogenous clinical phenotypes, FA patients are exquisitely sensitive to treatments with crosslinking agents that create interstrand crosslinks (ICL). In contrast to bacteria and yeast, in which ICLs are repaired through replication-dependent and -independent mechanisms, it is thought that ICLs are repaired primarily during DNA replication in vertebrates. However, recent data indicate that replication-independent ICL repair also operates in vertebrates. While the precise role of the FA pathway in ICL repair remains elusive, increasing evidence suggests that FA proteins function at different steps in the sensing, recognition and processing of ICLs, as well as in signaling from these very toxic lesions, which can be generated by a wide variety of cancer chemotherapeutic drugs. Here, we discuss some of the recent findings that have shed light on the role of the FA pathway in ICL repair, with special emphasis on the implications of these findings for cancer therapy since disruption of FA genes have been associated with cancer predisposition.

  9. Pathway-based screening strategy for multitarget inhibitors of diverse proteins in metabolic pathways.

    Directory of Open Access Journals (Sweden)

    Kai-Cheng Hsu

    Full Text Available Many virtual screening methods have been developed for identifying single-target inhibitors based on the strategy of "one-disease, one-target, one-drug". The hit rates of these methods are often low because they cannot capture the features that play key roles in the biological functions of the target protein. Furthermore, single-target inhibitors are often susceptible to drug resistance and are ineffective for complex diseases such as cancers. Therefore, a new strategy is required for enriching the hit rate and identifying multitarget inhibitors. To address these issues, we propose the pathway-based screening strategy (called PathSiMMap to derive binding mechanisms for increasing the hit rate and discovering multitarget inhibitors using site-moiety maps. This strategy simultaneously screens multiple target proteins in the same pathway; these proteins bind intermediates with common substructures. These proteins possess similar conserved binding environments (pathway anchors when the product of one protein is the substrate of the next protein in the pathway despite their low sequence identity and structure similarity. We successfully discovered two multitarget inhibitors with IC50 of <10 µM for shikimate dehydrogenase and shikimate kinase in the shikimate pathway of Helicobacter pylori. Furthermore, we found two selective inhibitors (IC50 of <10 µM for shikimate dehydrogenase using the specific anchors derived by our method. Our experimental results reveal that this strategy can enhance the hit rates and the pathway anchors are highly conserved and important for biological functions. We believe that our strategy provides a great value for elucidating protein binding mechanisms and discovering multitarget inhibitors.

  10. Phase 1 study of the E-selectin inhibitor GMI 1070 in patients with sickle cell anemia.

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    Ted Wun

    Full Text Available BACKGROUND: Sickle cell anemia is an inherited disorder of hemoglobin that leads to a variety of acute and chronic complications. Abnormal cellular adhesion, mediated in part by selectins, has been implicated in the pathophysiology of the vaso-occlusion seen in sickle cell anemia, and selectin inhibition was able to restore blood flow in a mouse model of sickle cell disease. METHODS: We performed a Phase 1 study of the selectin inhibitor GMI 1070 in patients with sickle cell anemia. Fifteen patients who were clinically stable received GMI 1070 in two infusions. RESULTS: The drug was well tolerated without significant adverse events. There was a modest increase in total peripheral white blood cell count without clinical symptoms. Plasma concentrations were well-described by a two-compartment model with an elimination T1/2 of 7.7 hours and CLr of 19.6 mL/hour/kg. Computer-assisted intravital microscopy showed transient increases in red blood cell velocity in 3 of the 4 patients studied. CONCLUSIONS: GMI 1070 was safe in stable patients with sickle cell anemia, and there was suggestion of increased blood flow in a subset of patients. At some time points between 4 and 48 hours after treatment with GMI 1070, there were significant decreases in biomarkers of endothelial activation (sE-selectin, sP-selectin, sICAM, leukocyte activation (MAC-1, LFA-1, PM aggregates and the coagulation cascade (tissue factor, thrombin-antithrombin complexes. Development of GMI 1070 for the treatment of acute vaso-occlusive crisis is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT00911495.

  11. Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers.

    Science.gov (United States)

    Goda, Jayant S; Pachpor, Tejaswini; Basu, Trinanjan; Chopra, Supriya; Gota, Vikram

    2016-02-01

    Cellular resistance in tumour cells to different therapeutic approaches has been a limiting factor in the curative treatment of cancer. Resistance to therapeutic radiation is a common phenomenon which significantly reduces treatment options and impacts survival. One of the mechanisms of acquiring resistance to ionizing radiation is the overexpression or activation of various oncogenes like the EGFR (epidermal growth factor receptor), RAS (rat sarcoma) oncogene or loss of PTEN (phosphatase and tensin homologue) which in turn activates the phosphatidyl inositol 3-kinase/protein kinase B (PI3-K)/AKT pathway responsible for radiation resistance in various tumours. Blocking the pathway enhances the radiation response both in vitro and in vivo. Due to the differential activation of this pathway (constitutively activated in tumour cells and not in the normal host cells), it is an excellent candidate target for molecular targeted therapy to enhance radiation sensitivity. In this regard, HIV protease inhibitors (HPIs) known to interfere with PI3-K/AKT signaling in tumour cells, have been shown to sensitize various tumour cells to radiation both in vitro and in vivo. As a result, HPIs are now being investigated as possible radiosensitizers along with various chemotherapeutic drugs. This review describes the mechanisms by which PI3-K/AKT pathway causes radioresistance and the role of HIV protease inhibitors especially nelfinavir as a potential candidate drug to target the AKT pathway for overcoming radioresistance and its use in various clinical trials for different malignancies.

  12. Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers

    Directory of Open Access Journals (Sweden)

    Jayant S Goda

    2016-01-01

    Full Text Available Cellular resistance in tumour cells to different therapeutic approaches has been a limiting factor in the curative treatment of cancer. Resistance to therapeutic radiation is a common phenomenon which significantly reduces treatment options and impacts survival. One of the mechanisms of acquiring resistance to ionizing radiation is the overexpression or activation of various oncogenes like the EGFR (epidermal growth factor receptor, RAS (rat sarcoma oncogene or loss of PTEN (phosphatase and tensin homologue which in turn activates the phosphatidyl inositol 3-kinase/protein kinase B (PI3-K/AKT pathway responsible for radiation resistance in various tumours. Blocking the pathway enhances the radiation response both in vitro and in vivo. Due to the differential activation of this pathway (constitutively activated in tumour cells and not in the normal host cells, it is an excellent candidate target for molecular targeted therapy to enhance radiation sensitivity. In this regard, HIV protease inhibitors (HPIs known to interfere with PI3-K/AKT signaling in tumour cells, have been shown to sensitize various tumour cells to radiation both in vitro and in vivo. As a result, HPIs are now being investigated as possible radiosensitizers along with various chemotherapeutic drugs. This review describes the mechanisms by which PI3-K/AKT pathway causes radioresistance and the role of HIV protease inhibitors especially nelfinavir as a potential candidate drug to target the AKT pathway for overcoming radioresistance and its use in various clinical trials for different malignancies.

  13. Pernicious anemia

    Science.gov (United States)

    ... malabsorption); Anemia - intrinsic factor; Anemia - IF; Anemia - atrophic gastritis ... of pernicious anemia include: Weakened stomach lining (atrophic gastritis) An autoimmune condition in which the body's immune ...

  14. Systems Biology-Based Identification of Crosstalk between E2F Transcription Factors and the Fanconi Anemia Pathway

    Directory of Open Access Journals (Sweden)

    Moe Tategu

    2007-01-01

    Full Text Available Fanconi anemia (FA is an autosomal recessive disorder characterized by congenital abnormalities, bone marrow failure, chromosome fragility, and cancer susceptibility. At least eleven members of the FA gene family have been identified using complementation experiments. Ubiquitin-proteasome has been shown to be a key regulator of FA proteins and their involvement in the repair of DNA damage. Here, we identifi ed a novel functional link between the FA/BRCA pathway and E2F-mediated cell cycle regulome. In silico mining of a transcriptome database and promoter analyses revealed that a significant number of FA gene members were regulated by E2F transcription factors, known to be pivotal regulators of cell cycle progression – as previously described for BRCA1. Our findings suggest that E2Fs partly determine cell fate through the FA/BRCA pathway.

  15. Mouse models of Fanconi anemia

    Energy Technology Data Exchange (ETDEWEB)

    Parmar, Kalindi; D' Andrea, Alan [Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115 (United States); Niedernhofer, Laura J., E-mail: niedernhoferl@upmc.edu [Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine and Cancer Institute, 5117 Centre Avenue, Hillman Cancer Center, Research Pavilion 2.6, Pittsburgh, PA 15213-1863 (United States)

    2009-07-31

    Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.

  16. Novel Small Molecule Inhibitors of Cancer Stem Cell Signaling Pathways.

    Science.gov (United States)

    Abetov, Danysh; Mustapova, Zhanar; Saliev, Timur; Bulanin, Denis; Batyrbekov, Kanat; Gilman, Charles P

    2015-12-01

    The main aim of oncologists worldwide is to understand and then intervene in the primary tumor initiation and propagation mechanisms. This is essential to allow targeted elimination of cancer cells without altering normal mitotic cells. Currently, there are two main rival theories describing the process of tumorigenesis. According to the Stochastic Model, potentially any cell, once defunct, is capable of initiating carcinogenesis. Alternatively the Cancer Stem Cell (CSC) Model posits that only a small fraction of undifferentiated tumor cells are capable of triggering carcinogenesis. Like healthy stem cells, CSCs are also characterized by a capacity for self-renewal and the ability to generate differentiated progeny, possibly mediating treatment resistance, thus leading to tumor recurrence and metastasis. Moreover, molecular signaling profiles are similar between CSCs and normal stem cells, including Wnt, Notch and Hedgehog pathways. Therefore, development of novel chemotherapeutic agents and proteins (e.g., enzymes and antibodies) specifically targeting CSCs are attractive pharmaceutical candidates. This article describes small molecule inhibitors of stem cell pathways Wnt, Notch and Hedgehog, and their recent chemotherapy clinical trials.

  17. Mouse models of Fanconi anemia

    OpenAIRE

    Parmar, Kalindi; D'Andrea, Alan; Niedernhofer, Laura J.

    2009-01-01

    Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis ...

  18. Tissue factor pathway inhibitor relates to fibrin degradation in patients with acute deep venous thrombosis

    DEFF Research Database (Denmark)

    Sidelmann, Johannes J; Bladbjerg, Else-Marie; Gram, Jørgen

    2008-01-01

    Reduced concentration of tissue factor pathway inhibitor is a risk factor for development of deep venous thrombosis, whereas elevated concentrations of tissue factor pathway inhibitor are observed in patients with acute myocardial infarction and disseminated intravascular coagulation. Presently, we...... studied the association between inflammation, endothelial cell perturbation, fibrin degradation and the concentration of tissue factor pathway inhibitor in patients suspected for acute deep venous thrombosis. We determined the tissue factor pathway inhibitor -33T/C polymorphism, free and total tissue...... factor pathway inhibitor, C-reactive protein, von Willebrand factor and D-Dimer in 160 consecutive patients admitted to hospital with a tentative diagnosis of acute deep venous thrombosis. Deep venous thrombosis was identified in 57 patients (18 distal and 39 proximal). The distribution of the tissue...

  19. Ouabain, a cardiac glycoside, inhibits the Fanconi anemia/BRCA pathway activated by DNA interstrand cross-linking agents.

    Directory of Open Access Journals (Sweden)

    Dong Wha Jun

    Full Text Available Modulation of the DNA repair pathway is an emerging target for the development of anticancer drugs. DNA interstrand cross-links (ICLs, one of the most severe forms of DNA damage caused by anticancer drugs such as cisplatin and mitomycin C (MMC, activates the Fanconi anemia (FA/BRCA DNA repair pathway. Inhibition of the FA/BRCA pathway can enhance the cytotoxic effects of ICL-inducing anticancer drugs and can reduce anticancer drug resistance. To find FA/BRCA pathway inhibitory small molecules, we established a cell-based high-content screening method for quantitating the activation of the FA/BRCA pathway by measuring FANCD2 foci on DNA lesions and then applied our method to chemical screening. Using commercial LOPAC1280 chemical library screening, ouabain was identified as a competent FA/BRCA pathway inhibitory compound. Ouabain, a member of the cardiac glycoside family, binds to and inhibits Na(+/K(+-ATPase and has been used to treat heart disease for many years. We observed that ouabain, as well as other cardiac glycoside family members--digitoxin and digoxin--down-regulated FANCD2 and FANCI mRNA levels, reduced monoubiquitination of FANCD2, inhibited FANCD2 foci formation on DNA lesions, and abrogated cell cycle arrest induced by MMC treatment. These inhibitory activities of ouabain required p38 MAPK and were independent of cellular Ca(2+ ion increase or the drug uptake-inhibition effect of ouabain. Furthermore, we found that ouabain potentiated the cytotoxic effects of MMC in tumor cells. Taken together, we identified an additional effect of ouabain as a FA/BRCA pathway-inhibiting chemosensitization compound. The results of this study suggest that ouabain may serve as a chemosensitizer to ICL-inducing anticancer drugs.

  20. [Sideroblastic anemias].

    Science.gov (United States)

    Matthes, T

    2006-01-01

    Sideroblastic anemias are a heterogenous group of disorders characterized by the presence of sideroblasts in the bone marrow aspirate. Current classification schemes distinguish between diseases of the heme synthesis pathway and diseases of other mitochondrial pathways which can either be of primary origin (defects in mitochondrial DNA) or of secondary origin (defects in nuclear DNA). Although several distinct hereditary forms exist, sideroblastic anemias are most frequently acquired diseases and belong to the group of myelodysplastic syndromes with the propensity to develop into overt leukemia. Treatment is mainly supportive (vitamins, blood transfusions, cytokines) and only rarely are bone marrow transplantations performed. The molecular defects of a few hereditary forms have already been elucidated, but the genes involved in the acquired forms are still largely unknown.

  1. Polymerase I pathway inhibitor ameliorates experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Achiron, Anat; Mashiach, Roi; Zilkha-Falb, Rina; Meijler, Michael M; Gurevich, Michael

    2013-10-15

    Applying high throughput gene expression microarrays we identified that the suppression of polymerase 1 (POL1) pathway is associated with benign course of multiple sclerosis (MS). This finding supports the rationale for direct targeting of the POL1 transcription machinery as an innovative strategy to suppress MS. To evaluate the effects of a specific polymerase I inhibitor (POL1-I) on experimental autoimmune encephalomyelitis (EAE), we immunized female C57BL/6J mice (8 weeks) with MOG35-55/CFA. A new POL1-I was administered at a daily dose of 12.5mg/kg body weight by oral gavage either from the day of immunization until disease onset (EAE score 1.0, immunization model), at disease onset (EAE score=1.0) for the following 14 days (treatment model), or by alternate daily dose of 25.0mg/kg body weight, by oral gavage from the day of immunization for the following 25 days (combined model). POL1-I remarkably suppressed EAE in the immunization model; while in the Vehicle group the onset of EAE occurred on day 10.0±0.4 with maximal clinical score of 3.2±0.2, in the POL1-I treated mice onset was significantly delayed and occurred on day 16.9±1.1 (p=0.001), and maximal disease score 2.0±0.1 was reduced (p=0.004). In the treatment model POL1-I treatment significantly reduced disease activity; maximal score was 2.0±0.5 while in the Vehicle group it reached a mean maximal score of 3.9±0.1, (p=0.0008). In the combined model, POL1-I treatment completely inhibited disease activity. The effect of POL1-I treatment was modulated through decreased expression of POL1 pathway key-related genes LRPPRC, pre-RNA, POLR1D and RRN3 together with activation of P53 dependent apoptosis of CD4+ splenocytes. Our findings demonstrate that POL1 pathway inhibition delayed and suppressed the development of EAE and ameliorated the disease in mice with persistent clinical signs.

  2. Therapeutic Inhibitors of LIN28/let-7 Pathway in Ovarian Cancer

    Science.gov (United States)

    2015-09-01

    AWARD NUMBER: W81XWH-14-1-0138 TITLE: Therapeutic Inhibitors of LIN28/let-7 Pathway in Ovarian Cancer PRINCIPAL INVESTIGATOR: John P. Hagan...2015 4. TITLE AND SUBTITLE Therapeutic Inhibitors of LIN28/let-7 Pathway in Ovarian Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1...prognosis in multiple cancer types, including ovarian. Silent in almost all adult cells, the Lin28/let-7 pathway is implicated directly in cancer stem

  3. Live-cell microscopy reveals small molecule inhibitor effects on MAPK pathway dynamics.

    Directory of Open Access Journals (Sweden)

    Daniel J Anderson

    Full Text Available Oncogenic mutations in the mitogen activated protein kinase (MAPK pathway are prevalent in human tumors, making this pathway a target of drug development efforts. Recently, ATP-competitive Raf inhibitors were shown to cause MAPK pathway activation via Raf kinase priming in wild-type BRaf cells and tumors, highlighting the need for a thorough understanding of signaling in the context of small molecule kinase inhibitors. Here, we present critical improvements in cell-line engineering and image analysis coupled with automated image acquisition that allow for the simultaneous identification of cellular localization of multiple MAPK pathway components (KRas, CRaf, Mek1 and Erk2. We use these assays in a systematic study of the effect of small molecule inhibitors across the MAPK cascade either as single agents or in combination. Both Raf inhibitor priming as well as the release from negative feedback induced by Mek and Erk inhibitors cause translocation of CRaf to the plasma membrane via mechanisms that are additive in pathway activation. Analysis of Erk activation and sub-cellular localization upon inhibitor treatments reveals differential inhibition and activation with the Raf inhibitors AZD628 and GDC0879 respectively. Since both single agent and combination studies of Raf and Mek inhibitors are currently in the clinic, our assays provide valuable insight into their effects on MAPK signaling in live cells.

  4. Multiple myeloma acquires resistance to EGFR inhibitor via induction of pentose phosphate pathway.

    Science.gov (United States)

    Chen, Yan; Huang, Ruibin; Ding, Jianghua; Ji, Dexiang; Song, Bing; Yuan, Liya; Chang, Hong; Chen, Guoan

    2015-04-20

    Multiple myeloma (MM) was characterized by frequent mutations in KRAS/NRAS/BRAF within the EGFR pathway that could induce resistance to EGFR inhibitors. We here report that EGFR inhibition solely exhibited moderate inhibition in KRAS/NRAS/BRAF wildtype (triple-WT) MM cells, whilst had no effect in myeloma cells with any of the mutated genes. The moderate inhibitory effect was conferred by induction of pentose phosphate pathway (PPP) when cells were treated with Gefitinib, the EGFR inhibitor. Combination of Gefitinib with PPP inhibitor 6AN effected synergistically in triple-WT cells. The inhibition could be restored by addition of NADPH. Dual EGFR/ERBB2 inhibitor Afatinib also exhibited similar effects. Further genetic silencing of EGFR, ERBB2 and mTOR indicated that major effect conferred by ERBB2 was via convergence to EGFR pathway in MM. Our results contributed to the individualized targeted therapy with EGFR inhibitors in MM.

  5. Las anemias, sin anemia

    OpenAIRE

    Villamarin V., A.; Villamarin C., Maria José

    2011-01-01

    Estudiando las anemias idiopáticas, encontramos dos tipos: la anemia hipócroma megalocítica u enfermedad de Biermer y la anemia hipócroma microcítica o clorosis; en la mayoría de los casos estos dos tipos, se oponen por su figura hematológica, sus manifestaciones clínicas, su evolución y su terapéutica. La anemia de Biermer, tiene por remedio heroico el hígado a altas dosis; la segunda, el hierro en forma química. Pero debemos reconocer que ciertos síntomas son comunes a las anemias idiopátic...

  6. Hemolytic anemia

    Science.gov (United States)

    Anemia - hemolytic ... bones that helps form all blood cells. Hemolytic anemia occurs when the bone marrow isn't making ... destroyed. There are several possible causes of hemolytic anemia. Red blood cells may be destroyed due to: ...

  7. Anemia Due to Excessive Bleeding

    Science.gov (United States)

    ... Anemia Vitamin Deficiency Anemia Anemia of Chronic Disease Aplastic Anemia Autoimmune Hemolytic Anemia Sickle Cell Disease Hemoglobin C, S- ... Anemia Vitamin Deficiency Anemia Anemia of Chronic Disease Aplastic Anemia Autoimmune Hemolytic Anemia Sickle Cell Disease Hemoglobin C, S- ...

  8. Lung Cancer Cell Line Screen Links Fanconi Anemia/BRCA Pathway Defects to Increased Relative Biological Effectiveness of Proton Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Qi; Ghosh, Priyanjali; Magpayo, Nicole [Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Testa, Mauro; Tang, Shikui [Division of Radiation Physics, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Gheorghiu, Liliana [Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Biggs, Peter; Paganetti, Harald [Division of Radiation Physics, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Efstathiou, Jason A. [Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Lu, Hsiao-Ming [Division of Radiation Physics, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Held, Kathryn D. [Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Willers, Henning, E-mail: hwillers@mgh.harvard.edu [Laboratory of Cellular and Molecular Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States)

    2015-04-01

    Purpose: Growing knowledge of genomic heterogeneity in cancer, especially when it results in altered DNA damage responses, requires re-examination of the generic relative biological effectiveness (RBE) of 1.1 of protons. Methods and Materials: For determination of cellular radiosensitivity, we irradiated 17 lung cancer cell lines at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer, 2.5 keV/μm). For comparison, 250-kVp X rays and {sup 137}Cs γ-rays were used. To estimate the RBE of protons relative to {sup 60}Co (Co60eq), we assigned an RBE(Co60Eq) of 1.1 to X rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor damage responses. FANCD2 was depleted using RNA interference. Results: Five lung cancer cell lines (29.4%) exhibited reduced clonogenic survival after proton irradiation compared with X-irradiation with the same physical doses. This was confirmed in a 3-dimensional sphere assay. Corresponding proton RBE(Co60Eq) estimates were statistically significantly different from 1.1 (P≤.05): 1.31 to 1.77 (for a survival fraction of 0.5). In 3 of these lines, increased RBE was correlated with alterations in the Fanconi anemia (FA)/BRCA pathway of DNA repair. In Calu-6 cells, the data pointed toward an FA pathway defect, leading to a previously unreported persistence of proton-induced RAD51 foci. The FA/BRCA-defective cells displayed a 25% increase in the size of subnuclear 53BP1 foci 18 hours after proton irradiation. Conclusions: Our cell line screen has revealed variations in proton RBE that are partly due to FA/BRCA pathway defects, suggesting that the use of a generic RBE for cancers should be revisited. We propose that functional biomarkers, such as size of residual 53BP1 foci, may be used to identify cancers with increased sensitivity to proton radiation.

  9. SALO, a novel classical pathway complement inhibitor from saliva of the sand fly Lutzomyia longipalpis

    Science.gov (United States)

    Ferreira, Viviana P.; Fazito Vale, Vladimir; Pangburn, Michael K.; Abdeladhim, Maha; Ferreira Mendes-Sousa, Antonio; Coutinho-Abreu, Iliano V.; Rasouli, Manoochehr; Brandt, Elizabeth A.; Meneses, Claudio; Lima, Kolyvan Ferreira; Nascimento Araújo, Ricardo; Horácio Pereira, Marcos; Kotsyfakis, Michalis; Oliveira, Fabiano; Kamhawi, Shaden; Ribeiro, Jose M. C.; Gontijo, Nelder F.; Collin, Nicolas; Valenzuela, Jesus G.

    2016-01-01

    Blood-feeding insects inject potent salivary components including complement inhibitors into their host’s skin to acquire a blood meal. Sand fly saliva was shown to inhibit the classical pathway of complement; however, the molecular identity of the inhibitor remains unknown. Here, we identified SALO as the classical pathway complement inhibitor. SALO, an 11 kDa protein, has no homology to proteins of any other organism apart from New World sand flies. rSALO anti-complement activity has the same chromatographic properties as the Lu. longipalpis salivary gland homogenate (SGH)counterparts and anti-rSALO antibodies blocked the classical pathway complement activity of rSALO and SGH. Both rSALO and SGH inhibited C4b deposition and cleavage of C4. rSALO, however, did not inhibit the protease activity of C1s nor the enzymatic activity of factor Xa, uPA, thrombin, kallikrein, trypsin and plasmin. Importantly, rSALO did not inhibit the alternative or the lectin pathway of complement. In conclusion our data shows that SALO is a specific classical pathway complement inhibitor present in the saliva of Lu. longipalpis. Importantly, due to its small size and specificity, SALO may offer a therapeutic alternative for complement classical pathway-mediated pathogenic effects in human diseases. PMID:26758086

  10. Endocannabinoids are conserved inhibitors of the Hedgehog pathway.

    Science.gov (United States)

    Khaliullina, Helena; Bilgin, Mesut; Sampaio, Julio L; Shevchenko, Andrej; Eaton, Suzanne

    2015-03-17

    Hedgehog ligands control tissue development and homeostasis by alleviating repression of Smoothened, a seven-pass transmembrane protein. The Hedgehog receptor, Patched, is thought to regulate the availability of small lipophilic Smoothened repressors whose identity is unknown. Lipoproteins contain lipids required to repress Smoothened signaling in vivo. Here, using biochemical fractionation and lipid mass spectrometry, we identify these repressors as endocannabinoids. Endocannabinoids circulate in human and Drosophila lipoproteins and act directly on Smoothened at physiological concentrations to repress signaling in Drosophila and mammalian assays. Phytocannabinoids are also potent Smo inhibitors. These findings link organismal metabolism to local Hedgehog signaling and suggest previously unsuspected mechanisms for the physiological activities of cannabinoids.

  11. Structural investigation of inhibitor designs targeting 3-dehydroquinate dehydratase from the shikimate pathway of Mycobacterium tuberculosis

    Energy Technology Data Exchange (ETDEWEB)

    Dias, Marcio V.B.; Snee, William C.; Bromfield, Karen M.; Payne, Richard J.; Palaninathan, Satheesh K.; Ciulli, Alessio; Howard, Nigel I.; Abell, Chris; Sacchettini, James C.; Blundell, Tom L. (TAM); (Cambridge)

    2011-09-06

    The shikimate pathway is essential in Mycobacterium tuberculosis and its absence from humans makes the enzymes of this pathway potential drug targets. In the present paper, we provide structural insights into ligand and inhibitor binding to 3-dehydroquinate dehydratase (dehydroquinase) from M. tuberculosis (MtDHQase), the third enzyme of the shikimate pathway. The enzyme has been crystallized in complex with its reaction product, 3-dehydroshikimate, and with six different competitive inhibitors. The inhibitor 2,3-anhydroquinate mimics the flattened enol/enolate reaction intermediate and serves as an anchor molecule for four of the inhibitors investigated. MtDHQase also forms a complex with citrazinic acid, a planar analogue of the reaction product. The structure of MtDHQase in complex with a 2,3-anhydroquinate moiety attached to a biaryl group shows that this group extends to an active-site subpocket inducing significant structural rearrangement. The flexible extensions of inhibitors designed to form {pi}-stacking interactions with the catalytic Tyr{sup 24} have been investigated. The high-resolution crystal structures of the MtDHQase complexes provide structural evidence for the role of the loop residues 19-24 in MtDHQase ligand binding and catalytic mechanism and provide a rationale for the design and efficacy of inhibitors.

  12. Weight loss induced by tyrosine kinase inhibitors of the vascular endothelial growth factor pathway.

    Science.gov (United States)

    Desar, Ingrid M E; Thijs, Annemarie M J; Mulder, Sasja F; Tack, Cees J J; van Herpen, Carla M L; van der Graaf, Winette T A

    2012-02-01

    Weight loss, cachexia and sarcopenia are profound problems in the frail oncologic patients. With the development and increasing use of angiogenesis inhibitors in metastatic cancer patients, the question arises as to their influence on body weight and composition. Angiogenesis is not only important for the growth, development and metastatic potential of tumors but also for physiological processes in adipogenesis. A less known approach of angiogenesis inhibitors is their experimental use in obese models. This review focuses on the effects on the body weight and composition of angiogenesis inhibitors, especially of those targeting the vascular endothelial growth factor pathway.

  13. Aplastic Anemia

    Science.gov (United States)

    Aplastic anemia is a rare but serious blood disorder. If you have it, your bone marrow doesn't make ... blood cells. There are different types, including Fanconi anemia. Causes include Toxic substances, such as pesticides, arsenic, ...

  14. Avian anemia's

    Directory of Open Access Journals (Sweden)

    Raukar Jelena

    2005-01-01

    Full Text Available This paper deals with avian anemia's classified by MCHC/MCV and with types of anemia's. Father hematological and immunological research is needed to secure information on hematological parameters in different avian species at their earliest age. Anemia is a common clinical finding in birds because the avian erythrocyte half - life is much shorter than the mammalian. Therefore anemia should be determined as soon as possible. Researchers should standardize hematological parameters for every single avian species.

  15. Involvement of the Fanconi's anemia protein FAC in a pathway that signals to the cyclin B/cdc2 kinase

    NARCIS (Netherlands)

    Kruyt, FAE; Dijkmans, LM; Arwert, F; Joenje, H

    1997-01-01

    Lymphoblastoid cell lines derived from patients with the chromosomal instability disorder Fauconi's anemia (FA) are hyperresponsive to G(2) delay and apoptosis induced by cross-linking agents such as mitomycin C (MMC), Here, we investiPated whether the protein defective in FA complementation group C

  16. Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors

    Directory of Open Access Journals (Sweden)

    Tadas K. Rimkus

    2016-02-01

    Full Text Available The sonic hedgehog (Shh signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate. Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO and glioma-associated oncogene homolog (GLI family of zinc finger transcription factors. Both are regarded as important targets for cancer therapeutics. While most efforts have been devoted towards pharmacologically targeting SMO, developing GLI-targeted approach has its merit because of the fact that GLI proteins can be activated by both Shh ligand-dependent and -independent mechanisms. To date, two SMO inhibitors (LDE225/Sonidegib and GDC-0449/Vismodegib have received FDA approval for treating basal cell carcinoma while many clinical trials are being conducted to evaluate the efficacy of this exciting class of targeted therapy in a variety of cancers. In this review, we provide an overview of the biology of the Shh pathway and then detail the current landscape of the Shh-SMO-GLI pathway inhibitors including those in preclinical studies and clinical trials.

  17. The Fanconi anemia/BRCA pathway is involved in DNA interstrand cross-link repair of adriamycin-resistant leukemia cells.

    Science.gov (United States)

    Yao, Chenjiao; Du, Wei; Chen, Haibing; Xiao, Sheng; Huang, Lihua; Chen, Fangping

    2015-03-01

    The Fanconi anemia/BRCA (FA/BRCA) pathway plays a vital role in DNA damage repair induced by DNA cross-linking agents and is closely related to drug response in cancer treatment. Here we demonstrate that the FA/BRCA pathway contributes to acquired drug resistance in adriamycin (ADR)-resistant leukemia cell lines, and disruption of this pathway partially reverses the drug resistance. We observed that ADR-resistant cells have reduced DNA interstrand cross-links (ICL) compared with ADR-sensitive cells. Western blot studies demonstrated enhanced FA protein expression in ADR-resistant cells. Using siRNA to knock down FANCF in K562/R drug-resistant cells showed increases in sensitivity to ADR and ADR-induced DNA damage, and demonstrated a direct relationship between the FA/BRCA pathway and drug sensitivity. Overexpression of FANCF in K562 drug-sensitive cells partially reproduced the drug-resistant phenotype. These results show that the FA/BRCA pathway is involved in acquired ADR resistance of leukemia cells. The FA/BRCA pathway may be a new target to reverse ADR resistance in leukemia treatment.

  18. Histone Deacetylase Inhibitors Antagonize Distinct Pathways to Suppress Tumorigenesis of Embryonal Rhabdomyosarcoma.

    Directory of Open Access Journals (Sweden)

    Terra Vleeshouwer-Neumann

    Full Text Available Embryonal rhabdomyosarcoma (ERMS is the most common soft tissue cancer in children. The prognosis of patients with relapsed or metastatic disease remains poor. ERMS genomes show few recurrent mutations, suggesting that other molecular mechanisms such as epigenetic regulation might play a major role in driving ERMS tumor biology. In this study, we have demonstrated the diverse roles of histone deacetylases (HDACs in the pathogenesis of ERMS by characterizing effects of HDAC inhibitors, trichostatin A (TSA and suberoylanilide hydroxamic acid (SAHA; also known as vorinostat in vitro and in vivo. TSA and SAHA suppress ERMS tumor growth and progression by inducing myogenic differentiation as well as reducing the self-renewal and migratory capacity of ERMS cells. Differential expression profiling and pathway analysis revealed downregulation of key oncogenic pathways upon HDAC inhibitor treatment. By gain-of-function, loss-of-function, and chromatin immunoprecipitation (ChIP studies, we show that Notch1- and EphrinB1-mediated pathways are regulated by HDACs to inhibit differentiation and enhance migratory capacity of ERMS cells, respectively. Our study demonstrates that aberrant HDAC activity plays a major role in ERMS pathogenesis. Druggable targets in the molecular pathways affected by HDAC inhibitors represent novel therapeutic options for ERMS patients.

  19. Combination of a Selective HSP90α/β Inhibitor and a RAS-RAF-MEK-ERK Signaling Pathway Inhibitor Triggers Synergistic Cytotoxicity in Multiple Myeloma Cells.

    Directory of Open Access Journals (Sweden)

    Rikio Suzuki

    Full Text Available Heat shock protein (HSP90 inhibitors have shown significant anti-tumor activities in preclinical settings in both solid and hematological tumors. We previously reported that the novel, orally available HSP90α/β inhibitor TAS-116 shows significant anti-MM activities. In this study, we further examined the combination effect of TAS-116 with a RAS-RAF-MEK-ERK signaling pathway inhibitor in RAS- or BRAF-mutated MM cell lines. TAS-116 monotherapy significantly inhibited growth of RAS-mutated MM cell lines and was associated with decreased expression of downstream target proteins of the RAS-RAF-MEK-ERK signaling pathway. Moreover, TAS-116 showed synergistic growth inhibitory effects with the farnesyltransferase inhibitor tipifarnib, the BRAF inhibitor dabrafenib, and the MEK inhibitor selumetinib. Importantly, treatment with these inhibitors paradoxically enhanced p-C-Raf, p-MEK, and p-ERK activity, which was abrogated by TAS-116. TAS-116 also enhanced dabrafenib-induced MM cytotoxicity associated with mitochondrial damage-induced apoptosis, even in the BRAF-mutated U266 MM cell line. This enhanced apoptosis in RAS-mutated MM triggered by combination treatment was observed even in the presence of bone marrow stromal cells. Taken together, our results provide the rationale for novel combination treatment with HSP90α/β inhibitor and RAS-RAF-MEK-ERK signaling pathway inhibitors to improve outcomes in patients with in RAS- or BRAF-mutated MM.

  20. Combination of a Selective HSP90α/β Inhibitor and a RAS-RAF-MEK-ERK Signaling Pathway Inhibitor Triggers Synergistic Cytotoxicity in Multiple Myeloma Cells.

    Science.gov (United States)

    Suzuki, Rikio; Kikuchi, Shohei; Harada, Takeshi; Mimura, Naoya; Minami, Jiro; Ohguchi, Hiroto; Yoshida, Yasuhiro; Sagawa, Morihiko; Gorgun, Gullu; Cirstea, Diana; Cottini, Francesca; Jakubikova, Jana; Tai, Yu-Tzu; Chauhan, Dharminder; Richardson, Paul G; Munshi, Nikhil; Ando, Kiyoshi; Utsugi, Teruhiro; Hideshima, Teru; Anderson, Kenneth C

    2015-01-01

    Heat shock protein (HSP)90 inhibitors have shown significant anti-tumor activities in preclinical settings in both solid and hematological tumors. We previously reported that the novel, orally available HSP90α/β inhibitor TAS-116 shows significant anti-MM activities. In this study, we further examined the combination effect of TAS-116 with a RAS-RAF-MEK-ERK signaling pathway inhibitor in RAS- or BRAF-mutated MM cell lines. TAS-116 monotherapy significantly inhibited growth of RAS-mutated MM cell lines and was associated with decreased expression of downstream target proteins of the RAS-RAF-MEK-ERK signaling pathway. Moreover, TAS-116 showed synergistic growth inhibitory effects with the farnesyltransferase inhibitor tipifarnib, the BRAF inhibitor dabrafenib, and the MEK inhibitor selumetinib. Importantly, treatment with these inhibitors paradoxically enhanced p-C-Raf, p-MEK, and p-ERK activity, which was abrogated by TAS-116. TAS-116 also enhanced dabrafenib-induced MM cytotoxicity associated with mitochondrial damage-induced apoptosis, even in the BRAF-mutated U266 MM cell line. This enhanced apoptosis in RAS-mutated MM triggered by combination treatment was observed even in the presence of bone marrow stromal cells. Taken together, our results provide the rationale for novel combination treatment with HSP90α/β inhibitor and RAS-RAF-MEK-ERK signaling pathway inhibitors to improve outcomes in patients with in RAS- or BRAF-mutated MM.

  1. A small molecule inhibitor partitions two distinct pathways for trafficking of tonoplast intrinsic proteins in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Efrain E Rivera-Serrano

    Full Text Available Tonoplast intrinsic proteins (TIPs facilitate the membrane transport of water and other small molecules across the plant vacuolar membrane, and members of this family are expressed in specific developmental stages and tissue types. Delivery of TIP proteins to the tonoplast is thought to occur by vesicle-mediated traffic from the endoplasmic reticulum to the vacuole, and at least two pathways have been proposed, one that is Golgi-dependent and another that is Golgi-independent. However, the mechanisms for trafficking of vacuolar membrane proteins to the tonoplast remain poorly understood. Here we describe a chemical genetic approach to unravel the mechanisms of TIP protein targeting to the vacuole in Arabidopsis seedlings. We show that members of the TIP family are targeted to the vacuole via at least two distinct pathways, and we characterize the bioactivity of a novel inhibitor that can differentiate between them. We demonstrate that, unlike for TIP1;1, trafficking of markers for TIP3;1 and TIP2;1 is insensitive to Brefeldin A in Arabidopsis hypocotyls. Using a chemical inhibitor that may target this BFA-insensitive pathway for membrane proteins, we show that inhibition of this pathway results in impaired root hair growth and enhanced vacuolar targeting of the auxin efflux carrier PIN2 in the dark. Our results indicate that the vacuolar targeting of PIN2 and the BFA-insensitive pathway for tonoplast proteins may be mediated in part by common mechanisms.

  2. Plasma Tissue Factor Pathway Inhibitor Levels in Angiographically Defined Coronary Artery Disease Among Saudis

    Directory of Open Access Journals (Sweden)

    Syed Shahid Habib

    2013-05-01

    Full Text Available Objectives: This study was aimed to determine plasma levels of total (TFPI-T and free (TFPI-F tissue factor pathway inhibitor, plasminogen activator inhibitor-1 (PAI-1, and tissue plasminogen activator (t-PA in a cohort of Saudi patients with chronic stable angiographically defined coronary artery disease (CAD and to determine its correlation with its severity.Methods: This cross sectional study was conducted in the department of physiology and department of cardiology, College of Medicine, and King Khalid University Hospital and King Saud University, Riyadh. Sixty known cases of CAD who had undergone angiography (35 males and 25 females were selected. A control group included 39 (20 males and 19 females healthy subjects. Fasting venous blood samples were analyzed for total (TFPI-T and free (TFPI-F tissue factor pathway inhibitor, plasminogen activator inhibitor-1 (PAI-1, and tissue plasminogen activator (t-PA. Gensini scores and vessel scores were determined for assessing CAD severity.Results: There were non-significant differences between age, body mass index (BMI and Blood pressure between the controls and CAD subjects. A comparison of hemostatic markers between control and CAD patients showed significantly higher levels of Fibrinogen, PAI-1, TFPI-T and TFPI-F in CAD patients compared to control subjects. But there was no difference in plasma t-PA levels. TFPI-T had a significant positive correlation with severity of disease determined by Gensini Scores (r=0.344; p=0.006 and vessel scores (r=0.338; p=0.015.Conclusion: Plasma levels of total tissue factor pathway inhibitor are significantly related with the presence and severity of CAD. Elevated levels of TFPI-T may be considered as useful diagnostic and prognostic markers in patients with CAD.

  3. Deficiency of terminal complement pathway inhibitor promotes neuronal tau pathology and degeneration in mice

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    Britschgi Markus

    2012-09-01

    Full Text Available Abstract Background The neuronal microtubule-associated protein tau becomes hyperphosphorylated and forms aggregates in tauopathies but the processes leading to this pathological hallmark are not understood. Because tauopathies are accompanied by neuroinflammation and the complement cascade forms a key innate immune pathway, we asked whether the complement system has a role in the development of tau pathology. Findings We tested this hypothesis in two mouse models, which expressed either a central inhibitor of complement or lacked an inhibitor of the terminal complement pathway. Complement receptor-related gene/protein y is the natural inhibitor of the central complement component C3 in rodents. Expressing a soluble variant (sCrry reduced the number of phospho-tau (AT8 epitope positive neurons in the brain stem, cerebellum, cortex, and hippocampus of aged P301L mutant tau/sCrry double-transgenic mice compared with tau single-transgenic littermates (JNPL3 line. CD59a is the major inhibitor of formation of the membrane attack complex in mice. Intrahippocampal injection of adeno-associated virus encoding mutant human P301L tau into Cd59a−/− mice resulted in increased numbers of AT8-positive cells compared with wild-type controls. This was accompanied by neuronal and synaptic loss and reduced dendritic integrity. Conclusions Our data in two independent mouse models with genetic changes in key regulators of the complement system support the hypothesis that the terminal pathway has an active role in the development of tau pathology. We propose that inhibition of the terminal pathway may be beneficial in tauopathies.

  4. In silico simulation of inhibitor drug effects on nuclear factor-kappaB pathway dynamics.

    Science.gov (United States)

    Sung, Myong-Hee; Simon, Richard

    2004-07-01

    NF-kappaB is a transcription factor family that activates numerous genes that are related to cell survival, apoptosis, and cell migration. Its persistent activity is associated with tumor formation, growth, metastasis, and drug resistance in many cancer types, including lymphoma, colon cancer, and breast cancer. Current therapeutic efforts for inhibiting this central "switch" include using small molecules to block a selected target in this pathway. Recognizing the regulatory network structure of the NF-kappaB pathway, we examine in silico the effects of inhibitors targeting various network components, using a kinetic model of the pathway. By simulating the corresponding perturbed system dynamics, we show the resulting time course of inhibition has distinct target-specific profiles. In particular, greater oscillatory potential exists for inhibition of upstream events than for direct inhibition of NF-kappaB, at low drug concentrations. This phenomenon is observed also when we examine the dynamic effects of the recently approved proteasome inhibitor, bortezomib (PS-341), and compare it with other inhibitors, taking its pharmacokinetics into consideration. Such kinetic analyses of the "drugged" molecular system will facilitate optimal drug target selection and the development of treatment protocols for a molecularly targeted therapy.

  5. Pregnancy Complications: Anemia

    Science.gov (United States)

    ... Close X Home > Complications & Loss > Pregnancy complications > Anemia Anemia E-mail to a friend Please fill in ... anemia at a prenatal care visit . What causes anemia? Usually, a woman becomes anemic (has anemia) because ...

  6. Chemical 'Jekyll and Hyde's: small-molecule inhibitors of developmental signaling pathways.

    Science.gov (United States)

    Sakata, Tomoyo; Chen, James K

    2011-08-01

    Small molecules that perturb developmental signaling pathways can have devastating effects on embryonic patterning, as evidenced by the chemically induced onset of cyclopic lambs and children with severely shortened limbs during the 1950s. Recent studies, however, have revealed critical roles for these pathways in human disorders and diseases, spurring the re-examination of these compounds as new targeted therapies. In this tutorial review, we describe four case studies of teratogenic compounds, including inhibitors of the Hedgehog (Hh), Wnt, and bone morphogenetic protein (BMP) pathways. We discuss how these teratogens were discovered, their mechanisms of action, their utility as molecular probes, and their potential as therapeutic agents. We also consider current challenges in the field and possible directions for future research.

  7. Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway.

    Directory of Open Access Journals (Sweden)

    Mohammad Atefi

    Full Text Available BACKGROUND: The sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204 in patients with BRAF(V600 mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression. Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors. However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway. METHODOLOGY/PRINCIPAL FINDINGS: The sensitivity to vemurafenib or the MEK inhibitor AZD6244 was tested in sensitive and resistant human melanoma cell lines exploring differences in activation-associated phosphorylation levels of major signaling molecules, leading to the testing of co-inhibition of the AKT/mTOR pathway genetically and pharmacologically. There was a high degree of cross-resistance to vemurafenib and AZD6244, except in two vemurafenib-resistant cell lines that acquired a secondary mutation in NRAS. In other cell lines, acquired resistance to both drugs was associated with persistence or increase in activity of AKT pathway. siRNA-mediated gene silencing and combination therapy with an AKT inhibitor or rapamycin partially or completely reversed the resistance. CONCLUSIONS/SIGNIFICANCE: Primary and acquired resistance to vemurafenib in these in vitro models results in frequent cross resistance to MEK inhibitors, except when the resistance is the result of a secondary NRAS mutation. Resistance to BRAF or MEK inhibitors is associated with the induction or persistence of activity within the AKT pathway in the presence of these drugs. This resistance can be potentially reversed by the combination of a RAF or MEK inhibitor with an AKT or mTOR inhibitor. These combinations should be available for clinical testing in patients progressing on BRAF inhibitors.

  8. Microangiopathic Hemolytic Anemia in 57-year-old woman with Borderline Serous Tumor of the Ovary:Real-Time Management of Common Pathways of Hemostatic Failure

    Directory of Open Access Journals (Sweden)

    Gloria Joan Morris

    2012-05-01

    Full Text Available We present a case of a 57-year-old woman who underwent surgery for the removal of an ovarian mass but subsequently experienced microangioathic hemolytic anemia post-operatively, associated with fevers, renal insufficiency, hypertension, and hemolysis. While her clinical situations was initially suspicious for thrombotic thrombocytopenic purpura (TTP, further sorting of clinical information led to other explanations of these findings, including a systemic inflammatory response. Multiple triggers of the coagulation system which can lead to a common pathway of hemostatic failure were considered, and specific criteria seen in disseminated intravascular coagulation (DIC, TTP, heparin-induced thrombocytopenia (HIT, catastrophic antiphospholipid anitbody syndrom (APS, all of which can seem to overlap when a physician is faced with distinguishing the diagnosis clinically. We propose a chronologic and strategic approach for the clinician to consider when approaching this diagnostic dilemma.

  9. Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFα inhibitors in patients with rheumatoid arthritis

    DEFF Research Database (Denmark)

    Krintel, Sophine B; Palermo, Giuseppe; Johansen, Julia S;

    2012-01-01

    Recently, two genome-wide association studies identified single nucleotide polymorphisms (SNPs) significantly associated with the treatment response to tumor necrosis factor α (TNFα) inhibitors in patients with rheumatoid arthritis (RA). We aimed to replicate these results and identify SNPs...... and the possible biological pathways associated with the treatment response to TNFα inhibitors....

  10. Analysis of the G2/M Checkpoint in fanconi anemia cells via examinating chromosomal instability during G2-phase and mitosis

    OpenAIRE

    Sauer, Rica

    2013-01-01

    Fanconi anemia is a genetical and phenotypical heterogenous disease, characterized through loss of one of the 15 identified genes of the Fanconi anemia pathway what causes congenital anomalies, bone marrow failure and solid tumors. In this work the G2/M checkpoint is analysed by use of the phosphatase inhibitor Calyculin A to examine the chromosomal instability, which is typical for fanconi anemia cells, not only in mitoses but also in the G2 phase of the cell cycle. It is proved that the che...

  11. Tissue factor pathway inhibitor-2: a novel gene involved in zebrafish central nervous system development.

    Science.gov (United States)

    Zhang, Yanli; Wang, Lina; Zhou, Wenhao; Wang, Huijun; Zhang, Jin; Deng, Shanshan; Li, Weihua; Li, Huawei; Mao, Zuohua; Ma, Duan

    2013-09-01

    Tissue factor pathway inhibitor-2 (Tfpi-2) is an important serine protease inhibitor in the extracellular matrix (ECM), but its precise physiological significance remains unknown. This work is part of a series of studies intended to investigate functional roles of Tfpi-2 and explore the underlying molecular mechanisms. First, we cloned and identified zebrafish Tfpi-2 (zTfpi-2) as an evolutionarily conserved protein essential for zebrafish development. We also demonstrated that ztfpi-2 is mainly expressed in the central nervous system (CNS) of zebrafish, and embryonic depletion of ztfpi-2 caused severe CNS defects. In addition, changes of neural markers, including pax2a, egr2b, huC, ngn1, gfap and olig2, confirmed the presence of developmental abnormalities in the relevant regions of ztfpi-2 morphants. Using microarray analysis, we found that members of the Notch pathway, especially her4 and mib, which mediate lateral inhibition in CNS development, were also downregulated. Intriguingly, both her4 and mib were able to partially rescue the ztfpi-2 morphant phenotype. Furthermore, Morpholino knockdown of ztfpi-2 resulted in upregulation of neuronal markers while downregulation of glial markers, providing evidence that the Notch pathway is probably involved in ztfpi-2-mediated CNS development.

  12. 1,3,8-Triazaspiro[4.5]decane-2,4-diones as efficacious pan-inhibitors of hypoxia-inducible factor prolyl hydroxylase 1-3 (HIF PHD1-3) for the treatment of anemia.

    Science.gov (United States)

    Vachal, Petr; Miao, Shouwu; Pierce, Joan M; Guiadeen, Deodial; Colandrea, Vincent J; Wyvratt, Matthew J; Salowe, Scott P; Sonatore, Lisa M; Milligan, James A; Hajdu, Richard; Gollapudi, Anantha; Keohane, Carol A; Lingham, Russell B; Mandala, Suzanne M; DeMartino, Julie A; Tong, Xinchun; Wolff, Michael; Steinhuebel, Dietrich; Kieczykowski, Gerard R; Fleitz, Fred J; Chapman, Kevin; Athanasopoulos, John; Adam, Gregory; Akyuz, Can D; Jena, Dhirendra K; Lusen, Jeffrey W; Meng, Juncai; Stein, Benjamin D; Xia, Lei; Sherer, Edward C; Hale, Jeffrey J

    2012-04-12

    The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.

  13. Genetic/metabolic effect of iron metabolism and rare anemias

    Directory of Open Access Journals (Sweden)

    Clara Camaschella

    2013-03-01

    Full Text Available Advances in iron metabolism have allowed a novel classification of iron disorders and to identify previously unknown diseases. These disorders include genetic iron overload (hemochromatosis and inherited iron-related anemias, in some cases accompanied by iron overload. Rare inherited anemias may affect the hepcidin pathway, iron absorption, transport, utilization and recycling. Among the genetic iron-related anemias the most common form is likely the iron-refractory iron-deficiency anemia (IRIDA, due to mutations of the hepcidin inhibitor TMPRSS6 encoding the serine protease matriptase-2. IRIDA is characterized by hepcidin up-regulation, decrease iron absorption and macrophage recycling and by microcytic- hypochromic anemia, unresponsive to oral iron. High serum hepcidin levels may suggest the diagnosis, which requires demonstrating the causal TMPRSS6 mutations by gene sequencing. Other rare microcytic hypochromic anemias associated with defects of iron transport-uptake are the rare hypotransferrinemia, and DMT1 and STEAP3 mutations. The degree of anemia is variable and accompanied by secondary iron overload even in the absence of blood transfusions. This is due to the iron-deficient or expanded erythropoiesis that inhibits hepcidin transcription, increases iron absorption, through the erythroid regulator, as in untransfused beta-thalassemia. Sideroblastic anemias are due to decreased mitochondrial iron utilization for heme or sulfur cluster synthesis. Their diagnosis requires demonstrating ringed sideroblasts by Perl’s staining of the bone marrow smears. The commonest X-linked form is due to deltaamino- levulinic-synthase-2-acid (ALAS2 mutations. The recessive, more severe form, affects SLC25A38, which encodes a potential mitochondrial importer of glycine, an amino acid essential for ALA synthesis and thus results in heme deficiency. Two disorders affect iron/sulfur cluster biogenesis: deficiency of the ATP-binding cassette B7 (ABCB7 causes X

  14. Biosynthetic pathway of the phytohormone auxin in insects and screening of its inhibitors.

    Science.gov (United States)

    Suzuki, Hiroyoshi; Yokokura, Junpei; Ito, Tsukasa; Arai, Ryoma; Yokoyama, Chiaki; Toshima, Hiroaki; Nagata, Shinji; Asami, Tadao; Suzuki, Yoshihito

    2014-10-01

    Insect galls are abnormal plant tissues induced by galling insects. The galls are used for food and habitation, and the phytohormone auxin, produced by the insects, may be involved in their formation. We found that the silkworm, a non-galling insect, also produces an active form of auxin, indole-3-acetic acid (IAA), by de novo synthesis from tryptophan (Trp). A detailed metabolic analysis of IAA using IAA synthetic enzymes from silkworms indicated an IAA biosynthetic pathway composed of a three-step conversion: Trp → indole-3-acetaldoxime → indole-3-acetaldehyde (IAAld) → IAA, of which the first step is limiting IAA production. This pathway was shown to also operate in gall-inducing sawfly. Screening of a chemical library identified two compounds that showed strong inhibitory activities on the conversion step IAAld → IAA. The inhibitors can be efficiently used to demonstrate the importance of insect-synthesized auxin in gall formation in the future.

  15. Synchronization of cells with activator-inhibitor pathways through adaptive environment-mediated coupling

    Science.gov (United States)

    Ghomsi, P. Guemkam; Moukam Kakmeni, F. M.; Tchawoua, C.; Kofane, T. C.

    2015-11-01

    In this paper, we report the synchronized dynamics of cells with activator-inhibitor pathways via an adaptive environment-mediated coupling scheme with feedbacks and control mechanisms. The adaptive character of the extracellular medium is modeled via its damping parameter as a physiological response aiming at annihilating the cellular differentiation existing between the chaotic biochemical pathways of the cells, in order to preserve homeostasis. We perform an investigation on the existence and stability of the synchronization manifold of the coupled system under the proposed coupling pattern. Both mathematical and computational tools suggest the accessibility of conducive prerequisites (conditions) for the emergence of a robust synchronous regime. The relevance of a phase-synchronized dynamics is appraised and several numerical indicators advocate for the prevalence of this fascinating phenomenon among the interacting cells in the phase space.

  16. Immune hemolytic anemia

    Science.gov (United States)

    Anemia - immune hemolytic; Autoimmune hemolytic anemia (AIHA) ... for no reason, the condition is called idiopathic autoimmune hemolytic anemia . The antibodies may also be caused by: Complication ...

  17. A Review of mTOR Pathway Inhibitors in Gynecologic Cancer

    Science.gov (United States)

    Paulino, Eduardo; Garces, Álvaro Henrique Ingles

    2017-01-01

    The treatment of advanced gynecologic cancers remains palliative in most of cases. Although systemic treatment has entered into the era of targeted drugs the antitumor efficacies of current therapies are still limited. In this context there is a great need for more active treatment and rationally designed targeted therapies. The PI3K/AKT/mTOR is a signaling pathway in mammal cells that coordinates important cell activities. It has a critical function in the survival, growth, and proliferation of malignant cells and was object of important research in the last two decades. The mTOR pathway emerges as an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli and, through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Aberrant PI3K-dependent signaling occurs frequently in a wide range of tumor types, including endometrial, cervical, and ovarian cancers. The present study reviewed the available evidence regarding the potential impact of some mTOR pathway inhibitors in the treatment of gynecological cancer. Few advances in medical management have occurred in recent years in the treatment of advanced or recurrent gynecological malignancies, and a poor prognosis remains. Rationally designed molecularly targeted therapy is an emerging and important option in this setting; then more investigation in PI3K/AKT/mTOR pathway-targeted therapies is warranted. PMID:28286604

  18. A Review of mTOR Pathway Inhibitors in Gynecologic Cancer

    Directory of Open Access Journals (Sweden)

    Andréia Cristina de Melo

    2017-01-01

    Full Text Available The treatment of advanced gynecologic cancers remains palliative in most of cases. Although systemic treatment has entered into the era of targeted drugs the antitumor efficacies of current therapies are still limited. In this context there is a great need for more active treatment and rationally designed targeted therapies. The PI3K/AKT/mTOR is a signaling pathway in mammal cells that coordinates important cell activities. It has a critical function in the survival, growth, and proliferation of malignant cells and was object of important research in the last two decades. The mTOR pathway emerges as an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli and, through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Aberrant PI3K-dependent signaling occurs frequently in a wide range of tumor types, including endometrial, cervical, and ovarian cancers. The present study reviewed the available evidence regarding the potential impact of some mTOR pathway inhibitors in the treatment of gynecological cancer. Few advances in medical management have occurred in recent years in the treatment of advanced or recurrent gynecological malignancies, and a poor prognosis remains. Rationally designed molecularly targeted therapy is an emerging and important option in this setting; then more investigation in PI3K/AKT/mTOR pathway-targeted therapies is warranted.

  19. Pernicious Anemia

    Science.gov (United States)

    ... well, and live normal lives. Without treatment, pernicious anemia can lead to serious problems with the heart, nerves, and other parts of the body. Some of ... INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA NO FEAR ACT OIG ...

  20. A high Notch pathway activation predicts response to γ secretase inhibitors in proneural subtype of glioma tumor-initiating cells.

    Science.gov (United States)

    Saito, Norihiko; Fu, Jun; Zheng, Siyuan; Yao, Jun; Wang, Shuzhen; Liu, Diane D; Yuan, Ying; Sulman, Erik P; Lang, Frederick F; Colman, Howard; Verhaak, Roel G; Yung, W K Alfred; Koul, Dimpy

    2014-01-01

    Genomic, transcriptional, and proteomic analyses of brain tumors reveal subtypes that differ in pathway activity, progression, and response to therapy. However, a number of small molecule inhibitors under development vary in strength of subset and pathway-specificity, with molecularly targeted experimental agents tending toward stronger specificity. The Notch signaling pathway is an evolutionarily conserved pathway that plays an important role in multiple cellular and developmental processes. We investigated the effects of Notch pathway inhibition in glioma tumor-initiating cell (GIC, hereafter GIC) populations using γ secretase inhibitors. Drug cytotoxicity testing of 16 GICs showed differential growth responses to the inhibitors, stratifying GICs into responders and nonresponders. Responder GICs had an enriched proneural gene signature in comparison to nonresponders. Also gene set enrichment analysis revealed 17 genes set representing active Notch signaling components NOTCH1, NOTCH3, HES1, MAML1, DLL-3, JAG2, and so on, enriched in responder group. Analysis of The Cancer Genome Atlas expression dataset identified a group (43.9%) of tumors with proneural signature showing high Notch pathway activation suggesting γ secretase inhibitors might be of potential value to treat that particular group of proneural glioblastoma (GBM). Inhibition of Notch pathway by γ secretase inhibitor treatment attenuated proliferation and self-renewal of responder GICs and induces both neuronal and astrocytic differentiation. In vivo evaluation demonstrated prolongation of median survival in an intracranial mouse model. Our results suggest that proneural GBM characterized by high Notch pathway activation may exhibit greater sensitivity to γ secretase inhibitor treatment, holding a promise to improve the efficiency of current glioma therapy.

  1. Clinical development of VEGF signaling pathway inhibitors in childhood solid tumors.

    Science.gov (United States)

    Glade Bender, Julia; Yamashiro, Darrell J; Fox, Elizabeth

    2011-01-01

    Angiogenesis is a target shared by both adult epithelial cancers and the mesenchymal or embryonal tumors of childhood. Development of antiangiogenic agents for the pediatric population has been complicated by largely theoretical concern for toxicities specific to the growing child and prioritization among the many antiangiogenic agents being developed for adults. This review summarizes the mechanism of action and preclinical data relevant to childhood cancers and early-phase clinical trials in childhood solid tumors. Single-agent adverse event profiles in adults and children are reviewed with emphasis on cardiovascular, bone health, and endocrine side effects. In addition, pharmacological factors that may be relevant for prioritizing clinical trials of these agents in children are reviewed. Considerations for further clinical evaluation should include preclinical data, relative potency, efficacy in adults, and the current U.S. Food and Drug Administration approval status. Toxicity profiles of vascular endothelial growth factor (VEGF) signaling pathway inhibitors may be age dependent and ultimately, their utility in the treatment of childhood cancer will require combination with standard cytotoxic drugs or other molecularly targeted agents. In combination studies, toxicity profiles, potential drug interactions, and late effects must be considered. Studies to assess the long-term impact of VEGF signaling pathway inhibitors on cardiovascular, endocrine, and bone health in children with cancer are imperative if these agents are to be administered to growing children and adolescents with newly diagnosed cancers.

  2. Types of Hemolytic Anemia

    Science.gov (United States)

    ... from the NHLBI on Twitter. Types of Hemolytic Anemia There are many types of hemolytic anemia. The ... the condition, but you develop it. Inherited Hemolytic Anemias With inherited hemolytic anemias, one or more of ...

  3. What Is Aplastic Anemia?

    Science.gov (United States)

    ... from the NHLBI on Twitter. What Is Aplastic Anemia? Aplastic anemia (a-PLAS-tik uh-NEE-me-uh) is ... heart, heart failure , infections, and bleeding. Severe aplastic anemia can even cause death. Overview Aplastic anemia is ...

  4. What Causes Anemia?

    Science.gov (United States)

    ... page from the NHLBI on Twitter. What Causes Anemia? The three main causes of anemia are: Blood ... the blood and can lead to anemia. Aplastic Anemia Some infants are born without the ability to ...

  5. Anemia (For Teens)

    Science.gov (United States)

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Anemia KidsHealth > For Teens > Anemia Print A A A ... Getting Enough Iron en español Anemia What Is Anemia? Lots of teens are tired. With all the ...

  6. What Is Fanconi Anemia?

    Science.gov (United States)

    ... Living With Clinical Trials Links Related Topics Anemia Aplastic Anemia Blood and Bone Marrow Transplant Congenital Heart Defects ... red blood cells. FA is a type of aplastic anemia . In aplastic anemia, the bone marrow stops making ...

  7. Anemia (For Teens)

    Science.gov (United States)

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Anemia KidsHealth > For Teens > Anemia A A A What's ... Getting Enough Iron en español Anemia What Is Anemia? Lots of teens are tired. With all the ...

  8. Vismodegib, a small-molecule inhibitor of the hedgehog pathway for the treatment of advanced cancers.

    Science.gov (United States)

    De Smaele, Enrico; Ferretti, Elisabetta; Gulino, Alberto

    2010-06-01

    Vismodegib (GDC-0449) is a small, orally administrable molecule, belonging to the 2-arylpyridine class, which was discovered by Genentech Inc under a collaboration with Curis Inc. Vismodegib inhibits the Hedgehog (Hh) pathway, which is involved in tumorigenesis, thus providing a strong rationale for its use in the treatment of a variety of cancers. Vismodegib suppresses Hh signaling by binding to and interfering with smoothened, a membrane protein that provides positive signals to the Hh signaling pathway. Preclinical studies demonstrated the antitumor activity of vismodegib in mouse models of medulloblastoma (MB) and in xenograft models of colorectal and pancreatic cancer. Phase I clinical trials in patients with advanced basal cell carcinoma (BCC) and MB highlighted an objective response to vismodegib. Reported side effects were minor, with only one grade 4 adverse event. Vismodegib is currently undergoing phase II clinical trials for the treatment of advanced BCC, metastatic colorectal cancer, ovarian cancer, MB and other solid tumors. Because of its low toxicity and specificity for the Hh pathway, this drug has potential advantages compared with conventional chemotherapy, and may also be used in combination treatments. Clinical trials with other Hh inhibitors are also ongoing and their therapeutic potential will need to be compared with vismodegib.

  9. Anemia (For Parents)

    Science.gov (United States)

    ... Old Feeding Your 1- to 2-Year-Old Anemia KidsHealth > For Parents > Anemia Print A A A ... Preventing Iron-Deficiency Anemia en español Anemia About Anemia Anemia happens when the level of healthy red ...

  10. Enzyme inhibitor studies reveal complex control of methyl-D-erythritol 4-phosphate (MEP pathway enzyme expression in Catharanthus roseus.

    Directory of Open Access Journals (Sweden)

    Mei Han

    Full Text Available In Catharanthus roseus, the monoterpene moiety exerts a strong flux control for monoterpene indole alkaloid (MIA formation. Monoterpene synthesis depends on the methyl-D-erythritol 4-phosphate (MEP pathway. Here, we have explored the regulation of this pathway in response to developmental and environmental cues and in response to specific enzyme inhibitors. For the MEP pathway entry enzyme 1-deoxy-D-xylulose 5-phosphate synthase (DXS, a new (type I DXS isoform, CrDXS1, has been cloned, which, in contrast to previous reports on type II CrDXS, was not transcriptionally activated by the transcription factor ORCA3. Regulation of the MEP pathway in response to metabolic perturbations has been explored using the enzyme inhibitors clomazone (precursor of 5-ketochlomazone, inhibitor of DXS and fosmidomycin (inhibitor of deoxyxylulose 5-phosphate reductoisomerase (DXR, respectively. Young leaves of non-flowering plants were exposed to both inhibitors, adopting a non-invasive in vivo technique. Transcripts and proteins of DXS (3 isoforms, DXR, and hydroxymethylbutenyl diphosphate synthase (HDS were monitored, and protein stability was followed in isolated chloroplasts. Transcripts for DXS1 were repressed by both inhibitors, whereas transcripts for DXS2A&B, DXR and HDS increased after clomazone treatment but were barely affected by fosmidomycin treatment. DXS protein accumulated in response to both inhibitors, whereas DXR and HDS proteins were less affected. Fosmidomycin-induced accumulation of DXS protein indicated substantial posttranscriptional regulation. Furthermore, fosmidomycin effectively protected DXR against degradation in planta and in isolated chloroplasts. Thus our results suggest that DXR protein stability may be affected by substrate binding. In summary, the present results provide novel insight into the regulation of DXS expression in C. roseus in response to MEP-pathway perturbation.

  11. Enzyme inhibitor studies reveal complex control of methyl-D-erythritol 4-phosphate (MEP) pathway enzyme expression in Catharanthus roseus.

    Science.gov (United States)

    Han, Mei; Heppel, Simon C; Su, Tao; Bogs, Jochen; Zu, Yuangang; An, Zhigang; Rausch, Thomas

    2013-01-01

    In Catharanthus roseus, the monoterpene moiety exerts a strong flux control for monoterpene indole alkaloid (MIA) formation. Monoterpene synthesis depends on the methyl-D-erythritol 4-phosphate (MEP) pathway. Here, we have explored the regulation of this pathway in response to developmental and environmental cues and in response to specific enzyme inhibitors. For the MEP pathway entry enzyme 1-deoxy-D-xylulose 5-phosphate synthase (DXS), a new (type I) DXS isoform, CrDXS1, has been cloned, which, in contrast to previous reports on type II CrDXS, was not transcriptionally activated by the transcription factor ORCA3. Regulation of the MEP pathway in response to metabolic perturbations has been explored using the enzyme inhibitors clomazone (precursor of 5-ketochlomazone, inhibitor of DXS) and fosmidomycin (inhibitor of deoxyxylulose 5-phosphate reductoisomerase (DXR)), respectively. Young leaves of non-flowering plants were exposed to both inhibitors, adopting a non-invasive in vivo technique. Transcripts and proteins of DXS (3 isoforms), DXR, and hydroxymethylbutenyl diphosphate synthase (HDS) were monitored, and protein stability was followed in isolated chloroplasts. Transcripts for DXS1 were repressed by both inhibitors, whereas transcripts for DXS2A&B, DXR and HDS increased after clomazone treatment but were barely affected by fosmidomycin treatment. DXS protein accumulated in response to both inhibitors, whereas DXR and HDS proteins were less affected. Fosmidomycin-induced accumulation of DXS protein indicated substantial posttranscriptional regulation. Furthermore, fosmidomycin effectively protected DXR against degradation in planta and in isolated chloroplasts. Thus our results suggest that DXR protein stability may be affected by substrate binding. In summary, the present results provide novel insight into the regulation of DXS expression in C. roseus in response to MEP-pathway perturbation.

  12. Embryofetal development study of vismodegib, a hedgehog pathway inhibitor, in rats.

    Science.gov (United States)

    Morinello, Eric; Pignatello, Michael; Villabruna, Loris; Goelzer, Petra; Bürgin, Heinrich

    2014-04-01

    Vismodegib (Erivedge) is a first-in-class small-molecule hedgehog pathway inhibitor for the treatment of adults with advanced basal-cell carcinoma. Because this pathway is known to play key roles in patterning and growth during vertebrate development, vismodegib was anticipated to be embryotoxic. To support marketing applications, an embryofetal development study was completed in which a limited number of pregnant rats (n = 6/group) was administered vismodegib by oral gavage on gestation days 6 to 17. When vismodegib was administered at ≥60 mg/kg/day, doses associated with evidence of pharmacologic activity in previous rat toxicity studies, all conceptuses were resorbed at an early embryonic stage in the absence of significant maternal toxicity. When administered at 10 mg/kg/day, corresponding to an exposure (AUC0-24h ) approximately 15% of the median in patients at steady state, a variety of malformations were observed, including absent/fused digits in the hindlimb of multiple fetuses, multiple craniofacial abnormalities in one fetus, and an anorectal defect in one fetus. In addition, the incidence of variations, including dilated renal pelvis or ureter and incompletely or unossified skeletal elements, was significantly greater when compared with the controls. These results confirmed that vismodegib is likely to be embryotoxic at clinically relevant maternal exposures, and doses ≥60 mg/kg/day resulted in a 100% incidence of embryolethality that likely resulted from severe defects in early embryonic development. In contrast, craniofacial defects typically associated with hedgehog pathway inhibition were only observed in one fetus at the low dose of 10 mg/kg/day, which likely reflected minimal or intermittent pathway inhibition at low exposures.

  13. Synchronization dynamics of chemically coupled cells with activator–inhibitor pathways

    Energy Technology Data Exchange (ETDEWEB)

    Guemkam Ghomsi, P. [Complex Systems and Theoretical Biology Group, Laboratory of Research on Advanced Materials and Nonlinear Science (LaRAMaNS), Department of Physics, Faculty of Science, University of Buea, P.O. Box 63, Buea (Cameroon); Laboratoire de Mécanique, Department of Physics, Faculty of Science, University of Yaoundé I, P.O. Box 812, Yaoundé (Cameroon); Moukam Kakmeni, F.M., E-mail: moukam.kakmeni@ubuea.cm [Complex Systems and Theoretical Biology Group, Laboratory of Research on Advanced Materials and Nonlinear Science (LaRAMaNS), Department of Physics, Faculty of Science, University of Buea, P.O. Box 63, Buea (Cameroon); Kofane, T.C.; Tchawoua, C. [Laboratoire de Mécanique, Department of Physics, Faculty of Science, University of Yaoundé I, P.O. Box 812, Yaoundé (Cameroon)

    2014-08-01

    Systems of interacting cells containing an activator–inhibitor pathway, regulating naturally in their inner parts their end-product concentrations through a sequence of biochemical reactions with feedback-loops: an end-product inhibition of the first substrate, and an autocatalytic activation of the end-product through an allosteric enzyme-mediated reaction are investigated. The individual cells are considered to be identical and are described by nonlinear differential equations recently proposed following the concerted transition model. The chemical and electrical coupling types, realized by exchange of metabolites across concentration of the cells are used in order to analyze the onset of phase and complete synchronization in the biochemical system. It is found that depending on the coupling nature and the range of coupling strength, cells enter into different synchronization regimes going from low-quality to high-quality synchronization. The synchronization manifold's stability is analyzed. The results are supported by numerical simulations using indicators such as the conditional Lyapunov exponents and the rate of change of the Lyapunov function. The results indicate that the system cannot completely synchronize under the single action of the chemical coupling. The combined effect of both chemical and electrical couplings is found to be of capital importance in the onset of complete synchronization and high quality synchronization. - Highlights: • We investigate the dynamics and synchronization of cells with activator–inhibitor pathways. • A complete study of fixed points' stability and bifurcations of the system is done. • It is found that chemically coupled cells only display phase synchronization. • Electrical coupling is important for complete synchronization in the coupled cells. • High quality synchronization is observed in the coupled cells.

  14. BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model.

    Science.gov (United States)

    Perna, Daniele; Karreth, Florian A; Rust, Alistair G; Perez-Mancera, Pedro A; Rashid, Mamunur; Iorio, Francesco; Alifrangis, Constantine; Arends, Mark J; Bosenberg, Marcus W; Bollag, Gideon; Tuveson, David A; Adams, David J

    2015-02-10

    BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors elicit a transient anti-tumor response in ∼ 80% of BRAF(V600)-mutant melanoma patients that almost uniformly precedes the emergence of resistance. Here we used a mouse model of melanoma in which melanocyte-specific expression of Braf(V618E) (analogous to the human BRAF(V600E) mutation) led to the development of skin hyperpigmentation and nevi, as well as melanoma formation with incomplete penetrance. Sleeping Beauty insertional mutagenesis in this model led to accelerated and fully penetrant melanomagenesis and synchronous tumor formation. Treatment of Braf(V618E) transposon mice with the BRAF inhibitor PLX4720 resulted in tumor regression followed by relapse. Analysis of transposon insertions identified eight genes including Braf, Mitf, and ERas (ES-cell expressed Ras) as candidate resistance genes. Expression of ERAS in human melanoma cell lines conferred resistance to PLX4720 and induced hyperphosphorylation of AKT (v-akt murine thymoma viral oncogene homolog 1), a phenotype reverted by combinatorial treatment with PLX4720 and the AKT inhibitor MK2206. We show that ERAS expression elicits a prosurvival signal associated with phosphorylation/inactivation of BAD, and that the resistance of hepatocyte growth factor-treated human melanoma cells to PLX4720 can be reverted by treatment with the BAD-like BH3 mimetic ABT-737. Thus, we define a role for the AKT/BAD pathway in resistance to BRAF inhibition and illustrate an in vivo approach for finding drug resistance genes.

  15. The Levels of Tissue Factor Pathway Inhibitor in Sepsis Patients Receiving Prophylactic Enoxaparin

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    Hadil A. Al Otair

    2016-05-01

    Full Text Available Objective: Sepsis syndrome is usually accompanied by activation of blood coagulation mechanisms. Earlier studies found deficiencies of the 3 main natural anticoagulants, antithrombin, protein C, and protein S. However, none of these inhibitors block tissue factor, the prime trigger of coagulation during sepsis that is controlled specifically by the tissue factor pathway inhibitor (TFPI. The aim of this study was to characterize the fluctuations in the levels of natural anticoagulants, particularly TFPI, in the course of sepsis and to find out their association with the anticoagulant action of the lowmolecular-weight heparin enoxaparin. Materials and Methods: We studied 51 consecutive patients with sepsis. Blood samples were collected from patients at baseline (0 h and at 4, 12, and 24 h after enoxaparin administration. The following assays were undertaken using commercial kits: activated partial thromboplastin time, prothrombin time, thrombin time, total and free TFPI, protein C and protein S, antithrombin, fibrinogen, and anti-factor Xa. Results: Before enoxaparin administration, there was significant prolongation of the prothrombin time and activated partial thromboplastin time, and this remained the case in the 3 subsequent samples. There was marked reduction in the levels of antithrombin, protein C, and total and free protein S to below control values throughout the study. In contrast, plasma levels of both total and free TFPI were markedly elevated and increased after enoxaparin therapy. Anti-factor Xa levels were within the therapeutic range throughout. There was no difference in TFPI levels between those patients who died and those who survived. Conclusion: Sepsis triggered marked release of TFPI from endothelial cells. This persisted and was increased further following the administration of enoxaparin. In contrast, there was marked consumption of the natural coagulation inhibitors antithrombin, protein C, and protein S. These results go

  16. Reduced expression of tissue factor pathway inhibitor-2 contributes to apoptosis and angiogenesis in cervical cancer

    Directory of Open Access Journals (Sweden)

    Zhang Qiao

    2012-01-01

    Full Text Available Abstract Background Tissue factor pathway inhibitor-2 (TFPI-2 is an extracellular matrix associated broad-spectrum Kunitz-type serine proteinase inhibitor. Recently, down regulation of TFPI-2 was suggested to be involved in tumor invasion and metastasis in some cancers. Methods This study involved 12 normal cervical squamous epithelia, 48 cervical intraepithelial neoplasia (CIN, and 68 cervical cancer. The expression of TFPI-2, Ki-67 and vascular endothelial growth factor (VEGF were investigated by immunohistochemistry staining. The apoptolic index(AI was determined with an in situ end-labeling assay(TUNEL. And the marker of CD34 staining was used as an indicator of microvessel density (MVD. Results TFPI-2 expression has a decreasing trend with the progression of cervical cancer and was significantly correlated with FIGO stage, lymph node metastasis and HPV infection. In addition, there were significant positive correlations between the grading of TFPI-2 expression and AI(P = 0.004. In contrast, the expression of TFPI-2 and VEGF or MVD was negatively correlated (both p Conclusions The results suggested that the expression of TFPI-2 had a decreasing trend with tumor progression of cervical cancer. There was a close association between the expression of TFPI-2 and tumor cell apoptosis and angiogenesis in patients with cervical cancer. TFPI-2 may play an inhibitive role during the development of cervical cancer.

  17. Tissue factor pathway inhibitor-2 may interact with nuclear protein RASSF1C

    Institute of Scientific and Technical Information of China (English)

    Xudong Chen; Zhenwu Li; Jin Zhang; Zuohua Mao; Duan Ma; Huijun Wang

    2012-01-01

    Tissue factor pathway inhibitor-2 (TFPI-2) is a 32 kDa matrix-associated Kunitz-type serine proteinase inhibitor consisting of a short amino-terminal region,three tandem Kunitz-type domains,and a positively charged carboxyterminal tail.Human TFPI-2 (hTFPI-2) inhibits a broad spectrum of serine proteinases (including trypsin,plasmin,plasma kallikrein,XIa,and chymotrypsin) almost exclusively via its first Kunitz-type domain,and potentially plays an important role in the regulation of extracellular matrix digestion and remodeling [1].Reduced TFPI-2 synthesis has been related to numerous pathophysiological processes such as inflammation,angiogenesis,atherosclerosis [2,3],retinal degeneration,and tumor growth/metastasis [4-6].It has been suggested that TFPI-2 is a tumor suppressor gene in some cancers [7,8].However,the specific physiological functions of hTFPI-2 in humans are unclear,particularly its interactions with other proteins.To better understand the physiological function of hTFPI-2,we used yeast two-hybrid system screening and bioinformatics analysis to identify its interacting proteins and confirm its interactions with nuclear protein RASSF1C using confocal microscopy and co-immunoprecipitation.

  18. A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways

    Science.gov (United States)

    Spring, Bryan Q.; Bryan Sears, R.; Zheng, Lei Zak; Mai, Zhiming; Watanabe, Reika; Sherwood, Margaret E.; Schoenfeld, David A.; Pogue, Brian W.; Pereira, Stephen P.; Villa, Elizabeth; Hasan, Tayyaba

    2016-04-01

    Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and evade treatment. Here, we introduce a photoactivable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with a photoinitiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)—a multikinase inhibitor—encapsulated inside. Near-infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release while reducing systemic drug exposure and associated toxicities.

  19. The nuclease hSNM1B/Apollo is linked to the Fanconi anemia pathway via its interaction with FANCP/SLX4.

    Science.gov (United States)

    Salewsky, Bastian; Schmiester, Maren; Schindler, Detlev; Digweed, Martin; Demuth, Ilja

    2012-11-15

    The recessive genetic disorder Fanconi anemia (FA) is clinically characterized by congenital defects, bone marrow failure and an increased incidence of cancer. Cells derived from FA patients exhibit hypersensitivity to DNA interstrand crosslink (ICL)-inducing agents. We have earlier reported a similar cellular phenotype for human cells depleted of hSNM1B/Apollo (siRNA). In fact, hSNM1B/Apollo has a dual role in the DNA damage response and in generation and maintenance of telomeres, the latter function involving interaction with the shelterin protein TRF2. Here we find that ectopically expressed hSNM1B/Apollo co-immunoprecipitates with SLX4, a protein recently identified as a new FA protein, FANCP, and known to interact with several structure-specific nucleases. As shown by immunofluorescence analysis, FANCP/SLX4 depletion (siRNA) resulted in a significant reduction of hSNM1B/Apollo nuclear foci, supporting the functional relevance of this new protein interaction. Interestingly, as an additional consequence of FANCP/SLX4 depletion, we found a reduction of cellular TRF2, in line with its telomere-related function. Finally, analysis of human cells following double knockdown of hSNM1B/Apollo and FANCP/SLX4 indicated that they function epistatically. These findings further substantiate the role of hSNM1B/Apollo in a downstream step of the FA pathway during the repair of DNA ICLs.

  20. Peptide inhibitor of complement C1 (PIC1, a novel suppressor of classical pathway activation: mechanistic studies and clinical potential

    Directory of Open Access Journals (Sweden)

    Julia A Sharp

    2014-08-01

    Full Text Available The classical pathway of complement plays multiple physiological roles including modulating immunological effectors initiated by adaptive immune responses as well as an essential homeostatic role in the clearance of damaged self-antigens. However, dysregulated classical pathway activation is associated with antibody-initiated, inflammatory diseases processes like cold agglutinin disease (CAD, acute intravascular hemolytic transfusion reaction (AIHTR and acute/hyperacute transplantation rejection. To date, only one putative classical pathway inhibitor, C1 esterase inhibitor (C1-INH, is currently commercially available and its only approved indication is for replacement treatment in hereditary angioedema (HAE, which is predominantly a kinin pathway disease. Given the variety of disease conditions in which the classical pathway is implicated, development of therapeutics that specifically inhibit complement initiation represents a major unmet medical need. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement. In vitro studies have demonstrated that these Peptide Inhibitors of Complement C1 (PIC1 bind to the collagen-like region of the initiator molecule of the classical pathway, C1q. PIC1 binding to C1q blocks activation of the associated serine proteases (C1s-C1r-C1r-C1s and subsequent downstream complement activation. Rational design optimization of PIC1 has resulted in the generation of a highly potent derivative of fifteen amino acids. PIC1 inhibits classical pathway mediated complement activation in ABO incompatibility in vitro as well as inhibiting classical pathway activation in vivo in rats. This review will focus on the pre-clinical development of PIC1 and discuss its potential as a therapeutic in antibody-mediated classical pathway disease, specifically AIHTR.

  1. Cyclooxygenase-2 inhibitor, celecoxib, inhibits leiomyoma cell proliferation through the nuclear factor κB pathway.

    Science.gov (United States)

    Park, Seung Bin; Jee, Byung Chul; Kim, Seok Hyun; Cho, Yeon Jean; Han, Myoungseok

    2014-09-01

    Our aim was to investigate whether celecoxib, a cyclooxygenase 2 (COX-2) inhibitor, decreases the in vitro proliferation of leiomyoma cells if the inflammatory pathway is blocked. Menstruation is an inflammation of uterus that produces cytokines and prostanoids, but the inflammatory mechanism underlying the growth of leiomyoma remains unexplained. Using in vitro cultures of leiomyoma cells obtained from 5 patients who underwent hysterectomy, cell proliferation, inflammatory signaling, transcription factors, growth factors, and extracellular matrix were examined by (4,5-dimethylthiaxol-2-yi)-2,5-diphenyltetraxolium bromide assay, immunoblotting, and quantitative polymerase chain reaction. Prostaglandin E2 was used to induce menstruation-like condition in the cells. We found that celecoxib inhibited COX-2 through the expression of nuclear factor κB in the cells. Celcoxib also decreased the gene expression of interleukin 6, tumor necrosis factor α, collagen A, fibronectin, platelet-derived growth factor, epidermal growth factor, and transforming growth factor β. In conclusion, the present study indicated that celecoxib could inhibit leiomyoma cell proliferation through blocking the inflammatory pathway that is probably one of the mechanisms underlying its pathogenesis.

  2. Suppression of Autoimmune Arthritis by Small Molecule Inhibitors of the JAK/STAT Pathway

    Directory of Open Access Journals (Sweden)

    Charles J. Malemud

    2010-05-01

    Full Text Available A skewed ratio of pro-inflammatory to anti-inflammatory cytokines, elevated growth factor synthesis and T- and B-lymphocyte activation are 3 hallmarks of rheumatoid arthritis (RA pathology. Interleukin-6 (IL-6, IL-7, IL-17, IL-12/IL-23 and growth factors, granulocyte macrophage-colony stimulating factor, IL-3, and erythropoietin activate the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT pathway. Evidence showed that STAT protein phosphorylation (p-STAT by activated JAKs is permissive for p-STAT to act as transcription factors by binding to STAT-responsive gene promoter sequences. This event is critical for perpetuating RA, in part, by up-regulating pro-inflammatory cytokine gene transcription. Activation of JAK/STAT by cytokines and growth factors can induce ‘cross-talk’ with other signaling pathways by which Stress-Activated Protein/Mitogen-Activated Protein Kinase (SAP/MAPK and Phosphatidylinositide-3-Kinase (PI3K-mediated signaling are also activated. JAK-specific small molecule inhibitors (SMIs were developed to test whether JAK/STAT pathway blockade would regulate autoimmune-mediated inflammation. JAK-specific SMI blockade inhibited p-STAT induced by pro-inflammatory cytokines in vitro. Systemically administered JAK-specific SMI blockade also ameliorated biomarkers of inflammation in well-validated arthritis animal models. A few JAK-specific SMIs have made their way into RA clinical trials. In fact, the JAK3-specific SMI, CP-690,500 is the first JAK/STAT SMI to be assessed for clinical efficacy in a Phase III RA trial.

  3. Aplastic anemia

    Science.gov (United States)

    ... the number of these blood cell types. Aplastic anemia can be caused by: Use of certain drugs or exposure to toxic chemicals (such as benzene) Exposure to radiation or chemotherapy Autoimmune disorders Pregnancy Viruses Sometimes, the cause is unknown. In this ...

  4. Hemolytic Anemia

    Science.gov (United States)

    ... may require ongoing treatment. Acquired forms of hemolytic anemia may go away if the cause of the condition is found and corrected. Rate This Content: NEXT >> Updated: March 21, 2014 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA NO FEAR ACT OIG ...

  5. The PI3K inhibitor GS-1101 synergistically potentiates HDAC inhibitor-induced proliferation inhibition and apoptosis through the inactivation of PI3K and ERK pathways

    Science.gov (United States)

    Bodo, Juraj; Zhao, Xiaoxian; Sharma, Arishya; Hill, Brian T.; Portell, Craig A.; Lannutti, Brian J.; Almasan, Alexandru; Hsi, Eric D.

    2013-01-01

    Previously, we showed that inhibition of the protein kinase C β (PKCβ)/AKT pathway augments engagement of the histone deacetylase inhibitor (HDI)-induced apoptosis in lymphoma cells. In the present study, we investigated the cytotoxicity and mechanisms of cell death induced by the delta isoform-specific phosphatidylinositide 3-kinase (PI3K) inhibitor, GS-1101, in combination with the HDI, panobinostat (LBH589) and suberoylanilide hydroxamic acid (SAHA). Lymphoma cell lines and primary Non-Hodgkin Lymphoma (NHL) and chronic lymphocytic leukaemia (CLL) cells were simultaneously treated with the HDI, LBH589 and GS-1101. An interaction of the LBH589/GS-1101 combination was formally examined by using various concentrations of LBH589 and GS-1101. Combined treatment resulted in a synergistic inhibition of proliferation and showed synergistic effect on apoptotic induction in all tested cell lines and primary NHL and CLL cells. This study indicates that interference with PI3K signalling dramatically increases HDI-mediated apoptosis in malignant haematopoietic cells, possibly through both AKT-dependent or AKT- independent mechanisms. Moreover, the increase in HDI-related apoptosis observed in PI3K inhibitor-treated cells appears to be related to the disruption of the extracellular signal-regulated kinase (ERK) signalling pathway. This study provides a strong rational for testing the combination of PI3K inhibitors and HDI in the clinic. PMID:23889282

  6. Warm autoimmune hemolytic anemia.

    Science.gov (United States)

    Naik, Rakhi

    2015-06-01

    Warm autoimmune hemolytic anemia (AIHA) is defined as the destruction of circulating red blood cells (RBCs) in the setting of anti-RBC autoantibodies that optimally react at 37°C. The pathophysiology of disease involves phagocytosis of autoantibody-coated RBCs in the spleen and complement-mediated hemolysis. Thus far, treatment is aimed at decreasing autoantibody production with immunosuppression or reducing phagocytosis of affected cells in the spleen. The role of complement inhibitors in warm AIHA has not been explored. This article addresses the diagnosis, etiology, and treatment of warm AIHA and highlights the role of complement in disease pathology.

  7. Advanced basal cell carcinoma, the hedgehog pathway, and treatment options – role of smoothened inhibitors

    Directory of Open Access Journals (Sweden)

    Fecher LA

    2015-11-01

    Full Text Available Leslie A Fecher,1,3 William H Sharfman2 1Department of Internal Medicine and Dermatology, Indiana University Health Simon Cancer Center, Indianapolis, IN, USA; 2The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA, 3Department of Internal Medicine and Dermatology, University of Michigan, MI, USA Abstract: Cutaneous basal cell carcinoma (BCC is the most common human cancer and its incidence is rising worldwide. Ultraviolet radiation exposure, including tanning bed use, as well as host factors play a role in its development. The majority of cases are treated and cured with local therapies including surgery. Yet, the health care costs of diagnosis and treatment of BCCs in the US is substantial. In the United States, the cost of nonmelanoma skin cancer care in the Medicare population is estimated to be US$426 million per year. While rare, locally advanced BCCs that can no longer be controlled with surgery and/or radiation, and metastatic BCCs do occur and can be associated with significant morbidity and mortality. Vismodegib (GDC-0449, a smoothened inhibitor targeted at the hedgehog pathway, is the first US Food and Drug Association (FDA-approved agent in the treatment of locally advanced, unresectable, and metastatic BCCs. This class of agents appears to be changing the survival rates in advanced BCC patients, but appropriate patient selection and monitoring are important. Multidisciplinary assessments are essential for the optimal care and management of these patients. For some patients with locally advanced BCC, treatment with a hedgehog inhibitor may eliminate the need for an excessively disfiguring or morbid surgery. Keywords: basal cell carcinoma, hedgehog, smoothened, vismodegib, Gorlin, basal cell nevus syndrome

  8. A feedback regulatory pathway between LDL and alpha-1 proteinase inhibitor in chronic inflammation and infection.

    Science.gov (United States)

    Bristow, Cynthia L; Modarresi, Rozbeh; Babayeva, Mariya A; LaBrunda, Michelle; Mukhtarzad, Roya; Trucy, Maylis; Franklin, Aaron; Reeves, Rudy E R; Long, Allegra; Mullen, Michael P; Cortes, Jose; Winston, Ronald

    2013-11-01

    Dietary lipids are transported via lymph to the liver and transformed to lipoproteins which bind to members of the low density lipoprotein receptor family (LDL-RFMs). Certain LDL-RFMs, e.g., very low density lipoprotein receptor (VLDLR), are also bound by inactivated proteinase inhibitors, the most abundant being α1proteinase inhibitor (α1PI, α1antitrypsin). Inflammation/infection, including HIV-1 infection, is accompanied by low levels of CD4+ T cells and active α1PI and high levels of inactivated α1PI. By inducing LDL-RFMs-mediated cellular locomotion, active α1PI regulates the number of CD4+ T cells. We sought to investigate whether CD4+ T cells and α1PI directly impact lipoprotein levels. At the cellular level, we show that active α1PI is required for VLDLR-mediated uptake of receptor-associated cargo, specifically CD4-bound HIV-1. We show that active α1PI levels linearly correlate with LDL levels in HIV-1 infected individuals (P<0.001) and that therapeutic, weekly infusions of active α1PI elevate the number of CD4+ T cells and HDL levels while lowering LDL levels in patients on antiretroviral therapy with controlled HIV-1. Based on the unusual combination of lipodystrophy and low levels of α1PI and CD4+ T cells in HIV-1 disease, we reveal that LDL and α1PI participate in a feedback regulatory pathway. We demonstrate integral roles for sequentially acting active and inactive α1PI in the uptake and recycling of receptors and cargo aggregated with VLDLR including CD4 and chemokine receptors. Evidence supports a role for α1PI as a primary sentinel to deploy the immune system as a consequence of its role in lipoprotein transport.

  9. A Targeted Inhibitor of the Alternative Complement Pathway Accelerates Recovery From Smoke-Induced Ocular Injury

    Science.gov (United States)

    Woodell, Alex; Jones, Bryan W.; Williamson, Tucker; Schnabolk, Gloriane; Tomlinson, Stephen; Atkinson, Carl; Rohrer, Bärbel

    2016-01-01

    Purpose Morphologic and genetic evidence exists that an overactive complement system driven by the complement alternative pathway (AP) is involved in pathogenesis of age-related macular degeneration (AMD). Smoking is the only modifiable risk factor for AMD. As we have shown that smoke-related ocular pathology can be prevented in mice that lack an essential activator of AP, we ask here whether this pathology can be reversed by increasing inhibition in AP. Methods Mice were exposed to either cigarette smoke (CS) or filtered air (6 hours/day, 5 days/week, 6 months). Smoke-exposed animals were then treated with the AP inhibitor (CR2-fH) or vehicle control (PBS) for the following 3 months. Spatial frequency and contrast sensitivity were assessed by optokinetic response paradigms at 6 and 9 months; additional readouts included assessment of retinal morphology by electron microscopy (EM) and gene expression analysis by quantitative RT-PCR. Results The CS mice treated with CR2-fH showed significant improvement in contrast threshold compared to PBS-treated mice, whereas spatial frequency was unaffected by CS or pharmacologic intervention. Treatment with CR2-fH in CS animals reversed thinning of the retina observed in PBS-treated mice as analyzed by spectral-domain optical coherence tomography, and reversed most morphologic changes in RPE and Bruch's membrane seen in CS animals by EM. Conclusions Taken together, these findings suggest that AP inhibitors not only prevent, but have the potential to accelerate the clearance of complement-mediated ocular injury. Improving our understanding of the regulation of the AP is paramount to developing novel treatment approaches for AMD. PMID:27064393

  10. Anemia in Pregnancy

    OpenAIRE

    Umran Kucukgoz Gulec; Fatma Tuncay Ozgunen; Ismail Cuneyt Evruke; Suleyman Cansun Demir

    2013-01-01

    Iron deficiency anemia (IDA) is the most frequent form of anemia in pregnant women. Folic acid, vitamin B12 deficiency, and hemoglobinopathies are other causes of anemia in pregnancy. Finding the underlying cause are crucial to the management of the anemia. Anemia is defined as hemoglobin of

  11. APLASTIC ANEMIA

    Directory of Open Access Journals (Sweden)

    Ni Made Dharma Laksmi

    2013-07-01

    Full Text Available Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 Aplastic Anemia describes a disorder of the clinical syndrome is marked by a deficiency of red blood cells, neutrophils, monocytes and platelets in the absence of other forms of bone marrow damage. Aplastic anemia is classified as a rare disease in developed countries the incidence of 3-6 cases / 1 million inhabitants / year. The exact cause of someone suffering from aplastic anemia also can not be established with certainty, but there are several sources of potential risk factors. Prognosis or course of the disease varies widely aplastic anemia, but without treatment generally gives a poor prognosis /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;}

  12. Small molecule inhibitors of the Candida albicans budded-to-hyphal transition act through multiple signaling pathways.

    Directory of Open Access Journals (Sweden)

    John Midkiff

    Full Text Available The ability of the pathogenic yeast Candida albicans to interconvert between budded and hyphal growth states, herein termed the budded-to-hyphal transition (BHT, is important for C. albicans development and virulence. The BHT is under the control of multiple cell signaling pathways that respond to external stimuli, including nutrient availability, high temperature, and pH. Previous studies identified 21 small molecules that could inhibit the C. albicans BHT in response to carbon limitation in Spider media. However, the studies herein show that the BHT inhibitors had varying efficacies in other hyphal-inducing media, reflecting their varying abilities to block signaling pathways associated with the different media. Chemical epistasis analyses suggest that most, but not all, of the BHT inhibitors were acting through either the Efg1 or Cph1 signaling pathways. Notably, the BHT inhibitor clozapine, a FDA-approved drug used to treat atypical schizophrenia by inhibiting G-protein-coupled dopamine receptors in the brain, and several of its functional analogs were shown to act at the level of the Gpr1 G-protein-coupled receptor. These studies are the first step in determining the target and mechanism of action of these BHT inhibitors, which may have therapeutic anti-fungal utility in the future.

  13. Enhanced migration of tissue inhibitor of metalloproteinase overexpressing hepatoma cells is attributed to gelatinases:Relevance to intracellular signaling pathways

    Institute of Scientific and Technical Information of China (English)

    Elke Roeb; Anja-Katrin Bosserhoff; Sabine Hamacher; Bettina Jansen; Judith Dahmen; Sandra Wagner; Siegfried Matern

    2005-01-01

    AIM: To study the effect of gelatinases (especially MMP-9)on migration of tissue inhibitor of metalloproteinase (TIMP-1) overexpressing hepatoma cells.METHODS: Wild type HepG2 cells, cells stably transfected with TIMP-1 and TIMP-1 antagonist (MMP-9-H401A, a catalytically inactive matrix metalloproteinase (MMP) which still binds and neutralizes TIMP-1) were incubated in Boyden chambers either with or without Galardin (a synthetic inhibitor of MMP-1, -2, -3, -8, -9) or a specific inhibitor of gelatinases.RESULTS: Compared to wild type HepG2 cells, the cells overexpressing TIMP-1 showed 115% migration (P<0.05)and the cells overexpressing MMP-9-H401A showed 62% migration (P<0.01). Galardin reduced cell migration dose dependently in all cases. The gelatinase inhibitor reduced migration in TIMP-1 overexpressing cells predominantly.Furthermore, we examined intracellular signal transduction pathways of TIMP-1-dependent HepG2 cells. TIMP-1deactivates cell signaling pathways of MMP-2 and MMP-9involving p38 mitogen-activated protein kinase. Specific blockade of the ERK pathway suppresses gelatinase expression either in the presence or absence of TIMP-1.CONCLUSION: Overexpressing functional TIMP-1-enhanced migration of HepG2-TIMP-1 cells depends on enhanced MMP-activity, especially MMP-9.

  14. Endogenous tissue factor pathway inhibitor has a limited effect on host defence in murine pneumococcal pneumonia.

    Science.gov (United States)

    van den Boogaard, Florry E; van 't Veer, Cornelis; Roelofs, Joris J T H; Meijers, Joost C M; Schultz, Marcus J; Broze, George J; van der Poll, Tom

    2015-07-01

    Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia. Coagulation and inflammation interact in the host response to infection. Tissue factor pathway inhibitor (TFPI) is a natural anticoagulant protein that inhibits tissue factor (TF), the main activator of inflammation-induced coagulation. It was the objective of this study to investigate the effect of endogenous TFPI levels on coagulation, inflammation and bacterial growth during S. pneumoniae pneumonia in mice. The effect of low endogenous TFPI levels was studied by administration of a neutralising anti-TFPI antibody to wild-type mice, and by using genetically modified mice expressing low levels of TFPI, due to a genetic deletion of the first Kunitz domain of TFPI (TFPIK1(-/-)) rescued with a human TFPI transgene. Pneumonia was induced by intranasal inoculation with S. pneumoniae and samples were obtained at 6, 24 and 48 hours after infection. Anti-TFPI reduced TFPI activity by ~50 %. Homozygous lowTFPI mice and heterozygous controls had ~10 % and ~50 % of normal TFPI activity, respectively. TFPI levels did not influence bacterial growth or dissemination. Whereas lung pathology was unaffected in all groups, mice with ~10 % (but not with ~50 %) of TFPI levels displayed elevated lung cytokine and chemokine concentrations 24 hours after infection. None of the groups with low TFPI levels showed an altered procoagulant response in lungs or plasma during pneumonia. These data argue against an important role for endogenous TFPI in the antibacterial, inflammatory and procoagulant response during pneumococcal pneumonia.

  15. Bifunctional apoptosis inhibitor (BAR) protects neurons from diverse cell death pathways.

    Science.gov (United States)

    Roth, W; Kermer, P; Krajewska, M; Welsh, K; Davis, S; Krajewski, S; Reed, J C

    2003-10-01

    The bifunctional apoptosis regulator (BAR) is a multidomain protein that was originally identified as an inhibitor of Bax-induced apoptosis. Immunoblot analysis of normal human tissues demonstrated high BAR expression in the brain, compared to low or absent expression in other organs. Immunohistochemical staining of human adult tissues revealed that the BAR protein is predominantly expressed by neurons in the central nervous system. Immunofluorescence microscopy indicated that BAR localizes mainly to the endoplasmic reticulum (ER) of cells. Overexpression of BAR in CSM 14.1 neuronal cells resulted in significant protection from a broad range of cell death stimuli, including agents that activate apoptotic pathways involving mitochondria, TNF-family death receptors, and ER stress. Downregulation of BAR by antisense oligonucleotides sensitized neuronal cells to induction of apoptosis. Moreover, the search for novel interaction partners of BAR identified several candidate proteins that might contribute to the regulation of neuronal apoptosis (HIP1, Hippi, and Bap31). Taken together, the expression pattern and functional data suggest that the BAR protein is involved in the regulation of neuronal survival.

  16. Factor VII activating protease (FSAP) promotes the proteolysis and inhibition of tissue factor pathway inhibitor (TFPI)

    Science.gov (United States)

    Kanse, Sandip M.; Declerck, Paul J.; Ruf, Wolfram; Broze, George; Etscheid, Michael

    2013-01-01

    Objectives Factor VII activating protease (FSAP) activates FVII as well as pro-urokinase and inhibits platelet-derived growth factor-BB, thus regulating haemostasis- and remodeling-associated processes in the vasculature. A genetic variant of FSAP (Marburg I polymorphism) results in low enzymatic activity and is associated with an enhanced risk for carotid stenosis and stroke. We postulate that there are additional substrates for FSAP that will help to explain its role in vascular biology and have searched for such a substrate. Results and Methods Using screening procedures to determine the influence of FSAP on various haemostasis-related processes on endothelial cells we discovered that FSAP inhibited tissue factor pathway inhibitor (TFPI), a major anti-coagulant secreted by these cells. Proteolytic degradation of TFPI by FSAP could also be demonstrated by Western blotting and the exact cleavage sites were determined by N-terminal sequencing. The Marburg I variant of FSAP had a diminished ability to inhibit TFPI. A monoclonal antibody to FSAP, that specifically inhibited FSAP binding to TFPI, reversed the inhibitory effect of FSAP on TFPI. Conclusions The identification of TFPI as a sensitive substrate for FSAP increases our understanding of its role in regulating haemostasis and proliferative remodeling events in the vasculature. PMID:22116096

  17. Folate-deficiency anemia

    Science.gov (United States)

    ... medlineplus.gov/ency/article/000551.htm Folate-deficiency anemia To use the sharing features on this page, please enable JavaScript. Folate-deficiency anemia is a decrease in red blood cells (anemia) ...

  18. Fanconi Anemia Research Fund

    Science.gov (United States)

    ... Support Publications Fundraising News What is the Fanconi Anemia Research Fund? Fanconi anemia is an inherited disease that can lead to ... population. Lynn and Dave Frohnmayer started the Fanconi Anemia Research Fund, in 1989 to find effective treatments ...

  19. Anemia and Pregnancy

    Science.gov (United States)

    ... Advocacy Toolkit Home For Patients Blood Disorders Anemia Anemia and Pregnancy Your body goes through significant changes ... becoming anemic. back to top Is Pregnancy-Related Anemia Preventable? Good nutrition is the best way to ...

  20. Cooley's Anemia Foundation

    Science.gov (United States)

    ... role in their lives. Welcome to the Cooley's Anemia Foundation Website The Cooley's Anemia Foundation is dedicated to serving people afflicted with ... major form of this genetic blood disease, Cooley's anemia/thalassemia major. Our mission is advancing the treatment ...

  1. Anemia - B12 deficiency

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/000574.htm Vitamin B12 deficiency anemia To use the sharing features on ... tissues. There are many types of anemia. Vitamin B12 deficiency anemia is a low red blood cell ...

  2. Vitamin Deficiency Anemia

    Science.gov (United States)

    Vitamin deficiency anemia Overview By Mayo Clinic Staff Vitamin deficiency anemia is a lack of healthy red ... you have lower than normal amounts of certain vitamins. Vitamins linked to vitamin deficiency anemia include folate, ...

  3. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Events Spokespeople Email Alerts E-Newsletters About NHLBI Organization NHLBI Director Budget, Planning, & Legislative Advisory Committees Jobs ... food. Overview Iron-deficiency anemia is a common type of anemia . The term "anemia" usually refers to ...

  4. The crossregulation between ERK and PI3K signaling pathways determines the tumoricidal efficacy of MEK inhibitor

    Institute of Scientific and Technical Information of China (English)

    Jae-Kyung Won; Hee Won Yang; Sung-Young Shin; Jong Hoon Lee; Won Do Heo; Kwang-Hyun Cho

    2012-01-01

    MEK inhibitor has been highlighted as a promising anti-tumor drug but its effect has been reported as varying over a wide range depending on patho-physiological conditions.In this study,we employed a systems approach by combining biochemical experimentation with in silico simulations to investigate the resistance mechanism and functional consequences of MEK inhibitor.To this end,we have developed an extended integrative model of ERK and PI3K signaling pathways by considering the crosstalk between Ras and PI3K,and analyzed the resistance mechanism to the MEK inhibitor under various mutational conditions.We found that the phospho-Akt level under the Raf mutation was remarkably augmented by MEK inhibitor,while the phospho-ERK level was almost completely repressed.These results suggest that bypassing of the ERK signal to the PI3K signal causes the resistance to the MEK inhibitor in a complex oncogenic signaling network.We further investigated the underlying mechanism of the drug resistance and revealed that the MEK inhibitor disrupts the negative feedback loops from ERK to SOS and GAB1,but activates the positive feedback loop composed of GAB1,Ras,and PI3K,which induces the bypass of the ERK signal to the PI3K signal.Based on these core feedback circuits,we suggested promising candidates for combination therapy and examined the improved inhibitory effects.

  5. Minimal and inducible regulation of tissue factor pathway inhibitor-2 in human gliomas.

    Science.gov (United States)

    Konduri, Santhi D; Osman, Francis Ali; Rao, Chilukuri N; Srinivas, Harish; Yanamandra, Niranjan; Tasiou, Anastasia; Dinh, Dzung H; Olivero, William C; Gujrati, Meena; Foster, Donald C; Kisiel, Walter; Kouraklis, Gregory; Rao, Jasti S

    2002-01-31

    Tissue factor pathway inhibitor-2 (TFPI-2), a serine protease inhibitor abundant in the extra cellular matrix, is highly expressed in non-invasive cells but undetectable levels in highly invasive human glioma cells. The mechanisms responsible for its transcriptional regulation are not well elucidated. In this study, we made several deletion constructs from a 3.6 kb genomic fragment from Hs683 cells containing the 5'-flanking region of the TFPI-2 gene, transiently transfected with these constructs into non-invasive (Hs683) and highly invasive (SNB19) human glioma cells, and assessed their expression by using a luciferase reporter gene. Three constructs showed high promoter activity (pTF5, -670 to +1; pTF6, -312 to +1; pTF2, -1511 to +1). Another construct, pTF8 (-81 to +1), showed no activity. PTF9, a variant of pTF5 in which a further 231 bp fragment (-312 to -81) was deleted, from the [-670 to +1] pTF5 region, also showed no promoter activity. Hence, (-312 to -81) this region is essential for the transcription of TFPI-2 in glioma cells. Sequencing of this promoter region revealed that it has a high G+C content, contains potential SP1 and AP1 binding motifs, and lacks canonical TATA and CAAT boxes immediately upstream of the major transcriptional initiation site, although CAAT boxes were found about -3000 bp upstream of the transcription start site. We also found a strong repressor in the region between -927 to -1181, upstream of the major transcriptional initiation site, followed by positive elements or enhancers between -1511 to -1181. These positive elements masked the silencer effect. Finally TFPI-2 was induced in Hs683 cells transfected with the pTF6 construct (-312 to +1) and stimulated with phorbol-12-myristate-13-acetate (PMA). We conclude that the -312 to +1 region is critical for the minimal and inducible regulation of TFPI-2 in non-invasive (Hs683) and highly invasive (SNB19) human glioma cell lines.

  6. The Phosphoinositide 3-OH Kinase/AKT2 Pathway as a Critical Target for Farnesyltransferase Inhibitor-Induced Apoptosis

    OpenAIRE

    Jiang, Kun; Coppola, Domenico; Crespo, Nichole C.; Nicosia, Santo V.; Hamilton, Andrew D.; Sebti, Said M.; Cheng, Jin Q.

    2000-01-01

    Farnesyltransferase inhibitors (FTIs) represent a novel class of anticancer drugs that exhibit a remarkable ability to inhibit malignant transformation without toxicity to normal cells. However, the mechanism by which FTIs inhibit tumor growth is not well understood. Here, we demonstrate that FTI-277 inhibits phosphatidylinositol 3-OH kinase (PI 3-kinase)/AKT2-mediated growth factor- and adhesion-dependent survival pathways and induces apoptosis in human cancer cells that overexpress AKT2. Fu...

  7. Blockade of sonic hedgehog signal pathway enhances antiproliferative effect of EGFR inhibitor in pancreatic cancer cells

    Institute of Scientific and Technical Information of China (English)

    Wei-guo HU; Tao LIU; Jiong-xin XIONG; Chun-you WANG

    2007-01-01

    Aim: To investigate the expression of sonic hedgehog (SHH) and epidermal growth factor receptor (EGFR) signal molecules in pancreatic cancer cells, and to assess the inhibitory effects through the blockade of the SHH and EGFR signaling path- ways by cyclopamine and Iressa, respectively. Methods: The expression of SHH and EGFR in pancreatic cancer cell lines (PANC-1, SUIT-2, and ASPC-1) was de-tected by RT-PCR and Western blot analysis. After treatment with different con-centrations of cyclopamine, alone or in combination with Iressa, the antiproliferative effect on pancreatic cancer cells was analyzed by methyl thiazolyl tetrazolium assays. A flow cytometry analysis was used to detect the cellular cycle distribu-tion and apoptosis of pancreatic cancer cells. Results: All of the 3 pancreatic cancer cell lines expressed SHH, Smoothened (SMO), and EGFR. Cyclopamine could downregulate the expression of EGFR in all cell lines. Cyclopamine or Iressa could induce a growth inhibitory effect in a dose-dependent manner. Moreover,the combined use of 2.5 μmol/L cyclopamine and 1 μmol/L Iressa induced an enhanced inhibitory effect and a greater apoptosis rate than any agent alone. The percentage of the cell population of the G0/G1 and sub-G1 phases was significantly increased along with the increasing dose of cyclopamine and/or Iressa. Conclusion: The blockade of the sonic hedgehog signal pathway enhances the antiproliferative effect of the EGFR inhibitor through the downregulation of its expression in pancreatic cancer cells. The simultaneous blockade of SHH and EGFR signaling represents possible targets of new treatment strategies for pan-creatic carcinoma.

  8. Inhibitor of Nicotinamide Phosphoribosyltransferase Sensitizes Glioblastoma Cells to Temozolomide via Activating ROS/JNK Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Jun Feng

    2016-01-01

    Full Text Available Overcoming temozolomide (TMZ resistance is a great challenge in glioblastoma (GBM treatment. Nicotinamide phosphoribosyltransferase (NAMPT is a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide and has a crucial role in cancer cell metabolism. In this study, we investigated whether FK866 and CHS828, two specific NAMPT inhibitors, could sensitize GBM cells to TMZ. Low doses of FK866 and CHS828 (5 nM and 10 nM, resp. alone did not significantly decrease cell viability in U251-MG and T98 GBM cells. However, they significantly increased the antitumor action of TMZ in these cells. In U251-MG cells, administration of NAMPT inhibitors increased the TMZ (100 μM-induced apoptosis and LDH release from GBM cells. NAMPT inhibitors remarkably enhanced the activities of caspase-1, caspase-3, and caspase-9. Moreover, NAMPT inhibitors increased reactive oxygen species (ROS production and superoxide anion level but reduced the SOD activity and total antioxidative capacity in GBM cells. Treatment of NAMPT inhibitors increased phosphorylation of c-Jun and JNK. Administration of JNK inhibitor SP600125 or ROS scavenger tocopherol with TMZ and NAMPT inhibitors substantially attenuated the sensitization of NAMPT inhibitor on TMZ antitumor action. Our data indicate a potential value of NAMPT inhibitors in combined use with TMZ for GBM treatment.

  9. Blocking NOTCH Pathway can Enhance the Effect of EGFR Inhibitor through Targeting CD133+ Endometrial Cancer Cells.

    Science.gov (United States)

    Shang, Chao; Lang, Bin; Meng, Li-Rong

    2016-10-28

    ABSTACT Although the molecular therapeutics targeting key biomarkers such as epithelial growth factor receptor (EGFR), PI3K/AKT/mTOR, and vascular endothelial growth factor (VEGF) shows some success in clinical trials, some internally existing challenges in endothelial cancer biology hinder the drug effects. One of the major challenges stems from cancer stem cell-derived drug resistance. CD133 positive cells are well believed as cancer stem cells (CSC) in endometrial cancers and NOTCH pathway plays a critical role in retaining CD133+ cells by promoting CSC self-renewal and chemoresistance. Here, we initiated a therapeutic strategy to improve effects of EGFR inhibition by targeting NOTCH pathway of CD133+ cells in endometrial cancers. We first detected and purified the CD133+ cell fraction in endometrial cancer cell line Ishikawa (IK), and validated activation of NOTCH pathway in the CD133+ cells that have higher proliferation rate and lower apoptosis rate, comparing to CD133- cells. Results of nude mouse xenograft experiments further demonstrated CD133+ cells retain higher tumorigenesis capacity than CD133- cells, indicating their tumor-initiating property. Last, we applied both NOTCH inhibitor DAPT and EGFR inhibitor AG1478 treatment on endometrial cancer lines IK and HEC-1A and the results suggested improvement effects of the combination therapy compared to the treatments of DAPT or AG1478 alone. These findings indicated targeting NOTCH pathway in CD133+ cells, combining with EGFR inhibition, which provides a novel therapeutic strategy for endometrial cancer diseases.

  10. Bisphosphonate inhibitors reveal a large elasticity of plastidic isoprenoid synthesis pathway in isoprene-emitting hybrid aspen.

    Science.gov (United States)

    Rasulov, Bahtijor; Talts, Eero; Kännaste, Astrid; Niinemets, Ülo

    2015-06-01

    Recently, a feedback inhibition of the chloroplastic 1-deoxy-D-xylulose 5-phosphate (DXP)/2-C-methyl-D-erythritol 4-phosphate (MEP) pathway of isoprenoid synthesis by end products dimethylallyl diphosphate (DMADP) and isopentenyl diphosphate (IDP) was postulated, but the extent to which DMADP and IDP can build up is not known. We used bisphosphonate inhibitors, alendronate and zoledronate, that inhibit the consumption of DMADP and IDP by prenyltransferases to gain insight into the extent of end product accumulation and possible feedback inhibition in isoprene-emitting hybrid aspen (Populus tremula × Populus tremuloides). A kinetic method based on dark release of isoprene emission at the expense of substrate pools accumulated in light was used to estimate the in vivo pool sizes of DMADP and upstream metabolites. Feeding with fosmidomycin, an inhibitor of DXP reductoisomerase, alone or in combination with bisphosphonates was used to inhibit carbon input into DXP/MEP pathway or both input and output. We observed a major increase in pathway intermediates, 3- to 4-fold, upstream of DMADP in bisphosphonate-inhibited leaves, but the DMADP pool was enhanced much less, 1.3- to 1.5-fold. In combined fosmidomycin/bisphosphonate treatment, pathway intermediates accumulated, reflecting cytosolic flux of intermediates that can be important under strong metabolic pull in physiological conditions. The data suggested that metabolites accumulated upstream of DMADP consist of phosphorylated intermediates and IDP. Slow conversion of the huge pools of intermediates to DMADP was limited by reductive energy supply. These data indicate that the DXP/MEP pathway is extremely elastic, and the presence of a significant pool of phosphorylated intermediates provides an important valve for fine tuning the pathway flux.

  11. A novel targeted inhibitor of the alternative pathway of complement and its therapeutic application in ischemia/reperfusion injury.

    Science.gov (United States)

    Huang, Yuxiang; Qiao, Fei; Atkinson, Carl; Holers, V Michael; Tomlinson, Stephen

    2008-12-01

    Bioavailability and therapeutic efficacy of soluble Crry, a mouse inhibitor of all complement activation pathways, is significantly enhanced when linked to a fragment of complement receptor 2 (CR2), a receptor that targets C3 activation products. In this study, we characterize alternative pathway-specific inhibitors consisting of a single or dimeric N-terminal region of mouse factor H (fH; short consensus repeats 1-5) linked to the same CR2 fragment (CR2-fH and CR2-fHfH). Both CR2-fH and CR2-fHfH were highly effective at inhibiting the alternative pathway in vitro and demonstrated a higher specific activity than CR2-Crry. CR2-fH was also more effective than endogenous serum fH in blocking target deposition of C3. Target binding and complement inhibitory activity of CR2-fH/CR2-fHfH was dependent on CR2- and C3-mediated interactions. The alternative pathway of complement plays a role in intestine ischemia/reperfusion injury. However, serum fH fails to provide protection against intestine ischemia/reperfusion injury although it can bind to and provide cell surfaces with protection from complement and is present in plasma at a high concentration. In a mouse model, CR2-fH and CR2-fHfH provided complete protection from local (intestine) and remote (lung) injury. CR2-fH targeted to the site of local injury and greatly reduced levels of tissue C3 deposition. Thus, the targeting mechanism significantly enhances alternative pathway-specific complement inhibitory activity of the N-terminal domain of fH and has the potential to reduce side effects that may be associated with systemic complement blockade. The data further indicate alternative pathway dependence for local and remote injury following intestinal ischemia/reperfusion in a clinically relevant therapeutic paradigm.

  12. Effect of Candesartan Cilexetil as a Sensitive and Effective Inhibitor of SHP-1 on Insulin Signaling Pathway

    Institute of Scientific and Technical Information of China (English)

    ZHANG Lei; ZHANG Shi-tao; ZHANG Xiao-ping; SUN Jing; WANG Yong-sen; LIU Yue-long; XUE Miao-miao

    2013-01-01

    The protein tyrosine phosphatases(PTPs) comprise a family of enzymes that specifically dephosphorylate tyrosyl residues.Among them,SHP-1 has been regarded as one of the best validated intracellular tyrosine phosphatases.Downregulation of SHP-1 has shown remarkable efficacy in improving insulin sensitivity in vivo in insulin signaling pathway.In this study,we found the role of Candesartan cilexetil targeting at SHP-1.The results indicate that Candesartan cilexetil was a competitive inhibitor to SHP-1(IC50=85.6 μmol/L and Ki=24 μmol/L).We also found that Candesartan cilexetil was more sensitive towards SHP-1 compared with other PTPs.Through the consequence of Western blotting,it showed that Candesartan cilexetil can strengthen the level of tyrosine phosphorylation of several key cellular proteins[such as insulin receptor(IR),insulin receptor substrate(IRS) and ERK] in insulin signaling pathway in HepG2 cells and improve the insulin sensitivity through inhibiting the protein phosphorylation of SHP-1.These findings showed that Candesartan cilexetil might be an important inhibitor of SHP-1 and had a great application potential in the treatment of diabetes through inhibiting the level of SHP-1 in insulin signaling pathway.

  13. Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins.

    Science.gov (United States)

    Göbel, Andy; Browne, Andrew J; Thiele, Stefanie; Rauner, Martina; Hofbauer, Lorenz C; Rachner, Tilman D

    2015-12-01

    The Wnt-inhibitor dickkopf-1 (DKK-1) promotes cancer-induced osteolytic bone lesions by direct inhibition of osteoblast differentiation and indirect activation of osteoclasts. DKK-1 is highly expressed in human breast cancer cells and can be suppressed by inhibitors of the mevalonate pathway such as statins and amino-bisphosphonates. However, supraphysiological concentrations are required to suppress DKK-1. We show that a sequential mevalonate pathway blockade using statins and amino-bisphosphonates suppresses DKK-1 more significantly than the individual agents alone. Thus, the reduction of the DKK-1 expression and secretion in the human osteotropic tumor cell lines MDA-MB-231, MDA-MET, and MDA-BONE by zoledronic acid was potentiated by the combination with low concentrations of statins (atorvastatin, simvastatin, and rosuvastatin) by up to 75% (p cancer-derived DKK-1-mediated inhibition of osteogenic markers in C2C12 cells (p pathway blockade allows for the combined use of low concentration of statins and amino-bisphosphonates. This combination still significantly suppresses breast cancer-derived DKK-1 to levels where it can no longer inhibit Wnt-mediated osteoblast differentiation.

  14. Vismodegib, itraconazole and sonidegib as hedgehog pathway inhibitors and their relative competencies in the treatment of basal cell carcinomas.

    Science.gov (United States)

    Wahid, Mohd; Jawed, Arshad; Mandal, Raju K; Dar, Sajad A; Khan, Saif; Akhter, Naseem; Haque, Shafiul

    2016-02-01

    The advent of more sophisticated studies published has clarified the understating of the root cause of various skin cancers or basal cell carcinomas (BCCs). The remarkable role is played by the comprehensive work done on unraveling the mechanism controlling the function of hedgehog (Hh) pathway. The defective Hh pathway has been found as the major cause for BCCs as activated Hh signaling within primary cilia plays a key role in the pathogenesis of BCCs. The BCC accounts for up to 40% of all cancers in the US, with growing incidences in other countries as well. Thus, it is considered to be utmost important by the researchers all over the world developing drugs for the treatment of skin cancers targeting Hh pathway. Fewer drugs like vismodegib, itraconazole and sonidegib have shown promising results inhibiting the awry function of Hh pathway resulting in treatment of different forms of skin cancers. These drugs have shown positive results but failed to prove their potential as expected. Vismodegib and sonidegib are better but fail in case of resistant tumors. This review article describes the mechanism of actions of these Hh pathway inhibitors and provides the rationale for their effectiveness/non-effectiveness for the treatment of metastatic or locally advanced BCC.

  15. Inhibition of the NOTCH pathway using γ-secretase inhibitor RO4929097 has limited antitumor activity in established glial tumors.

    Science.gov (United States)

    Dantas-Barbosa, Carmela; Bergthold, Guillaume; Daudigeos-Dubus, Estelle; Blockus, Heike; Boylan, John F; Ferreira, Celine; Puget, Stephanie; Abely, Michel; Vassal, Gilles; Grill, Jacques; Geoerger, Birgit

    2015-03-01

    Notch signaling is altered in many cancers. Our previous findings in primary pediatric ependymoma support a role for NOTCH in glial oncogenesis. The present study evaluates the γ-secretase inhibitor RO4929097 in glial tumor models. The expression of Notch pathway genes was evaluated using real-time RT-PCR in 21 ependymoma and glioma models. NOTCH1 mutations were analyzed by DNA sequencing. RO4929097 activity was evaluated in vitro and in vivo, as a single agent and in combination, in glioma and ependymoma models. Notch pathway genes are overexpressed in ependymomas and gliomas along with FBXW7 downregulation. NOTCH1 mutations in the TAD domain were observed in 20% (2/10) of ependymoma primary cultures. Blocking the Notch pathway with the γ-secretase inhibitor RO4929097 reduced cell density and viability in ependymoma short-term cultures. When combined with chemotherapeutic agents, RO4929097 enhanced temozolomide effects in ependymoma short-term cultures and potentiated the cytotoxicity of etoposide, cisplatinum, and temozolomide in glioma cells. RO4929097, in combined treatment with mTOR inhibition, potentiated cytotoxicity in vitro, but did not enhance antitumor effects in vivo. In contrast, RO4929097 enhanced irradiation effects in glioma and ependymoma xenografts and showed tumor growth inhibition in advanced-stage IGRG121 glioblastoma xenografts. RO4929097-mediated effects were independent of NOTCH1 mutation status or expression levels, but associated with low IL-6 levels. In established glial tumor models, NOTCH inhibition had limited effects as a single agent, but enhanced efficacy when combined with DNA-interfering agents. These preclinical data need to be considered for further clinical development of NOTCH inhibitors in glial tumors.

  16. Identification of Benzimidazole Diamides as Selective Inhibitors of the Nucleotide-Binding Oligomerization Domain 2 (NOD2) Signaling Pathway

    Science.gov (United States)

    Rickard, David J.; Sehon, Clark A.; Kasparcova, Viera; Kallal, Lorena A.; Zeng, Xin; Montoute, Monica N.; Chordia, Tushar; Poore, Derek D.; Li, Hu; Wu, Zining; Eidam, Patrick M.; Haile, Pamela A.; Yu, Jong; Emery, John G.; Marquis, Robert W.; Gough, Peter J.; Bertin, John

    2013-01-01

    NOD2 is an intracellular pattern recognition receptor that assembles with receptor-interacting protein (RIP)-2 kinase in response to the presence of bacterial muramyl dipeptide (MDP) in the host cell cytoplasm, thereby inducing signals leading to the production of pro-inflammatory cytokines. The dysregulation of NOD2 signaling has been associated with various inflammatory disorders suggesting that small-molecule inhibitors of this signaling complex may have therapeutic utility. To identify inhibitors of the NOD2 signaling pathway, we utilized a cell-based screening approach and identified a benzimidazole diamide compound designated GSK669 that selectively inhibited an MDP-stimulated, NOD2-mediated IL-8 response without directly inhibiting RIP2 kinase activity. Moreover, GSK669 failed to inhibit cytokine production in response to the activation of Toll-like receptor (TLR)-2, tumor necrosis factor receptor (TNFR)-1 and closely related NOD1, all of which share common downstream components with the NOD2 signaling pathway. While the inhibitors blocked MDP-induced NOD2 responses, they failed to block signaling induced by NOD2 over-expression or single stranded RNA, suggesting specificity for the MDP-induced signaling complex and activator-dependent differences in NOD2 signaling. Investigation of structure-activity relationship allowed the identification of more potent analogs that maintained NOD2 selectivity. The largest boost in activity was achieved by N-methylation of the C2-ethyl amide group. These findings demonstrate that the NOD2 signaling pathway is amenable to modulation by small molecules that do not target RIP2 kinase activity. The compounds we identified should prove useful tools to investigate the importance of NOD2 in various inflammatory processes and may have potential clinical utility. PMID:23936340

  17. Identification of benzimidazole diamides as selective inhibitors of the nucleotide-binding oligomerization domain 2 (NOD2 signaling pathway.

    Directory of Open Access Journals (Sweden)

    David J Rickard

    Full Text Available NOD2 is an intracellular pattern recognition receptor that assembles with receptor-interacting protein (RIP-2 kinase in response to the presence of bacterial muramyl dipeptide (MDP in the host cell cytoplasm, thereby inducing signals leading to the production of pro-inflammatory cytokines. The dysregulation of NOD2 signaling has been associated with various inflammatory disorders suggesting that small-molecule inhibitors of this signaling complex may have therapeutic utility. To identify inhibitors of the NOD2 signaling pathway, we utilized a cell-based screening approach and identified a benzimidazole diamide compound designated GSK669 that selectively inhibited an MDP-stimulated, NOD2-mediated IL-8 response without directly inhibiting RIP2 kinase activity. Moreover, GSK669 failed to inhibit cytokine production in response to the activation of Toll-like receptor (TLR-2, tumor necrosis factor receptor (TNFR-1 and closely related NOD1, all of which share common downstream components with the NOD2 signaling pathway. While the inhibitors blocked MDP-induced NOD2 responses, they failed to block signaling induced by NOD2 over-expression or single stranded RNA, suggesting specificity for the MDP-induced signaling complex and activator-dependent differences in NOD2 signaling. Investigation of structure-activity relationship allowed the identification of more potent analogs that maintained NOD2 selectivity. The largest boost in activity was achieved by N-methylation of the C2-ethyl amide group. These findings demonstrate that the NOD2 signaling pathway is amenable to modulation by small molecules that do not target RIP2 kinase activity. The compounds we identified should prove useful tools to investigate the importance of NOD2 in various inflammatory processes and may have potential clinical utility.

  18. Anemia in pregnancy.

    Science.gov (United States)

    Horowitz, Kari M; Ingardia, Charles J; Borgida, Adam F

    2013-06-01

    Hemodynamic changes occur in pregnancy to prepare for expected blood loss at delivery. Physiologic anemia occurs in pregnancy because plasma volume increases more quickly than red cell mass. Anemia is most commonly classified as microcytic, normocytic, or macrocytic. Iron deficiency anemia accounts for 75% of all anemias in pregnancy. Oral iron supplementation is the recommended treatment of iron deficiency anemia in pregnancy. Parenteral iron and erythropoietin can also be used in severe or refractory cases. Outcomes and treatments for other forms of inherited and acquired anemias in pregnancy vary by disease, and include nutritional supplementation, corticosteroids, supportive transfusions, and splenectomy.

  19. Emergence of chemoresistance in a metastatic basal cell carcinoma patient after complete response to hedgehog pathway inhibitor vismodegib (GDC-0449).

    Science.gov (United States)

    Meani, Rowena E; Lim, Shueh-Wen; Chang, Anne Lynn S; Kelly, John W

    2014-08-01

    Vismodegib (GDC-0449, Genentech, USA), a small molecule inhibitor of the Hedgehog signalling pathway, has potent anti-tumour activity in advanced basal cell carcinoma (BCC). We report a case of a 67-year-old Australian man with metastatic BCC including pulmonary disease with malignant effusion who showed a dramatic complete response to vismodegib but subsequently experienced a recurrence of pulmonary disease, indicative of chemoresistance to vismodegib. This case is the first to illustrate chemoresistance in a patient with metastatic BCC, and demonstrates the need for closely monitoring metastatic BCC patients even after an apparently complete response.

  20. Impact of the Smoothened inhibitor, IPI-926, on smoothened ciliary localization and Hedgehog pathway activity.

    Directory of Open Access Journals (Sweden)

    Marisa O Peluso

    Full Text Available A requisite step for canonical Hedgehog (Hh pathway activation by Sonic Hedgehog (Shh ligand is accumulation of Smoothened (Smo to the primary cilium (PC. Activation of the Hh pathway has been implicated in a broad range of cancers, and several Smo antagonists are being assessed clinically, one of which is approved for the treatment of advanced basal cell carcinoma. Recent reports demonstrate that various Smo antagonists differentially impact Smo localization to the PC while still exerting inhibitory activity. In contrast to other synthetic small molecule Smo antagonists, the natural product cyclopamine binds to and promotes ciliary accumulation of Smo and "primes" cells for Hh pathway hyper-responsiveness after compound withdrawal. We compared the properties of IPI-926, a semi-synthetic cyclopamine analog, to cyclopamine with regard to potency, ciliary Smo accumulation, and Hh pathway activity after compound withdrawal. Like cyclopamine, IPI-926 promoted accumulation of Smo to the PC. However, in contrast to cyclopamine, IPI-926 treatment did not prime cells for hyper-responsiveness to Shh stimulation after compound withdrawal, but instead demonstrated continuous inhibition of signaling. By comparing the levels of drug-induced ciliary Smo accumulation with the degree of Hh pathway activity after compound withdrawal, we propose that a critical threshold of ciliary Smo is necessary for "priming" activity to occur. This "priming" appears achievable with cyclopamine, but not IPI-926, and is cell-line dependent. Additionally, IPI-926 activity was evaluated in a murine tumor xenograft model and a pharmacokinetic/pharmacodynamic relationship was examined to assess for in vivo evidence of Hh pathway hyper-responsiveness. Plasma concentrations of IPI-926 correlated with the degree and duration of Hh pathway suppression, and pathway activity did not exceed baseline levels out to 96 hours post dose. The overall findings suggest that IPI-926 possesses

  1. Hypericin biosynthesis in Hypericum hookerianum Wight and Arn: investigation on biochemical pathways using metabolite inhibitors and suppression subtractive hybridization.

    Science.gov (United States)

    Pillai, Padmesh P; Nair, Aswati R

    2014-10-01

    The biochemical pathway to hypericin biosynthesis is presumed to be polyketide synthase (PKS) mediated, but it has not been experimentally validated, and no alternate route (chorismate/o-succinylbenzoate pathway) has been analyzed. We report here our earlier developed auxin inducible culture systems of Hypericum hookerianum as a model, to study the metabolic pathway to hypericin synthesis. Inhibitors of the alternate pathway at varying concentrations showed steady synthesis of total hypericins with means of 2.80±0.22, 18.75±0.01; 16.39±3.75, 29.60±1.90 (mevinolin) 2.53±0.10, 18.12±0.56; 0.14±0.01, 14.28±1.11 (fosmidomycin) and 2.7±0.35, 18.75±0.61; 0.14±0.01, 12.80±1.09 mg g(-1) DW (glyphosate) in the control and auxin-induced shoot and shoot-forming callus cultures, respectively. SSH analysis classified the differentially expressed sequences into protein synthesis (38%), modification (20%), electron transport (9%) and remaining as unclassified (11%) and unknown proteins (22%). Functional annotation of sequences indicates the presence of additional protein components besides PKS activity. Our results demonstrate direct biochemical and molecular evidence of PKS hypothesis of hypericin biosynthesis for the first time.

  2. Sickle Cell Anemia

    Science.gov (United States)

    Sickle cell anemia is a disease in which your body produces abnormally shaped red blood cells. The cells ... red blood cells. This leads to anemia. The sickle cells also get stuck in blood vessels, blocking blood ...

  3. Sickle cell anemia.

    OpenAIRE

    ŘÍHOVÁ, Tereza

    2013-01-01

    This thesis is about the disease called sickle cell anemia, or drepanocytosis. In this thesis is described the history of the disease, pathophysiology, laboratory features, various clinical features, diferencial diagnosis, quality of life in sickle cell anemia and therapy.

  4. Anemia in the Newborn

    Science.gov (United States)

    ... Doctor About Emotional Struggles Additional Content Medical News Anemia in the Newborn By Arthur E. Kopelman, MD, ... of Prematurity Necrotizing Enterocolitis (NEC) Jaundice in Newborns Anemia in the Newborn Polycythemia in the Newborn Thyroid ...

  5. [Common anemias in neonatology].

    Science.gov (United States)

    Humbert, J; Wacker, P

    1999-01-28

    We describe the four most common groups of neonatal anemia and their treatments, with particular emphasis on erythropoietin therapy. The hemolytic anemias include the ABO incompatibility (much more frequent, nowadays, than the Rh incompatibility, which has nearly disappeared following the use of anti-D immunoglobulin in postpartum Rh-negative mothers), hereditary spherocytosis and G-6-PD deficiency. Among hypoplastic anemias, that caused by Parvovirus B19 predominates, by far, over Diamond-Blackfan anemia, alpha-thalassemia and the rare sideroblastic anemias. "Hemorrhagic" anemias occur during twin-to-twin transfusions, or during feto-maternal transfusions. Finally, the multifactorial anemia of prematurity develops principally as a result of the rapid expansion of the blood volume in this group of patients. Erythropoietin therapy, often at doses much higher than those used in the adult, should be seriously considered in most cases of non-hypoplastic neonatal anemias, to minimise maximally the use of transfusions.

  6. The Anemias of Athletes.

    Science.gov (United States)

    Eichner, Edward R.

    1986-01-01

    Diagnosing anemia in athletes is complicated because athletes normally have a pseudoanemia that needs no treatment. Athletes, however, can develop anemia from iron deficiency or footstrike hemolysis, which require diagnosis and treatment. (Author/MT)

  7. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... or an inability to absorb enough iron from food. Overview Iron-deficiency anemia is a common type ... of the condition. Treatments may include dietary changes, medicines, and surgery. Severe iron-deficiency anemia may require ...

  8. Bowman-Birk inhibitor affects pathways associated with energy metabolism in Drosophila melanogaster

    Science.gov (United States)

    Bowman-Birk inhibitor (BBI) is toxic when fed to certain insects, including the fruit fly, Drosophila melanogaster. Dietary BBI has been demonstrated to slow growth and increase insect mortality by inhibiting the digestive enzymes trypsin and chymotrypsin, resulting in a reduced supply of amino acid...

  9. Weight loss induced by tyrosine kinase inhibitors of the vascular endothelial growth factor pathway.

    NARCIS (Netherlands)

    Desar, I.M.E.; Thijs, A.M.J.; Mulder, S.F.; Tack, C.J.J.; Herpen, C.M.L. van; Graaf, W.T.A. van der

    2012-01-01

    Weight loss, cachexia and sarcopenia are profound problems in the frail oncologic patients. With the development and increasing use of angiogenesis inhibitors in metastatic cancer patients, the question arises as to their influence on body weight and composition. Angiogenesis is not only important f

  10. Complement in hemolytic anemia.

    Science.gov (United States)

    Brodsky, Robert A

    2015-01-01

    Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. For optimal therapy, it is critical, but often difficult, to distinguish aHUS from other TMAs, such as thrombotic thrombocytopenic purpura; however, novel bioassays are being developed. In cold agglutinin disease (CAD), immunoglobulin M autoantibodies fix complement on the surface of red cells, resulting in extravascular hemolysis by the reticuloendothelial system. Drugs that inhibit complement activation are increasingly being used to treat these diseases. This article discusses the pathophysiology, diagnosis, and therapy for PNH, aHUS, and CAD.

  11. Novel irreversible EGFR tyrosine kinase inhibitor 324674 sensitizes human colon carcinoma HT29 and SW480 cells to apoptosis by blocking the EGFR pathway

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Zhiwei; Cui, Binbin; Jin, Yinghu; Chen, Haipeng [Division of Colorectal Surgery, Third Affiliated Hospital of Harbin Medical University, Harbin (China); Wang, Xishan, E-mail: wxshan_oncologist@yahoo.com.cn [Division of Colorectal Surgery, Third Affiliated Hospital of Harbin Medical University, Harbin (China)

    2011-08-12

    Highlights: {yields} This article described the effects of the EGFR tyrosine kinase inhibitor on the cell proliferation and the apoptosis induction of the colon carcinoma cell lines. {yields} Demonstrated that 326474 is a more potent EGFR inhibitor on colon cancer cells than other three TKIs. {yields} It can be important when considering chemotherapy for colonic cancer patients. -- Abstract: Background: Epidermal growth factor receptor (EGFR) is widely expressed in multiple solid tumors including colorectal cancer by promoting cancer cell growth and proliferation. Therefore, the inhibition of EGFR activity may establish a clinical strategy of cancer therapy. Methods: In this study, using human colon adenocarcinoma HT29 and SW480 cells as research models, we compared the efficacy of four EGFR inhibitors in of EGFR-mediated pathways, including the novel irreversible inhibitor 324674, conventional reversible inhibitor AG1478, dual EGFR/HER2 inhibitor GW583340 and the pan-EGFR/ErbB2/ErbB4 inhibitor. Cell proliferation was assessed by MTT analysis, and apoptosis was evaluated by the Annexin-V binding assay. EGFR and its downstream signaling effectors were examined by western blotting analysis. Results: Among the four inhibitors, the irreversible EGFR inhibitor 324674 was more potent at inhibiting HT29 and SW480 cell proliferation and was able to efficiently induce apoptosis at lower concentrations. Western blotting analysis revealed that AG1478, GW583340 and pan-EGFR/ErbB2/ErbB4 inhibitors failed to suppress EGFR activation as well as the downstream mitogen-activated protein kinase (MAPK) and PI3K/AKT/mTOR (AKT) pathways. In contrast, 324674 inhibited EGFR activation and the downstream AKT signaling pathway in a dose-dependent manner. Conclusion: Our studies indicated that the novel irreversible EGFR inhibitor 324674 may have a therapeutic application in colon cancer therapy.

  12. Megaloblastic anemia in pregnancy.

    Science.gov (United States)

    Campbell, B A

    1995-09-01

    Megaloblastic anemia is one of the acquired nutritional anemias that may complicate pregnancy. It is most often secondary to folic acid deficiency because folate requirements are increased during gestation. When the diagnosis of megaloblastic anemia is confirmed, appropriate therapy will initiate a rapid reversal of the anemia process. Because of the association between neural tube defects and folate deficiency, it is recommended that women of reproductive age take folic acid supplementation.

  13. The Hypoxia-Inducible Factor Pathway, Prolyl Hydroxylase Domain Protein Inhibitors, and Their Roles in Bone Repair and Regeneration

    Directory of Open Access Journals (Sweden)

    Lihong Fan

    2014-01-01

    Full Text Available Hypoxia-inducible factors (HIFs are oxygen-dependent transcriptional activators that play crucial roles in angiogenesis, erythropoiesis, energy metabolism, and cell fate decisions. The group of enzymes that can catalyse the hydroxylation reaction of HIF-1 is prolyl hydroxylase domain proteins (PHDs. PHD inhibitors (PHIs activate the HIF pathway by preventing degradation of HIF-α via inhibiting PHDs. Osteogenesis and angiogenesis are tightly coupled during bone repair and regeneration. Numerous studies suggest that HIFs and their target gene, vascular endothelial growth factor (VEGF, are critical regulators of angiogenic-osteogenic coupling. In this brief perspective, we review current studies about the HIF pathway and its role in bone repair and regeneration, as well as the cellular and molecular mechanisms involved. Additionally, we briefly discuss the therapeutic manipulation of HIFs and VEGF in bone repair and bone tumours. This review will expand our knowledge of biology of HIFs, PHDs, PHD inhibitors, and bone regeneration, and it may also aid the design of novel therapies for accelerating bone repair and regeneration or inhibiting bone tumours.

  14. Activation of the Wnt/β-catenin pathway and tissue inhibitor of metalloprotease 1 during tertiary dentinogenesis.

    Science.gov (United States)

    Yoshioka, Seisuke; Takahashi, Yusuke; Abe, Makoto; Michikami, Ikumi; Imazato, Satoshi; Wakisaka, Satoshi; Hayashi, Mikako; Ebisu, Shigeyuki

    2013-01-01

    Tertiary dentin is deposited inside teeth after various stimuli and serves as a major defensive wall to preserve pulp cells. However, the molecular mechanisms of the activation of quiescent odontoblasts, immature pulp cells and tertiary dentin formation are still unclear. Therefore, we performed a comprehensive gene expression analysis of pulp cells after cavity preparation of 9-week-old rat molars to clarify the critical molecules in tertiary dentinogenesis. As a result, mRNA expression of various molecules was up- or down-regulated. Notably, several members of the matrix metalloprotease family and their endogenous inhibitors were up-regulated after cavity preparation. In situ hybridization showed that tissue inhibitor of metalloprotease 1 (Timp1) was widely and continuously distributed in the pulp beneath the cavity in vivo. We also observed accumulation of β-catenin in the pulp cells beneath the cavity by fluorescence immunohistochemistry. Furthermore, Timp1 transcription was repressed by a dominant-negative TCF4 in immature undifferentiated mesenchymal cells, but not altered in mature odontoblast-like cells. These results indicate that cavity preparation may activate the Wnt/β-catenin pathway and the Wnt/β-catenin pathway and Timp1 may be correlatively involved in pulp repair. Timp1 might play crucial roles in reactivation of immature pulp cells for tertiary dentinogenesis.

  15. A Kazal-type serine proteinase inhibitor from Cyclina sinensis is involved in immune response and signal pathway initiation.

    Science.gov (United States)

    Ren, Yipeng; Zhang, Hao; Pan, Baoping; Yan, Chuncai

    2015-11-01

    Serine protease inhibitors (SPIs) are an important group of protease inhibitors involved in a variety of biological processes. In the present study, a Kazal-type serine protease inhibitor homolog gene (designated as CsKPI) was identified from a Cyclina sinensis cDNA library. The open reading frame consists of 456 bp and encodes a protein of 151 amino acid residues with a theoretical molecular mass of 16.85 kDa and an isoelectric point of 5.74. Furthermore, using quantitative real-time PCR, we focused on the expression patterns of CsKPI found in tissues and on the stimulation of this gene's expression by bacteria. The results show that a higher-level mRNA expression of CsKPI was detected in hemocytes (P < 0.05) and was significantly upregulated at 3 h (P < 0.01) upon receiving bacterial challenges with Vibrio anguillarum. In addition, after the CsKPI gene was silenced by RNA interference, the expression of the CsTLR2 and CsMyD88 genes was extremely significantly decreased (P < 0.01) in C. sinensis. Finally, the recombinant CsKPI (rCsKPI) protein was purified and shown to exhibit less inhibitory activity than C-lyz against V. anguillarum in vitro. Hence, we propose that CsKPI plays an important role in the innate immunity and mediates TLR2 and MyD88-dependent pathway initiation in C. sinensis.

  16. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... the NHLBI on Twitter. What Is Iron-Deficiency Anemia? Español Iron-deficiency anemia is a common, easily ... Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented by the ...

  17. Iron deficiency anemia

    Science.gov (United States)

    Anemia - iron deficiency ... iron from old red blood cells. Iron deficiency anemia develops when your body's iron stores run low. ... You may have no symptoms if the anemia is mild. Most of the time, ... slowly. Symptoms may include: Feeling weak or tired more often ...

  18. Iron-Deficiency Anemia

    Science.gov (United States)

    ... the NHLBI on Twitter. What Is Iron-Deficiency Anemia? Español Iron-deficiency anemia is a common, easily ... Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented by the ...

  19. Your Guide to Anemia

    Science.gov (United States)

    ... 19 Who Is At Risk for Iron-Deficiency Anemia? Infants and children. Getting enough iron is essential for normal growth ... checkup to see whether they also might have anemia. If you have children or teens who have anemia, talk to them ...

  20. Iron-Deficiency Anemia

    Science.gov (United States)

    ... page from the NHLBI on Twitter. What Is Iron-Deficiency Anemia? Español Iron-deficiency anemia is a common, ... Content: NEXT >> Featured Video Living With and Managing Iron-Deficiency Anemia 05/18/2011 This video—presented by ...

  1. A Functional Genetic Screen Identifies the Phosphoinositide 3-kinase Pathway as a Determinant of Resistance to Fibroblast Growth Factor Receptor Inhibitors in FGFR Mutant Urothelial Cell Carcinoma.

    Science.gov (United States)

    Wang, Liqin; Šuštić, Tonći; Leite de Oliveira, Rodrigo; Lieftink, Cor; Halonen, Pasi; van de Ven, Marieke; Beijersbergen, Roderick L; van den Heuvel, Michel M; Bernards, René; van der Heijden, Michiel S

    2017-01-17

    Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A common problem with targeted therapeutics is intrinsic or acquired resistance of the cancer cells. To find potential drug targets that can act synergistically with FGFR inhibition, we performed a synthetic lethality screen for the FGFR inhibitor AZD4547 using a short hairpin RNA library targeting the human kinome in the UCC cell line RT112 (FGFR3-TACC3 translocation). We identified multiple members of the phosphoinositide 3-kinase (PI3K) pathway and found that inhibition of PIK3CA acts synergistically with FGFR inhibitors. The PI3K inhibitor BKM120 acted synergistically with inhibition of FGFR in multiple UCC and lung cancer cell lines having FGFR mutations. Consistently, we observed an elevated PI3K-protein kinase B pathway activity resulting from epidermal growth factor receptor or Erb-B2 receptor tyrosine kinase 3 reactivation caused by FGFR inhibition as the underlying molecular mechanism of the synergy. Our data show that feedback pathways activated by FGFR inhibition converge on the PI3K pathway. These findings provide a strong rationale to test FGFR inhibitors in combination with PI3K inhibitors in cancers harboring genetic activation of FGFR genes.

  2. Inhibitor of Apoptosis (IAP proteins in pediatric leukemia: Molecular pathways and novel approaches to therapy

    Directory of Open Access Journals (Sweden)

    Simone eFulda

    2014-01-01

    Full Text Available Inhibitor of Apoptosis (IAP proteins are a family of proteins with antiapoptotic functions that contribute to the evasion of apoptosis, a form of programmed cell death. IAP proteins are expressed at high levels in a variety of human cancers including childhood acute leukemia. This elevated expression has been associated with unfavorable prognosis and poor outcome. Therefore, IAP proteins are currently exploited as therapeutic targets for cancer drug discovery. Consequently, small-molecule inhibitors or antisense oligonucleotides directed against IAP proteins have been developed over the last years. Indeed, IAP antagonists proved to exhibit in vitro and in vivo antitumor activities against childhood pediatric leukemia in several preclinical studies. Thus, targeting IAP proteins represents a promising molecular targeted strategy to overcome apoptosis resistance in childhood leukemia which warrants further exploitation.

  3. The dual pathway inhibitor rigosertib is effective in direct patient tumor xenografts of head and neck squamous cell carcinomas.

    Science.gov (United States)

    Anderson, Ryan T; Keysar, Stephen B; Bowles, Daniel W; Glogowska, Magdalena J; Astling, David P; Morton, J Jason; Le, Phuong; Umpierrez, Adrian; Eagles-Soukup, Justin; Gan, Gregory N; Vogler, Brian W; Sehrt, Daniel; Takimoto, Sarah M; Aisner, Dara L; Wilhelm, Francois; Frederick, Barbara A; Varella-Garcia, Marileila; Tan, Aik-Choon; Jimeno, Antonio

    2013-10-01

    The dual pathway inhibitor rigosertib inhibits phosphoinositide 3-kinase (PI3K) pathway activation as well as polo-like kinase 1 (PLK1) activity across a broad spectrum of cancer cell lines. The importance of PIK3CA alterations in squamous cell carcinoma of the head and neck (HNSCC) has raised interest in exploring agents targeting PI3K, the product of PIK3CA. The genetic and molecular basis of rigosertib treatment response was investigated in a panel of 16 HNSCC cell lines, and direct patient tumor xenografts from eight patients with HNSCC [four HPV-serotype16 (HPV16)-positive]. HNSCC cell lines and xenografts were characterized by pathway enrichment gene expression analysis, exon sequencing, gene copy number, Western blotting, and immunohistochemistry (IHC). Rigosertib had potent antiproliferative effects on 11 of 16 HPV(-) HNSCC cell lines. Treatment sensitivity was confirmed in two cell lines using an orthotopic in vivo xenograft model. Growth reduction after rigosertib treatment was observed in three of eight HNSCC direct patient tumor lines. The responsive tumor lines carried a combination of a PI3KCA-activating event (amplification or mutation) and a p53-inactivating event (either HPV16- or mutation-mediated TP53 inactivation). In this study, we evaluated the in vitro and in vivo efficacy of rigosertib in both HPV(+) and HPV(-) HNSCCs, focusing on inhibition of the PI3K pathway. Although consistent inhibition of the PI3K pathway was not evident in HNSCC, we identified a combination of PI3K/TP53 events necessary, but not sufficient, for rigosertib sensitivity.

  4. Dissociation between skeletal muscle inhibitor-{kappa}B kinase/nuclear factor-{kappa}B pathway activity and insulin sensitivity in nondiabetic twins

    DEFF Research Database (Denmark)

    Friedrichsen, Martin; Ribel-Madsen, Rasmus; Wojtaszewski, Jørgen

    2010-01-01

    Context: Several studies suggest a link between increased activity of the inflammatory inhibitor-kappaB kinase/nuclear factor-kappaB (IKK/NF-kappaB) pathway in skeletal muscle and insulin resistance. Objective: We aimed to study the regulation of skeletal muscle IKK/NF-kappaB pathway activity...... as well as the association with glucose metabolism and skeletal muscle insulin signaling. Methods: The study population included a metabolically well-characterized cohort of young and elderly predominantly nondiabetic twins (n = 181). Inhibitor-kappaBbeta (IkappaBbeta) protein levels are negatively...... associated with IKK/NF-kappaB pathway activity and were used to evaluate pathway activity with p65 levels included as loading control. This indirect measure for IKK/NF-kappaB pathway activity was validated by a p65 binding assay. Results: Evaluating the effects of heritability, age, sex, obesity, aerobic...

  5. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy.

    LENUS (Irish Health Repository)

    Wander, Seth A

    2011-04-01

    Mammalian target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation, and survival via mTOR complex 1 (mTORC1) and mTORC2. The mTOR pathway is often aberrantly activated in cancers. While hypoxia, nutrient deprivation, and DNA damage restrain mTORC1 activity, multiple genetic events constitutively activate mTOR in cancers. Here we provide a brief overview of the signaling pathways up- and downstream of mTORC1 and -2, and discuss the insights into therapeutic anticancer targets - both those that have been tried in the clinic with limited success and those currently under clinical development - that knowledge of these pathways gives us.

  6. Novel bioassay for the discovery of inhibitors of the 2-C-methyl-D-erythritol 4-phosphate (MEP and terpenoid pathways leading to carotenoid biosynthesis.

    Directory of Open Access Journals (Sweden)

    Natália Corniani

    Full Text Available The 2-C-methyl-D-erythritol 4-phosphate (MEP pathway leads to the synthesis of isopentenyl diphosphate in plastids. It is a major branch point providing precursors for the synthesis of carotenoids, tocopherols, plastoquinone and the phytyl chain of chlorophylls, as well as the hormones abscisic acid and gibberellins. Consequently, disruption of this pathway is harmful to plants. We developed an in vivo bioassay that can measure the carbon flow through the carotenoid pathway. Leaf cuttings are incubated in the presence of a phytoene desaturase inhibitor to induce phytoene accumulation. Any compound reducing the level of phytoene accumulation is likely to interfere with either one of the steps in the MEP pathway or the synthesis of geranylgeranyl diphosphate. This concept was tested with known inhibitors of steps of the MEP pathway. The specificity of this in vivo bioassay was also verified by testing representative herbicides known to target processes outside of the MEP and carotenoid pathways. This assay enables the rapid screen of new inhibitors of enzymes preceding the synthesis of phytoene, though there are some limitations related to the non-specific effect of some inhibitors on this assay.

  7. NL-103, a novel dual-targeted inhibitor of histone deacetylases and hedgehog pathway, effectively overcomes vismodegib resistance conferred by Smo mutations.

    Science.gov (United States)

    Zhao, Jie; Quan, Haitian; Xie, Chengying; Lou, Liguang

    2014-06-01

    Misregulation of hedgehog (Hh) signaling has been implicated in the pathogenesis of basal cell carcinoma (BCC) and medulloblastoma. Vismodegib, an orally bioavailable Hh signal pathway inhibitor targeting Smo, has been approved for the treatment of advanced BCC. However, acquired drug resistance to vismodegib induced by point mutation in Smo is emerging as a major problem to vismodegib treatment. In this study, we designed and synthesized a novel chimeric compound NL-103, which comprises structural elements of Hh pathway inhibitor vismodegib, and histone deacetylase (HDAC) inhibitor vorinostat. NL-103 simultaneously and significantly inhibited both HDACs and Hh pathway. Importantly, NL-103, as well as vorinostat, effectively overcame vismodegib resistance induced by Smoothened point mutations. Moreover, NL-103 and vorinostat, but not vismodegib, significantly downregulated the expression of Gli2 which plays an important role in Hh pathway. These results indicate that HDAC inhibitory activity is essential for NL-103 to overcome vismodegib resistance and that dual inhibition of HDAC and Hh signaling pathway may be a rational strategy for overcoming vismodegib resistance. Our findings suggest that NL-103 may be a promising compound for clinical development as a more effective Hh pathway inhibitor.

  8. Peroxisome Proliferator-Activated Receptor γ Induces the Expression of Tissue Factor Pathway Inhibitor-1 (TFPI-1) in Human Macrophages

    Science.gov (United States)

    Copin, C.; Derudas, B.; Marx, N.

    2016-01-01

    Tissue factor (TF) is the initiator of the blood coagulation cascade after interaction with the activated factor VII (FVIIa). Moreover, the TF/FVIIa complex also activates intracellular signalling pathways leading to the production of inflammatory cytokines. The TF/FVIIa complex is inhibited by the tissue factor pathway inhibitor-1 (TFPI-1). Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that, together with PPARα and PPARβ/δ, controls macrophage functions. However, whether PPARγ activation modulates the expression of TFP1-1 in human macrophages is not known. Here we report that PPARγ activation increases the expression of TFPI-1 in human macrophages in vitro as well as in vivo in circulating peripheral blood mononuclear cells. The induction of TFPI-1 expression by PPARγ ligands, an effect shared by the activation of PPARα and PPARβ/δ, occurs also in proinflammatory M1 and in anti-inflammatory M2 polarized macrophages. As a functional consequence, treatment with PPARγ ligands significantly reduces the inflammatory response induced by FVIIa, as measured by variations in the IL-8, MMP-2, and MCP-1 expression. These data identify a novel role for PPARγ in the control of TF the pathway. PMID:28115923

  9. Deficiency of terminal complement pathway inhibitor promotes neuronal tau pathology and degeneration in mice

    OpenAIRE

    Britschgi Markus; Takeda-Uchimura Yoshiko; Rockenstein Edward; Johns Hudson; Masliah Eliezer; Wyss-Coray Tony

    2012-01-01

    Abstract Background The neuronal microtubule-associated protein tau becomes hyperphosphorylated and forms aggregates in tauopathies but the processes leading to this pathological hallmark are not understood. Because tauopathies are accompanied by neuroinflammation and the complement cascade forms a key innate immune pathway, we asked whether the complement system has a role in the development of tau pathology. Finding...

  10. In patients with chronic aplastic anemia, bone marrow–derived MSCs regulate the Treg/Th17 balance by influencing the Notch/RBP-J/FOXP3/RORγt pathway

    Science.gov (United States)

    Li, Hongbo; Wang, Lin; Pang, Yan; Jiang, Zujun; Liu, Zenghui; Xiao, Haowen; Chen, Haijia; Ge, Xiaohu; Lan, Hai; Xiao, Yang

    2017-01-01

    The standard treatment for aplastic anemia (AA) in young patients is a matched sibling hematopoietic stem cell transplant. Transfusion of a chronic AA patient with allogeneic bone marrow–derived mesenchymal stromal cells (BMMSCs) is currently being developed as a cell-based therapy, and the safety and efficacy of such transfusions are being continuously improved. Nevertheless, the mechanisms by which BMMSCs exert their therapeutic effects remain to be elucidated. In this study, mesenchymal stromal cells (MSCs) obtained from bone marrow donors were concentrated and intravenously injected into 15 chronic AA patients who had been refractory to prior immunosuppressive therapy. We showed that BMMSCs modulate the levels of Th1, Th2, Th17 and Treg cells, as well as their related cytokines in chronic AA patients. Furthermore, the percentages of Th1 and Th17 cells among the H-MSCs decreased significantly, while the percentage Treg cells increased. The Notch/RBP-J/FOXP3/RORγt pathway was involved in modulating the Treg/Th17 balance after MSCs were transfused in vitro. Additionally, the role played by transfused MSCs in regulating the Treg/Th17 balance via the Notch/RBP-J/FOXP3/RORγt pathway was further confirmed in an AA mouse model. In summary, in humans with chronic AA, BMMSCs regulate the Treg/Th17 balance by affecting the Notch/RBP-J/FOXP3/RORγt pathway. PMID:28195151

  11. Therapeutic complement inhibition in complement-mediated hemolytic anemias: Past, present and future.

    Science.gov (United States)

    Risitano, Antonio M; Marotta, Serena

    2016-06-01

    The introduction in the clinic of anti-complement agents represented a major achievement which gave to physicians a novel etiologic treatment for different human diseases. Indeed, the first anti-complement agent eculizumab has changed the treatment paradigm of paroxysmal nocturnal hemoglobinuria (PNH), dramatically impacting its severe clinical course. In addition, eculizumab is the first agent approved for atypical Hemolytic Uremic Syndrome (aHUS), a life-threatening inherited thrombotic microangiopathy. Nevertheless, such remarkable milestone in medicine has brought to the fore additional challenges for the scientific community. Indeed, the list of complement-mediated anemias is not limited to PNH and aHUS, and other human diseases can be considered for anti-complement treatment. They include other thrombotic microangiopathies, as well as some antibody-mediated hemolytic anemias. Furthermore, more than ten years of experience with eculizumab led to a better understanding of the individual steps of the complement cascade involved in the pathophysiology of different human diseases. Based on this, new unmet clinical needs are emerging; a number of different strategies are currently under development to improve current anti-complement treatment, trying to address these specific clinical needs. They include: (i) alternative anti-C5 agents, which may improve the heaviness of eculizumab treatment; (ii) broad-spectrum anti-C3 agents, which may improve the efficacy of anti-C5 treatment by intercepting the complement cascade upstream (i.e., preventing C3-mediated extravascular hemolysis in PNH); (iii) targeted inhibitors of selective complement activating pathways, which may prevent early pathogenic events of specific human diseases (e.g., anti-classical pathway for antibody-mediated anemias, or anti-alternative pathway for PNH and aHUS). Here we briefly summarize the status of art of current and future complement inhibition for different complement-mediated anemias

  12. Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma

    Science.gov (United States)

    Yauch, Robert L.; Dijkgraaf, Gerrit J. P.; Alicke, Bruno; Januario, Thomas; Ahn, Christina P.; Holcomb, Thomas; Pujara, Kanan; Stinson, Jeremy; Callahan, Christopher A.; Tang, Tracy; Bazan, J. Fernando; Kan, Zhengyan; Seshagiri, Somasekar; Hann, Christine L.; Gould, Stephen E.; Low, Jennifer A.; Rudin, Charles M.; de Sauvage, Frederic J.

    2017-01-01

    The Hedgehog (Hh) signaling pathway is inappropriately activated in certain human cancers, including medulloblastoma, an aggressive brain tumor. GDC-0449, a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened (SMO), has produced promising anti-tumor responses in early clinical studies of cancers driven by mutations in this pathway. To evaluate the mechanism of resistance in a medulloblastoma patient who had relapsed after an initial response to GDC-0449, we determined the mutational status of Hh signaling genes in the tumor after disease progression. We identified an amino acid substitution at a conserved aspartic acid residue of SMO that had no effect on Hh signaling but disrupted the ability of GDC-0449 to bind SMO and suppress this pathway. A mutation altering the same amino acid also arose in a GDC-0449–resistant mouse model of medulloblastoma. These findings show that acquired mutations in a serpentine receptor with features of a G protein–coupled receptor can serve as a mechanism of drug resistance in human cancer. PMID:19726788

  13. Heat shock protein 90 and calcineurin pathway inhibitors enhance the efficacy of triazoles against Scedosporium prolificans via induction of apoptosis

    Directory of Open Access Journals (Sweden)

    Fazal Shirazi

    2014-06-01

    Full Text Available Scedosporium prolificans is a pathogenic mold resistant to current antifungals, and infection results in high mortality. Simultaneous targeting of both ergosterol biosynthesis and heat shock protein 90 (Hsp90 or the calcineurin pathway in S. prolificans may be an important strategy for enhancing the potency of antifungal agents. We hypothesized that the inactive triazoles posaconazole (PCZ and itraconazole (ICZ acquire fungicidal activity when combined with the calcineurin inhibitor tacrolimus (TCR or Hsp90 inhibitor 17-demethoxy-17-(2-propenylamino geldanamycin (17AAG. PCZ, ICZ, TCR and 17AAG alone were inactive in vitro against S. prolificans spores (MICs > 128 μg/ml. In contrast, MICs for PCZ or ICZ in combination with TCR or 17AAG (0.125-0.50 μg/ml were much lower compared with drug alone. In addition PCZ and ICZ in combination with TCR or 17AAG became fungicidal. Because apoptosis is regulated by the calcineurin pathway in fungi and is under the control of Hsp90, we hypothesized that this synergistic fungicidal effect is mediated via apoptosis. This observed fungicidal activity was mediated by increased apoptosis of S. prolificans germlings, as evidenced by reactive oxygen species accumulation, decreased mitochondrial membrane potential, phosphatidylserine externalization, and DNA fragmentation. Furthermore, induction of caspase-like activity was correlated with TCR or 17AAG + PCZ/ICZ-induced cell death. In conclusion, we report for the first time that PCZ or ICZ in combination with TCR or 17AAG renders S. prolificans exquisitely sensitive to PCZ or ICZ via apoptosis. This finding may stimulate the development of new therapeutic strategies for patients infected with this recalcitrant fungus.

  14. Anemia in Chronic Kidney Disease

    Science.gov (United States)

    ... High Blood Pressure Heart Disease Mineral & Bone Disorder Anemia in Chronic Kidney Disease What is anemia? Anemia is a condition in which the body ... function as well as they should. How is anemia related to chronic kidney disease? Anemia commonly occurs ...

  15. Identification of potential inhibitors for AIRS from de novo purine biosynthesis pathway through molecular modeling studies - a computational approach.

    Science.gov (United States)

    Rao, R Guru Raj; Biswal, Jayashree; Dhamodharan, Prabhu; Kanagarajan, Surekha; Jeyaraman, Jeyakanthan

    2016-10-01

    In cancer, de novo pathway plays an important role in cell proliferation by supplying huge demand of purine nucleotides. Aminoimidazole ribonucleotide synthetase (AIRS) catalyzes the fifth step of de novo purine biosynthesis facilitating in the conversion of formylglycinamidine ribonucleotide to aminoimidazole ribonucleotide. Hence, inhibiting AIRS is crucial due to its involvement in the regulation of uncontrollable cancer cell proliferation. In this study, the three-dimensional structure of AIRS from P. horikoshii OT3 was constructed based on the crystal structure from E. coli and the modeled protein is verified for stability using molecular dynamics for a time frame of 100 ns. Virtual screening and induced fit docking were performed to identify the best antagonists based on their binding mode and affinity. Through mutational studies, the residues necessary for catalytic activity of AIRS were identified and among which the following residues Lys35, Asp103, Glu137, and Thr138 are important in determination of AIRS function. The mutational studies help to understand the structural and energetic characteristics of the specified residues. In addition to Molecular Dynamics, ADME properties, binding free-energy, and density functional theory calculations of the compounds were carried out to find the best lead molecule. Based on these analyses, the compound from the NCI database, NCI_121957 was adjudged as the best molecule and could be suggested as the suitable inhibitor of AIRS. In future studies, experimental validation of these ligands as AIRS inhibitors will be carried out.

  16. Expression and characterization of Kunitz domain 3 and C-terminal of human tissue factor pathway inhibitor-2

    Institute of Scientific and Technical Information of China (English)

    Lina Zhu; Jiping Wang; Jingui Mu; Huijun Wang; Chenqi Zhang; Jue Wang; Xingang Liu; Xiaomin Yan; Linsen Dai; Duan Ma

    2009-01-01

    Human tissue factor pathway inhibitor-2 (hTFPI-2) is a serine protease inhibitor and its inhibitory activity is enhanced by heparin. The Kunitz domain 3 and C-terminal of hTFPI-2 (bTFPI-2/KD3C), which has the activity toward heparin calcium, have been successfully expressed in Pichia pastoris and purified by SP-Sepharose and heparin-Sepharose chromatography. The Fourier transformed infrared spectroscopy (FTIR),Raman spectroscopy, and circular dichroism (CD)experiment results implied that hTFPI-2/KD3C con-tained small contents of or-helix and β-strand, but large amounts of random coil and two kinds of disulfide bonds, gauche-gauche-gauche (ggg) and trans-gauche-trans (tgt). The interaction of hTFPI-2/KD3C with heparin calcium was investigated by CD. It was found that heparin calcium induced β-strands in hTFPI-2/KD3C to different extents depending on the ratio of hTFPI-2/KD3C and heparin calcium.

  17. Canonical Wnt pathway inhibitor ICG-001 induces cytotoxicity of multiple myeloma cells in Wnt-independent manner.

    Directory of Open Access Journals (Sweden)

    Eileen R Grigson

    Full Text Available Canonical Wnt signaling has been implicated in the regulation of multiple myeloma (MM growth. Here, we investigated whether the targeting of this pathway with a novel pharmacological inhibitor ICG-001 would result in an anti-tumor effect and improvement of chemosensitivity in MM. As expected, ICG-001 specifically down-regulated β-catenin/TCF-mediated transcription in MM cells. Treatment with ICG-001 resulted in growth arrest and apoptosis in MM cell lines and primary MM cells. Moreover, ICG-001 enhanced the cytotoxic effects of doxorubicin and melphalan and abrogated chemoresistance of MM cells to these chemotherapeutics induced by bone marrow stroma. The cytotoxic effect of ICG-001 was caspase-dependent and mediated through transcriptional up-regulation of BH3-only pro-apoptotic members of the Bcl-2 family Noxa and Puma but not through inhibition of canonical Wnt signaling. ICG-001 selectively induced apoptosis in primary MM cells but did not affect non-MM cells of the bone marrow microenvironment. Experiments using a xenograft model of MM showed substantial anti-tumor effects of this compound in vivo. Thus, our study demonstrated that the small molecule inhibitor ICG-001 has strong anti-MM effects and could be developed further for therapeutic intervention in this disease.

  18. Drosophila-based in vivo assay for the validation of inhibitors of the epidermal growth factor receptor/Ras pathway

    Indian Academy of Sciences (India)

    Anuradha Aritakula; Annadurai Ramasamy

    2008-12-01

    Overexpression of epidermal growth factor receptor (EGFR) is a common phenomenon observed in most cancers. Clinical treatment of such cancer involves the use of chemotherapeutic agents such as gefitinib and erlotinib which are inhibitors of tyrosine kinase (TK). These small molecules bind to the ATP-binding sites of the TK domain of EGFR. Our in silico analysis suggests that the TK domains of Drosophila and human EGFR are highly conserved. We therefore employed the Drosophila system to validate the in silico observations made with two important anticancer drugs. Since a large number of mutant flies are available, it was possible to investigate the various components of the EGFR/Ras/Raf/ MAPK pathways and the phosphorylation status of diphosphorylated extracellular signal-regulated kinase (dp-ERK1/2). These studies confirm the binding of the anilinoquinazolines to the Drosophila EGFR protein and modulation of its activity. Thus, Drosophila appears to be a robust and simple model system for screening newer anticancer drugs that act as TK inhibitors (TKIs).

  19. Novel agents and associated toxicities of inhibitors of the pi3k/Akt/mtor pathway for the treatment of breast cancer

    OpenAIRE

    Chia, S.; Gandhi, S.; Joy, A.A.; Edwards, S.; Gorr, M.; Hopkins, S; Kondejewski, J.; Ayoub, J.P.; Califaretti, N.; Rayson, D.; Dent, S.F.

    2015-01-01

    The pi3k/Akt/mtor (phosphatidylinositol 3 kinase/ Akt/mammalian target of rapamycin) signalling pathway is an established driver of oncogenic activity in human malignancies. Therapeutic targeting of this pathway holds significant promise as a treatment strategy. Everolimus, an mtor inhibitor, is the first of this class of agents approved for the treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer. Everolimus has been associated with...

  20. Revealing the Mechanistic Pathway of Acid Activation of Proton Pump Inhibitors To Inhibit the Gastric Proton Pump: A DFT Study.

    Science.gov (United States)

    Jana, Kalyanashis; Bandyopadhyay, Tusar; Ganguly, Bishwajit

    2016-12-29

    Acid-related gastric diseases are associated with disorder of digestive tract acidification due to the acid secretion by gastric proton pump, H(+),K(+)-ATPase. Omeprazole is one of the persuasive irreversible inhibitor of the proton pump H(+),K(+)-ATPase. However, the reports on the mechanistic pathway of irreversible proton pump inhibitors (PPIs) on the acid activation and formation of disulfide complex are scarce in the literature. We have examined the acid activation PPIs, i.e., timoprazole, S-omeprazole and R-omeprazole using M062X/6-31++G(d,p) in aqueous phase with SMD solvation model. The proton pump inhibitor is a prodrug and activated in the acidic canaliculi of the gastric pump H(+),K(+)-ATPase to sulfenic acid which can either form another acid activate intermediate sulfenamide or a disulfide complex with cysteine amino acid of H(+),K(+)-ATPase. The quantum chemical calculations suggest that the transition state (TS5) for the disulfide complex formation is the rate-determining step of the multistep acid inhibition process by PPIs. The free energy barrier of TS5 is 5.5 kcal/mol higher for timoprazole compared to the S-omeprazole. The stability of the transition state for the formation of disulfide bond between S-omeprazole and cysteine amino acid of H(+),K(+)-ATPase is governed by inter- and intramolecular hydrogen bonding. The disulfide complex for S-omeprazole is thermodynamically more stable by 4.5 kcal/mol in aqueous phase compared to disulfide complex of timoprazole, which corroborates the less efficacy of timoprazole as irreversible PPI for acid inhibition process. It has been speculated that sulfenic acid can either form sulfenamide or a stable disulfide complex with cysteine amino acid residue of H(+),K(+)-ATPase. The M062X/6-31++G(d,p) level of theory calculated results reveal that the formation of tetra cyclic sulfenamide is unfavored by ∼17 kcal/mol for S-omeprazole and 11.5 kcal/mol for timoprazole compared to the disulfide complex formation

  1. The effector AWR5 from the plant pathogen Ralstonia solanacearum is an inhibitor of the TOR signalling pathway.

    Science.gov (United States)

    Popa, Crina; Li, Liang; Gil, Sergio; Tatjer, Laura; Hashii, Keisuke; Tabuchi, Mitsuaki; Coll, Núria S; Ariño, Joaquín; Valls, Marc

    2016-06-03

    Bacterial pathogens possess complex type III effector (T3E) repertoires that are translocated inside the host cells to cause disease. However, only a minor proportion of these effectors have been assigned a function. Here, we show that the T3E AWR5 from the phytopathogen Ralstonia solanacearum is an inhibitor of TOR, a central regulator in eukaryotes that controls the switch between cell growth and stress responses in response to nutrient availability. Heterologous expression of AWR5 in yeast caused growth inhibition and autophagy induction coupled to massive transcriptomic changes, unmistakably reminiscent of TOR inhibition by rapamycin or nitrogen starvation. Detailed genetic analysis of these phenotypes in yeast, including suppression of AWR5-induced toxicity by mutation of CDC55 and TPD3, encoding regulatory subunits of the PP2A phosphatase, indicated that AWR5 might exert its function by directly or indirectly inhibiting the TOR pathway upstream PP2A. We present evidence in planta that this T3E caused a decrease in TOR-regulated plant nitrate reductase activity and also that normal levels of TOR and the Cdc55 homologues in plants are required for R. solanacearum virulence. Our results suggest that the TOR pathway is a bona fide T3E target and further prove that yeast is a useful platform for T3E function characterisation.

  2. Wortmannin, PI3K/Akt signaling pathway inhibitor, attenuates thyroid injury associated with severe acute pancreatitis in rats.

    Science.gov (United States)

    Abliz, Ablikim; Deng, Wenhong; Sun, Rongze; Guo, Wenyi; Zhao, Liang; Wang, Weixing

    2015-01-01

    Increasing evidences suggest that PI3K/AKT pathway plays an important role in the pathogenesis of inflammatory diseases such as acute pancreatitis. However, the exact effect of PI3K/AKT on thyroid injury associated with acute pancreatitis has not been investigated. This study aimed to investigate the protective effects of wortmannin, PI3K/AKT inhibitor, on thyroid injury in a rat model of severe acute pancreatitis (SAP). Sixty male SD rats were randomly divided into four groups: sham operating group (SO), SAP group, wortmannin treatment (WOR) group and drug control (WOR-CON) group. Serum amylase (AMY), lipase (LIP) and thyroid hormone levels were evaluated. The morphological change of thyroid tissue was analyzed under the light and transmission electron microscopy. AKT, P38MAPK and NF-κB expression in the thyroid tissue was evaluated by immunohistochemical staining. Oxidative stress and inflammatory cytokines were detected. Results showed that wortmannin attenuated the following: (1) serum AMY, LIP and thyroid hormone (2) pancreatic and thyroid pathological injuries (3) thyroid MDA, (4) thyroid ultrastructural change, (5) serum TNF-α, IL-6 and IL-1β (6) AKT, MAPKP38 and NF-κB expression in thyroid tissues. These results suggested that wortmannin attenuates thyroid injury in SAP rats, presumably because of its role on prevent ROS generation and inhibits the activation of P38MAPK, NF-κB pathway. Our findings provide new therapeutic targets for thyroid injury associated with SAP.

  3. Inhibitors of Intracellular Signaling Pathways that Lead to Stimulated Epidermal Pigmentation: Perspective of Anti-Pigmenting Agents

    Directory of Open Access Journals (Sweden)

    Genji Imokawa

    2014-05-01

    Full Text Available Few anti-pigmenting agents have been designed and developed according to their known hyperpigmentation mechanisms and corresponding intracellular signaling cascades. Most anti-pigmenting agents developed so far are mechanistically involved in the interruption of constitutional melanogenic mechanisms by which skin color is maintained at a normal and unstimulated level. Thus, owing to the difficulty of confining topical application to a specific hyperpigmented skin area, potent anti-pigmenting agents capable of attenuating the natural unstimulated pigmentation process have the risk of leading to hypopigmentation. Since intracellular signaling pathways within melanocytes do not function substantially in maintaining normal skin color and are activated only by environmental stimuli such as UV radiation, specifically down-regulating the activation of melanogenesis to the constitutive level would be an appropriate strategy to develop new potent anti-pigmenting agents with a low risk of hypopigmentation. In this article, we review the hyperpigmentation mechanisms and intracellular signaling pathways that lead to the stimulation of melanogenesis. We also discuss a screening and evaluation system to select candidates for new anti-melanogenic substances by focusing on inhibitors of endothelin-1 or stem cell factor-triggered intracellular signaling cascades. From this viewpoint, we show that extracts of the herbs Withania somnifera and Melia toosendan and the natural chemicals Withaferin A and Astaxanthin are new candidates for potent anti-pigmenting substances that avoid the risk of hypopigmentation.

  4. Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI

    Science.gov (United States)

    Puy, Cristina; Tucker, Erik I.; Ivanov, Ivan S.; Gailani, David; Smith, Stephanie A.; Morrissey, James H.; Gruber, András; McCarty, Owen J. T.

    2016-01-01

    Introduction Factor (F) XI supports both normal human hemostasis and pathological thrombosis. Activated FXI (FXIa) promotes thrombin generation by enzymatic activation of FXI, FIX, FX, and FV, and inactivation of alpha tissue factor pathway inhibitor (TFPIα), in vitro. Some of these reactions are now known to be enhanced by short-chain polyphosphates (SCP) derived from activated platelets. These SCPs act as a cofactor for the activation of FXI and FV by thrombin and FXIa, respectively. Since SCPs have been shown to inhibit the anticoagulant function of TFPIα, we herein investigated whether SCPs could serve as cofactors for the proteolytic inactivation of TFPIα by FXIa, further promoting the efficiency of the extrinsic pathway of coagulation to generate thrombin. Methods and Results Purified soluble SCP was prepared by size-fractionation of sodium polyphosphate. TFPIα proteolysis was analyzed by western blot. TFPIα activity was measured as inhibition of FX activation and activity in coagulation and chromogenic assays. SCPs significantly accelerated the rate of inactivation of TFPIα by FXIa in both purified systems and in recalcified plasma. Moreover, platelet-derived SCP accelerated the rate of inactivation of platelet-derived TFPIα by FXIa. TFPIα activity was not affected by SCP in recalcified FXI-depleted plasma. Conclusions Our data suggest that SCP is a cofactor for TFPIα inactivation by FXIa, thus, expanding the range of hemostatic FXIa substrates that may be affected by the cofactor functions of platelet-derived SCP. PMID:27764259

  5. Laboratory Evaluation of Anemia

    OpenAIRE

    1987-01-01

    The laboratory evaluation of anemia begins with a complete blood count and reticulocyte count. The anemia is then categorized as microcytic, macrocytic or normocytic, with or without reticulocytosis. Examination of the peripheral smear and a small number of specific tests confirm the diagnosis. The serum iron level, total iron-binding capacity, serum ferritin level and hemoglobin electrophoresis generally separate the microcytic anemias. The erythrocyte size-distribution width may be particul...

  6. Iron deficiency anemia

    OpenAIRE

    Naigamwalla, Dinaz Z.; Webb, Jinelle A.; Giger, Urs

    2012-01-01

    Iron is essential to virtually all living organisms and is integral to multiple metabolic functions. The most important function is oxygen transport in hemoglobin. Iron deficiency anemia in dogs and cats is usually caused by chronic blood loss and can be discovered incidentally as animals may have adapted to the anemia. Severe iron deficiency is characterized by a microcytic, hypochromic, potentially severe anemia with a variable regenerative response. Iron metabolism and homeostasis will be ...

  7. How Is Pernicious Anemia Treated?

    Science.gov (United States)

    ... from the NHLBI on Twitter. How Is Pernicious Anemia Treated? Doctors treat pernicious anemia by replacing the missing vitamin B12 in the body. People who have pernicious anemia may need lifelong treatment. The goals of treating ...

  8. How Is Aplastic Anemia Treated?

    Science.gov (United States)

    ... from the NHLBI on Twitter. How Is Aplastic Anemia Treated? Treatments for aplastic anemia include blood transfusions , blood and marrow stem cell ... a transplant. Removing a known cause of aplastic anemia, such as exposure to a toxin, also may ...

  9. Genetics Home Reference: Fanconi anemia

    Science.gov (United States)

    ... Understand Genetics Home Health Conditions Fanconi anemia Fanconi anemia Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Fanconi anemia is a condition that affects many parts of ...

  10. Characterization of the sulfate uptake and assimilation pathway from Xanthomonas citri - targets for bacterial growth inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Tambascia, C.; Balan, A. [Laboratorio Nacional de Biociencias - LNBIO, Campinas, SP (Brazil)

    2012-07-01

    Full text: Microorganisms require sulfur for growth and obtain it either for inorganic sulfate or organosulfur compounds. ATP-Binding Cassete (SulT family) or major facilitator superfamily-type (SulP) transporters are responsible for the sulfate transport into the cell. In Xanthomonas citri, the phytopathogenic bacterium that causes the canker citrus disease, there are no reports related to the importance of these transporters during in vitro or in vivo infection. We identified in X. citri genome all the genes that belong to the well-characterized cys regulon from Escherichia coli and Salmonella typhimurium, which includes three ABC transporters and all the enzymes necessary for sulfate oxide reduction to sulfide and cysteine. Once these genes have been shown to be extremely important for bacteria growth and development in different environments, we chose the sbpcysWUA and cysDNCHIJG operons, which encodes the ABC inorganic sulfate ABC transporter and all the enzymes necessary for conversion of sulfate in cysteine, respectively. As a step for crystallization trials and resolution of their tridimensional structures, the referred genes were amplified and cloned into the cloning vector pGEM T-easy. In addition, using bioinformatics tools and molecular modeling we characterized all the protein functions as well as built tridimensional models of their structure for determination of the active sites. The importance of each protein is discussed aiming the discovery of a good target for development of inhibitors that could block the bacterium growth. (author)

  11. Tumour growth environment modulates Chk1 signalling pathways and Chk1 inhibitor sensitivity

    Science.gov (United States)

    Massey, Andrew J.

    2016-01-01

    Clinical development of Chk1 inhibitors is currently focussed on evaluating activity as monotherapy and as potentiators of chemotherapy. To aid translation of pre-clinical studies, we sought to understand the effects of the tumour growth environment on Chk1 signalling and sensitivity to small molecule Chk1 inhibition. Spheroid culture altered Chk1 signalling to a more xenograft like state but decreased sensitivity to Chk1 inhibition. Growth in low serum did not alter DDR signalling but increased the sensitivity of A2058 and U2OS tumour cells to Chk1 inhibition. An analysis of the expression levels of replication associated proteins identified a correlation between Cdc6 and pChk1 (S296) as well as total Chk1 in xenograft derived samples and between Cdc6 and total Chk1 in anchorage-dependent growth derived protein samples. No apparent correlation between Chk1 or Cdc6 expression and sensitivity to Chk1 inhibition in vitro was observed. A database analysis revealed upregulation of CDC6 mRNA expression in tumour compared to normal tissue and a correlation between CDC6 and CHEK1 mRNA expression in human cancers. We suggest that Cdc6 overexpression in human tumours requires a concomitant increase in Chk1 to counterbalance the deleterious effects of origin hyperactivation-induced DNA damage. PMID:27775084

  12. Hereditary sideroblastic anemias: pathophysiology, diagnosis, and treatment.

    Science.gov (United States)

    Camaschella, Clara

    2009-10-01

    Inherited sideroblastic anemia comprises several rare anemias due to heterogeneous genetic lesions, all characterized by the presence of ringed sideroblasts in the bone marrow. This morphological aspect reflects abnormal mitochondrial iron utilization by the erythroid precursors. The most common X-linked sideroblastic anemia (XLSA), due to mutations of the first enzyme of the heme synthetic pathway, delta-aminolevulinic acid synthase 2 (ALAS2), has linked heme deficiency to mitochondrial iron accumulation. The identification of other genes, such as adenosine triphosphate (ATP) binding cassette B7 (ABCB7) and glutaredoxin 5 (GLRX5), has strengthened the role of iron sulfur cluster biogenesis in sideroblast formation and revealed a complex interplay between pathways of mitochondrial iron utilization and cytosolic iron sensing by the iron-regulatory proteins (IRPs). As recently occurred with the discovery of the SLC25A38-related sideroblastic anemia, the identification of the genes responsible for as yet uncharacterized forms will provide further insights into mitochondrial iron metabolism of erythroid cells and the pathophysiology of sideroblastic anemia.

  13. Inborn anemias in mice

    Energy Technology Data Exchange (ETDEWEB)

    Bernstein, S.E.; Barker, J.E.; Russell, E.S.

    1981-06-01

    hereditary anemias of mice have been the chief objects of investigation. At present under study are four macrocytic anemias, five hemolytic anemias, nonhemolytic microcytic anemia, transitory siderocytic anemia, sex-linked iron-transport anemia, an ..cap alpha..-thalassemia, and a new target-cell anemia. Each of these blood dyscrasias is caused by the action of a unique mutant gene, which determines the structure of different intracellular molecules, and thus controls a different metabolic process. Thus our wide range of different hereditary anemias has considerable potential for uncovering many different aspects of hemopoietic homeostatic mechanisms in the mouse. Each anemia is studied through: (a) characterization of peripheral blood values, (b) determinations of radiosensitivity under a variety of conditions, (c) measurements of iron metabolism and heme synthesis, (d) histological and biochemical study of blood-forming tissue, (e) functional tests of the stem cell component, (f) examination of responses to erythroid stimuli, and (g) transplantation of tissue between individuals of differently affected genotypes.

  14. Anemia in Pregnancy

    Directory of Open Access Journals (Sweden)

    Umran Kucukgoz Gulec

    2013-06-01

    Full Text Available Iron deficiency anemia (IDA is the most frequent form of anemia in pregnant women. Folic acid, vitamin B12 deficiency, and hemoglobinopathies are other causes of anemia in pregnancy. Finding the underlying cause are crucial to the management of the anemia. Anemia is defined as hemoglobin of <11 g/dl in the first and third trimester and <10.5 g/dl in second trimester. According to the literature, anemia, particularly severe anemia (Hb<7g/dl is associated with increased risk of maternal and perinatal mortality and morbidity, and long term adverse effects in the newborn. The association of hemoglobin levels to perinatal outcome has been shown to be U shaped with both high and low hemoglobin levels being associated adverse perinatal outcome such as low birth weight, increased stillbirths. Anemia in pregnancy is a major public health problem. Ideally a woman should have adequate iron stores when she conceives, in order meet to additional requirements of pregnancy. This review focuses on the occurrence, types, maternal and perinatal outcomes, prevention and treatment of anemia during pregnancy. [Archives Medical Review Journal 2013; 22(3.000: 300-316

  15. Anemia in the Elderly

    OpenAIRE

    Sparling, Terence G.

    2013-01-01

    As the population ages, increasing attention has become focused on the prevalence of anemia in elderly individuals. Anemia occurs in more than 10% of individuals who are older than the age of 65 years, and it increases to more than 50% in individuals who are older than the age of 80 years. Although the anemia is typically mild and unlikely to result in symptoms, it is uniformly associated with increased morbidity and mortality as assessed in large cohort studies. Anemia is an independent pred...

  16. Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs

    Science.gov (United States)

    Bianco, R; Garofalo, S; Rosa, R; Damiano, V; Gelardi, T; Daniele, G; Marciano, R; Ciardiello, F; Tortora, G

    2008-01-01

    Inhibition of a single transduction pathway is often inefficient due to activation of alternative signalling. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation, survival and angiogenic pathways and has been implicated in the resistance to EGFR inhibitors. Thus, mTOR blockade is pursued to interfere at multiple levels with tumour growth. We used everolimus (RAD001) to inhibit mTOR, alone or in combination with anti-EGFR drugs gefitinib or cetuximab, on human cancer cell lines sensitive and resistant to EGFR inhibitors, both in vitro and in vivo. We demonstrated that everolimus is active against EGFR-resistant cancer cell lines and partially restores the ability of EGFR inhibitors to inhibit growth and survival. Everolimus reduces the expression of EGFR-related signalling effectors and VEGF production, inhibiting proliferation and capillary tube formation of endothelial cells, both alone and in combination with gefitinib. Finally, combination of everolimus and gefitinib inhibits growth of GEO and GEO-GR (gefitinib resistant) colon cancer xenografts, activation of signalling proteins and VEGF secretion. Targeting mTOR pathway with everolimus overcomes resistance to EGFR inhibitors and produces a cooperative effect with EGFR inhibitors, providing a valid therapeutic strategy to be tested in a clinical setting. PMID:18319715

  17. Nanoparticle-Mediated Expression of a Wnt Pathway Inhibitor Ameliorates Ocular Neovascularization

    Science.gov (United States)

    Wang, Zhongxiao; Cheng, Rui; Lee, Kyungwon; Puneet, Tyagi; Ding, Lexi; Kompella, Uday B.; Chen, Jing; Xu, Xun; Ma, Jian-xing

    2015-01-01

    Objective The deficiency of very low-density lipoprotein receptor (VLDLR) resulted in Wnt signaling activation and neovascularization (NV) in the retina. The present study sought to determine if the VLDLR extracellular domain (VLN) is responsible for the inhibition of Wnt signaling in ocular tissues. Approach and Results A plasmid expressing the soluble VLN was encapsulated with poly (lactide-co-glycolide acid) (PLGA) to form VLN nanoparticles (VLN-NP). Nanoparticles containing a plasmid expressing the low-density lipoprotein receptor extracellular domain (LN-NP) were used as negative control. MTT, modified Boyden chamber and Matrigel (™) assays were used to evaluate the inhibitory effect of VLN-NP on Wnt3a-stimulated endothelial cell (EC) proliferation, migration and tube formation. Vldlr−/− mice, oxygen-induced retinopathy (OIR) and alkali burn-induced corneal NV models were used to evaluate the effect of VLN-NP on ocular NV. Wnt reporter mice (BAT-gal), Western blotting and luciferase assay were used to evaluate Wnt pathway activity. Our results showed that VLN-NP specifically inhibited Wnt3a-induced EC proliferation, migration and tube formation. Intravitreal injection of VLN-NP inhibited abnormal NV in Vldlr−/−, OIR and alkali burn-induced corneal NV models, compared with LN-NP. VLN-NP significantly inhibited the phosphorylation of LRP6, the accumulation of β-catenin and the expression of VEGF in vivo and in vitro. Conclusions Taken together, these results suggest that the soluble VLN is a negative regulator of the Wnt pathway and has anti-angiogenic activities. Nanoparticle-mediated expression of VLN may thus represent a novel therapeutic approach to treat pathologic ocular angiogenesis and potentially other vascular diseases impacted by Wnt signaling. PMID:25657312

  18. Genetically engineered fusion of MAP-1 and factor H domains 1-5 generates a potent dual upstream inhibitor of both the lectin and alternative complement pathways

    DEFF Research Database (Denmark)

    Nordmaj, Mie Anemone; Munthe-Fog, Lea; Hein, Estrid;

    2015-01-01

    Inhibition of the complement cascade has emerged as an option for treatment of a range of diseases. Mannose-binding lectin/ficolin/collectin-associated protein (MAP-1) is a pattern recognition molecule (PRM)-associated inhibitor of the lectin pathway. The central regulator of the alternative...

  19. The Levels of the Lectin Pathway Serine Protease MASP-1 and Its Complex Formation with C1 Inhibitor Are Linked to the Severity of Hereditary Angioedema

    DEFF Research Database (Denmark)

    Hansen, Cecilie Bo; Csuka, Dorottya; Munthe-Fog, Lea

    2015-01-01

    C1 inhibitor (C1-INH) is known to form complexes with the lectin complement pathway serine proteases MASP-1 and MASP-2. Deficiency of C1-INH is associated with hereditary angioedema (HAE), an autosomal inherited disease characterized by swelling attacks caused by elevated levels of bradykinin. MASP...

  20. The p38 MAP kinase inhibitor SB203580 enhances nuclear factor-kappa B transcriptional activity by a non-specific effect upon the ERK pathway

    NARCIS (Netherlands)

    Birkenkamp, KU; Tuyt, LML; Lummen, C; Wierenga, LTJ; Kruijer, W; Vellenga, E

    2000-01-01

    1 In the present study we investigated a possible role for the p38 mitogen-activated protein (MAP) kinase pathway in mediating nuclear factor-kappa B (NF-kappa B) transcriptional activity in the erythroleukaemic cell line TF-1. 2 TF-1 cells stimulated with the phosphatase inhibitor okadaic acid (OA)

  1. S-Propargyl-Cysteine, a Novel Hydrogen Sulfide Donor, Inhibits Inflammatory Hepcidin and Relieves Anemia of Inflammation by Inhibiting IL-6/STAT3 Pathway

    Science.gov (United States)

    Xin, Hong; Zhu, Yi Zhun

    2016-01-01

    Anemia of inflammation (AI) is clinically prevalent and greatly threatens public health. Traditional remedies have raised controversy during clinical practice, calling for alternative therapies. We have recently found that hydrogen sulfide (H2S) inhibits inflammatory hepcidin, the critical mediator of AI. However, due to the chemical property of H2S, there remains an urgent need for a stable H2S donor in AI treatment. Here we reported that S-propargyl-cysteine (SPRC), a novel water-soluble H2S donor, suppressed hepatic hepcidin and corrected hypoferremia induced by lipopolysaccharide. The effects of SPRC were reversed by inhibition of cystathionine γ-lyase, one of the major endogenous H2S synthases. Moreover, SPRC reduced serum hepcidin, improved transferrin saturation, and maintained erythrocyte membrane integrity in a chronic mouse AI model. Consistently, splenomegaly was ameliorated and splenic iron accumulation relieved. Mechanism study indicated that serum IL-6 content and hepatic Il-6 mRNA were decreased by SPRC, in parallel with reduced hepatic JAK2/STAT3 activation. On the whole, our data reveal the inhibition of inflammatory hepcidin by SPRC, and suggest SPRC as a potential remedy against AI. PMID:27649298

  2. The maturation pathway of microcin B17, a peptide inhibitor of DNA gyrase.

    Science.gov (United States)

    Yorgey, P; Davagnino, J; Kolter, R

    1993-08-01

    The maturation pathway of microcin B17 (MccB17), a ribosomally synthesized peptide antibiotic which inhibits DNA gyrase, has been characterized. Synthesis of MccB17 involves several steps beginning with the translation of the MccB17 structural gene, mcbA, to yield a 69 amino acid precursor, preMccB17. Pre-MccB17 is then modified and folded by the action of three gene products, McbBCD, to yield proMccB17. Mutations in mcbA were isolated that permit modifications of the resulting mutant peptides, but prevent folding, suggesting that modification and folding are sequential steps. ProMccB17 is subsequently converted to MccB17 by removal of the N-terminal 26-amino-acid leader by a chromosomally encoded protease. Removal of the leader resulted in aggregation of the peptide, suggesting that the leader may function to maintain peptide solubility during synthesis in the cell. Finally, polyclonal antibodies raised against MccB17 recognize both MccB17 and proMccB17, but do not recognize preMccB17. This demonstrates the dramatic structural changes that result from the modifications and has been used to distinguish intermediates in the steps of maturation.

  3. Novel riboswitch ligand analogs as selective inhibitors of guanine-related metabolic pathways.

    Directory of Open Access Journals (Sweden)

    Jérôme Mulhbacher

    2010-04-01

    Full Text Available Riboswitches are regulatory elements modulating gene expression in response to specific metabolite binding. It has been recently reported that riboswitch agonists may exhibit antimicrobial properties by binding to the riboswitch domain. Guanine riboswitches are involved in the regulation of transport and biosynthesis of purine metabolites, which are critical for the nucleotides cellular pool. Upon guanine binding, these riboswitches stabilize a 5'-untranslated mRNA structure that causes transcription attenuation of the downstream open reading frame. In principle, any agonistic compound targeting a guanine riboswitch could cause gene repression even when the cell is starved for guanine. Antibiotics binding to riboswitches provide novel antimicrobial compounds that can be rationally designed from riboswitch crystal structures. Using this, we have identified a pyrimidine compound (PC1 binding guanine riboswitches that shows bactericidal activity against a subgroup of bacterial species including well-known nosocomial pathogens. This selective bacterial killing is only achieved when guaA, a gene coding for a GMP synthetase, is under the control of the riboswitch. Among the bacterial strains tested, several clinical strains exhibiting multiple drug resistance were inhibited suggesting that PC1 targets a different metabolic pathway. As a proof of principle, we have used a mouse model to show a direct correlation between the administration of PC1 and the reduction of Staphylococcus aureus infection in mammary glands. This work establishes the possibility of using existing structural knowledge to design novel guanine riboswitch-targeting antibiotics as powerful and selective antimicrobial compounds. Particularly, the finding of this new guanine riboswitch target is crucial as community-acquired bacterial infections have recently started to emerge.

  4. 2,3-Diarylxanthones as Potential Inhibitors of Arachidonic Acid Metabolic Pathways.

    Science.gov (United States)

    Santos, Clementina M M; Ribeiro, Daniela; Silva, Artur M S; Fernandes, Eduarda

    2017-03-11

    In response to an inflammatory stimulus, arachidonic acid (AA), the main polyunsaturated fatty acid present in the phospholipid layer of cell membranes, is released and metabolized to a series of eicosanoids. These bioactive lipid mediators of inflammation arise physiologically through the action of the enzymes 5-lipoxygenase (5-LOX) and cyclooxygenases (constitutive COX-1 and inducible COX-2). It is believed that dual inhibition of 5-LOX and COXs may have a higher beneficial impact in the treatment of inflammatory disorders rather than the inhibition of each enzyme. With this demand for new dual-acting anti-inflammatory agents, a range of 2,3-diarylxanthones were tested through their ability to interact in the AA metabolism. In vitro anti-inflammatory activity was evaluated through the inhibition of 5-LOX-catalyzed leukotriene B4 (LTB4) formation in human neutrophils and inhibition of COX-1- and COX-2-catalyzed prostaglandin E2 (PGE2) formation in human whole blood. The results showed that some of the studied arylxanthones were able to prevent LTB4 production in human neutrophils, in a concentration-dependent manner. The xanthone with a 2-catechol was the most active one (IC50 ∼ 9 μM). The more effective arylxanthones in preventing COX-1-catalyzed PGE2 production presented IC50 values from 1 to 7 μM, exhibiting a structural feature with at least one non-substituted aryl group. All the studied arylxanthones were ineffective to prevent the formation of PGE2 catalyzed by COX-2, up to the maximum concentration of 100 μM. The ability of the tested 2,3-diarylxanthones to interact with both 5-LOX and COX-1 pathways constitutes an important step in the research of novel dual-acting anti-inflammatory drugs.

  5. Connecting Lignin-Degradation Pathway with Pre-Treatment Inhibitor Sensitivity of Cupriavidus necator

    Energy Technology Data Exchange (ETDEWEB)

    Wang, W. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Yang, S. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Hunsinger, G. B. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Pienkos, P. T. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Johnson, D. K. [National Renewable Energy Lab. (NREL), Golden, CO (United States)

    2014-05-27

    In order to produce lignocellulosic biofuels economically, the complete release of monomers from the plant cell wall components, cellulose, hemicellulose, and lignin, through pre-treatment and hydrolysis (both enzymatic and chemical), and the efficient utilization of these monomers as carbon sources, is crucial. In addition, the identification and development of robust microbial biofuel production strains that can tolerate the toxic compounds generated during pre-treatment and hydrolysis is also essential. In this work, Cupriavidus necator was selected due to its capabilities for utilizing lignin monomers and producing polyhydroxylbutyrate (PHB), a bioplastic as well as an advanced biofuel intermediate. We characterized the growth kinetics of C. necator in pre-treated corn stover slurry as well as individually in the pre-sence of 11 potentially toxic compounds in the saccharified slurry. We found that C. necator was sensitive to the saccharified slurry produced from dilute acid pre-treated corn stover. Five out of 11 compounds within the slurry were characterized as toxic to C. necator, namely ammonium acetate, furfural, hydroxymethylfurfural (HMF), benzoic acid, and p-coumaric acid. Aldehydes (e.g., furfural and HMF) were more toxic than the acetate and the lignin degradation products benzoic acid and p-coumaric acid; furfural was identified as the most toxic compound. Although toxic to C. necator at high concentration, ammonium acetate, benzoic acid, and p-coumaric acid could be utilized by C. necator with a stimulating effect on C. necator growth. Consequently, the lignin degradation pathway of C. necator was reconstructed based on genomic information and literature. The efficient conversion of intermediate catechol to downstream products of cis,cis-muconate or 2-hydroxymuconate-6-semialdehyde may help improve the robustness of C. necator to benzoic acid and p-coumaric acid as well as improve PHB productivity.

  6. Connecting lignin-degradation pathway with pretreatment inhibitor sensitivity of Cupriavidus necator

    Directory of Open Access Journals (Sweden)

    Wei eWang

    2014-05-01

    Full Text Available To produce lignocellulosic biofuels economically, the complete release of monomers from the plant cell wall components, cellulose, hemicellulose and lignin, through pretreatment and hydrolysis (both enzymatic and chemical, and the efficient utilization of these monomers as carbon sources, is crucial. In addition, the identification and development of robust microbial biofuel production strains that can tolerate the toxic compounds generated during pretreatment and hydrolysis is also essential. In this work, Cupriavidus necator was selected due to its capabilities for utilizing lignin monomers and producing polyhydroxylbutyrate (PHB, a bioplastic as well as an advanced biofuel intermediate. We characterized the growth kinetics of C. necator in pretreated corn stover slurry as well as individually in the presence of 11 potentially toxic compounds in the saccharified slurry. We found that C. necator was sensitive to the saccharified slurry produced from dilute acid pretreated corn stover. Five out of 11 compounds within the slurry were characterized as toxic to C. necator, namely ammonium acetate, furfural, hydroxymethylfurfural (HMF, benzoic acid, and p-coumaric acid. Aldehydes (e.g., furfural and HMF were more toxic than the acetate and the lignin degradation products benzoic acid and p-coumaric acid; furfural was identified as the most toxic compound. Although toxic to C. necator at high concentration, ammonium acetate, benzoic acid, and p-coumaric acid could be utilized by C. necator with a stimulating effect on C. necator growth. Consequently, the lignin degradation pathway of C. necator was reconstructed based on genomic information and literature. The efficient conversion of intermediate catechol to downstream products of cis,cis-muconate or 2-hydroxymuconate-6-semialdehyde may help improve the robustness of C. necator to benzoic acid and p-coumaric acid as well as improve PHB productivity.

  7. Clinical development of galunisertib (LY2157299 monohydrate, a small molecule inhibitor of transforming growth factor-beta signaling pathway

    Directory of Open Access Journals (Sweden)

    Herbertz S

    2015-08-01

    Full Text Available Stephan Herbertz,1 J Scott Sawyer,2 Anja J Stauber,2 Ivelina Gueorguieva,3 Kyla E Driscoll,4 Shawn T Estrem,2 Ann L Cleverly,3 Durisala Desaiah,2 Susan C Guba,2 Karim A Benhadji,2 Christopher A Slapak,2 Michael M Lahn21Lilly Deutschland GmbH, Bad Homburg, Germany; 2Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA; 3Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, UK; 4Lilly Research Laboratories, Eli Lilly and Company, New York, NY, USA Abstract: Transforming growth factor-beta (TGF-β signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab

  8. Xiv conferencia : anemias

    OpenAIRE

    Paredes Manrique, Raúl; Camacho Gamba, Jorge

    2012-01-01

    La anemia es la disminución por debajo de lo normal de la Hb. o del número de globulos rojos o del hematocrito, pero es difícil encontrar un cuadro clínico que corresponda a la realidad de la anemia en el cual no estén descendidos los tres elementos.

  9. Living with Anemia

    Science.gov (United States)

    ... by an inherited or chronic disease or trauma. Anemia and Children/Teens Infants and young children have a greater ... birth-weight babies often are watched closely for anemia. Talk with your child's doctor if you're feeding your infant breast ...

  10. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Blood Tests Blood Transfusion Restless Legs Syndrome Send a link to NHLBI to someone by E-MAIL | ... Iron-Deficiency Anemia? Español Iron-deficiency anemia is a common, easily treated condition that occurs if you ...

  11. A single dose mass balance study of the Hedgehog pathway inhibitor vismodegib (GDC-0449) in humans using accelerator mass spectrometry.

    Science.gov (United States)

    Graham, Richard A; Lum, Bert L; Morrison, Glenn; Chang, Ilsung; Jorga, Karin; Dean, Brian; Shin, Young G; Yue, Qin; Mulder, Teresa; Malhi, Vikram; Xie, Minli; Low, Jennifer A; Hop, Cornelis E C A

    2011-08-01

    Vismodegib (GDC-0449), a small-molecule Hedgehog pathway inhibitor, was well tolerated in patients with solid tumors and showed promising efficacy in advanced basal cell carcinoma in a Phase I trial. The purpose of the study presented here was to determine routes of elimination and the extent of vismodegib metabolism, including assessment and identification of metabolites in plasma, urine, and feces. Six healthy female subjects of nonchildbearing potential were enrolled; each received a single 30-ml oral suspension containing 150 mg of vismodegib with 6.5 μg of [(14)C]vismodegib to yield a radioactivity dose of approximately 37 kBq (1000 nCi). Plasma, urine, and feces samples were collected over 56 days to permit sample collection for up to 5 elimination half-lives. Nonradioactive vismodegib was measured in plasma using liquid chromatographic-tandem mass spectrometry, and total radioactivity in plasma, urine, and feces was measured using accelerator mass spectrometry. Vismodegib was slowly eliminated by a combination of metabolism and excretion of parent drug, most of which was recovered in feces. The estimated excretion of the administered dose was 86.6% on average, with 82.2 and 4.43% recovered in feces and urine, respectively. Vismodegib was predominant in plasma, with concentrations representing >98% of the total circulating drug-related components. Metabolic pathways of vismodegib in humans included oxidation, glucuronidation, and uncommon pyridine ring cleavage. We conclude that vismodegib and any associated metabolic products are mainly eliminated through feces after oral administration in healthy volunteers.

  12. Targeting Tuberculosis and HIV Infection-Specific Regulatory T Cells with MEK/ERK Signaling Pathway Inhibitors

    Science.gov (United States)

    Lieske, Nora V.; Tonby, Kristian; Kvale, Dag; Dyrhol-Riise, Anne M.; Tasken, Kjetil

    2015-01-01

    Human regulatory T cells (Tregs) are essential in maintaining immunological tolerance and suppress effector T cells. Tregs are commonly up-regulated in chronic infectious diseases such as tuberculosis (TB) and human immunodeficiency virus (HIV) infection and thereby hamper disease-specific immune responses and eradication of pathogens. The MEK/ERK signaling pathway is involved in regulation of the FoxP3 transcription factor, which directs a lineage-specific transcriptional program to define Tregs and control their suppressive function. Here, we aimed to target activation of disease-specific Tregs by inhibition of the MEK/ERK signaling pathway based on the hypothesis that this would improve anti-HIV and anti-TB immunity. Stimulation of T cells from untreated TB (n = 12) and HIV (n = 8) patients with disease-specific antigens in vitro in the presence of the MEK inhibitor (MEKI) trametinib (GSK1120212) resulted in significant down-regulation of both FoxP3 levels (MFI) and fractions of resting (CD45RA+FoxP3+) and activated (CD45RA−FoxP3++) Tregs. MEKI also reduced the levels of specific T effector cells expressing the pro-inflammatory cytokines (IFN-γ, TNF-α and IL-2) in both HIV and TB patients. In conclusion, MEKIs modulate disease antigen-specific Treg activation and may have potential application in new treatment strategies in chronic infectious diseases where reduction of Treg activity would be favorable. Whether MEKIs can be used in current HIV or TB therapy regimens needs to be further investigated. PMID:26544592

  13. Targeting Tuberculosis and HIV Infection-Specific Regulatory T Cells with MEK/ERK Signaling Pathway Inhibitors.

    Directory of Open Access Journals (Sweden)

    Nora V Lieske

    Full Text Available Human regulatory T cells (Tregs are essential in maintaining immunological tolerance and suppress effector T cells. Tregs are commonly up-regulated in chronic infectious diseases such as tuberculosis (TB and human immunodeficiency virus (HIV infection and thereby hamper disease-specific immune responses and eradication of pathogens. The MEK/ERK signaling pathway is involved in regulation of the FoxP3 transcription factor, which directs a lineage-specific transcriptional program to define Tregs and control their suppressive function. Here, we aimed to target activation of disease-specific Tregs by inhibition of the MEK/ERK signaling pathway based on the hypothesis that this would improve anti-HIV and anti-TB immunity. Stimulation of T cells from untreated TB (n = 12 and HIV (n = 8 patients with disease-specific antigens in vitro in the presence of the MEK inhibitor (MEKI trametinib (GSK1120212 resulted in significant down-regulation of both FoxP3 levels (MFI and fractions of resting (CD45RA+FoxP3+ and activated (CD45RA-FoxP3++ Tregs. MEKI also reduced the levels of specific T effector cells expressing the pro-inflammatory cytokines (IFN-γ, TNF-α and IL-2 in both HIV and TB patients. In conclusion, MEKIs modulate disease antigen-specific Treg activation and may have potential application in new treatment strategies in chronic infectious diseases where reduction of Treg activity would be favorable. Whether MEKIs can be used in current HIV or TB therapy regimens needs to be further investigated.

  14. Matrine induces the apoptosis of lung cancer cells through downregulation of inhibitor of apoptosis proteins and the Akt signaling pathway.

    Science.gov (United States)

    Niu, Huiyan; Zhang, Yifei; Wu, Baogang; Zhang, Yi; Jiang, Hongfang; He, Ping

    2014-09-01

    Lung cancer is the leading cause of cancer‑related mortality in humans. The prognosis for advanced lung cancer patients is extremely poor. Current standard care is rather ineffective for prolonging patient life while preserving satisfactory quality of life due to adverse side-effects. Matrine extracted from the traditional Chinese herbal plant Sophora flavescens was shown to induce cancer cell death in vitro. The aim of this study was to investigate the effect of matrine on the proliferation and apoptosis of lung cancer cells and the molecular basis of matrine-induced apoptosis. The results showed that matrine inhibited cell proliferation and induced apoptosis in lung cancer A549 and 95D cells in a dose- and time-dependent manner. The apoptotic effects of matrine on lung cancer cells appeared to act via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathway and downregulation of the expression of the inhibitor of apoptosis protein (IAP) family proteins. Matrine exerts its cancer-killing effect via promoting apoptosis in lung cancer cells and may be a useful adjuvant therapeutic scheme for treating advanced lung cancer patients.

  15. MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors

    Directory of Open Access Journals (Sweden)

    Brian Shuch

    2015-01-01

    Full Text Available Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available. Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P=0.1. MET expression weakly correlated between primary and matched metastatic sites (R=0.5 and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P=0.39. Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents.

  16. Computational drugs repositioning identifies inhibitors of oncogenic PI3K/AKT/P70S6K-dependent pathways among FDA-approved compounds

    Science.gov (United States)

    Carrella, Diego; Manni, Isabella; Tumaini, Barbara; Dattilo, Rosanna; Papaccio, Federica; Mutarelli, Margherita; Sirci, Francesco; Amoreo, Carla A.; Mottolese, Marcella; Iezzi, Manuela; Ciolli, Laura; Aria, Valentina; Bosotti, Roberta; Isacchi, Antonella; Loreni, Fabrizio; Bardelli, Alberto; Avvedimento, Vittorio E.; di Bernardo, Diego; Cardone, Luca

    2016-01-01

    The discovery of inhibitors for oncogenic signalling pathways remains a key focus in modern oncology, based on personalized and targeted therapeutics. Computational drug repurposing via the analysis of FDA-approved drug network is becoming a very effective approach to identify therapeutic opportunities in cancer and other human diseases. Given that gene expression signatures can be associated with specific oncogenic mutations, we tested whether a “reverse” oncogene-specific signature might assist in the computational repositioning of inhibitors of oncogenic pathways. As a proof of principle, we focused on oncogenic PI3K-dependent signalling, a molecular pathway frequently driving cancer progression as well as raising resistance to anticancer-targeted therapies. We show that implementation of “reverse” oncogenic PI3K-dependent transcriptional signatures combined with interrogation of drug networks identified inhibitors of PI3K-dependent signalling among FDA-approved compounds. This led to repositioning of Niclosamide (Niclo) and Pyrvinium Pamoate (PP), two anthelmintic drugs, as inhibitors of oncogenic PI3K-dependent signalling. Niclo inhibited phosphorylation of P70S6K, while PP inhibited phosphorylation of AKT and P70S6K, which are downstream targets of PI3K. Anthelmintics inhibited oncogenic PI3K-dependent gene expression and showed a cytostatic effect in vitro and in mouse mammary gland. Lastly, PP inhibited the growth of breast cancer cells harbouring PI3K mutations. Our data indicate that drug repositioning by network analysis of oncogene-specific transcriptional signatures is an efficient strategy for identifying oncogenic pathway inhibitors among FDA-approved compounds. We propose that PP and Niclo should be further investigated as potential therapeutics for the treatment of tumors or diseases carrying the constitutive activation of the PI3K/P70S6K signalling axis. PMID:27542212

  17. DMPD: Ubiquitin: tool and target for intracellular NF-kappaB inhibitors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16982211 Ubiquitin: tool and target for intracellular NF-kappaB inhibitors. Wullaer...vg) (.html) (.csml) Show Ubiquitin: tool and target for intracellular NF-kappaB inhibitors. PubmedID 16982211 Title Ubiquitin: tool

  18. The phosphatidylinositol 3-kinases (PI3K) inhibitor GS-1101 synergistically potentiates histone deacetylase inhibitor-induced proliferation inhibition and apoptosis through the inactivation of PI3K and extracellular signal-regulated kinase pathways.

    Science.gov (United States)

    Bodo, Juraj; Zhao, Xiaoxian; Sharma, Arishya; Hill, Brian T; Portell, Craig A; Lannutti, Brian J; Almasan, Alexandru; Hsi, Eric D

    2013-10-01

    Previously, we showed that inhibition of the protein kinase C β (PKCβ)/AKT pathway augments engagement of the histone deacetylase inhibitor (HDI)-induced apoptosis in lymphoma cells. In the present study, we investigated the cytotoxicity and mechanisms of cell death induced by the delta isoform-specific phosphatidylinositide 3-kinase (PI3K) inhibitor, GS-1101, in combination with the HDI, panobinostat (LBH589) and suberoylanilide hydroxamic acid (SAHA). Lymphoma cell lines, primary non-Hodgkin Lymphoma (NHL) and chronic lymphocytic leukaemia (CLL) cells were simultaneously treated with the HDI, LBH589 and GS-1101. An interaction of the LBH589/GS-1101 combination was formally examined by using various concentrations of LBH589 and GS-1101. Combined treatment resulted in a synergistic inhibition of proliferation and showed synergistic effect on apoptotic induction in all tested cell lines and primary NHL and CLL cells. This study indicates that interference with PI3K signalling dramatically increases HDI-mediated apoptosis in malignant haematopoietic cells, possibly through both AKT-dependent or AKT- independent mechanisms. Moreover, the increase in HDI-related apoptosis observed in PI3K inhibitor-treated cells appears to be related to the disruption of the extracellular signal-regulated kinase (ERK) signalling pathway. This study provides a strong rational for testing the combination of PI3K inhibitors and HDI in the clinic.

  19. Evaluation of Macrocytic Anemias.

    Science.gov (United States)

    Green, Ralph; Dwyre, Denis M

    2015-10-01

    Macrocytic anemia, defined as a mean cell volume (MCV) ≥100 fL in adults, has a narrow differential diagnosis that requires evaluation of the peripheral blood smear as well as additional laboratory testing taken in conjunction with clinical information that includes patient history and physical examination findings. This review is an update on the approach to a patient with macrocytic anemia with attention paid to the differentiation of megaloblastic and non-megaloblastic macrocytic anemias. Critical to the determination of the diagnosis is the judicious use of laboratory testing and the evaluation of those findings in conjunction with the patient medical, surgical, and medication history.

  20. What Is Anemia?

    Science.gov (United States)

    ... Treatment will depend on the cause of the anemia and how severe it is. Rate This Content: NEXT >> Updated: May 18, 2012 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA NO FEAR ACT OIG ...

  1. What Causes Aplastic Anemia?

    Science.gov (United States)

    ... blood and bone marrow diseases, such as aplastic anemia. // Non Object? Updated: August 22, 2012 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA NO FEAR ACT OIG ...

  2. Living with Fanconi Anemia

    Science.gov (United States)

    ... from the NHLBI on Twitter. Living With Fanconi Anemia Improvements in blood and marrow stem cell transplants ... November 1, 2011 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA NO FEAR ACT OIG ...

  3. Living with Aplastic Anemia

    Science.gov (United States)

    ... blood and bone marrow diseases, such as aplastic anemia. // Non Object? Updated: August 22, 2012 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA NO FEAR ACT OIG ...

  4. How Is Anemia Treated?

    Science.gov (United States)

    ... such as beef or liver), as well as chicken, turkey, pork, fish, and shellfish. Nonmeat foods that ... cause of anemia. Some of these medicines include: Antibiotics to treat infections. Hormones to treat heavy menstrual ...

  5. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... chest pain, and other symptoms. Severe iron-deficiency anemia can lead to heart problems, infections, problems with growth and development in children, and other complications. Infants and young children and ...

  6. Equine Infectious Anemia

    OpenAIRE

    Hoopes, Karl H.

    2017-01-01

    This fact sheet gives information on equine infectious anemia, a blood-borne infectious viral disease of horses, donkeys, and mules. It describes transmission, clinical disease, diagnosis and control.

  7. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... CAUSES WHO IS AT RISK SIGNS & SYMPTOMS DIAGNOSIS TREATMENTS PREVENTION LIVING WITH CLINICAL TRIALS LINKS Related Topics ... Doctors usually can successfully treat iron-deficiency anemia. Treatment will depend on the cause and severity of ...

  8. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... Digg. Share this page from the NHLBI on Facebook. Add this link to the NHLBI to my ... Deficiency Anemia article. Updated: March 26, 2014 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA ...

  9. Targeting Vascular Endothelial Growth Factor Receptor 2 and Protein Kinase D1 Related Pathways by a Multiple Kinase Inhibitor in Angiogenesis and Inflammation Related Processes In Vitro

    OpenAIRE

    Attila Varga; Pál Gyulavári; Zoltán Greff; Krisztina Futosi; Tamás Németh; Laura Simon-Szabó; Krisztina Kerekes; Csaba Szántai-Kis; Diána Brauswetter; Márton Kokas; Gábor Borbély; Anna Erdei; Attila Mócsai; György Kéri; Tibor Vántus

    2015-01-01

    Emerging evidence suggests that the vascular endothelial growth factor receptor 2 (VEGFR2) and protein kinase D1 (PKD1) signaling axis plays a critical role in normal and pathological angiogenesis and inflammation related processes. Despite all efforts, the currently available therapeutic interventions are limited. Prior studies have also proved that a multiple target inhibitor can be more efficient compared to a single target one. Therefore, development of novel inflammatory pathway-specific...

  10. New functional assays to selectively quantify the activated protein C- and tissue factor pathway inhibitor-cofactor activities of protein S in plasma.

    Science.gov (United States)

    Alshaikh, N A; Rosing, J; Thomassen, M C L G D; Castoldi, E; Simioni, P; Hackeng, T M

    2017-02-17

    Essentials Protein S is a cofactor of activated protein C (APC) and tissue factor pathway inhibitor (TFPI). There are no assays to quantify separate APC and TFPI cofactor activities of protein S in plasma. We developed assays to measure the APC- and TFPI-cofactor activities of protein S in plasma. The assays were sensitive to protein S deficiency, and not affected by the Factor V Leiden mutation.

  11. NL-103, a novel dual-targeted inhibitor of histone deacetylases and hedgehog pathway, effectively overcomes vismodegib resistance conferred by Smo mutations

    OpenAIRE

    Zhao, Jie; Quan, Haitian; Xie, Chengying; Lou, Liguang

    2014-01-01

    Misregulation of hedgehog (Hh) signaling has been implicated in the pathogenesis of basal cell carcinoma (BCC) and medulloblastoma. Vismodegib, an orally bioavailable Hh signal pathway inhibitor targeting Smo, has been approved for the treatment of advanced BCC. However, acquired drug resistance to vismodegib induced by point mutation in Smo is emerging as a major problem to vismodegib treatment. In this study, we designed and synthesized a novel chimeric compound NL-103, which comprises stru...

  12. Dequalinium induces cytotoxicity in human leukemia NB4 cells by downregulation of Raf/MEK/ERK and PI3K/Akt signaling pathways and potentiation of specific inhibitors of these pathways.

    Science.gov (United States)

    García-Pérez, Ana I; Galeano, Eva; Nieto, Elena; Estañ, M Cristina; Sancho, Pilar

    2014-07-01

    Delocalized lipophilic cation dequalinium (DQA) selectively accumulates in mitochondria and displays anticancer activity in different malignancies. Our previous studies indicate a DQA-induced cytotoxicity in human acute promyelocytic leukemia NB4 cells by early disturbance in mitochondrial function and oxidative stress. This study shows the ability of DQA to downregulate Raf/MEK/ERK1/2 and PI3K/Akt signaling pathways in NB4 cells which leads to cell death by apoptosis and/or necrosis. Moreover, DQA potentiates the action of specific inhibitors of these pathways. These DQA effects could be mediated by redox regulation of Akt. Our results contribute to a better understanding of the cytotoxic DQA mechanism on leukemia cells and encourage the performance of further studies in combination with other agents such as kinase inhibitors for improving the efficacy of therapies against acute promyelocytic leukemia.

  13. Efficacy of unfractionated heparin, low molecular weight heparin and both combined for releasing total and free tissue factor pathway inhibitor.

    Science.gov (United States)

    Altman, R; Scazziota, A; Rouvier, J

    1998-01-01

    Unfractionated heparin (UFH) exerts its anticoagulant properties by increasing the inactivation of thrombin and activated factor X by antithrombin III. Apart from this main action release of tissue factor pathway inhibitor (TFPI) from endothelial cells could also be important for the antithrombotic activity of heparins. Four different heparin preparations were injected subcutaneously into 5 healthy volunteers 1 week apart: (1) UFH 2,500 IU fix dose (FixUFH), (2) 1 mg/kg body weight of low molecular weight heparin (LMWH), (3) the combined LMWH-adjusted dose plus UFH 2,500 IU fix dose (ComHep) and (4) UFH 2,500 IU/10 kg body weight (UFHvar). Plasma samples were drawn before and 1, 2, 4, 6, 12 and 24 h afterwards. FixUFH did not affect the concentration of total and free TFPI. Total TFPI increased in the 1st hour after LMWH injection from 74 to 124 ng/ml (p < 0.01), after ComHep from 82 to 144 ng/ml (p < 0.01), and after UFHvar from 91 to 113 ng/ml (p < 0.05). All observed elevations were significant at the peak value (+/- 2 h, p < 0.01 compared with baselines). The increase of free TFPI produced by UFHvar (74.5 and 70.5 ng/ml) was significantly higher than with LMWH (42.8 and 38.0 ng/ml) at 2 and 4 h (p < 0.001 and p < 0.01, respectively). UFHvar and ComHep but not LMWH produced a statistically significant increase of free TFPI compared with FixUFH at 2, 4 and 6 h (p < 0. 01). We concluded that at comparable therapeutic doses, subcutaneous UFHvar released more free TFPI than LMWH and ComHep. A synergism between LMWH and low dose of UFH was found in 4-, 6- and 12-hour blood samples.

  14. [New insights on hepcidin in anemia of chronic disease].

    Science.gov (United States)

    Wang, Feng-Dan; Zhou, Dao-Bin

    2009-12-01

    Anemia of chronic disease is normocytic and normochromic. One of the mechanisms is misbalance of iron metabolism. Hepcidin, a kind of protein secreted by liver is considered to be the hormone regulating iron metabolism. It binds to ferroportin and induces the latter one's internalization. Thus, iron transportation from iron storage cells to serum is reduced. Cytokines are elevated in chronic disease. They stimulate hepcidin expression in liver through JAK2/STAT3 pathway. As a result, iron absorption and reabsorption is blocked, which leads to the misbalance of iron metabolism in anemia of chronic disease. In this article, the hepcidin and its relation to iron metabolism and anemia in chronic disease are reviewed.

  15. Nutritional anemia and AIDS

    OpenAIRE

    Ruíz, Óscar; Instituto de Investigaciones Clínicas, UNMSM; Díaz, David; Instituto de Investigaciones Clínicas, Facultad de Medicina, UNMSM, y Hospital Nacional Dos de Mayo; Castillo, Óscar; Instituto de Investigaciones Clínicas, UNMSM; Reyes, Rafael; Instituto de Investigaciones Clínicas, UNMSM; Marangoni, Manuela; Programa PROCETSS, Hospital Nacional Dos de Mayo; Ronceros, Gerardo; Instituto de Investigaciones Clínicas, Facultad de Medicina, UNMSM

    2013-01-01

    Objectives: To determine the type of anemia most frequent in patients with AIDS and the various degrees of anemia. Material and methods: One hundred patients 18 to 60 year-old infected with human immune deficiency virus (HIV) with residence in Lima and Callao were studied from January to December 2001 for blood count bone marrow aspiration, serum iron, transferrin, ferritin, folate and vitamin B12 levels. Samples were evaluated at the “Dos de Mayo” Hospital Clinical Pathology Department. Resu...

  16. Use of enzyme inhibitors to evaluate the conversion pathways of ester and amide prodrugs: a case study example with the prodrug ceftobiprole medocaril.

    Science.gov (United States)

    Eichenbaum, Gary; Skibbe, Jennifer; Parkinson, Andrew; Johnson, Mark D; Baumgardner, Dawn; Ogilvie, Brian; Usuki, Etsuko; Tonelli, Fred; Holsapple, Jeff; Schmitt-Hoffmann, Anne

    2012-03-01

    An approach was developed that uses enzyme inhibitors to support the assessment of the pathways that are responsible for the conversion of intravenously administered ester and amide prodrugs in different biological matrices. The methodology was applied to ceftobiprole medocaril (BAL5788), the prodrug of the cephalosporin antibiotic, ceftobiprole. The prodrug was incubated in plasma, postmitochondrial supernatant fractions from human liver (impaired and nonimpaired), kidney, and intestine as well as erythrocytes, in the presence and absence of different enzyme inhibitors (acetylcholinesterase, pseudocholinesterase, retinyl palmitoyl hydrolase, serine esterases, amidases, and cholinesterase). Hydrolysis was rapid, extensive, and not dependent on the presence of β-nicotinamide-adenine dinucleotide phosphate (reduced form) in all matrices tested, suggesting the involvement of carboxylesterases but not P450 enzymes. Hydrolysis in healthy human plasma was rapid and complete and only partially inhibited in the presence of paraoxonase inhibitors or in liver from hepatic impaired patients, suggesting involvement of nonparaoxonase pathways. The results demonstrate the utility of this approach in confirming the presence of multiple conversion pathways of intravenously administered prodrugs and in the case of BAL5788 demonstrated that this prodrug is unlikely to be affected by genetic polymorphisms, drug interactions, or other environmental factors that might inhibit or induce the enzymes involved in its conversion.

  17. Megaloblastic anemia in Japan

    Directory of Open Access Journals (Sweden)

    Taguchi,Hirokuni

    1978-08-01

    Full Text Available Since 1903, 744 cases of megaloblastic anemia have been reported in Japan: 490 cases of pernicious anemia; 95 cases associated with pregnancy; 66 cases after gastrectomy; 22 cases of megaloblastic anemia of infants; 21 cases of folic acid deficiency other than pregnancy and 19 cases of vitamin B12 malabsorption after ileal resection. It is generally agreed among hematologists in Japan that pernicious anemia is relatively rare, as in other Asian countries. The diagnosis of pernicious anemia in Japan is usually made by stained marrow films, radioisotopic assay of serum vitamin B12, Schilling test and good response to vitamin B12 therapy. Serum folate level, intrinsic factor or its antibody, methylmalonic acid excretion, formiminoglutamic acid excretion and deoxyuridine suppression test are performed only at a small number of laboratories. The drugs of choice are hydroxocobalamin, deoxyadenosylcobalamin and methylcobalamin. Cyanocobalamin has nearly disappeared from commercial sources in Japan. Vitamin B12 administration is common in patients with neurological disorders. Megaloblastic anemia due to folic acid deficiency is extremely rare in Japan. Low serum folate levels are frequently observed among patients receiving anticonvulsants or in pregnant women, but in such samples megaloblastic anemia is almost never detected. The folic acid content of hospital diets indicates that satisfactory amounts of folate are taken in Japan. The intake of folic acid from rice is well over the minimum daily requirement of folate. Other factors in folic acid deficiency, such as food taboos, severe alcoholism and malabsorption syndrome are not frequently found in Japanese. The inadequate intake of folate was the critical factor in most reported cases.

  18. Responsiveness to PI3K and MEK inhibitors in breast cancer. Use of a 3D culture system to study pathways related to hormone independence in mice.

    Directory of Open Access Journals (Sweden)

    Maria Laura Polo

    Full Text Available BACKGROUND: A significant proportion of breast cancer patients face failure of endocrine therapy due to the acquisition of endocrine resistance. We have explored mechanisms involved in such disease progression by using a mouse breast cancer model that is induced by medroxyprogesterone acetate (MPA. These tumors transit through different stages of hormone sensitivity. However, when cells from tumor variants were seeded on plastic, all were stimulated by progestins and inhibited by antiprogestins such as RU486. Furthermore, cells from a RU486-resistant tumor variant recovered antiprogestin sensitivity. HYPOTHESIS: A three-dimensional (3D culture system, by maintaining differential cellular organization that is typical of each tumor variant, may allow for the maintenance of particular hormone responses and thus be appropriate for the study of the effects of specific inhibitors of signaling pathways associated with disease progression. METHOD: We compared the behavior of tumors growing in vivo and cancer cells ex vivo (in 3D Matrigel. In this system, we evaluated the effects of kinase inhibitors and hormone antagonists on tumor growth. PRINCIPAL FINDINGS: LY294002, a PI3K/AKT pathway inhibitor, decreased both tumor growth in vivo and cell survival in Matrigel in MPA-independent tumors with higher AKT activity. Induction of cell death by anti-hormones such as ICI182780 and ZK230211 was more effective in MPA-dependent tumors with lower AKT activity. Inhibition of MEK with PD98059 did not affect tumor growth in any tested variant. Finally, while Matrigel reproduced differential responsiveness of MPA-dependent and -independent breast cancer cells, it was not sufficient to preserve antiprogestin resistance of RU486-resistant tumors. CONCLUSION: We demonstrated that the PI3K/AKT pathway is relevant for MPA-independent tumor growth. Three-dimensional cultures were useful to test the effects of kinase inhibitors on breast cancer growth and highlight the

  19. A critical role for mTORC1 in erythropoiesis and anemia.

    Science.gov (United States)

    Knight, Zachary A; Schmidt, Sarah F; Birsoy, Kivanc; Tan, Keith; Friedman, Jeffrey M

    2014-09-08

    Red blood cells (RBC) must coordinate their rate of growth and proliferation with the availability of nutrients, such as iron, but the signaling mechanisms that link the nutritional state to RBC growth are incompletely understood. We performed a screen for cell types that have high levels of signaling through mTORC1, a protein kinase that couples nutrient availability to cell growth. This screen revealed that reticulocytes show high levels of phosphorylated ribosomal protein S6, a downstream target of mTORC1. We found that mTORC1 activity in RBCs is regulated by dietary iron and that genetic activation or inhibition of mTORC1 results in macrocytic or microcytic anemia, respectively. Finally, ATP competitive mTOR inhibitors reduced RBC proliferation and were lethal after treatment with phenylhydrazine, an inducer of hemolysis. These results identify the mTORC1 pathway as a critical regulator of RBC growth and proliferation and establish that perturbations in this pathway result in anemia.

  20. Could Anemia Cause Hearing Loss?

    Science.gov (United States)

    ... https://medlineplus.gov/news/fullstory_162793.html Could Anemia Cause Hearing Loss? Iron deficiency might keep ear ... Hearing loss may be linked to iron deficiency anemia -- a combination of low levels of iron and ...

  1. Aplastic Anemia & MDS International Foundation

    Science.gov (United States)

    ... Menu Donate I'm Like You. "The Aplastic Anemia and MDS International Foundation is helping patients like ... cope with bone marrow failure disease." Diseases Aplastic Anemia Myelodysplastic Syndromes (MDS) Paroxysmal Nocturnal Hemoglobinuria (PNH) Related ...

  2. MPT0B098, a Microtubule Inhibitor, Suppresses JAK2/STAT3 Signaling Pathway through Modulation of SOCS3 Stability in Oral Squamous Cell Carcinoma.

    Directory of Open Access Journals (Sweden)

    Hsuan-Yu Peng

    Full Text Available Microtubule inhibitors have been shown to inhibit Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3 signal transduction pathway in various cancer cells. However, little is known of the mechanism by which the microtubule inhibitors inhibit STAT3 activity. In the present study, we examined the effect of a novel small-molecule microtubule inhibitor, MPT0B098, on STAT3 signaling in oral squamous cell carcinoma (OSCC. Treatment of various OSCC cells with MPT0B098 induced growth inhibition, cell cycle arrest and apoptosis, as well as increased the protein level of SOCS3. The accumulation of SOCS3 protein enhanced its binding to JAK2 and TYK2 which facilitated the ubiquitination and degradation of JAK2 and TYK2, resulting in a loss of STAT3 activity. The inhibition of STAT3 activity led to sensitization of OSCC cells to MPT0B098 cytotoxicity, indicating that STAT3 is a key mediator of drug resistance in oral carcinogenesis. Moreover, the combination of MPT0B098 with the clinical drug cisplatin or 5-FU significantly augmented growth inhibition and apoptosis in OSCC cells. Taken together, our results provide a novel mechanism for the action of MPT0B098 in which the JAK2/STAT3 signaling pathway is suppressed through the modulation of SOCS3 protein level. The findings also provide a promising combinational therapy of MPT0B098 for OSCC.

  3. Compound library screening identified Akt/PKB kinase pathway inhibitors as potential key molecules for the development of new chemotherapeutics against schistosomiasis.

    Science.gov (United States)

    Morel, Marion; Vanderstraete, Mathieu; Cailliau, Katia; Lescuyer, Arlette; Lancelot, Julien; Dissous, Colette

    2014-12-01

    Protein kinases (PKs) are one of the largest protein families in most eukaryotic organisms. These enzymes are involved in the control of cell proliferation, differentiation and metabolism and a large number of the anticancer drugs currently used are directed against PKs. The structure and function of PKs are well conserved throughout evolution. In schistosome parasites, PKs were shown to be involved in essential functions at every stage of the parasite life cycle, making these enzymes promising anti-parasite drug targets. In this study, we tested a panel of commercial inhibitors for various PKs and analyzed their effects on pairing and egg production by schistosomes as well as their toxicity towards schistosomula larvae. Results obtained confirmed the deleterious effect of PK targeting on Schistosoma mansoni physiology and the important function of different tyrosine and serine/threonine kinases in the biology and reproduction of this parasite. They also indicated for the first time that the Protein kinase B (also called Akt) which is a major downstream target of many receptor tyrosine kinases and a central player at the crossroads of signal transduction pathways activated in response to growth factors and insulin, can constitute a novel target for anti-schistosome chemotherapy. Structural and functional studies have shown that SmAkt is a conserved kinase and that its activity can be inhibited by commercially available Akt inhibitors. In treated adult worms, Akt/PKB kinase pathway inhibitors induced profound alterations in pairing and egg laying and they also greatly affected the viability of schistosomula larvae.

  4. Iron refractory iron deficiency anemia

    OpenAIRE

    De Falco, Luigia; Sanchez, Mayka; Silvestri, Laura; Kannengiesser, Caroline; Muckenthaler, Martina U; Iolascon, Achille; Gouya, Laurent; Camaschella, Clara; Beaumont, Carole

    2013-01-01

    Iron refractory iron deficiency anemia is a hereditary recessive anemia due to a defect in the TMPRSS6 gene encoding Matriptase-2. This protein is a transmembrane serine protease that plays an essential role in down-regulating hepcidin, the key regulator of iron homeostasis. Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation and normal/high serum hepcidin values. The anemia appears in the post-natal period, although in some cases it is only diagnosed in ad...

  5. [Autoimmune hemolytic anemia in children].

    Science.gov (United States)

    Becheur, M; Bouslama, B; Slama, H; Toumi, N E H

    2015-01-01

    Autoimmune hemolytic anemia is a rare condition in children which differs from the adult form. It is defined by immune-mediated destruction of red blood cells caused by autoantibodies. Characteristics of the autoantibodies are responsible for the various clinical entities. Classifications of autoimmune hemolytic anemia include warm autoimmune hemolytic anemia, cold autoimmune hemolytic anemia, and paroxysmal cold hemoglobinuria. For each classification, this review discusses the epidemiology, etiology, clinical presentation, laboratory evaluation, and treatment options.

  6. DIAGNOSIS LABORATORIK ANEMIA DEFISIENSI BESI

    OpenAIRE

    Dina Sophia Margina; Sianny Herawati; I W P Sutirta Yasa

    2014-01-01

    Iron deficiency anemia is a decreament of iron level in the body. Iron deficiency anemiais oftenly seen, especially in the tropical countries or the third world country thatassociated with social economic rate. Iron deficiency anemia happens in more than onethird world’s population. Iron deficiency anemia can be caused by chronic hemorrhage,low intake of iron, absorption disturbance, and increasement of demand. To diagnose irondeficiency anemia, laboratoric examination is needed. The treatmen...

  7. Anemia in People with Cancer

    Science.gov (United States)

    ... Managing Cancer-related Side Effects Low Blood Counts Anemia in People With Cancer What is anemia? When you don’t have enough healthy red ... the symptoms that bother people most. What causes anemia? There are many different reasons a person with ...

  8. How Is Fanconi Anemia Diagnosed?

    Science.gov (United States)

    ... from the NHLBI on Twitter. How Is Fanconi Anemia Diagnosed? People who have Fanconi anemia (FA) are born with the disorder. They may ... questions about: Any personal or family history of anemia Any surgeries you’ve had related to the ...

  9. How Is Aplastic Anemia Diagnosed?

    Science.gov (United States)

    ... from the NHLBI on Twitter. How Is Aplastic Anemia Diagnosed? Your doctor will diagnose aplastic anemia based on your medical and family histories, a ... your primary care doctor thinks you have aplastic anemia, he or she may refer you to a ...

  10. Severe Anemia in Malawian Children

    NARCIS (Netherlands)

    Calis, J.C.J.; Kamija, S.P.; Faragher, E.B.; Brabin, B.J.; Bates, I.; Cuevas, L.E.; Haan, de R.J.; Phiri, A.I.; Malange, P.; Khoka, M.; Hulshof, P.J.M.; Lieshout, L.; Beld, M.G.H.M.; Teo, Y.Y.; Rockett, K.A.; Richardson, A.; Kwiatkowski, D.P.; Molyneux, M.E.; Hensbroek, van M.B.

    2008-01-01

    Background Severe anemia is a major cause of sickness and death in African children, yet the causes of anemia in this population have been inadequately studied. Methods We conducted a case¿control study of 381 preschool children with severe anemia (hemoglobin concentration,

  11. Aplastic Anemia and Myelodysplastic Syndromes

    Science.gov (United States)

    ... have aplastic anemia. Most new cases of aplastic anemia in children are due to inherited bone marrow failure syndromes. MDS are typically diagnosed between the ages of 70 and 80 years. Although a cause is not found in most cases of aplastic anemia and MDS, the diseases may be triggered by ...

  12. Genetically engineered fusion of MAP-1 and factor H domains 1-5 generates a potent dual upstream inhibitor of both the lectin and alternative complement pathways.

    Science.gov (United States)

    Nordmaj, Mie Anemone; Munthe-Fog, Lea; Hein, Estrid; Skjoedt, Mikkel-Ole; Garred, Peter

    2015-12-01

    Inhibition of the complement cascade has emerged as an option for treatment of a range of diseases. Mannose-binding lectin/ficolin/collectin-associated protein (MAP-1) is a pattern recognition molecule (PRM)-associated inhibitor of the lectin pathway. The central regulator of the alternative pathway (AP) is complement factor H (FH). Our aim was to design a dual upstream inhibitor of both human lectin and APs by fusing MAP-1 with a part of FH. There were 2 different recombinant chimeric proteins comprising full-length human MAP-1 and the first 5 N-terminal domains of human FH designed. The FH domains were orientated either in the N- or C-terminal part of MAP-1. The complement inhibition potential in human serum was assessed. Both chimeric constructs displayed the characteristics of the native molecules and bound to the PRMs with an EC50 of ∼ 2 nM. However, when added to serum diluted 1:4 in a solid-phase functional assay, only the first 5 N-terminal domains of complement FH fused to the C-terminal part of full-length MAP-1 chimeric construct were able to combine inhibition of lectin and AP activation with an half maximal inhibitory concentration of ∼ 100 and 20 nM, respectively. No effect was seen on the classical pathway. Fusion of MAP-1 with FH domains represents a novel therapeutic approach for selective targeting upstream and central complement activation at sites of inflammation.

  13. Didymin Alleviates Hepatic Fibrosis Through Inhibiting ERK and PI3K/Akt Pathways via Regulation of Raf Kinase Inhibitor Protein

    Directory of Open Access Journals (Sweden)

    Xing Lin

    2016-12-01

    Full Text Available Background: Didymin has been reported to have anti-cancer potential. However, the effect of didymin on liver fibrosis remains illdefined. Methods: Hepatic fibrosis was induced by CCl4 in rats. The effects of didymin on liver pathology and collagen accumulation were observed by hematoxylin-eosin and Masson's trichrome staining, respectively. Serum transaminases activities and collagen-related indicators levels were determined by commercially available kits. Moreover, the effects of didymin on hepatic stellate cell apoptosis and cell cycle were analyzed by flow cytometry. Mitochondrial membrane potential was detected by using rhodamine-123 dye. The expression of Raf kinase inhibitor protein (RKIP and the phosphorylation of the ERK/MAPK and PI3K/Akt pathways were assessed by Western blot. Results: Didymin significantly ameliorated chronic liver injury and collagen deposition. It strongly inhibited hepatic stellate cells proliferation, induced apoptosis and caused cell cycle arrest in G2/M phase. Moreover, didymin notably attenuated mitochondrial membrane potential, accompanied by release of cytochrome C. Didymin significantly inhibited the ERK/MAPK and PI3K/Akt pathways. The effects of didymin on the collagen accumulation in rats and on the biological behaviors of hepatic stellate cells were largely abolished by the specific RKIP inhibitor locostatin. Conclusion: Didymin alleviates hepatic fibrosis by inhibiting ERK/MAPK and PI3K/Akt pathways via regulation of RKIP expression.

  14. Control of Hes7 expression by Tbx6, the Wnt pathway and the chemical Gsk3 inhibitor LiCl in the mouse segmentation clock.

    Directory of Open Access Journals (Sweden)

    Aitor González

    Full Text Available The mouse segmentation is established from somites, which are iteratively induced every two hours from the presomitic mesoderm (PSM by a system known as the segmentation clock. A crucial component of the segmentation clock is the gene Hes7, which is regulated by the Notch and Fgf/Mapk pathways, but its relation to other pathways is unknown. In addition, chemical alteration of the Wnt pathway changes the segmentation clock period but the mechanism is unclear.To clarify these questions, we have carried out Hes7 promoter analysis in transgenic mouse embryos and have identified an essential 400 bp region, which contains binding sites of Tbx6 and the Wnt signaling effector Lef1. We have found that the Hes7 promoter is activated by Tbx6, and normal activity of the Hes7 promoter in the mouse PSM requires Tbx6 binding sites. Our results demonstrate that Wnt pathway molecules activate the Hes7 promoter cooperatively with Tbx6 in cell culture and are necessary for its proper expression in the mouse PSM. Furthermore, it is shown that the chemical Gsk3 inhibitor LiCl lengthens the oscillatory period of Hes7 promoter activity.Our data suggest that Tbx6 and the Wnt pathway cooperatively regulate proper Hes7 expression. Furthermore, proper Hes7 promoter activity and expression is important for the normal pace of oscillation.

  15. JAK2 inhibitor combined with DC-activated AFP-specific T-cells enhances tantitumor function in a Fas/FasL signal-independent pathway

    Directory of Open Access Journals (Sweden)

    Liu Y

    2016-07-01

    Full Text Available Yang Liu,1 Yue-ru Wang,2 Guang-hui Ding,1 Ting-song Yang,1 Le Yao,1 Jie Hua,1 Zhi-gang He,1 Ming-ping Qian1 1Department of Hepatobiliary Surgery, Shanghai 10th People’s Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2Department of Infection, Shanghai First People’s Hospital Affiliated to Jiaotong University, Shanghai, People’s Republic of China Objective: Combination therapy for cancer is more effective than using only standard chemo- or radiotherapy. Our previous results showed that dendritic cell-activated α-fetoprotein (AFP-specific T-cells inhibit tumor in vitro and in vivo. In this study, we focused on antitumor function of CD8+ T-cells combined with or without JAK2 inhibitor. Methods: Proliferation and cell cycle were analyzed by CCK-8 and flow cytometry. Western blot was used to analyze the expression level of related protein and signaling pathway. Results: We demonstrated reduced viability and induction of apoptosis of tumor cells with combination treatment. Intriguingly, cell cycle was blocked at the G1 phase by using AFP-specific CD8+ T-cells combined with JAK2 inhibitor (AG490. Furthermore, an enhanced expression of BAX but no influence on Fas/FasL was detected from the tumor cells. Conclusion: These results indicate a Fas/FasL-independent pathway for cellular apoptosis in cancer therapies with the treatment of AFP-specific CD8+ T-cells combined with JAK2 inhibitor. Keywords: AFP-specific CD8+ T-cells, JAK2 inhibitor, Fas/FasL signal, antitumor, apoptosis 

  16. A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors.

    Science.gov (United States)

    El Meskini, Rajaa; Iacovelli, Anthony J; Kulaga, Alan; Gumprecht, Michelle; Martin, Philip L; Baran, Maureen; Householder, Deborah B; Van Dyke, Terry; Weaver Ohler, Zoë

    2015-01-01

    Current therapies for glioblastoma multiforme (GBM), the highest grade malignant brain tumor, are mostly ineffective, and better preclinical model systems are needed to increase the successful translation of drug discovery efforts into the clinic. Previous work describes a genetically engineered mouse (GEM) model that contains perturbations in the most frequently dysregulated networks in GBM (driven by RB, KRAS and/or PI3K signaling and PTEN) that induce development of Grade IV astrocytoma with properties of the human disease. Here, we developed and characterized an orthotopic mouse model derived from the GEM that retains the features of the GEM model in an immunocompetent background; however, this model is also tractable and efficient for preclinical evaluation of candidate therapeutic regimens. Orthotopic brain tumors are highly proliferative, invasive and vascular, and express histology markers characteristic of human GBM. Primary tumor cells were examined for sensitivity to chemotherapeutics and targeted drugs. PI3K and MAPK pathway inhibitors, when used as single agents, inhibited cell proliferation but did not result in significant apoptosis. However, in combination, these inhibitors resulted in a substantial increase in cell death. Moreover, these findings translated into the in vivo orthotopic model: PI3K or MAPK inhibitor treatment regimens resulted in incomplete pathway suppression and feedback loops, whereas dual treatment delayed tumor growth through increased apoptosis and decreased tumor cell proliferation. Analysis of downstream pathway components revealed a cooperative effect on target downregulation. These concordant results, together with the morphologic similarities to the human GBM disease characteristics of the model, validate it as a new platform for the evaluation of GBM treatment.

  17. Protein and lipid kinase inhibitors as targeted anticancer agents of the Ras/Raf/MEK and PI3K/PKB pathways.

    Science.gov (United States)

    García-Echeverría, Carlos

    2009-03-01

    The identification and characterization of the components of individual signal transduction cascades, and advances in our understanding on how these biological signals are integrated in cancer initiation and progression, have provided new strategies for therapeutic intervention in solid tumors and hematological malignancies. To this end, pharmaceutical efforts have been directed to target different components of the Ras/Raf/MEK and PI3K/PKB pathways. This review article covers recent salient achievements in the identification and development of Raf, MEK, and PI3K inhibitors.

  18. Enhanced cerebrovascular expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 via the MEK/ERK pathway during cerebral ischemia in the rat

    DEFF Research Database (Denmark)

    Maddahi, Aida; Chen, Qingwen; Edvinsson, Lars

    2009-01-01

    microscopy revealed enhanced expression of MMP-9, TIMP-1, and phosphorylated ERK1/2 in the smooth muscle cells of the ischemic MCA and associated intracerebral microvessels. The specific MEK1/2 inhibitor U0126, given intraperitoneal zero or 6 hours after the ischemic event, reduced the infarct volume...... significantly (11.8 +/- 2% and 14.6 +/- 3%, respectively; P ERK1/2, and reduced expression of MMP-9 and TIMP-1 in the vessel walls. Administration of U0126 12 hours after MCAO did not alter the expression of MMP-9......, are transcriptionally regulated via the MEK/ERK pathway....

  19. Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages.

    Science.gov (United States)

    Garbati, Michael R; Hays, Laura E; Rathbun, R Keaney; Jillette, Nathaniel; Chin, Kathy; Al-Dhalimy, Muhsen; Agarwal, Anupriya; Newell, Amy E Hanlon; Olson, Susan B; Bagby, Grover C

    2016-03-01

    The Fanconi anemia proteins participate in a canonical pathway that repairs cross-linking agent-induced DNA damage. Cells with inactivated Fanconi anemia genes are universally hypersensitive to such agents. Fanconi anemia-deficient hematopoietic stem cells are also hypersensitive to inflammatory cytokines, and, as importantly, Fanconi anemia macrophages overproduce such cytokines in response to TLR4 and TLR7/8 agonists. We questioned whether TLR-induced DNA damage is the primary cause of aberrantly regulated cytokine production in Fanconi anemia macrophages by quantifying TLR agonist-induced TNF-α production, DNA strand breaks, crosslinker-induced chromosomal breakage, and Fanconi anemia core complex function in Fanconi anemia complementation group C-deficient human and murine macrophages. Although both M1 and M2 polarized Fanconi anemia cells were predictably hypersensitive to mitomycin C, only M1 macrophages overproduced TNF-α in response to TLR-activating signals. DNA damaging agents alone did not induce TNF-α production in the absence of TLR agonists in wild-type or Fanconi anemia macrophages, and mitomycin C did not enhance TLR responses in either normal or Fanconi anemia cells. TLR4 and TLR7/8 activation induced cytokine overproduction in Fanconi anemia macrophages. Also, although TLR4 activation was associated with induced double strand breaks, TLR7/8 activation was not. That DNA strand breaks and chromosome breaks are neither necessary nor sufficient to account for the overproduction of inflammatory cytokines by Fanconi anemia cells suggests that noncanonical anti-inflammatory functions of Fanconi anemia complementation group C contribute to the aberrant macrophage phenotype and suggests that suppression of macrophage/TLR hyperreactivity might prevent cytokine-induced stem cell attrition in Fanconi anemia.

  20. Prevalence and association of post-renal transplant anemia

    Directory of Open Access Journals (Sweden)

    Hesham Elsayed

    2012-01-01

    Full Text Available In some renal allograft recipients, anemia persists or develops following transplantation. Anemia is associated with pre-operative blood loss and allograft dysfunction, including delayed graft function, acute rejection and chronic allograft dysfunction. To study the prevalence and association of post-renal transplant anemia, we studied 200 renal transplant recipients; 131 (65.5% patients were males and 69 (34.5% patients were females, and age ranged from 17 to 67 years, with a mean of 37.7 ± 10.8 years. All patients were receiving cyclosporine, prednisolone and mycophenolate mofetil (MMF. Complete blood count was done at two times: three and six months post-renal transplant. There were 74% anemic patients three months after renal transplantation and 45% anemic patients six months after renal transplantation. High creatinine value, female gender, delayed graft function, episodes of acute rejection, perioperative blood loss and infections were the only significant independent risk factors for prevalence of anemia post-renal transplant. In our study, we did not find an association between MMF and cyclosporine nor angiotensin-converting enzyme inhibitors (ACEIs or angiotensin receptors blocker (ARBs with anemia. This study demonstrates that anemia is a common complication during the first six months after kidney transplantation, with several risk factors precipitating this complication.

  1. Evaluation of anemia in children.

    Science.gov (United States)

    Janus, Jennifer; Moerschel, Sarah K

    2010-06-15

    Anemia is defined as a hemoglobin level of less than the 5th percentile for age. Causes vary by age. Most children with anemia are asymptomatic, and the condition is detected on screening laboratory evaluation. Screening is recommended only for high-risk children. Anemia is classified as microcytic, normocytic, or macrocytic, based on the mean corpuscular volume. Mild microcytic anemia may be treated presumptively with oral iron therapy in children six to 36 months of age who have risk factors for iron deficiency anemia. If the anemia is severe or is unresponsive to iron therapy, the patient should be evaluated for gastrointestinal blood loss. Other tests used in the evaluation of microcytic anemia include serum iron studies, lead levels, and hemoglobin electrophoresis. Normocytic anemia may be caused by chronic disease, hemolysis, or bone marrow disorders. Workup of normocytic anemia is based on bone marrow function as determined by the reticulocyte count. If the reticulocyte count is elevated, the patient should be evaluated for blood loss or hemolysis. A low reticulocyte count suggests aplasia or a bone marrow disorder. Common tests used in the evaluation of macrocytic anemias include vitamin B12 and folate levels, and thyroid function testing. A peripheral smear can provide additional information in patients with anemia of any morphology.

  2. Sickle Cell Anemia Bibliography.

    Science.gov (United States)

    Christy, Steven C.

    Presents sources for the acquisition of medical, social, psychological, educational, and practical knowledge of sickle cell anemia. The materials listed are designed to help parents, educators, and public service workers. Materials include journal articles, films, brochures, slides, and fact sheets. The usual bibliographic information is given.…

  3. Anemia and School Participation

    Science.gov (United States)

    Bobonis, Gustavo J.; Miguel, Edward; Puri-Sharma, Charu

    2006-01-01

    Anemia is among the most widespread health problems for children in developing countries. This paper evaluates the impact of a randomized health intervention delivering iron supplementation and deworming drugs to Indian preschool children. At baseline, 69 percent were anemic and 30 percent had intestinal worm infections. Weight increased among…

  4. Iron-Deficiency Anemia

    Medline Plus

    Full Text Available ... a lower than normal number of red blood cells. Red blood cells carry oxygen and remove carbon dioxide (a waste ... Anemia also can occur if your red blood cells don't contain enough hemoglobin (HEE-muh-glow- ...

  5. Twin anemia polycythemia sequence

    NARCIS (Netherlands)

    Slaghekke, Femke

    2014-01-01

    In this thesis we describe that Twin Anemia Polycythemia Sequence (TAPS) is a form of chronic feto-fetal transfusion in monochorionic (identical) twins based on a small amount of blood transfusion through very small anastomoses. For the antenatal diagnosis of TAPS, Middle Cerebral Artery – Peak Syst

  6. Anemia (For Parents)

    Science.gov (United States)

    ... rich foods to a child's diet or reducing milk intake. If your teenage daughter is anemic and has heavy or irregular menstrual periods, the doctor may prescribe hormonal treatment to help regulate the bleeding. Folic acid and vitamin B12 supplements may be recommended for anemia due to ...

  7. Sickle cell anemia

    Science.gov (United States)

    ... Anemia - sickle cell; Hemoglobin SS disease (Hb SS); Sickle cell disease Images Red blood cells, sickle cell Red blood cells, normal Red blood ... multiple sickle cells Red blood cells, sickle cells Red blood cells, sickle and ... Heeney MM, Ware RE. Sickle cell disease. In: Orkin SH, Fisher DE, Ginsburg D, Look ...

  8. Autoimmune Hemolytic Anemia.

    Science.gov (United States)

    Liebman, Howard A; Weitz, Ilene C

    2017-03-01

    Autoimmune hemolytic anemia is an acquired autoimmune disorder resulting in the production of antibodies directed against red blood cell antigens causing shortened erythrocyte survival. The disorders can present as a primary disorder (idiopathic) or secondary to other autoimmune disorders, malignancies, or infections. Treatment involves immune modulation with corticosteroids and other agents.

  9. Multidisciplinary approach to anemia

    Directory of Open Access Journals (Sweden)

    Anca Ghiațău

    2015-08-01

    Full Text Available Introduction: We present the case of a 65 years- old woman who was admitted with a severe macrocytic anemia Hb= 5.7g/dl and diffuse bone pain. Biologically she has moderate thrombocytopenia 35 000/µl, a hepatic cytolysis and cholestatic syndrome. Material and method: The patient was extensively evaluated before presentation for a mild iron - deficiency anemia for which she underwent endoscopic examination of the upper and lower gastrointestinal tract- normal. The bone marrow aspiration on admission revealed a marked hyperplasia of the erythroblastic line with ~50% basophilic erythroblasts suggesting a regenerative erythroid hyperplasia. These changes along with the marked reticulocytosis on the peripheral blood smear oriented us towards a hemolytic anemia; Folic acid, vitamin B12, autoimmune tests and hemolytic tests were all normal. We continued the investigations with a thoraco-abdominopelvic computed tomography which identified diffuse demineralization, vertebral compactation and pelvic stress fractures. The breast examination revealed a right breast nodule, but the breast ultrasonography pleaded for benignity. Lacking a clear definitive diagnosis we decided to perform a bone marrow biopsy. Results: The osteo- medullary biopsy pointed towards a medullar invasion from a lobular mammary carcinoma; In these circumstances we performed an ultrasound guided biopsy of the right mammary lump thus histologically confirming a tumoral invasion of the bone marrow with subsequent anemia. The patient started chemotherapy in the Oncology ward. Conclusion: The particularity of this case consists in the pattern of anemia, which initially seemed iron deficient and afterwards macrocytic – apparently hemolytic and was actually due to the tumoral medullar invasion and also the nonspecific ultrasonographic appearance of the breast tumor.

  10. Derivation and evaluation of adverse outcome pathways for the effects of cyclooxygenase inhibitors on reproductive processes in fish

    Science.gov (United States)

    Cyclooxygenase (COX) inhibition is of concern in fish because COX inhibitors (e.g., ibuprofen) are ubiquitous in aquatic systems/fish tissues, and can disrupt synthesis of prostaglandins that modulate a variety of essential biological functions (e.g., reproduction). This study ut...

  11. Tissue Factor Pathway Inhibitor-1 Is a Valuable Marker for the Prediction of Deep Venous Thrombosis and Tumor Metastasis in Patients with Lung Cancer

    Science.gov (United States)

    Yuan, Wufeng

    2017-01-01

    Activation of blood coagulation contributes to cancer progression. Tissue factor pathway inhibitor-1 (TFPI-1) is the main inhibitor of extrinsic coagulation pathway. The aim of this study is to assess the predicting significance of TFPI-1 for thrombotic complication and metastasis in lung cancer patients. Total of 188 non-small cell lung cancer (NSCLC) patients were included in this study. Plasma TFPI-1, D-dimer (D-D), antithrombin (AT), Fibrinogen (Fbg), and coagulating factor VIII activity (FVIII:C) were measured. In NSCLC patients, significantly decreased TFPI-1 and AT and increased D-D, Fbg, and FVIII:C levels were observed, and there was a significant correlation between TFPI-1 and other hemostatic parameters (P metastasis had significantly lower TFPI-1 levels than those without DVT or metastasis (P metastasis in NSCLC patients [OR: 4.15 or 3.28, P metastasis (P metastasis, respectively. Combination of TFPI-1 and D-D measurements can improve the predicting power for DVT or metastasis in NSCLC patients. Our findings suggested that TFPI-1 was a valuable predictor of DVT and tumor metastasis in NSCLC patients.

  12. A diacylglycerol kinase inhibitor, R59022, stimulates glucose transport through a MKK3/6-p38 signaling pathway in skeletal muscle cells.

    Science.gov (United States)

    Takahashi, Nobuhiko; Nagamine, Miho; Tanno, Satoshi; Motomura, Wataru; Kohgo, Yutaka; Okumura, Toshikatsu

    2007-08-17

    Diacylglycerol kinase (DGK) is one of lipid-regulating enzymes, catalyzes phosphorylation of diacylglycerol to phosphatidic acid. Because skeletal muscle, a major insulin-target organ for glucose disposal, expresses DGK, we investigated in the present study a role of DGK on glucose transport in skeletal muscle cells. PCR study showed that C2C12 myotubes expressed DGKalpha, delta, epsilon, zeta, or theta isoform mRNA. R59022, a specific inhibitor of DGK, significantly increased glucose transport, p38 and MKK3/6 activation in C2C12 myotubes. The R59022-induced glucose transport was blocked by SB203580, a specific p38 inhibitor. In contrast, R59022 failed to stimulate both possible known mechanisms to enhance glucose transport, an IRS1-PI3K-Akt pathway, muscle contraction signaling or GLUT1 and 4 expression. All these results suggest that DGK may play a role in glucose transport in the skeletal muscle cells through modulating a MKK3/6-p38 signaling pathway.

  13. AT-101, a small molecule inhibitor of anti-apoptotic Bcl-2 family members, activates the SAPK/JNK pathway and enhances radiation-induced apoptosis

    Directory of Open Access Journals (Sweden)

    Rooswinkel Rogier

    2009-10-01

    Full Text Available Abstract Background Gossypol, a naturally occurring polyphenolic compound has been identified as a small molecule inhibitor of anti-apoptotic Bcl-2 family proteins. It induces apoptosis in a wide range of tumor cell lines and enhances chemotherapy- and radiation-induced cytotoxicity both in vitro and in vivo. Bcl-2 and related proteins are important inhibitors of apoptosis and frequently overexpressed in human tumors. Increased levels of these proteins confer radio- and chemoresistance and may be associated with poor prognosis. Consequently, inhibition of the anti-apoptotic functions of Bcl-2 family members represents a promising strategy to overcome resistance to anticancer therapies. Methods We tested the effect of (--gossypol, also denominated as AT-101, radiation and the combination of both on apoptosis induction in human leukemic cells, Jurkat T and U937. Because activation of the SAPK/JNK pathway is important for apoptosis induction by many different stress stimuli, and Bcl-XL is known to inhibit activation of SAPK/JNK, we also investigated the role of this signaling cascade in AT-101-induced apoptosis using a pharmacologic and genetic approach. Results AT-101 induced apoptosis in a time- and dose-dependent fashion, with ED50 values of 1.9 and 2.4 μM in Jurkat T and U937 cells, respectively. Isobolographic analysis revealed a synergistic interaction between AT-101 and radiation, which also appeared to be sequence-dependent. Like radiation, AT-101 activated SAPK/JNK which was blocked by the kinase inhibitor SP600125. In cells overexpressing a dominant-negative mutant of c-Jun, AT-101-induced apoptosis was significantly reduced. Conclusion Our data show that AT-101 strongly enhances radiation-induced apoptosis in human leukemic cells and indicate a requirement for the SAPK/JNK pathway in AT-101-induced apoptosis. This type of apoptosis modulation may overcome treatment resistance and lead to the development of new effective combination

  14. Compound library screening identified Akt/PKB kinase pathway inhibitors as potential key molecules for the development of new chemotherapeutics against schistosomiasis

    Directory of Open Access Journals (Sweden)

    Marion Morel

    2014-12-01

    Full Text Available Protein kinases (PKs are one of the largest protein families in most eukaryotic organisms. These enzymes are involved in the control of cell proliferation, differentiation and metabolism and a large number of the anticancer drugs currently used are directed against PKs. The structure and function of PKs are well conserved throughout evolution. In schistosome parasites, PKs were shown to be involved in essential functions at every stage of the parasite life cycle, making these enzymes promising anti-parasite drug targets. In this study, we tested a panel of commercial inhibitors for various PKs and analyzed their effects on pairing and egg production by schistosomes as well as their toxicity towards schistosomula larvae. Results obtained confirmed the deleterious effect of PK targeting on Schistosoma mansoni physiology and the important function of different tyrosine and serine/threonine kinases in the biology and reproduction of this parasite. They also indicated for the first time that the Protein kinase B (also called Akt which is a major downstream target of many receptor tyrosine kinases and a central player at the crossroads of signal transduction pathways activated in response to growth factors and insulin, can constitute a novel target for anti-schistosome chemotherapy. Structural and functional studies have shown that SmAkt is a conserved kinase and that its activity can be inhibited by commercially available Akt inhibitors. In treated adult worms, Akt/PKB kinase pathway inhibitors induced profound alterations in pairing and egg laying and they also greatly affected the viability of schistosomula larvae.

  15. Activating the Wnt/β-Catenin Pathway for the Treatment of Melanoma--Application of LY2090314, a Novel Selective Inhibitor of Glycogen Synthase Kinase-3.

    Directory of Open Access Journals (Sweden)

    Jennifer M Atkinson

    Full Text Available It has previously been observed that a loss of β-catenin expression occurs with melanoma progression and that nuclear β-catenin levels are inversely proportional to cellular proliferation, suggesting that activation of the Wnt/β-catenin pathway may provide benefit for melanoma patients. In order to further probe this concept we tested LY2090314, a potent and selective small-molecule inhibitor with activity against GSK3α and GSK3β isoforms. In a panel of melanoma cell lines, nM concentrations of LY2090314 stimulated TCF/LEF TOPFlash reporter activity, stabilized β-catenin and elevated the expression of Axin2, a Wnt responsive gene and marker of pathway activation. Cytotoxicity assays revealed that melanoma cell lines are very sensitive to LY2090314 in vitro (IC50 ~10 nM after 72hr of treatment in contrast to other solid tumor cell lines (IC50 >10 uM as evidenced by caspase activation and PARP cleavage. Cell lines harboring mutant B-RAF or N-RAS were equally sensitive to LY2090314 as were those with acquired resistance to the BRAF inhibitor Vemurafenib. shRNA studies demonstrated that β-catenin stabilization is required for apoptosis following treatment with the GSK3 inhibitor since the sensitivity of melanoma cell lines to LY290314 could be overcome by β-catenin knockdown. We further demonstrate that in vivo, LY2090314 elevates Axin2 gene expression after a single dose and produces tumor growth delay in A375 melanoma xenografts with repeat dosing. The activity of LY2090314 in preclinical models suggests that the role of Wnt activators for the treatment of melanoma should be further explored.

  16. Lessons learned from adult clinical experience to inform evaluations of VEGF pathway inhibitors in children with cancer.

    Science.gov (United States)

    Smith, Malcolm A

    2014-08-01

    Agents targeting the vascular endothelial growth factor (VEGF) pathway have been studied in adults with cancer for nearly two decades. It is important to assess the lessons learned from this adult experience and to see how these lessons can help inform pediatric development of agents in this class. The benefit achieved from the use of VEGF pathway targeted agents for adult cancers has primarily been to delay for several months disease progression and less commonly time to death for conditions in which cure is not a reasonable expectation. VEGF pathway targeted agents have shown no efficacy when applied in the adjuvant setting. For adults with advanced cancer, prolongation of survival by 2-3 months is considered an important achievement in some settings. However, the primary goal of pediatric oncology clinical research is to identify treatments that allow children to be cured of their cancer and to grow to adulthood without treatment-induced limitations that lower their quality of survival. An important question for the pediatric oncology research community, pharmaceutical companies, and regulatory agencies to address in planning for future clinical trials is whether existing data support a role for VEGF pathway targeted agents in contributing to a therapeutic pathway to cure for children with cancer.

  17. [Anemia in the elderly].

    Science.gov (United States)

    Maerevoet, M; Sattar, L; Bron, D; Gulbis, B; Pepersack, T

    2014-09-01

    Anaemia is a problem that affects almost 10% over 65 years and 20% over 85 years. There is no physiological anaemia in the elderly. Any anaemia expresses the existence of a pathological process, regardless of its severity. Anaemia in the elderly is always associated with a poor prognosis that is in terms of mortality, morbidity and risk of fragility. The diagnostic approach to anemia in the elderly is the same as in younger individual. There are many causes of anaemia; anaemia balance is a complex diagnostic process. Most anaemias are due to a deficiency, chronic inflammation or comorbidity. However, in the elderly, the etiology of anaemia is often multifactorial. In a number of cases remain unexplained anaemia. In a number of cases, anemia remain unexplained. Treatment of anaemia is the treatment of the cause, but specific therapeutic aspects to the elderly should be considered, as among other martial substitution or use of erythropoietin (EPO).

  18. Anti-neuroinflammatory efficacy of the aldose reductase inhibitor FMHM via phospholipase C/protein kinase C-dependent NF-κB and MAPK pathways

    Energy Technology Data Exchange (ETDEWEB)

    Zeng, Ke-Wu [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China); Li, Jun [Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029 (China); Dong, Xin; Wang, Ying-Hong; Ma, Zhi-Zhong; Jiang, Yong; Jin, Hong-Wei [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China); Tu, Peng-Fei, E-mail: pengfeitu@vip.163.com [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China); Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029 (China)

    2013-11-15

    Aldose reductase (AR) has a key role in several inflammatory diseases: diabetes, cancer and cardiovascular diseases. Therefore, AR inhibition seems to be a useful strategy for anti-inflammation therapy. In the central nervous system (CNS), microglial over-activation is considered to be a central event in neuroinflammation. However, the effects of AR inhibition in CNS inflammation and its underlying mechanism of action remain unknown. In the present study, we found that FMHM (a naturally derived AR inhibitor from the roots of Polygala tricornis Gagnep.) showed potent anti-neuroinflammatory effects in vivo and in vitro by inhibiting microglial activation and expression of inflammatory mediators. Mechanistic studies showed that FMHM suppressed the activity of AR-dependent phospholipase C/protein kinase C signaling, which further resulted in downstream inactivation of the IκB kinase/IκB/nuclear factor-kappa B (NF-κB) inflammatory pathway. Therefore, AR inhibition-dependent NF-κB inactivation negatively regulated the transcription and expression of various inflammatory genes. AR inhibition by FMHM exerted neuroprotective effects in lipopolysaccharide-induced neuron–microglia co-cultures. These findings suggested that AR is a potential target for neuroinflammation inhibition and that FMHM could be an effective agent for treating or preventing neuroinflammatory diseases. - Highlights: • FMHM is a natural-derived aldose reductase (AR) inhibitor. • FMHM inhibits various neuroinflammatory mediator productions in vitro and in vivo. • FMHM inhibits neuroinflammation via aldose reductase/PLC/PKC-dependent NF-κB pathway. • FMHM inhibits neuroinflammation via aldose reductase/PLC/PKC-dependent MAPK pathway. • FMHM protects neurons against inflammatory injury in microglia-neuron co-cultures.

  19. In vitro and in vivo inhibition of breast cancer cell growth by targeting the Hedgehog/GLI pathway with SMO (GDC-0449) or GLI (GANT-61) inhibitors.

    Science.gov (United States)

    Benvenuto, Monica; Masuelli, Laura; De Smaele, Enrico; Fantini, Massimo; Mattera, Rosanna; Cucchi, Danilo; Bonanno, Elena; Di Stefano, Enrica; Frajese, Giovanni Vanni; Orlandi, Augusto; Screpanti, Isabella; Gulino, Alberto; Modesti, Andrea; Bei, Roberto

    2016-02-23

    Aberrant Hedgehog (Hh)/glioma-associated oncogene (GLI) signaling has been implicated in cancer progression. Here, we analyzed GLI1, Sonic Hedgehog (Shh) and NF-κB expression in 51 breast cancer (ductal carcinoma) tissues using immunohistochemistry. We found a positive correlation between nuclear GLI1 expression and tumor grade in ductal carcinoma cases. Cytoplasmic Shh staining significantly correlated with a lower tumor grade. Next, the in vitro effects of two Hh signaling pathway inhibitors on breast cancer cell lines were evaluated using the Smoothened (SMO) antagonist GDC-0449 and the direct GLI1 inhibitor GANT-61. GDC-0449 and GANT-61 exhibited the following effects: a) inhibited breast cancer cell survival; b) induced apoptosis; c) inhibited Hh pathway activity by decreasing the mRNA expression levels of GLI1 and Ptch and inhibiting the nuclear translocation of GLI1; d) increased/decreased EGFR and ErbB2 protein expression, reduced p21-Ras and ERK1/ERK2 MAPK activities and inhibited AKT activation; and e) decreased the nuclear translocation of NF-κB. However, GANT-61 exerted these effects more effectively than GDC-0449. The in vivo antitumor activities of GDC-0449 and GANT-61 were analyzed in BALB/c mice that were subcutaneously inoculated with mouse breast cancer (TUBO) cells. GDC-0449 and GANT-61 suppressed tumor growth of TUBO cells in BALB/c mice to different extents. These findings suggest that targeting the Hh pathway using antagonists that act downstream of SMO is a more efficient strategy than using antagonists that act upstream of SMO for interrupting Hh signaling in breast cancer.

  20. Thiamine– Responsive Megaloblastic Anemia Syndrome

    Directory of Open Access Journals (Sweden)

    F Motavaselian

    2009-01-01

    Full Text Available Thiamine Responsive megaloblastic anemia in DIDMOA (Wolfram syndrome has an autosomal- recessive mode of inheritance . Megaloblastic anemia and sideroblastic anemia is accompanied by diabetes insipidus (DI, diabetes mellitus (DM ,optic atrophy (OA and deafness (D. Neutropenia and thrombocytopenia are also present. We report a 7 month old girl with congenital macrocytic anemia; a rare clinical feature of Wolfram,s syndrome with increased plasma levels of blood glucose, both of which dramatically responded to administration of thiamine in large doses . The patient also had neurosensorial deafness, but no improvement was observed in the deafness. We presented the case because thiamine-responsive megaloblastic anemia is a rare clinical presentation of Wolfram syndrome and after institution of treatment with thiamine, the anemia and hyperglycemia returned to normal.

  1. Iron deficiency anemia in pregnancy.

    Science.gov (United States)

    Di Renzo, Gian Carlo; Spano, Filippo; Giardina, Irene; Brillo, Eleonora; Clerici, Graziano; Roura, Luis Cabero

    2015-11-01

    Anemia is the most frequent derailment of physiology in the world throughout the life of a woman. It is a serious condition in countries that are industrialized and in countries with poor resources. The main purpose of this manuscript is to give the right concern of anemia in pregnancy. The most common causes of anemia are poor nutrition, iron deficiencies, micronutrients deficiencies including folic acid, vitamin A and vitamin B12, diseases like malaria, hookworm infestation and schistosomiasis, HIV infection and genetically inherited hemoglobinopathies such as thalassemia. Depending on the severity and duration of anemia and the stage of gestation, there could be different adverse effects including low birth weight and preterm delivery. Treatment of mild anemia prevents more severe forms of anemia, strictly associated with increased risk of fetal-maternal mortality and morbidity.

  2. Understanding anemia of chronic disease.

    Science.gov (United States)

    Fraenkel, Paula G

    2015-01-01

    The anemia of chronic disease is an old disease concept, but contemporary research in the role of proinflammatory cytokines and iron biology has shed new light on the pathophysiology of the condition. Recent epidemiologic studies have connected the anemia of chronic disease with critical illness, obesity, aging, and kidney failure, as well as with the well-established associations of cancer, chronic infection, and autoimmune disease. Functional iron deficiency, mediated principally by the interaction of interleukin-6, the iron regulatory hormone hepcidin, and the iron exporter ferroportin, is a major contributor to the anemia of chronic disease. Although anemia is associated with adverse outcomes, experimental models suggest that iron sequestration is desirable in the setting of severe infection. Experimental therapeutic approaches targeting interleukin-6 or the ferroportin-hepcidin axis have shown efficacy in reversing anemia in either animal models or human patients, although these agents have not yet been approved for the treatment of the anemia of chronic disease.

  3. [Anemia: guidelines comparison].

    Science.gov (United States)

    Del Vecchio, Lucia

    2009-01-01

    The development of recombinant human erythropoietin and its introduction into the market in the late 1980s has significantly improved the quality of life of patients with chronic kidney disease (CKD) and reduced the need for blood transfusions. Starting from a cautious target, a progressive increase in the recommended hemoglobin levels has been observed over the years, in parallel with an increase in the obtained levels. This trend has gone together with the publication of findings of observational studies showing a relationship between the increase in hemoglobin levels and a reduction in the mortality risk, with the conduction of clinical trials testing the effects of complete anemia correction, and with the compilation of guidelines on anemia control in CKD patients by scientific societies and organizations. In the last two years, evidence of a possible increase in the mortality risk in those patients who were randomized to high hemoglobin levels has resulted in a decrease in the upper limit of the recommended Hb target to be obtained with erythropoietin stimulating agents (ESA), and consequently in a narrowing of the target range. Comparison of guidelines on anemia control in CKD patients is an interesting starting point to discuss single recommendations, strengthen their importance, or suggest new topics of research to fill up important gaps in knowledge.

  4. Management of Iron Deficiency Anemia

    OpenAIRE

    Jimenez, Kristine; Kulnigg-Dabsch, Stefanie; Gasche, Christoph

    2015-01-01

    Anemia affects one-fourth of the world’s population, and iron deficiency is the predominant cause. Anemia is associated with chronic fatigue, impaired cognitive function, and diminished well-being. Patients with iron deficiency anemia of unknown etiology are frequently referred to a gastroenterologist because in the majority of cases the condition has a gastrointestinal origin. Proper management improves quality of life, alleviates the symptoms of iron deficiency, and reduces the need for blo...

  5. Iron-Deficiency Anemia (For Parents)

    Science.gov (United States)

    ... Your 1- to 2-Year-Old Iron-Deficiency Anemia KidsHealth > For Parents > Iron-Deficiency Anemia Print A ... common nutritional deficiency in children. About Iron-Deficiency Anemia Every red blood cell in the body contains ...

  6. Special Issues for People with Aplastic Anemia

    Science.gov (United States)

    ... Menu Donate Special Issues for People with Aplastic Anemia Because you have aplastic anemia , everyday events can ... bleeding, such as contact sports. Pregnancy and Aplastic Anemia Pregnancy is possible for women who have been ...

  7. Drug-induced immune hemolytic anemia

    Science.gov (United States)

    Immune hemolytic anemia secondary to drugs; Anemia - immune hemolytic - secondary to drugs ... Drugs that can cause this type of hemolytic anemia include: Cephalosporins (a class of antibiotics), most common ...

  8. Iron-Deficiency Anemia (For Parents)

    Science.gov (United States)

    ... Your 1- to 2-Year-Old Iron-Deficiency Anemia KidsHealth > For Parents > Iron-Deficiency Anemia A A ... common nutritional deficiency in children. About Iron-Deficiency Anemia Every red blood cell in the body contains ...

  9. Reduced Hsp70 and Glutamine in Pediatric Severe Malaria Anemia

    DEFF Research Database (Denmark)

    Kempaiah, Prakasha; Dokladny, Karol; Karim, Zachary

    2016-01-01

    Severe malarial anemia [SMA, hemoglobin (Hb) <5.0 g/dL] is a leading cause of global morbidity and mortality among children residing in Plasmodium falciparum transmission regions. Exploration of molecular pathways through global gene expression profiling revealed that SMA was characterized by dec...

  10. An Activating Mutation in sos-1 Identifies Its Dbl Domain as a Critical Inhibitor of the Epidermal Growth Factor Receptor Pathway during Caenorhabditis elegans Vulval Development▿

    Science.gov (United States)

    Modzelewska, Katarzyna; Elgort, Marc G.; Huang, Jingyu; Jongeward, Gregg; Lauritzen, Amara; Yoon, Charles H.; Sternberg, Paul W.; Moghal, Nadeem

    2007-01-01

    Proper regulation of receptor tyrosine kinase (RTK)-Ras-mitogen-activated protein kinase (MAPK) signaling pathways is critical for normal development and the prevention of cancer. SOS is a dual-function guanine nucleotide exchange factor (GEF) that catalyzes exchange on Ras and Rac. Although the physiologic role of SOS and its CDC25 domain in RTK-mediated Ras activation is well established, the in vivo function of its Dbl Rac GEF domain is less clear. We have identified a novel gain-of-function missense mutation in the Dbl domain of Caenorhabditis elegans SOS-1 that promotes epidermal growth factor receptor (EGFR) signaling in vivo. Our data indicate that a major developmental function of the Dbl domain is to inhibit EGF-dependent MAPK activation. The amount of inhibition conferred by the Dbl domain is equal to that of established trans-acting inhibitors of the EGFR pathway, including c-Cbl and RasGAP, and more than that of MAPK phosphatase. In conjunction with molecular modeling, our data suggest that the C. elegans mutation, as well as an equivalent mutation in human SOS1, activates the MAPK pathway by disrupting an autoinhibitory function of the Dbl domain on Ras activation. Our work suggests that functionally similar point mutations in humans could directly contribute to disease. PMID:17339331

  11. An activating mutation in sos-1 identifies its Dbl domain as a critical inhibitor of the epidermal growth factor receptor pathway during Caenorhabditis elegans vulval development.

    Science.gov (United States)

    Modzelewska, Katarzyna; Elgort, Marc G; Huang, Jingyu; Jongeward, Gregg; Lauritzen, Amara; Yoon, Charles H; Sternberg, Paul W; Moghal, Nadeem

    2007-05-01

    Proper regulation of receptor tyrosine kinase (RTK)-Ras-mitogen-activated protein kinase (MAPK) signaling pathways is critical for normal development and the prevention of cancer. SOS is a dual-function guanine nucleotide exchange factor (GEF) that catalyzes exchange on Ras and Rac. Although the physiologic role of SOS and its CDC25 domain in RTK-mediated Ras activation is well established, the in vivo function of its Dbl Rac GEF domain is less clear. We have identified a novel gain-of-function missense mutation in the Dbl domain of Caenorhabditis elegans SOS-1 that promotes epidermal growth factor receptor (EGFR) signaling in vivo. Our data indicate that a major developmental function of the Dbl domain is to inhibit EGF-dependent MAPK activation. The amount of inhibition conferred by the Dbl domain is equal to that of established trans-acting inhibitors of the EGFR pathway, including c-Cbl and RasGAP, and more than that of MAPK phosphatase. In conjunction with molecular modeling, our data suggest that the C. elegans mutation, as well as an equivalent mutation in human SOS1, activates the MAPK pathway by disrupting an autoinhibitory function of the Dbl domain on Ras activation. Our work suggests that functionally similar point mutations in humans could directly contribute to disease.

  12. Anemia of Chronic Liver Diseases

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Hyun Chung; Lee, Jhung Sang; Koh, Chang Soon; Lee, Mun Ho [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1971-09-15

    The pathogenetic mechanisms of anemia in patients with chronic liver disease were observed. Seventeen patients with moderate to advanced hepatic diseases were studied by various methods. Only patients without previous blood loss were included : 14 had cirrhosis, 2 had active chronic hepatitis, and one had inferior vena cava obstruction with associated liver cirrhosis. The followings were the results: 1. The anemia based on red blood cell count, Hb., and Ht. was found in 76.5-78.6% of the patients. 2. Red cell indices indicated that normo-macrocytic and normochromic anemia was present is the majority of the patients. 3. No evidence of megaloblastic anemia was found on the basis of the morphological examinations. 4. Serum iron, TIBC, % saturation and iron content in the bone marrow indicated that iron deficiency anemia was present in about half of the patients. 5. In the view of the erythrocyte dynamics, primary increase in the red cell destruction was ascribed to the cause of the anemia. 6. Decrease in the red cell survival time was not correlated with MCV, % saturation and S.L. ratio. Also, hemoglobin level was not correlated with MCV, % saturation and T{sub 50} Cr. Therefore, multiple causes may be involved in the pathogenesis of the anemia. 7. Anemia as determined by the red cell volume was found in only 60% of the patients. It may be possible that hemodilutional anemia is present.

  13. Iron Deficiency Anemia in Pregnancy.

    Science.gov (United States)

    Breymann, Christian

    2015-10-01

    Anemia is a common problem in obstetrics and perinatal care. Any hemoglobin below 10.5 g/dL can be regarded as true anemia regardless of gestational age. Reasons for anemia in pregnancy are mainly nutritional deficiencies, parasitic and bacterial diseases, and inborn red blood cell disorders such as thalassemias. The main cause of anemia in obstetrics is iron deficiency, which has a worldwide prevalence between estimated 20%-80% and consists of a primarily female population. Stages of iron deficiency are depletion of iron stores, iron-deficient erythropoiesis without anemia, and iron deficiency anemia, the most pronounced form of iron deficiency. Pregnancy anemia can be aggravated by various conditions such as uterine or placental bleedings, gastrointestinal bleedings, and peripartum blood loss. In addition to the general consequences of anemia, there are specific risks during pregnancy for the mother and the fetus such as intrauterine growth retardation, prematurity, feto-placental miss ratio, and higher risk for peripartum blood transfusion. Besides the importance of prophylaxis of iron deficiency, the main therapy options for the treatment of pregnancy anemia are oral iron and intravenous iron preparations.

  14. Cameron lesion: An unusual cause of anemia

    Directory of Open Access Journals (Sweden)

    Jovanović Ivan

    2010-01-01

    Full Text Available Introduction. Cameron lesions are linear gastric ulcers or erosions positioned on the crests of mucosal folds at the diaphragmatic impression, in patients with large hiatal hernia, and can cause iron deficiency anaemia. Case report. We present a case of a 56-year-old woman who was referred to our institution for further investigation after she was examined in gastroenterology emergency room (GER for signs and symptoms of severe hypochromic microcytic anemia without signs of acute gastrointestinal bleeding and with no obvious cause of chronic blood loss. Endoscopy showed linear ulceration at the level of diaphragm-Cameron lesions with large hiated hernia. She was treated with proton pump inhibitors and iron supplements. The laparoscopic fundoplication was done. Six months later she was asymptomatic. Conclusion. Large hiatus hernia may cause iron deficiency anemia due to occult bleeding from Cameron erosions. The current therapy concept includes the surgical reconstruction of the hiatus together with gastric fundoplication in combination with the proton pump inhibitor therapy.

  15. ANEMIA SEL SABIT

    Directory of Open Access Journals (Sweden)

    Gede Agus Suwiryawan

    2013-09-01

    Full Text Available Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 Anemia is a form of blood disorder most often occurs in the community. Sickle cell anemia is anemia due to hemoglobinopathy caused by a change in the amino acid-6 of the ? globin chain. Sickle cell anemia is common in tropical areas of Africa and some parts of the region Saudi Arabia, India and the Mediterranean as well as black people in America. In addition there are also careers in various European countries. In pathophysiology, there are amino acid change from glutamic acid to valine in the ?-globin chain that causes red blood cells become sickle-shaped when deoxygenatied, but still be able to return to its normal shape when experiencing oxygenation. When the red blood cell membrane have been amended, the polymerization of red blood cells has become irreversible. Clinical picture seen in sickle cell anemia can be divided into two, namely: acute and chronic. Diagnosis can be done is to distinguish between heterozygous or homozygous sickle cell. Treatment provided in accordance with the clinical picture appears. Treatment that can be done is by blood transfusion, bone marrow transplant, anti-sickling drug delivery, and drug delivery to trigger the synthesis of HbF. Treatment still in the development stage is to use stem cells. /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;}

  16. The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-Stage Alzheimer-Type Tauopathy.

    Directory of Open Access Journals (Sweden)

    Robert Siman

    Full Text Available The perforant pathway projection from layer II of the entorhinal cortex to the hippocampal dentate gyrus is especially important for long-term memory formation, and is preferentially vulnerable to developing a degenerative tauopathy early in Alzheimer's disease (AD that may spread over time trans-synaptically. Despite the importance of the perforant pathway to the clinical onset and progression of AD, a therapeutic has not been identified yet that protects it from tau-mediated toxicity. Here, we used an adeno-associated viral vector-based mouse model of early-stage AD-type tauopathy to investigate effects of the mTOR inhibitor and autophagy stimulator rapamycin on the tau-driven loss of perforant pathway neurons and synapses. Focal expression of human tau carrying a P301L mutation but not eGFP as a control in layer II of the lateral entorhinal cortex triggered rapid degeneration of these neurons, loss of lateral perforant pathway synapses in the dentate gyrus outer molecular layer, and activation of neuroinflammatory microglia and astroglia in the two locations. Chronic systemic rapamycin treatment partially inhibited phosphorylation of a mechanistic target of rapamycin substrate in brain and stimulated LC3 cleavage, a marker of autophagic flux. Compared with vehicle-treated controls, rapamycin protected against the tau-induced neuronal loss, synaptotoxicity, reactive microgliosis and astrogliosis, and activation of innate neuroimmunity. It did not alter human tau mRNA or total protein levels. Finally, rapamycin inhibited trans-synaptic transfer of human tau expression to the dentate granule neuron targets for the perforant pathway, likely by preventing the synaptic spread of the AAV vector in response to pathway degeneration. These results identify systemic rapamycin as a treatment that protects the entorhinal cortex and perforant pathway projection from tau-mediated neurodegeneration, axonal and synapse loss, and neuroinflammatory reactive

  17. Hemolytic anemia caused by chemicals and toxins

    Science.gov (United States)

    ... This list is not all-inclusive. Alternative Names Anemia - hemolytic - caused by chemicals or toxins References Michel M. Autoimmune and intravascular hemolytic anemias. In: Goldman L, Schafer ...

  18. [INHIBITORS OF MAP-KINASE PATHWAY U0126 AND PD98059 DIFFERENTLY AFFECT ORGANIZATION OF TUBULIN CYTOSKELETON AFTER STIMULATION OF EGF RECEPTOR ENDOCYTOSIS].

    Science.gov (United States)

    Zlobina, M V; Steblyanko, Yu Yu; Shklyaeva, M A; Kharchenko, V V; Salova, A V; Kornilova, E S

    2015-01-01

    phospho-ERK2 could be detected after 60 min of endocytosis. In both cases, MAP-kinase activation dynamics was significantly different from the control. Our results suggest involvement of EGF-stimulated MAP-kinase pathway in cytoskeleton regulation. At the same time, they demonstrate that the two studied and widely used inhibitors are not equivalent with respect to not only the effect on MAP-kinase activity but also to such interdependent processes such as changes in cytoskeleton organization and signaling receptor' endocytosis.

  19. The effect of MEP pathway and other inhibitors on the intracellular localization of a plasma membrane-targeted, isoprenylable GFP reporter protein in tobacco BY-2 cells [v1; ref status: indexed, http://f1000r.es/yx

    Directory of Open Access Journals (Sweden)

    Michael Hartmann

    2013-08-01

    Full Text Available We have established an in vivo visualization system for the geranylgeranylation of proteins in a stably transformed tobacco BY-2 cell line, based on the expression of a dexamethasone-inducible GFP fused to the carboxy-terminal basic domain of the rice calmodulin CaM61, which naturally bears a CaaL geranylgeranylation motif (GFP-BD-CVIL. By using pathway-specific inhibitors it was demonstrated that inhibition of the methylerythritol phosphate (MEP pathway with known inhibitors like oxoclomazone and fosmidomycin, as well as inhibition of the protein geranylgeranyltransferase type 1 (PGGT-1, shifted the localization of the GFP-BD-CVIL protein from the membrane to the nucleus. In contrast, the inhibition of the mevalonate (MVA pathway with mevinolin did not affect the localization. During the present work, this test system has been used to examine the effect of newly designed inhibitors of the MEP pathway and inhibitors of sterol biosynthesis such as squalestatin, terbinafine and Ro48-8071. In addition, we also studied the impact of different post-prenylation inhibitors or those suspected to affect the transport of proteins to the plasma membrane on the localization of the geranylgeranylable fusion protein GFP-BD-CVIL.

  20. Nicotinic and muscarinic agonists and acetylcholinesterase inhibitors stimulate a common pathway to enhance GluN2B-NMDAR responses

    Science.gov (United States)

    Ishibashi, Masaru; Yamazaki, Yoshihiko; Miledi, Ricardo; Sumikawa, Katumi

    2014-01-01

    Nicotinic and muscarinic ACh receptor agonists and acetylcholinesterase inhibitors (AChEIs) can enhance cognitive function. However, it is unknown whether a common signaling pathway is involved in the effect. Here, we show that in vivo administration of nicotine, AChEIs, and an m1 muscarinic (m1) agonist increase glutamate receptor, ionotropic, N-methyl D-aspartate 2B (GluN2B)-containing NMDA receptor (NR2B-NMDAR) responses, a necessary component in memory formation, in hippocampal CA1 pyramidal cells, and that coadministration of the m1 antagonist pirenzepine prevents the effect of cholinergic drugs. These observations suggest that the effect of nicotine is secondary to increased release of ACh via the activation of nicotinic ACh receptors (nAChRs) and involves m1 receptor activation through ACh. In vitro activation of m1 receptors causes the selective enhancement of NR2B-NMDAR responses in CA1 pyramidal cells, and in vivo exposure to cholinergic drugs occludes the in vitro effect. Furthermore, in vivo exposure to cholinergic drugs suppresses the potentiating effect of Src on NMDAR responses in vitro. These results suggest that exposure to cholinergic drugs maximally stimulates the m1/guanine nucleotide-binding protein subunit alpha q/PKC/proline-rich tyrosine kinase 2/Src signaling pathway for the potentiation of NMDAR responses in vivo, occluding the in vitro effects of m1 activation and Src. Thus, our results indicate not only that nAChRs, ACh, and m1 receptors are on the same pathway involving Src signaling but also that NR2B-NMDARs are a point of convergence of cholinergic and glutamatergic pathways involved in learning and memory. PMID:25114227

  1. Class I phosphatidylinositol 3-kinase inhibitor LY294002 activates autophagy and induces apoptosis through p53 pathway in gastric cancer cell line SGC7901

    Institute of Scientific and Technical Information of China (English)

    Chungen Xing; Baosong Zhu; Huihui Liu; Huihua Yao; Lifeng Zhang

    2008-01-01

    We aimed to study the effects of LY294002, an inhibitor of classIphosphatidylinositol 3-kinase (PDK), on proliferation,apoptosis, and autophagy in gastric cancer cell line SGC7901.In this study, we showed that LY294002 inhibited the viability of gastric cancer SGC7901 cells.We also showed that LY294002 increased the expression of microtubule-associated protein 1 light chain 3(LC3),and increased monodansylcadaverine(MDC)-labeled vesicles.LY294002 activated autophagy by activating p53 and caspase-3,and induced apoptosis by up-regulating p53 and p53-up-regulated modulator of apoptosis(PUMA).Therefore,LY294002 might induce cytotoxicity in SGC7901 cells through activation of p53 and the downstream point PUMA.These findings suggest that inhibition of the class I PI3K signaling pathway is a potential strategy for managing gastric cancers.

  2. In vitro effects of heparin and tissue factor pathway inhibitor on factor VII assays. possible implications for measurements in vivo after heparin therapy

    DEFF Research Database (Denmark)

    Bladbjerg, E-M; Larsen, L F; Ostergaard, P;

    2000-01-01

    The coagulant activity of blood coagulation factor VII (FVII:C) can be lowered by changes in lifestyle and by therapeutic intervention, e.g. heparin infusion. The question is, however, whether FVII:C determined ex vivo is a valid measure of the FVII activity in vivo. We measured plasma FVII......:C, activated FVII (FVIIa), FVII protein (FVII:Ag), tissue factor pathway inhibitor (TFPI), triglycerides, and free fatty acids (FFA) before and 15 min after infusion of a bolus of unfractionated heparin (50 IU/kg body weight) in 12 healthy subjects. Additionally, we conducted in vitro experiments...... to investigate the effect of unfractionated heparin and TFPI, which is released from the endothelium by heparin, on FVII:C, FVIIa, and FVII:Ag. Heparin infusion decreased triglycerides and increased FFA and TFPI. This was accompanied by significant reductions in FVIIa, FVII:C and FVII:Ag. In vitro, anti...

  3. Tissue Factor Pathway Inhibitor-1 Is a Valuable Marker for the Prediction of Deep Venous Thrombosis and Tumor Metastasis in Patients with Lung Cancer

    Directory of Open Access Journals (Sweden)

    Xianming Fei

    2017-01-01

    Full Text Available Activation of blood coagulation contributes to cancer progression. Tissue factor pathway inhibitor-1 (TFPI-1 is the main inhibitor of extrinsic coagulation pathway. The aim of this study is to assess the predicting significance of TFPI-1 for thrombotic complication and metastasis in lung cancer patients. Total of 188 non-small cell lung cancer (NSCLC patients were included in this study. Plasma TFPI-1, D-dimer (D-D, antithrombin (AT, Fibrinogen (Fbg, and coagulating factor VIII activity (FVIII:C were measured. In NSCLC patients, significantly decreased TFPI-1 and AT and increased D-D, Fbg, and FVIII:C levels were observed, and there was a significant correlation between TFPI-1 and other hemostatic parameters (P<0.001, resp.. NSCLC patients with deep venous thrombosis (DVT or metastasis had significantly lower TFPI-1 levels than those without DVT or metastasis (P<0.01, resp.. Multivariate regression revealed that TFPI-1 acted as a predictor for DVT or tumor metastasis in NSCLC patients [OR: 4.15 or 3.28, P<0.05, resp.]. The area under ROC curve of TFPI-1 was 0.905 (95% CI, 0.842~0.967 or 0.828 (95% CI, 0.742~0.915 for predicting DVT or metastasis (P<0.001, resp.. The optimal point of TFPI-1 was 57.7 or 54.3 ng/mL for predicting DVT or metastasis, respectively. Combination of TFPI-1 and D-D measurements can improve the predicting power for DVT or metastasis in NSCLC patients. Our findings suggested that TFPI-1 was a valuable predictor of DVT and tumor metastasis in NSCLC patients.

  4. Assessment of the Role of NO-cGMP Pathway in Orthodontic Tooth Movement Using PDE5 Inhibitors: An Animal Study

    Science.gov (United States)

    Mirhashemi, Amir Hossein; Akhoundi, Mohammad Sadegh Ahmad; Ghazanfari, Rezvaneh; Etemad-Moghadam, Shahroo; Alaeddini, Mojgan; Khorshidian, Azam; Dehpour, Ahmad Reza

    2016-01-01

    Objectives: Nitric oxide (NO) is a signaling molecule that mediates mechanical bone loading. Cyclic guanosine 3′, 5′ monophosphate (cGMP) is a NO-induced effector molecule. The aim of this study was to assess the effect of NO-cGMP pathway on orthodontic tooth movement (OTM) in rats by use of two phosphodiesterase 5 (PDE5) inhibitors namely sildenafil and tadalafil as chemical tools. Materials and Methods: Forty-five male Wistar rats were divided into three equal groups (n=15) based on the substance they received. The first group received daily injections of tadalafil; the second group received daily injections of sildenafil and the third group received daily injections of normal saline. The orthodontic appliances consisted of nickel-titanium closed-coil spring ligated between the maxillary right incisor and the first molar of the animals for 21 days. The amount of tooth movement was measured in all three groups at the end of this period. Histological analysis was performed to assess root resorption lacunae, osteoclast number and periodontal ligament (PDL) thickness. Results: All appliance-treated molars in the experimental and control groups showed evidence of tooth movement. The mean OTM was calculated to be 0.39±0.16, 0.32±0.16 and 0.26±0.16mm in tadalafil, sildenafil and control groups, respectively and there were no significant differences in OTM among the study groups (P>0.05). In the tadalafil group, significantly greater root resorption on the tension side was seen when compared with controls (P≤0.05). Conclusions: Tadalafil and sildenafil PDE-5 inhibitors affecting the NO-cGMP pathway did not affect OTM in rats.

  5. HMG-CoA reductase inhibitors decrease angiotensin II-induced vascular fibrosis: role of RhoA/ROCK and MAPK pathways.

    Science.gov (United States)

    Rupérez, Mónica; Rodrigues-Díez, Raquel; Blanco-Colio, Luis Miguel; Sánchez-López, Elsa; Rodríguez-Vita, Juan; Esteban, Vanesa; Carvajal, Gisselle; Plaza, Juan José; Egido, Jesús; Ruiz-Ortega, Marta

    2007-08-01

    3-Hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) present beneficial effects in cardiovascular diseases. Angiotensin II (Ang II) contributes to cardiovascular damage through the production of profibrotic factors, such as connective tissue growth factor (CTGF). Our aim was to investigate whether HMG-CoA reductase inhibitors could modulate Ang II responses, evaluating CTGF expression and the mechanisms underlying this process. In cultured vascular smooth muscle cells (VSMCs) atorvastatin and simvastatin inhibited Ang II-induced CTGF production. The inhibitory effect of statins on CTGF upregulation was reversed by mevalonate and geranylgeranylpyrophosphate, suggesting that RhoA inhibition could be involved in this process. In VSMCs, statins inhibited Ang II-induced Rho membrane localization and activation. In these cells Ang II regulated CTGF via RhoA/Rho kinase activation, as shown by inhibition of Rho with C3 exoenzyme, RhoA dominant-negative overexpression, and Rho kinase inhibition. Furthermore, activation of p38MAPK and JNK, and redox process were also involved in Ang II-mediated CTGF upregulation, and were downregulated by statins. In rats infused with Ang II (100 ng/kg per minute) for 2 weeks, treatment with atorvastatin (5 mg/kg per day) diminished aortic CTGF and Rho activation without blood pressure modification. Rho kinase inhibition decreased CTGF upregulation in rat aorta, mimicking statin effect. CTGF is a vascular fibrosis mediator. Statins diminished extracellular matrix (ECM) overexpression caused by Ang II in vivo and in vitro. In summary, HMG-CoA reductase inhibitors inhibit several intracellular signaling systems activated by Ang II (RhoA/Rho kinase and MAPK pathways and redox process) involved in the regulation of CTGF. Our results may explain, at least in part, some beneficial effects of statins in cardiovascular diseases.

  6. Adhesion of ZAP-70+ chronic lymphocytic leukemia cells to stromal cells is enhanced by cytokines and blocked by inhibitors of the PI3-kinase pathway.

    Science.gov (United States)

    Lafarge, Sandrine T; Johnston, James B; Gibson, Spencer B; Marshall, Aaron J

    2014-01-01

    CLL cell survival and proliferation is enhanced through direct contact with supporting cells present in lymphoid tissues. PI3Ks are critical signal transduction enzymes controlling B cell survival and activation. PI3K inhibitors have entered clinical trials and show promising therapeutic activity; however, it is unclear whether PI3K inhibitor drugs differentially affect ZAP-70 positive versus negative CLL cells or target specific microenvironmental interactions. Here we provide evidence that CD40L+IL-4, IL-8 or IL-6 enhance adhesion to stromal cells, with IL-6 showing a selective effect on ZAP-70 positive cells. Stimulatory effects of IL-8 or IL-6 are fully reversed by PI3K inhibition, while the effects of CD40L+IL-4 are partially reversed. While CD40L+IL-4 is the only stimulation increasing CLL cell survival for all patient groups, IL-6 protects ZAP-70 positive cells from cell death induced by PI3K inhibition. Altogether, our results indicate that targeting the PI3K pathway can reverse protective CLL-microenvironment interactions in both ZAP-70 positive and negative CLL despite their differences in cytokine responsiveness.

  7. PI3Kδ inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma.

    Science.gov (United States)

    Meadows, Sarah A; Vega, Francisco; Kashishian, Adam; Johnson, Dave; Diehl, Volker; Miller, Langdon L; Younes, Anas; Lannutti, Brian J

    2012-02-23

    GS-1101 (CAL-101) is an oral PI3Kδ-specific inhibitor that has shown preclinical and clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. To investigate the potential role of PI3Kδ in Hodgkin lymphoma (HL), we screened 5 HL cell lines and primary samples from patients with HL for PI3Kδ isoform expression and constitutive PI3K pathway activation. Inhibition of PI3Kδ by GS-1101 resulted in the inhibition of Akt phosphorylation. Cocultures with stroma cells induced Akt activation in HL cells, and this effect was blocked by GS-1101. Conversely, production of the stroma-stimulating chemokine, CCL5, by HL cells was reduced by GS-1101. GS-1101 also induced dose-dependent apoptosis of HL cells at 48 hours. Reductions in cell viability and apoptosis were enhanced when combining GS-1101 with the mTOR inhibitor everolimus. Our findings suggest that excessive PI3Kδ activity is characteristic in HL and support clinical evaluation of GS-1101, alone and in combination, as targeted therapy for HL.

  8. The NEDD8 inhibitor MLN4924 increases the size of the nucleolus and activates p53 through the ribosomal-Mdm2 pathway.

    Science.gov (United States)

    Bailly, A; Perrin, A; Bou Malhab, L J; Pion, E; Larance, M; Nagala, M; Smith, P; O'Donohue, M-F; Gleizes, P-E; Zomerdijk, J; Lamond, A I; Xirodimas, D P

    2016-01-28

    The ubiquitin-like molecule NEDD8 is essential for viability, growth and development, and is a potential target for therapeutic intervention. We found that the small molecule inhibitor of NEDDylation, MLN4924, alters the morphology and increases the surface size of the nucleolus in human and germline cells of Caenorhabditis elegans in the absence of nucleolar fragmentation. SILAC proteomics and monitoring of rRNA production, processing and ribosome profiling shows that MLN4924 changes the composition of the nucleolar proteome but does not inhibit RNA Pol I transcription. Further analysis demonstrates that MLN4924 activates the p53 tumour suppressor through the RPL11/RPL5-Mdm2 pathway, with characteristics of nucleolar stress. The study identifies the nucleolus as a target of inhibitors of NEDDylation and provides a mechanism for p53 activation upon NEDD8 inhibition. It also indicates that targeting the nucleolar proteome without affecting nucleolar transcription initiates the required signalling events for the control of cell cycle regulators.

  9. Treatment of gastrointestinal neuroendocrine tumors with inhibitors of growth factor receptors and their signaling pathways: Recent advances and future perspectives

    Institute of Scientific and Technical Information of China (English)

    Michael H(o)pfner; Detlef Schuppan; Hans Scherübl

    2008-01-01

    The limited efficacy of conventional cytotoxic treatment regimes for advanced gastrointestinal neuroendocrine cancers emphasizes the need for novel and more effective medical treatment options.Recent findings on the specific biological features of this family of neoplasms has led to the development of new targeted therapies,which take into account the high vascularization and abundant expression of specific growth factors and cognate tyrosine kinase receptors.This review will briefly summarize the status and future perspectives of antiangiogenic, mTOR- or growth factor receptor-based pharmacological approaches for the innovative treatment of gastrointestinal neuroendocrine tumors.In view of the multitude of novel targeted approaches, the rationale for innovative combination therapies, i.e.combining growth factor (receptor)-targeting agents with chemoor biotherapeutics or with other novel anticancer drugs such as HDAC or proteasome inhibitors will be taken into account.

  10. New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates--Nrf2 activators and GSK-3 inhibitors.

    Science.gov (United States)

    Maes, Michael; Fišar, Zdenĕk; Medina, Miguel; Scapagnini, Giovanni; Nowak, Gabriel; Berk, Michael

    2012-06-01

    This paper reviews new drug targets in the treatment of depression and new drug candidates to treat depression. Depression is characterized by aberrations in six intertwined pathways: (1) inflammatory pathways as indicated by increased levels of proinflammatory cytokines, e.g. interleukin-1 (IL-1), IL-6, and tumour necrosis factor α. (2) Activation of cell-mediated immune pathways as indicated by an increased production of interferon γ and neopterin. (3) Increased reactive oxygen and nitrogen species and damage by oxidative and nitrosative stress (O&NS), including lipid peroxidation, damage to DNA, proteins and mitochondria. (4) Lowered levels of key antioxidants, such as coenzyme Q10, zinc, vitamin E, glutathione, and glutathione peroxidase. (5) Damage to mitochondria and mitochondrial DNA and reduced activity of respiratory chain enzymes and adenosine triphosphate production. (6) Neuroprogression, which is the progressive process of neurodegeneration, apoptosis, and reduced neurogenesis and neuronal plasticity, phenomena that are probably caused by inflammation and O&NS. Antidepressants tend to normalize the above six pathways. Targeting these pathways has the potential to yield antidepressant effects, e.g. using cytokine antagonists, minocycline, Cox-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants, and neurotrophic factors. These six pathways offer new, pathophysiologically guided drug targets suggesting that novel therapies could be developed that target these six pathways simultaneously. Both nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators and glycogen synthase kinase-3 (GSK-3) inhibitors target the six above-mentioned pathways. GSK-3 inhibitors have antidepressant effects in animal models of depression. Nrf2 activators and GSK-3 inhibitors have the potential to be advanced to phase-2 clinical trials to examine whether they augment the efficacy of antidepressants or are useful as monotherapy.

  11. Gamma-Secretase Inhibitor IX (GSI) Impairs Concomitant Activation of Notch and wnt-beta-catenin Pathways in CD44(+) Gastric Cancer Stem Cells.

    Science.gov (United States)

    Barat, Samarpita; Chen, Xi; Cuong Bui, Khac; Bozko, Przemyslaw; Götze, Julian; Christgen, Matthias; Krech, Till; Malek, Nisar P; Plentz, Ruben R

    2017-02-03

    Cancer stem cells (CSC) are associated with tumor resistance and are characterized in gastric cancer (GC). Studies have indicated that Notch and wnt-beta-catenin pathways are crucial for CSC development. Using CD44(+) CSCs, we investigated the role of these pathways in GC carcinogenesis. We performed cell proliferation, wound healing, invasion, tumorsphere, and apoptosis assays. Immunoblot analysis of downstream signaling targets of Notch and wnt-beta-catenin were tested after gamma-secretase inhibitor IX (GSI) treatment. Immunohistochemistry, immunofluorescence, and Fluorescence activated cell sorting (FACS) were used to determine CD44 and Hairy enhancer of split-1 (Hes1) expression in human GC tissues. CD44(+) CSCs were subcutaneously injected into NMR-nu/nu mice and treated with vehicle or GSI. GC patients with expression of CD44 and Hes1 showed overall reduced survival. CD44(+) CSCs showed high expression of Hes1. GSI treatment showed effective inhibition of cell proliferation, migration, invasion, tumor sphere formation of CD44(+) CSCs, and induced apoptosis. Importanly, Notch1 was found to be important in mediating a crosstalk between Notch and wnt-beta-catenin in CD44(+) CSCs. Our study highlights a crosstalk between Notch and wnt-beta-catenin in gastric CD44(+) CSCs. Expression of CD44 and Hes1 is associated with patient overall survival. GSI could be an alternative drug to treat GC. © Stem Cells Translational Medicine 2017.

  12. Studies on metabolites and metabolic pathways of bulleyaconitine A in rat liver microsomes using LC-MS(n) combined with specific inhibitors.

    Science.gov (United States)

    Bi, Yunfeng; Zhuang, Xiaoyu; Zhu, Hongbin; Song, Fengrui; Liu, Zhiqiang; Liu, Shuying

    2015-07-01

    Bulleyaconitine A (BLA) from Aconitum bulleyanum plants is usually used as anti-inflammatory drug in some Asian countries. It has a variety of bioactivities, and at the same time some toxicities. Since the bioactivities and toxicities of BLA are closely related to its metabolism, the metabolites and the metabolic pathways of BLA in rat liver microsomes were investigated by HPLC-MS(n). In this research, the 12 metabolites of BLA were identified according to the results of HPLC-MS(n) data and the relevant literature. The results showed that there are multiple metabolites of BLA in rat liver microsomes, including demethylation, deacetylation, dehydrogenation deacetylation and hydroxylation. The major metabolic pathways of BLA in rat liver microsomes were clarified by HPLC-MS combined with specific inhibitors of CYP450 isoforms. As a result, CYP3A and 2C were found to be the principal CYP isoforms contributing to the metabolism of BLA. Moreover, CYP2D6 and 2E1 are also more important CYP isoforms for the metabolism of BLA. While CYP1A2 only affected the formation rate of M11, its effect on the metabolism of BLA is very small.

  13. Cyclic ADP-ribose as an endogenous inhibitor of the mTOR pathway downstream of dopamine receptors in the mouse striatum.

    Science.gov (United States)

    Higashida, Haruhiro; Kamimura, Shin-Ya; Inoue, Takeshi; Hori, Osamu; Islam, Mohammad Saharul; Lopatina, Olga; Tsuji, Chiharu

    2016-12-26

    The role of cyclic ADP-ribose (cADPR) as a second messenger and modulator of the mTOR pathway downstream of dopamine (DA) receptors and/or CD38 was re-examined in the mouse. ADP-ribosyl activity was low in the membranes of neonates, but DA stimulated it via both D1- and D2-like receptors. ADP-ribosyl cyclase activity increased significantly during development in association with increased expression of CD38. The cADPR binding proteins, FKBP12 and FKBP12.6, were expressed in the adult mouse striatum. The ratio of phosphorylated to non-phosphorylated S6 kinase (S6K) in whole mouse striatum homogenates decreased after incubation of adult mouse striatum with extracellular cADPR for 5 min. This effect of cADPR was much weaker in MPTP-treated Parkinson's disease model mice. The inhibitory effects of cADPR and rapamycin were identical. These data suggest that cADPR is an endogenous inhibitor of the mTOR signaling pathway downstream of DA receptors in the mouse striatum and that cADPR plays a certain role in the brain in psychiatric and neurodegenerative diseases.

  14. KRASness and PIK3CAness in patients with advanced colorectal cancer: outcome after treatment with early-phase trials with targeted pathway inhibitors.

    Directory of Open Access Journals (Sweden)

    Ignacio Garrido-Laguna

    Full Text Available PURPOSE: To evaluate clinicopathologic and molecular features of patients with metastatic colorectal cancer (mCRC and their outcomes in early-phase trials using pathway-targeting agents. PATIENTS AND METHODS: We analyzed characteristics of 238 patients with mCRC referred to the phase 1 trials unit at MD Anderson Cancer Center. KRAS, PIK3CA and BRAF status were tested using PCR-based DNA sequencing. RESULTS: Fifty-one percent of patients harbored KRAS mutations; 15% had PIK3CA mutations. In the multivariate regression model for clinical characteristics KRAS mutations were associated with an increased incidence of lung and bone metastases and decreased incidence of adrenal metastases; PIK3CA mutations were marginally correlated with mucinous tumors (p = 0.05. In the univariate analysis, KRAS and PIK3CA mutations were strongly associated. Advanced Duke's stage (p<0.0001 and KRAS mutations (p = 0.01 were the only significant independent predictors of poor survival (Cox proportional hazards model. Patients with PIK3CA mutations had a trend toward shorter progression-free survival when treated with anti-EGFR therapies (p = 0.07. Eighteen of 78 assessable patients (23% treated with PI3K/Akt/mTOR axis inhibitors achieved stable disease [SD] ≥6 months or complete response/partial response (CR/PR, only one of whom were in the subgroup (N = 15 with PIK3CA mutations, perhaps because 10 of these 15 patients (67% had coexisting KRAS mutations. No SD ≥6 months/CR/PR was observed in the 10 patients treated with mitogen-activating protein kinase (MAPK pathway targeting drugs. CONCLUSIONS: KRAS and PIK3CA mutations frequently coexist in patients with colorectal cancer, and are associated with clinical characteristics and outcome. Overcoming resistance may require targeting both pathways.

  15. Intracerebroventricular administration of ouabain, a Na/K-ATPase inhibitor, activates mTOR signal pathways and protein translation in the rat frontal cortex.

    Science.gov (United States)

    Kim, Se Hyun; Yu, Hyun-Sook; Park, Hong Geun; Ha, Kyooseob; Kim, Yong Sik; Shin, Soon Young; Ahn, Yong Min

    2013-08-01

    Intracerebroventricular (ICV) injection of ouabain, a specific Na/K-ATPase inhibitor, induces behavioral changes in rats in a putative animal model of mania. The binding of ouabain to Na/K-ATPase affects signaling molecules in vitro, including ERK1/2 and Akt, which promote protein translation. We have also reported that ERK1/2 and Akt in the brain are involved in the ouabain-induced hyperactivity of rats. In this study, rats were given an ICV injection of ouabain, and then their frontal cortices were examined to determine the effects of ouabain on the mTOR/p70S6K/S6 signaling pathway and protein translation, which are important in modifications of neural circuits and behavior. Rats showed ouabain-induced hyperactivity up to 8h following injection, and increased phosphorylation levels of mTOR, p70S6K, S6, eIF4B, and 4E-BP at 1, 2, 4, and 8h following ouabain injection. Immunohistochemical analyses revealed that increased p-S6 immunoreactivity in the cytoplasm of neurons by ouabain was evident in the prefrontal, cingulate, and orbital cortex. These findings suggested increased translation initiation in response to ouabain. The rate of protein synthesis was measured as the amount of [(3)H]-leucine incorporation in the cell-free extracts of frontal cortical tissues, and showed a significant increase at 8h after ouabain injection. These results suggest that ICV injection of ouabain induced activation of the protein translation initiation pathway regulated by ERK1/2 and Akt, and prolonged hyperactivity in rats. In conclusion, protein translation pathway could play an important role in ouabain-induced hyperactivity in a rodent model of mania.

  16. Sequential Androgen Receptor Pathway Inhibitor in Prostate Cancer: Piling-Up The Benefits or a Case for Cross-Resistance?

    Directory of Open Access Journals (Sweden)

    Bertrand Tombal

    2014-11-01

    Full Text Available In the last 10 years, there has been accumulating evidence that, even in a low serum testosterone environment, the androgen receptor (AR remains the main driver of prostate cancer progression. This has led to the discovery and clinical development of new anti-androgens and androgen biosynthesis inhibitors. Enzalutamide and abiraterone acetate are the lead compounds of this new generation of agents, but multiple other agents are on their way. Because they both target the ligand-dependent regulation of AR activity, it is plausible that cross-resistance may exist when both drugs are used sequentially, and that the benefit of these agents may fade away when sequencing them. As the exact mechanisms for cross- resistance between AR-targeted agents remain unclear at this point, additional clinical studies are crucial to define the exact combination or sequencing order that could yield highest clinical benefits. Moreover, new molecular targets are needed in order to address these resistances, as well as establishing biomarkers to improve patient selection that could most benefit from AR-targeted therapies, but also help develop novel agents to improve and optimise the management of castration-resistant prostate cancer and metastatic, castration-resistant prostate cancer.

  17. A novel angiogenesis inhibitor impairs lovo cell survival via targeting against human VEGFR and its signaling pathway of phosphorylation.

    Science.gov (United States)

    Zhang, Y M; Dai, B L; Zheng, L; Zhan, Y Z; Zhang, J; Smith, W W; Wang, X L; Chen, Y N; He, L C

    2012-10-11

    Colorectal cancer represents the fourth commonest malignancy, and constitutes a major cause of significant morbidity and mortality among other diseases. However, the chemical therapy is still under development. Angiogenesis plays an important role in colon cancer development. We developed HMQ18-22 (a novel analog of taspine) with the aim to target angiogenesis. We found that HMQ18-22 significantly reduced angiogenesis of chicken chorioallantoic membrane (CAM) and mouse colon tissue, and inhibited cell migration and tube formation as well. Then, we verified the interaction between HMQ18-22 and VEGFR2 by AlphaScreen P-VEGFR assay, screened the targets on angiogenesis by VEGF Phospho Antibody Array, validated the target by western blot and RNAi in lovo cells. We found HMQ18-22 could decrease phosphorylation of VEGFR2(Tyr(1214)), VEGFR1(Tyr(1333)), Akt(Tyr(326)), protein kinase Cα (PKCα) (Tyr(657)) and phospholipase-Cγ-1 (PLCγ-1) (Tyr(771)). Most importantly, HMQ18-22 inhibited proliferation of lovo cell and tumor growth in a human colon tumor xenografted model of athymic mice. Compared with normal lovo cells proliferation, the inhibition on proliferation of knockdown cells (VEGFR2, VEGFR1, Akt, PKCα and PLCγ-1) by HMQ18-22 decreased. These results suggested that HMQ18-22 is a novel angiogenesis inhibitor and can be a useful therapeutic candidate for colon cancer intervention.

  18. Colorectal cancer stem cell and chemoresistant colorectal cancer cell phenotypes and increased sensitivity to Notch pathway inhibitor.

    Science.gov (United States)

    Huang, Rui; Wang, Guiyu; Song, Yanni; Tang, Qingchao; You, Qi; Liu, Zheng; Chen, Yinggang; Zhang, Qian; Li, Jiaying; Muhammand, Shan; Wang, Xishan

    2015-08-01

    Colorectal cancer stem cells (Co-CSCs) are a small subpopulation of tumor cells which have been proposed to be tumor-initiating cells in colorectal cancer (CRC) and to be implicated in resistance to standard chemotherapy. Chemoresistance is a common problem in the clinic. However, the interrelation between Co-CSCs and chemoresistant cells has yet to be elucidated. The present study investigated the Co-CSC phenotype in colonospheres and chemoresistant CRC cell lines and aimed to identify targets for therapy. Colonospheres and chemoresistant CRC cells were found to be enriched with the CSC markers CD133 and CD44, and exhibited similar phenotypes. Furthermore, it was found that Notch signaling may simultaneously regulate Co-CSCs and chemoresistant cells and may represent a novel strategy for targeting this pathway in CRC.

  19. Different pH-sensitivity patterns of 30 sodium channel inhibitors suggest chemically different pools along the access pathway

    Science.gov (United States)

    Lazar, Alexandra; Lenkey, Nora; Pesti, Krisztina; Fodor, Laszlo; Mike, Arpad

    2015-01-01

    The major drug binding site of sodium channels is inaccessible from the extracellular side, drug molecules can only access it either from the membrane phase, or from the intracellular aqueous phase. For this reason, ligand-membrane interactions are as important determinants of inhibitor properties, as ligand-protein interactions. One-way to probe this is to modify the pH of the extracellular fluid, which alters the ratio of charged vs. uncharged forms of some compounds, thereby changing their interaction with the membrane. In this electrophysiology study we used three different pH values: 6.0, 7.3, and 8.6 to test the significance of the protonation-deprotonation equilibrium in drug access and affinity. We investigated drugs of several different indications: carbamazepine, lamotrigine, phenytoin, lidocaine, bupivacaine, mexiletine, flecainide, ranolazine, riluzole, memantine, ritanserin, tolperisone, silperisone, ambroxol, haloperidol, chlorpromazine, clozapine, fluoxetine, sertraline, paroxetine, amitriptyline, imipramine, desipramine, maprotiline, nisoxetine, mianserin, mirtazapine, venlafaxine, nefazodone, and trazodone. We recorded the pH-dependence of potency, reversibility, as well as onset/offset kinetics. As expected, we observed a strong correlation between the acidic dissociation constant (pKa) of drugs and the pH-dependence of their potency. Unexpectedly, however, the pH-dependence of reversibility or kinetics showed diverse patterns, not simple correlation. Our data are best explained by a model where drug molecules can be trapped in at least two chemically different environments: A hydrophilic trap (which may be the aqueous cavity within the inner vestibule), which favors polar and less lipophilic compounds, and a lipophilic trap (which may be the membrane phase itself, and/or lipophilic binding sites on the channel). Rescue from the hydrophilic and lipophilic traps can be promoted by alkalic and acidic extracellular pH, respectively. PMID:26441665

  20. Different pH-sensitivity patterns of 30 sodium channel inhibitors suggest chemically different pools along the access pathway.

    Directory of Open Access Journals (Sweden)

    Alexandra eLazar

    2015-09-01

    Full Text Available The major drug binding site of sodium channels is inaccessible from the extracellular side, drug molecules can only access it either from the membrane phase, or from the intracellular aqueous phase. For this reason, ligand-membrane interactions are as important determinants of inhibitor properties, as ligand-protein interactions. One way to probe this is to modify the pH of the extracellular fluid, which alters the ratio of charged vs. uncharged forms of some compounds, thereby changing their interaction with the membrane. In this electrophysiology study we used three different pH values: 6.0, 7.3 and 8.6 to test the significance of the protonation-deprotonation equilibrium in drug access and affinity. We investigated drugs of several different indications: carbamazepine, lamotrigine, phenytoin, lidocaine, bupivacaine, mexiletine, flecainide, ranolazine, riluzole, memantine, ritanserin, tolperisone, silperisone, ambroxol, haloperidol, chlorpromazine, clozapine, fluoxetine, sertraline, paroxetine, amitriptyline, imipramine, desipramine, maprotiline, nisoxetine, mianserin, mirtazapine, venlafaxine, nefazodone and trazodone. We recorded the pH-dependence of potency, reversibility, as well as onset/offset kinetics. As expected, we observed a strong correlation between the acidic dissociation constant (pKa of drugs and the pH-dependence of their potency. Unexpectedly, however, the pH-dependence of reversibility or kinetics showed diverse patterns, not simple correlation. Our data are best explained by a model where drug molecules can be trapped in at least two chemically different environments: A hydrophilic trap (which may be the aqueous cavity within the inner vestibule, which favors polar and less lipophilic compounds, and a lipophilic trap (which may be the membrane phase itself, and/or lipophilic binding sites on the channel. Rescue from the hydrophilic and lipophilic traps can be promoted by alkalic and acidic extracellular pH, respectively.

  1. Severe autoimmune hemolytic anemia with renal neoplasm.

    Science.gov (United States)

    Rhodes, Emily C; Parikh, Sahil P; Bhattacharyya, Nishith

    2014-02-01

    Autoimmune hemolytic anemia is a type of hemolytic anemia characterized by autoantibodies directed against red blood cells shortening their survival. When autoimmune hemolytic anemia is secondary to a paraneoplastic process, severe anemia can occur leading to significant morbidity and even mortality. Here we discuss the literature and present the case of a child with autoimmune hemolytic anemia from a paraneoplastic syndrome secondary to a renal tumor.

  2. Anemia in the general population

    DEFF Research Database (Denmark)

    Martinsson, Andreas; Andersson, Charlotte; Andell, Pontus

    2014-01-01

    Low hemoglobin concentration is associated with increased mortality, but there is disagreement with regard to the clinical definition of anemia. We aimed to evaluate the prevalence, clinical correlates and association with total and cause-specific long-term mortality across the hemoglobin...... distribution and for previously proposed definitions of anemia. Blood hemoglobin concentration and mean corpuscular volume was measured in participants of the Malmö diet and cancer study-a prospective cohort study, and related to baseline characteristics and outcomes during follow-up. Primary endpoints were...... of anemia, hazard ratio: 1.36, 1.94 and 2.16 for hemoglobin

  3. Complexity generation in fungal peptidyl alkaloid biosynthesis: a two-enzyme pathway to the hexacyclic MDR export pump inhibitor ardeemin.

    Science.gov (United States)

    Haynes, Stuart W; Gao, Xue; Tang, Yi; Walsh, Christopher T

    2013-04-19

    Ardeemins are hexacyclic peptidyl alkaloids isolated from Aspergillus fischeri as agents that block efflux of anticancer drugs by MultiDrug Resistance (MDR) export pumps. To evaluate the biosynthetic logic and enzymatic machinery for ardeemin framework assembly, we sequenced the A. fischeri genome and identified the ardABC gene cluster. Through both genetic deletions and biochemical characterizations of purified ArdA and ArdB we show this ArdAB enzyme pair is sufficient to convert anthranilate (Ant), L-Ala, and L-Trp to ardeemin. ArdA is a 430 kDa trimodular nonribosomal peptide synthase (NRPS) that converts the three building blocks into a fumiquinazoline (FQ) regioisomer termed ardeemin FQ. ArdB is a prenyltransferase that takes tricyclic ardeemin FQ and dimethylallyl diphosphate to the hexacyclic ardeemin scaffold via prenylation at C2 of the Trp-derived indole moiety with intramolecular capture by an amide NH of the fumiquinazoline ring. The two-enzyme ArdAB pathway reveals remarkable efficiency in construction of the hexacyclic peptidyl alkaloid scaffold.

  4. L-F001, a novel multifunctional ROCK inhibitor, suppresses neuroinflammation in vitro and in vivo: Involvement of NF-κB inhibition and Nrf2 pathway activation.

    Science.gov (United States)

    Chen, Jingkao; Yin, Wei; Tu, Yalin; Wang, Shengnan; Yang, Xiaohong; Chen, Qiuhe; Zhang, Xiao; Han, Yifan; Pi, Rongbiao

    2017-03-16

    Microglia and astrocytes are largely responsible for inflammatory injury in the brain of Alzheimer's disease (AD). Increasing evidence has indicated that Rho kinase (ROCK) plays an important role in the regulation of neuroinflammation. Previously, we synthesized a new chemical entity L-F001 and proved its potential inhibitory effects on ROCK and oxidative stress. Here, we investigated the anti-inflammatory effects and the molecular mechanisms of L-F001 in vitro and in vivo. L-F001 remarkably suppressed lipopolysaccharides (LPS)-elevated expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as LPS-induced production of nitric oxide (NO), reactive oxygen species, interleukin-6 (IL-6) and tumor necreactive oxygen speciesis factor-α (TNF-α) in microglial BV-2 cells and in cultured astrocytes. Furthermore, L-F001 inhibited the degradation of IκB and nuclear translocation of nuclear factor kappa B (NF-κB) p65 subunit. Moreover, L-F001 induced the upregulation of heme-oxygenase-1 (HO-1) and glutamate cysteine ligase modifier subunit (GCLM) expression, two downstream effectors of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). It was interesting that L-F001 also activated phosphatidylinositol 3-kinase (PI3K) pathway and induced M1 (CD16/32, M1 marker)/ M2 (CD206, M2 maker) transition in BV-2 cells which was significantly blocked by a PI3K inhibitor, wortmannin. Finally, L-F001 markedly attenuated the level of pro-inflammatory mediators in a murine model of systemic acute brain inflammation induced by LPS. Taken together, these results indicate that the novel multifunctional ROCK inhibitor L-F001 suppresses neuroinflammation in vitro and in vivo via NF-κB inhibition and Nrf2 activation, suggesting that L-F001 may be a promising drug candidate for treating neuroinflammation-associated CNS diseases, including AD.

  5. Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model

    Energy Technology Data Exchange (ETDEWEB)

    Kurundkar, Deepali; Srivastava, Ritesh K.; Chaudhary, Sandeep C. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Ballestas, Mary E. [Department of Pediatrics Infectious Disease, Children' s of Alabama, School of Medicine, University of Alabama at Birmingham, AL (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, 6130 Executive Blvd., Suite 2114, Bethesda, MD 20892 (United States); Elmets, Craig A. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States)

    2013-01-15

    Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100 mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. -- Highlights: ► Vorinostat reduces SCC growth in a xenograft murine model. ► Vorinostat dampens proliferation and induces apoptosis in tumor cells. ► Diminution in mTOR, Akt and ERK signaling underlies inhibition in proliferation. ► Vorinostat by inhibiting HDACs inhibits epithelial–mesenchymal transition.

  6. Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis.

    Science.gov (United States)

    Iolascon, Achille; De Falco, Luigia; Beaumont, Carole

    2009-03-01

    Microcytic anemia is the most commonly encountered anemia in general medical practice. Nutritional iron deficiency and beta thalassemia trait are the primary causes in pediatrics, whereas bleeding disorders and anemia of chronic disease are common in adulthood. Microcytic hypochromic anemia can result from a defect in globin genes, in heme synthesis, in iron availability or in iron acquisition by the erythroid precursors. These microcytic anemia can be sideroblastic or not, a trait which reflects the implications of different gene abnormalities. Iron is a trace element that may act as a redox component and therefore is integral to vital biological processes that require the transfer of electrons as in oxygen transport, oxidative phosphorylation, DNA biosynthesis and xenobiotic metabolism. However, it can also be pro-oxidant and to avoid its toxicity, iron metabolism is strictly controlled and failure of these control systems could induce iron overload or iron deficient anemia. During the past few years, several new discoveries mostly arising from human patients or mouse models have highlighted the implication of iron metabolism components in hereditary microcytic anemia, from intestinal absorption to its final inclusion into heme. In this paper we will review the new information available on the iron acquisition pathway by developing erythrocytes and its regulation, and we will consider only inherited microcytosis due to heme synthesis or to iron metabolism defects. This information could be useful in the diagnosis and classification of these microcytic anemias.

  7. Adaptive response of the heart to long-term anemia induced by iron deficiency.

    Science.gov (United States)

    Naito, Yoshiro; Tsujino, Takeshi; Matsumoto, Mika; Sakoda, Tsuyoshi; Ohyanagi, Mitsumasa; Masuyama, Tohru

    2009-03-01

    Anemia is common in patients with chronic heart failure and an independent predictor of poor prognosis. Chronic anemia leads to left ventricular (LV) hypertrophy and heart failure, but its molecular mechanisms remain largely unknown. We investigated the mechanisms, including the molecular signaling pathway, of cardiac remodeling induced by iron deficiency anemia (IDA). Weanling Sprague-Dawley rats were fed an iron-deficient diet for 20 wk to induce IDA, and the molecular mechanisms of cardiac remodeling were evaluated. The iron-deficient diet initially induced severe anemia, which resulted in LV hypertrophy and dilation with preserved systolic function associated with increased serum erythropoietin (Epo) concentration. Cardiac STAT3 phosphorylation and VEGF gene expression increased by 12 wk of IDA, causing angiogenesis in the heart. Thereafter, sustained IDA induced upregulation of cardiac hypoxia inducible factor-1alpha gene expression and maintained upregulation of cardiac VEGF gene expression and cardiac angiogenesis; however, sustained IDA promoted cardiac fibrosis and lung congestion, with decreased serum Epo concentration and cardiac STAT3 phosphorylation after 20 wk of IDA compared with 12 wk. Upregulation of serum Epo concentration and cardiac STAT3 phosphorylation is associated with a beneficial adaptive mechanism of anemia-induced cardiac hypertrophy, and later decreased levels of these molecules may be critical for the transition from adaptive cardiac hypertrophy to cardiac dysfunction in long-term anemia. Understanding the mechanism of cardiac maladaptation to anemia may lead to a new strategy for treatment of chronic heart failure with anemia.

  8. ANEMIA DAN ANEMIA GIZI BESI PADA KEHAMILAN: HUBUNGANNYA DENGAN ASUPAN PROTEIN DAN ZAT GIZI MIKRO

    OpenAIRE

    Nur Handayani Utami; Bunga CH. Rosha

    2015-01-01

    Anemia masih menjadi permasalahan kesehatan pada wanita hamil. Zat besi dianggap sebagai salah satu zat gizi mikro yang berperan terhadap terjadinya anemia. Kekurangan gizi besi dalam tingkat lanjut dapat menyebabkan anemia, yang disebut sebagai anemia gizi besi. Tujuan studi ini adalah untuk menganalisis perbedaan antara asupan protein dan gizi mikro serta menghitung odd ratio (OR) kejadian anemia dan anemia gizi besi akibat asupan protein dan gizi mikro pada wanita hamil di lokasi studi. An...

  9. Diagnosis and treatment of sideroblastic anemias: from defective heme synthesis to abnormal RNA splicing.

    Science.gov (United States)

    Cazzola, Mario; Malcovati, Luca

    2015-01-01

    The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by the presence of ring sideroblasts in the bone marrow. X-linked sideroblastic anemia (XLSA) is caused by germline mutations in ALAS2. Hemizygous males have a hypochromic microcytic anemia, which is generally mild to moderate and is caused by defective heme synthesis and ineffective erythropoiesis. XLSA is a typical iron-loading anemia; although most patients are responsive to pyridoxine, treatment of iron overload is also important in the management of these patients. Autosomal recessive sideroblastic anemia attributable to mutations in SLC25A38, a member of the mitochondrial carrier family, is a severe disease: patients present in infancy with microcytic anemia, which soon becomes transfusion dependent. Conservative therapy includes regular red cell transfusion and iron chelation, whereas allogenic stem cell transplantation represents the only curative treatment. Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome characterized mainly by anemia attributable to ineffective erythropoiesis. The clinical course of RARS is generally indolent, but there is a tendency to worsening of anemia over time, so that most patients become transfusion dependent in the long run. More than 90% of these patients carry somatic mutations in SF3B1, a gene encoding a core component of the RNA splicing machinery. These mutations cause misrecognition of 3' splice sites in downstream genes, resulting in truncated gene products and/or decreased expression attributable to nonsense-mediated RNA decay; this explains the multifactorial pathogenesis of RARS. Variants of RARS include refractory cytopenia with multilineage dysplasia and ring sideroblasts, and RARS associated with marked thrombocytosis; these variants involve additional genetic lesions. Inhibitors of molecules of the transforming growth factor-β superfamily have been shown recently to target ineffective

  10. How Is Hemolytic Anemia Treated?

    Science.gov (United States)

    ... G6PD) deficiency can avoid substances that may trigger anemia. For example, avoid fava beans, naphthalene (a substance found in some moth balls), and certain ... INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA NO FEAR ACT OIG ...

  11. Malarial anemia and STAT6

    OpenAIRE

    Robson, Kathryn J.H.; Weatherall, David J

    2009-01-01

    Understanding the mechanisms behind malarial anemia should lead to new approaches to the management and treatment of children. In this perspective article Drs. Robson and Weatherall examine the pathophysiology of this condition. See related article on page 195.

  12. Autoimmune Hemolytic Anemia as a Complication of Nivolumab Therapy.

    Science.gov (United States)

    Palla, Amruth R; Kennedy, Devin; Mosharraf, Hossain; Doll, Donald

    2016-01-01

    Recently, immunotherapeutic drugs, including PD-1 inhibitors (nivolumab, pembrolizumab), PD-L1 inhibitors (atezolizumab, avelumab), and CTLA4 inhibitors (ipiliumumab), have emerged as important additions to the armamentarium against certain malignancies and have been incorporated into therapeutic protocols for first-, second-, or third-line agents for these metastatic cancers. Immune checkpoint inhibitor nivolumab is currently FDA approved for the treatment of patients with metastatic malignant melanoma [Redman et al.: BMC Med 2016;14: 20], metastatic non-small cell lung cancer [Guibert and Mazières: Expert Opin Biol Ther 2015;15: 1789-1797], metastatic renal cell cancer [Farolfi et al.: Expert Opin Drug Metab Toxicol 2016;12: 1089-1096], and relapsed or refractory classic Hodgkin's lymphoma [Villasboas and Ansell: Expert Rev Anticancer Ther 2016;16: 5-12]. Given the current and increasing indications for these drugs, it is essential for all physicians to become well versed with their common adverse effects and to be observant for other less documented clinical conditions that could be unmasked with the use of such medications. A definite association between autoimmune hemolytic anemia and the immune checkpoint inhibitor nivolumab has not been clearly documented, although a few cases have been reported recently [Kong et al.: Melanoma Res 2016;26: 202-204; Schwab et al.: Case Rep Oncol 2016;9: 373-378; Tardy et al.: Hematol Oncol 2016, DOI: 10.1002/hon.2338]. We report a case of fatal autoimmune hemolytic anemia refractory to steroids in a patient treated with nivolumab for metastatic lung cancer, and reflect on the other reported cases of autoimmune hemolytic anemia after the use of nivolumab.

  13. Sexuality and sickle cell anemia

    Directory of Open Access Journals (Sweden)

    Viviane de Almeida Côbo

    2013-01-01

    Full Text Available BACKGROUND: Sickle cell disease, the most common hereditary blood disease in the world, is the result of an atypical hemoglobin called S (Hb S which, when homozygous (Hb SS is the cause of sickle cell anemia. Changes of puberty, correlated with a delayed growth spurt, begin late in both male and female sickle cell anemia individuals with repercussions on sexuality and reproduction. The objectives of this exploratory and descriptive study were to characterize the development of sexuality in adults with sickle cell anemia by investigating the patient's perception of their sex life, as well as the information they had and needed on this subject. METHODS: Twenty male and female sickle cell anemia patients treated at the Hemocentro Regional de Uberaba (UFTM with ages between 19 and 47 years old were enrolled. A socioeconomic questionnaire and a semi-structured interview on sexuality, reproduction and genetic counseling were applied. RESULTS: This study shows that the sickle cell anemia patients lacked information on sexuality especially about the risks of pregnancy and the possible inheritance of the disease by their children. Moreover, the sexual life of the patients was impaired due to pain as well as discrimination and negative feelings experienced in close relationships. CONCLUSION: The health care of sickle cell anemia patients should take into account not only the clinical aspects of the disease, but also psychosocial aspects by providing counseling on sexuality, reproduction and genetics, in order to give this population the possibility of a better quality of life.

  14. Mieloma Múltiplo e anemia Multiple Myeloma and anemia

    Directory of Open Access Journals (Sweden)

    Rodolfo D. Cançado

    2007-03-01

    Full Text Available Anemia é uma complicação comum em pacientes com mieloma múltiplo (MM e ocorre em mais de 2/3 dos pacientes. Anemia de doença crônica, deficiência de eritropoetina (EPO devido à insuficiência renal e efeito mielossupressivo da quimioterapia são os principais mecanismos patofisiológicos que contribuem para o desenvolvimento de anemia no MM. Nos pacientes que obtêm remissão completa com tratamento quimioterápico, anemia usualmente se normaliza. Nos pacientes que não respondem ou apresentam recaída do mieloma, anemia freqüentemente persiste. As opções de tratamento dos pacientes anêmicos com MM incluem transfusões de hemácias e EPO recombinante humana. Essa proteína é biologicamente equivalente à EPO endógena e sua administração promove aumento dos valores de hemoglobina por tempo mais prolongado sem os riscos das transfusões de sangue. Vários estudos têm relatado melhora significante da eritropoese, redução da necessidade transfusional e melhora da qualidade de vida com o uso da EPO como tratamento a longo prazo da anemia associada ao mieloma. Nesse artigo, propomos o tratamento da anemia do MM baseado nas recomendações propostas pela Sociedade Americana de Hematologia (ASH em conjunto com a Sociedade Americana de Oncologia Clínica (ASCO, pela Organização Européia para Pesquisa e Tratamento do Câncer (EORTC, pelo IMF (Internacional Myeloma Foundation e pelo NCCN (National Comprehensive Cancer Network.Anemia is a common complication in patients with multiple myeloma (MM occurring in more than two thirds of all patients. Anemia of chronic diseases, erythropoietin (EPO deficiency due to renal impairment and the myelosuppressive effect of chemotherapy are the most important pathophysiological mechanisms contributing to the development of anemia in MM. In patients who achieve complete remission after chemotherapy, anemia usually normalizes. Non-responders and relapsing myeloma patients often continue to suffer

  15. The Nitrification Inhibitor Methyl 3-(4-Hydroxyphenyl)Propionate Modulates Root Development by Interfering with Auxin Signaling via the NO/ROS Pathway.

    Science.gov (United States)

    Liu, Yangyang; Wang, Ruling; Zhang, Ping; Chen, Qi; Luo, Qiong; Zhu, Yiyong; Xu, Jin

    2016-07-01

    Methyl 3-(4-hydroxyphenyl)propionate (MHPP) is a root exudate that functions as a nitrification inhibitor and as a modulator of the root system architecture (RSA) by inhibiting primary root (PR) elongation and promoting lateral root formation. However, the mechanism underlying MHPP-mediated modulation of the RSA remains unclear. Here, we report that MHPP inhibits PR elongation in Arabidopsis (Arabidopsis thaliana) by elevating the levels of auxin expression and signaling. MHPP induces an increase in auxin levels by up-regulating auxin biosynthesis, altering the expression of auxin carriers, and promoting the degradation of the auxin/indole-3-acetic acid family of transcriptional repressors. We found that MHPP-induced nitric oxide (NO) production promoted reactive oxygen species (ROS) accumulation in root tips. Suppressing the accumulation of NO or ROS alleviated the inhibitory effect of MHPP on PR elongation by weakening auxin responses and perception and by affecting meristematic cell division potential. Genetic analysis supported the phenotype described above. Taken together, our results indicate that MHPP modulates RSA remodeling via the NO/ROS-mediated auxin response pathway in Arabidopsis. Our study also revealed that MHPP significantly induced the accumulation of glucosinolates in roots, suggesting the diverse functions of MHPP in modulating plant growth, development, and stress tolerance in plants.

  16. A supersulfated low-molecular-weight heparin (IK-SSH) increases plasma levels of free and total tissue factor pathway inhibitor after intravenous and subcutaneous administration in humans.

    Science.gov (United States)

    Kaiser, B; Glusa, E; Hoppensteadt, D A; Breddin, H K; Amiral, J; Fareed, J

    1998-09-01

    Unfractionated as well as low-molecular-weight heparins (LMWH) are known to cause an increase in blood levels of tissue factor pathway inhibitor (TFPI). To study the effect of a newly developed supersulfated LMWH (IK-SSH, Iketon Farmaceutici) on TFPI concentrations in human plasma, the compound was injected into volunteers at doses of 0.14, 0.33 and 0.66 mg/kg intravenously or 0.33, 0.66 and 1.0 mg/kg subcutaneously. At certain known times blood was drawn and plasma levels of both total and free TFPI were measured using enzyme-linked immunosorbent assay methodology. Baseline plasma concentrations of TFPI were 72.2+/-3.1 ng/ml for total and 10.8+/-0.8 ng/ml for free TFPI. Intravenous or subcutaneous injection of IK-SSH led to a strong and long-lasting rise in TFPI levels which were increased more than 5-fold for total TFPI and more than 30-fold for free TFPI. Maximum TFPI levels were reached 5-10 min after intravenous and 60 min after subcutaneous administration. IK-SSH caused prolongation of ex-vivo clotting times in the APTT and Heptest assay, whereas thrombin time was not affected. Anticoagulant actions of IK-SSH showed a significant correlation to plasma concentrations of TFPI and they are thought to be based at least partially on the release of TFPI from vascular sites.

  17. Nedd8-activating enzyme inhibitor MLN4924 provides synergy with mitomycin C through interactions with ATR, BRCA1/BRCA2, and chromatin dynamics pathways.

    Science.gov (United States)

    Garcia, Khristofer; Blank, Jonathan L; Bouck, David C; Liu, Xiaozhen J; Sappal, Darshan S; Hather, Greg; Cosmopoulos, Katherine; Thomas, Michael P; Kuranda, Mike; Pickard, Michael D; Liu, Ray; Bandi, Syamala; Smith, Peter G; Lightcap, Eric S

    2014-06-01

    MLN4924 is an investigational small-molecule inhibitor of the Nedd8-activating enzyme currently in phase I clinical trials. MLN4924 induces DNA damage via rereplication in most cell lines. This distinct mechanism of DNA damage may affect its ability to combine with standard-of-care agents and may affect the clinical development of MLN4924. As such, we studied its interaction with other DNA-damaging agents. Mitomycin C, cisplatin, cytarabine, UV radiation, SN-38, and gemcitabine demonstrated synergy in combination with MLN4924 in vitro. The combination of mitomycin C and MLN4924 was shown to be synergistic in a mouse xenograft model. Importantly, depletion of genes within the ataxia telangiectasia and Rad3 related (ATR) and BRCA1/BRCA2 pathways, chromatin modification, and transcription-coupled repair reduced the synergy between mitomycin C and MLN4924. In addition, comet assay demonstrated increased DNA strand breaks with the combination of MLN4924 and mitomycin C. Our data suggest that mitomycin C causes stalled replication forks, which when combined with rereplication induced by MLN4924 results in frequent replication fork collisions, leading to cell death. This study provides a straightforward approach to understand the mechanism of synergy, which may provide useful information for the clinical development of these combinations.

  18. A targeted inhibitor of the complement alternative pathway reduces RPE injury and angiogenesis in models of age-related macular degeneration.

    Science.gov (United States)

    Rohrer, Bärbel; Long, Qin; Coughlin, Beth; Renner, Brandon; Huang, Yuxiang; Kunchithapautham, Kannan; Ferreira, Viviana P; Pangburn, Michael K; Gilkeson, Gary S; Thurman, Joshua M; Tomlinson, Stephen; Holers, V Michael

    2010-01-01

    Genetic variations in complement factor H (fH), an inhibitor of the complement alternative pathway (CAP), and oxidative stress are associated with age-related macular degeneration (AMD). Recently, novel complement therapeutics have been created with the capacity to be "targeted" to sites of complement activation. One example is our recombinant form of fH, CR2-fH, which consists of the N-terminus of mouse fH that contains the CAP-inhibitory domain, linked to a complement receptor 2 (CR2) targeting fragment that binds complement activation products. CR2-fH was investigated in vivo in the mouse model of choroidal neovascularization (CNV) and in vitro in oxidatively stressed RPE cell monolayers. RPE deterioration and CNV development were found to require CAP activation, and specific CAP inhibition by CR2-fH reduced the loss of RPE integrity and angiogenesis in CNV. In both the in vivo and in vitro paradigm of RPE damage, a model requiring molecular events known to be involved in AMD, complement-dependent VEGF production, was confirmed. These data may open new avenues for AMD treatment strategies.

  19. Feasibility and Safety of Local Treatment with Recombinant Human Tissue Factor Pathway Inhibitor in a Rat Model of Streptococcus pneumoniae Pneumonia.

    Directory of Open Access Journals (Sweden)

    Florry E van den Boogaard

    Full Text Available Pulmonary coagulopathy is intrinsic to pulmonary injury including pneumonia. Anticoagulant strategies could benefit patients with pneumonia, but systemic administration of anticoagulant agents may lead to suboptimal local levels and may cause systemic hemorrhage. We hypothesized nebulization to provide a safer and more effective route for local administration of anticoagulants. Therefore, we aimed to examine feasibility and safety of nebulization of recombinant human tissue factor pathway inhibitor (rh-TFPI in a well-established rat model of Streptococcus (S. pneumoniae pneumonia. Thirty minutes before and every 6 hours after intratracheal instillation of S. pneumonia causing pneumonia, rats were subjected to local treatment with rh-TFPI or placebo, and sacrificed after 42 hours. Pneumonia was associated with local as well as systemic activation of coagulation. Nebulization of rh-TFPI resulted in high levels of rh-TFPI in bronchoalveolar lavage fluid, which was accompanied by an attenuation of pulmonary coagulation. Systemic rh-TFPI levels remained undetectable, and systemic TFPI activity and systemic coagulation were not affected. Histopathology revealed no bleeding in the lungs. We conclude that nebulization of rh-TFPI seems feasible and safe; local anticoagulant treatment with rh-TFPI attenuates pulmonary coagulation, while not affecting systemic coagulation in a rat model of S. pneumoniae pneumonia.

  20. Feasibility and Safety of Local Treatment with Recombinant Human Tissue Factor Pathway Inhibitor in a Rat Model of Streptococcus pneumoniae Pneumonia.

    Science.gov (United States)

    van den Boogaard, Florry E; Hofstra, Jorrit J; van 't Veer, Cornelis; Levi, Marcel M; Roelofs, Joris J T H; van der Poll, Tom; Schultz, Marcus J

    2015-01-01

    Pulmonary coagulopathy is intrinsic to pulmonary injury including pneumonia. Anticoagulant strategies could benefit patients with pneumonia, but systemic administration of anticoagulant agents may lead to suboptimal local levels and may cause systemic hemorrhage. We hypothesized nebulization to provide a safer and more effective route for local administration of anticoagulants. Therefore, we aimed to examine feasibility and safety of nebulization of recombinant human tissue factor pathway inhibitor (rh-TFPI) in a well-established rat model of Streptococcus (S.) pneumoniae pneumonia. Thirty minutes before and every 6 hours after intratracheal instillation of S. pneumonia causing pneumonia, rats were subjected to local treatment with rh-TFPI or placebo, and sacrificed after 42 hours. Pneumonia was associated with local as well as systemic activation of coagulation. Nebulization of rh-TFPI resulted in high levels of rh-TFPI in bronchoalveolar lavage fluid, which was accompanied by an attenuation of pulmonary coagulation. Systemic rh-TFPI levels remained undetectable, and systemic TFPI activity and systemic coagulation were not affected. Histopathology revealed no bleeding in the lungs. We conclude that nebulization of rh-TFPI seems feasible and safe; local anticoagulant treatment with rh-TFPI attenuates pulmonary coagulation, while not affecting systemic coagulation in a rat model of S. pneumoniae pneumonia.

  1. Bisphenol A promotes X-linked inhibitor of apoptosis protein-dependent angiogenesis via G protein-coupled estrogen receptor pathway.

    Science.gov (United States)

    Liu, Jian; Jin, Xin; Zhao, Nana; Ye, Xiaolei; Ying, Chenjiang

    2015-11-01

    Bisphenol A (BPA), one of the high-volume chemicals worldwide, has a core structure resembling that of natural estradiol. Recent evidence has demonstrated that exposure to BPA has a relationship with the risk of cancer. The objective of our study is to investigate the mechanisms underlying the pro-angiogenic effects of BPA. We demonstrated that BPA markedly induces endothelial cell proliferation, migration and tube formation by activating endothelial nitric oxide synthase. BPA-induced nitric oxide generation appeared to be associated with the X-linked inhibitor of apoptosis protein (XIAP), which competes with endothelial nitric oxide synthase for caveolin-1. BPA was shown to exert its pro-angiogenic effect by upregulating XIAP expression via G protein-coupled estrogen receptor (ER) activation but not via ERα or ERβ. Our data suggest that 100 nM BPA promote angiogenesis in a G protein-coupled ER-dependent genomic pathway, and provide a novel insight into the potential role of XIAP in mediating the pro-angiogenic effects of BPA in endothelial cells.

  2. Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia.

    Directory of Open Access Journals (Sweden)

    J Pedro Fernández-Murray

    2016-01-01

    Full Text Available Sideroblastic anemias are acquired or inherited anemias that result in a decreased ability to synthesize hemoglobin in red blood cells and result in the presence of iron deposits in the mitochondria of red blood cell precursors. A common subtype of congenital sideroblastic anemia is due to autosomal recessive mutations in the SLC25A38 gene. The current treatment for SLC25A38 congenital sideroblastic anemia is chronic blood transfusion coupled with iron chelation. The function of SLC25A38 is not known. Here we report that the SLC25A38 protein, and its yeast homolog Hem25, are mitochondrial glycine transporters required for the initiation of heme synthesis. To do so, we took advantage of the fact that mitochondrial glycine has several roles beyond the synthesis of heme, including the synthesis of folate derivatives through the glycine cleavage system. The data were consistent with Hem25 not being the sole mitochondrial glycine importer, and we identify a second SLC25 family member Ymc1, as a potential secondary mitochondrial glycine importer. Based on these findings, we observed that high levels of exogenous glycine, or 5-aminolevulinic acid (5-Ala a metabolite downstream of Hem25 in heme biosynthetic pathway, were able to restore heme levels to normal in yeast cells lacking Hem25 function. While neither glycine nor 5-Ala could ameliorate SLC25A38 congenital sideroblastic anemia in a zebrafish model, we determined that the addition of folate with glycine was able to restore hemoglobin levels. This difference is likely due to the fact that yeast can synthesize folate, whereas in zebrafish folate is an essential vitamin that must be obtained exogenously. Given the tolerability of glycine and folate in humans, this study points to a potential novel treatment for SLC25A38 congenital sideroblastic anemia.

  3. What Are the Signs and Symptoms of Anemia?

    Science.gov (United States)

    ... Twitter. What Are the Signs and Symptoms of Anemia? The most common symptom of anemia is fatigue ( ... mild symptoms or none at all. Complications of Anemia Some people who have anemia may have arrhythmias ( ...

  4. Genetics Home Reference: iron-refractory iron deficiency anemia

    Science.gov (United States)

    ... refractory iron deficiency anemia iron-refractory iron deficiency anemia Enable Javascript to view the expand/collapse boxes. ... All Close All Description Iron-refractory iron deficiency anemia is one of many types of anemia , which ...

  5. Fanconi anemia and radiation

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, Asako; Komatsu, Kenshi [Hiroshima Univ. (Japan). Research Inst. for Nuclear Medicine and Biology

    1999-09-01

    Aplastic Fanconi anemia (FA) accompanying malformation was firstly reported in 1927. This review concerns the recent findings on FA. FA belongs to the chromosomal instability syndrome and its detailed molecular mechanism is still unknown. The disease has been defined to be highly sensitive to radiation, however, which is quite an important problem since irradiation with a large dose of radiation is required before its radical treatment (bone marrow transplantation). FA cells are also mitomycin C-sensitive and FA patients are said to be the mosaic of the sensitive and normal cells. This enables to classify FA into 8 types of A-H groups, whose genotypes (FAA-FAH, FANCA-FANCH) are becoming clear. However, the intracellular function of the FANC-expressed protein, although known to form a big complex, is not elucidated yet. There is an abnormality in DNA processing such as re-linkage of the double strand-broken DNA in FA cells. FA causal gene FANCG is found identical to XRCC9 which is associated to high sensitivity to radiation. Analysis of FANC genes will provide useful findings on molecular mechanism of DNA-repair. (K.H.)

  6. Hedgehog pathway inhibitor in combination with radiation therapy for basal cell carcinomas of the head and neck. First clinical experience with vismodegib for locally advanced disease

    Energy Technology Data Exchange (ETDEWEB)

    Schulze, Bjoern; Roedel, Claus; Balermpas, Panagiotis [University Hospital Johann Wolfgang Goethe University, Department of Radiation Oncology, Frankfurt (Germany); Meissner, Markus [University Hospital Johann Wolfgang Goethe University, Department of Dermatology, Frankfurt (Germany); Ghanaati, Shahram [University Hospital Johann Wolfgang Goethe University, Department of Craniofacial and Plastic Surgery, Frankfurt (Germany); Burck, Iris [University Hospital Johann Wolfgang Goethe University, Department of Diagnostic and Interventional Radiology, Frankfurt (Germany)

    2016-01-15

    Definitive radiotherapy and vismodegib, an oral inhibitor of the hedgehog pathway, are both established treatment options for locally advanced basal cell carcinomas (BCC). Both have shown good results in local tumor control; however, the effects concerning advanced tumors are often not of a lasting nature and to date no systematic data about the combination of the two modalities are available. We retrospectively analyzed four patients who received vismodegib and radiotherapy in combination. Radiation doses varied between 50.4 Gy and 66.0 Gy. Three patients had recurrent BCC. One patient had locoregional lymph node involvement. Vismodegib was taken once a day (150 mg) during the entire time of irradiation and beyond upon instructions of the attending dermatologist. In three cases a persistent complete response was observed, in one case the tumor remained stable for approximately 6 months until further tumor progression was documented. The combined therapy was well tolerated in all cases. No exceptional side effects pointing at a drug-radiation interaction were observed. The combination of vismodegib and radiation seems feasible and the initial results are promising. In our cohort, there was no increase in unexpected side effects. Further research is needed to evaluate the significance of this combined therapy. (orig.) [German] Sowohl definitive Radiotherapie als auch Vismodegib, ein oraler Inhibitor der Hedgehog-Signalkaskade, sind etablierte Behandlungsoptionen fuer lokal fortgeschrittene Basalzellkarzinome (BCC). Beide Therapien zeigen fuer sich gute Ansprechraten, aber die lokale Tumorkontrolle ist oft nicht dauerhaft und bis heute existieren kaum Daten ueber eine Kombination der beiden Modalitaeten. Wir analysierten retrospektiv vier Patientenfaelle nach simultaner Applikation von Vismodegib und Bestrahlung. Die Bestrahlungsdosis variierte zwischen 50,4 Gy und 66,0 Gy. Drei der Patienten hatten ein rezidiviertes BCC. Ein Patient hatte einen befallenen regionalen

  7. A rare cause of anemia due to upper gastrointestinal bleeding: Cameron lesion

    Directory of Open Access Journals (Sweden)

    Ismet Özaydın

    2014-01-01

    Full Text Available Asymptomatic large hiatal hernias may lead to iron deficiency anemia due to occult and massive bleeding from linear gastric erosions or ulcers on the mucosal folds at the level of the diaphragm called the Cameron lesions. The diagnosis is usually made during upper gastrointestinal system endoscopies. Current therapy includes the medication with proton pump inhibitors in combination with oral iron supplements and in some cases surgical reconstruction of hiatal hernia with fundoplication. We present a case of a 78-year-old woman who was admitted to the outpatient clinic with the diagnosis of iron deficiency anemia without signs of acute gastrointestinal bleeding. She was treated with medication and her follow-up gastroscopy showed a total cure. She is asymptomatic for two years after treatment with proton pump inhibitors and iron supplements. Cameron lesions should be kept in mind as an unusual cause of iron deficiency anemia due to gastrointestinal bleeding. 

  8. Anemia y enfermedad inflamatoria intestinal Anemia and inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    F. de la Morena

    2008-05-01

    Full Text Available La anemia es una de las complicaciones más comunes de la enfermedad inflamatoria intestinal. La alta frecuencia de valores bajos de hemoglobina en estos enfermos provoca en muchas ocasiones una infravaloración por parte del médico de esta circunstancia, lo que se traduce en la falta de un tratamiento eficaz. Por otro lado, el carácter complejo de los mecanismos de producción de la anemia en la enfermedad inflamatoria intestinal con frecuencia plantea dudas acerca del tratamiento más adecuado. La identificación correcta de los pacientes con anemia así como la instauración del tratamiento más idóneo serán los dos pilares fundamentales para la mejoría de la calidad de vida de los enfermos. El uso correcto de los suplementos de hierro y las nuevas formulaciones de hierro parenteral, con o sin eritropoyetina asociada, han revolucionado nuestro abordaje de esta complicación evolutiva de la enfermedad inflamatoria intestinalAnemia is a most common complication of inflammatory bowel disease. A high frequency of low hemoglobin values in these patients often leads physicians to subestimate this condition, which translates into ineffective treatment. On the other hand, the complex nature of anemia-inducing mechanisms in inflammatory bowel disease frequently raises doubt about the most appropriate therapy. A correct identification of patients with anemia, and adequate therapy are the essential pillars for improved quality of life. The right use of iron supplementation, and novel parenteral iron formulations, either with or without associated erythropoietin, have revolutionized our approach of this complication in the course of inflammatory bowel disease

  9. Classification of anemia for gastroenterologists.

    Science.gov (United States)

    Moreno Chulilla, Jose Antonio; Romero Colás, Maria Soledad; Gutiérrez Martín, Martín

    2009-10-07

    Most anemia is related to the digestive system by dietary deficiency, malabsorption, or chronic bleeding. We review the World Health Organization definition of anemia, its morphological classification (microcytic, macrocytic and normocytic) and pathogenic classification (regenerative and hypo regenerative), and integration of these classifications. Interpretation of laboratory tests is included, from the simplest (blood count, routine biochemistry) to the more specific (iron metabolism, vitamin B12, folic acid, reticulocytes, erythropoietin, bone marrow examination and Schilling test). In the text and various algorithms, we propose a hierarchical and logical way to reach a diagnosis as quickly as possible, by properly managing the medical interview, physical examination, appropriate laboratory tests, bone marrow examination, and other complementary tests. The prevalence is emphasized in all sections so that the gastroenterologist can direct the diagnosis to the most common diseases, although the tables also include rare diseases. Digestive diseases potentially causing anemia have been studied in preference, but other causes of anemia have been included in the text and tables. Primitive hematological diseases that cause anemia are only listed, but are not discussed in depth. The last section is dedicated to simplifying all items discussed above, using practical rules to guide diagnosis and medical care with the greatest economy of resources and time.

  10. Who Is at Risk for Anemia?

    Science.gov (United States)

    ... history of inherited anemia, such as sickle cell anemia or thalassemia Rate This Content: NEXT >> Updated: May 18, 2012 Twitter Facebook YouTube Google+ SITE INDEX ACCESSIBILITY PRIVACY STATEMENT FOIA NO FEAR ACT OIG ...

  11. Undetectable Glycosylated Hemoglobin in Autoimmune Hemolytic Anemia

    OpenAIRE

    Mitani, Noriyuki; Taguchi, Akihiko; Sakuragi, Shizu; Matsui, Kumiko; Tanaka, Yoshinori; Matsuda, Kazuhiro; Shinohara, Kenji

    2005-01-01

    We encountered two cases of autoimmune hemolytic anemia (AIHA) with undetectable glycosylated hemoglobin (HbA1C) level at diagnosis. Hemolytic anemia improved by administration of prednisolone (PSL) and HbA1C became measurable after response.

  12. FastStats: Anemia or Iron Deficiency

    Science.gov (United States)

    ... this? Submit What's this? Submit Button NCHS Home Anemia or Iron Deficiency Recommend on Facebook Tweet Share ... visits Number of visits to emergency departments with anemia as the primary hospital discharge diagnosis: 146,000 ...

  13. Genetics Home Reference: congenital dyserythropoietic anemia

    Science.gov (United States)

    ... Understand Genetics Home Health Conditions CDA congenital dyserythropoietic anemia Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Congenital dyserythropoietic anemia ( CDA ) is an inherited blood disorder that affects ...

  14. Anemia caused by low iron - children

    Science.gov (United States)

    ... Disorders of iron and copper metabolism, the sideroblastic anemias, and lead toxicity. In: Orkin SH, Fisher DE, Ginsburg D, ... Philadelphia, PA: Elsevier; 2016:chap 455. Read More Anemia Hemoglobin Lead poisoning Review Date 2/11/2016 Updated by: ...

  15. Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response.

    Science.gov (United States)

    Richardson, Chanté L; Delehanty, Lorrie L; Bullock, Grant C; Rival, Claudia M; Tung, Kenneth S; Kimpel, Donald L; Gardenghi, Sara; Rivella, Stefano; Goldfarb, Adam N

    2013-08-01

    The unique sensitivity of early red cell progenitors to iron deprivation, known as the erythroid iron restriction response, serves as a basis for human anemias globally. This response impairs erythropoietin-driven erythropoiesis and underlies erythropoietic repression in iron deficiency anemia. Mechanistically, the erythroid iron restriction response results from inactivation of aconitase enzymes and can be suppressed by providing the aconitase product isocitrate. Recent studies have implicated the erythroid iron restriction response in anemia of chronic disease and inflammation (ACDI), offering new therapeutic avenues for a major clinical problem; however, inflammatory signals may also directly repress erythropoiesis in ACDI. Here, we show that suppression of the erythroid iron restriction response by isocitrate administration corrected anemia and erythropoietic defects in rats with ACDI. In vitro studies demonstrated that erythroid repression by inflammatory signaling is potently modulated by the erythroid iron restriction response in a kinase-dependent pathway involving induction of the erythroid-inhibitory transcription factor PU.1. These results reveal the integration of iron and inflammatory inputs in a therapeutically tractable erythropoietic regulatory circuit.

  16. Retkulocyte production index in various anemia

    OpenAIRE

    Setyawati, Setyawati

    2015-01-01

    Background: Reticulocyte production index (IPR) is used to determine the classification of functional anemia. More specific laboratory parameters are used in managing patient. There were some inappropriate of IPR correlation with the diagnosis of anemia in clinical practice.Objectives: The study was designed to know normal hematocrit in Sardjito General Hospital, to determine IPR in various anemia and to compare with standard IPR and final diagnosis in anemia. Methods: Observational study was...

  17. Manifestasi Anemia Pernisiosa Di Rongga Mulut

    OpenAIRE

    Nona Aini

    2008-01-01

    Anemia pernisiosa adalah salah satu penyakit kronis berupa berkurangnya produksi sel darah merah akibat defisiensi vitamin 812 dan asam folat, Salah satu fungsi vitamin 812 adalah untuk pembentukan sel darah merah di dalam sum-sum tulang menjadi aktif. Akibat defisiensi vitamin 812 dapat menyebabkan terganggunya sintesa DNA dan RNA. Terganggunya sintesa DNA akan menyebabkan anemia di sum-sum tulang dalam bentuk anemia makrositik dan di dalam darah dalam bentuk anemia megaloblastik. Sedangk...

  18. The mechanism of action of the histone deacetylase inhibitor vorinostat involves interaction with the insulin-like growth factor signaling pathway.

    Directory of Open Access Journals (Sweden)

    Rive Sarfstein

    Full Text Available A correlation between components of the insulin-like growth factor (IGF system and endometrial cancer risk has been shown in recent studies. The antitumor action of vorinostat, a histone deacetylase inhibitor, involves changes in the expression of specific genes via acetylation of histones and transcription factors. The aim of this study was to establish whether vorinostat can modify the expression of specific genes related to the IGF-I receptor (IGF-IR signaling pathway and revert the transformed phenotype. Human endometrioid (Type I, Ishikawa and uterine serous papillary (Type II, USPC-2 endometrial cancer cell lines were treated with vorinostat in the presence or absence of IGF-I. Vorinostat increased IGF-IR phosphorylation, produced acetylation of histone H3, up-regulated pTEN and p21 expression, and reduced p53 and cyclin D1 levels in Ishikawa cells. Vorinostat up-regulated IGF-IR and p21 expression, produced acetylation of histone H3, and down-regulated the expression of total AKT, pTEN and cyclin D1 in USPC-2 cells. Of interest, IGF-IR activation was associated with a major elevation in IGF-IR promoter activity. In addition, vorinostat treatment induced apoptosis in both cell lines and abolished the anti-apoptotic activity of IGF-I both in the absence or presence of a humanized monoclonal IGF-IR antibody, MK-0646. Finally, vorinostat treatment led to a significant decrease in proliferation and colony forming capability in both cell lines. In summary, our studies demonstrate that vorinostat exhibits a potent apoptotic and anti-proliferative effect in both Type I and II endometrial cancer cells, thus suggesting that endometrial cancer may be therapeutically targeted by vorinostat.

  19. Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signaling pathways.

    Science.gov (United States)

    Farabegoli, F; Vettraino, M; Manerba, M; Fiume, L; Roberti, M; Di Stefano, G

    2012-11-20

    Galloflavin (GF), a recently identified lactate dehydrogenase inhibitor, hinders the proliferation of cancer cells by blocking glycolysis and ATP production. The aim of the present experiments was to study the effect of this compound on breast cancer cell lines reproducing different pathological subtypes of this tumor: MCF-7 (the well differentiated form), MDA-MB-231 (the aggressive triple negative tumor) and MCF-Tam (a sub-line of MCF-7 with acquired tamoxifen resistance). We observed marked differences in the energetic metabolism of these cell lines. Compared to MCF-7 cells, both MDA-MB-231 and MCF-Tam cells exhibited higher LDH levels and glucose uptake and showed lower capacity of oxygen consumption. In spite of these differences, GF exerted similar growth inhibitory effects. This result was explained by the finding of a constitutively activated stress response in MDA-MB-231 and MCF-Tam cells, which reproduce the poor prognosis tumor forms. As a further proof, different signaling pathways were found to be involved in the antiproliferative action of GF. In MCF-7 cells we observed a down regulation of the ERα-mediated signaling needed for cell survival. On the contrary, in MCF-Tam and MDA-MB-231 cells growth inhibition appeared to be contributed by an oxidative stress condition. The prevalent mechanism of cell death was found to be apoptosis induction. Because of the clinical relevance of breast cancer forms having the triple negative and/or chemoresistant phenotype, our results showing comparable effects of GF even on aggressively growing cells encourage further studies to verify the potential of this compound in improving the chemotherapy of breast cancer.

  20. Iron deficiency anemia in children.

    Science.gov (United States)

    Subramaniam, Girish; Girish, Meenakshi

    2015-06-01

    Iron deficiency is not just anemia; it can be responsible for a long list of other manifestations. This topic is of great importance, especially in infancy and early childhood, for a variety of reasons. Firstly, iron need is maximum in this period. Secondly, diet in infancy is usually deficient in iron. Thirdly and most importantly, iron deficiency at this age can result in neurodevelopmental and cognitive deficits, which may not be reversible. Hypochromia and microcytosis in a complete blood count (CBC) makes iron deficiency anemia (IDA) most likely diagnosis. Absence of response to iron should make us look for other differential diagnosis like β thalassemia trait and anemia of chronic disease. Celiac disease is the most important cause of true IDA not responding to oral iron therapy. While oral ferrous sulphate is the cheapest and most effective therapy for IDA, simple nonpharmacological and pharmacological measures can go a long way in prevention of iron deficiency.

  1. Pernicious Anemia with Autoimmune Hemolytic Anemia: A Case Report and Literature Review

    OpenAIRE

    Sri Lakshmi Hyndavi Yeruva; Raj Pal Manchandani; Patricia Oneal

    2016-01-01

    Pernicious anemia is a common cause of vitamin B12 deficiency. Here, we discuss a case of a young woman who presented with severe anemia along with a history of iron deficiency anemia. After a review of her clinical presentation and laboratory data, we identified an autoimmune hemolytic anemia and a concomitant pernicious anemia. The concurrence of both these hematological diagnoses in a patient is rare.

  2. Pernicious Anemia with Autoimmune Hemolytic Anemia: A Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Sri Lakshmi Hyndavi Yeruva

    2016-01-01

    Full Text Available Pernicious anemia is a common cause of vitamin B12 deficiency. Here, we discuss a case of a young woman who presented with severe anemia along with a history of iron deficiency anemia. After a review of her clinical presentation and laboratory data, we identified an autoimmune hemolytic anemia and a concomitant pernicious anemia. The concurrence of both these hematological diagnoses in a patient is rare.

  3. Syngeneic transplantation in aplastic anemia

    DEFF Research Database (Denmark)

    Gerull, Sabine; Stern, Martin; Apperley, Jane

    2013-01-01

    Aplastic anemia is usually treated with immunosuppression or allogeneic transplant, depending on patient and disease characteristics. Syngeneic transplant offers a rare treatment opportunity with minimal transplant-related mortality, and offers an insight into disease mechanisms. We present here...... a retrospective analysis of all syngeneic transplants for aplastic anemia reported to the European Group for Blood and Marrow Transplantation. Between 1976 and 2009, 88 patients received 113 transplants. Most transplants (n=85) were preceded by a conditioning regimen, 22 of these including anti-thymocyte globulin...

  4. Anemia and survival in human immunodeficiency virus

    DEFF Research Database (Denmark)

    Lundgren, Jens Dilling; Mocroft, Amanda

    2003-01-01

    The prospective, multicenter cohort study EuroSIDA has previously reported on predictors and outcomes of anemia in patients infected with human immunodeficiency virus. In a Cox proportional-hazards model with serial measures of CD4+ cell count, plasma viral load, and degrees of anemia fitted...... as time-dependent variables, the relative hazard of death increased markedly for patients with anemia versus no anemia. A clinical scoring system was developed and validated for patients receiving highly active antiretroviral therapy using the most recent laboratory measures. Mild and severe anemia were...... independently (Panemia. The mechanisms underlying why hemoglobin is such a strong prognostic...

  5. Hubungan Anemia Defisiensi Besi Terhadap Gangguan Konsentrasi

    OpenAIRE

    Meutirani, Riska

    2015-01-01

    Iron deficiency anemia is dedecrease in the number of red blood cells caused by too little iron. Iron deficiency anemia is the most common form of anemia. About 20% of women, 50% of pregnant womenand 3% of men do not have enough iron on their body. Anemia develops slowly after the normal iron stores in the body and bone marrowhave run out. In general, womwn have smaller stores of iron than men because they lose more through menstruation. Iron deficiency anemia may also be caused by poor absor...

  6. Iron deficiency anemia in sports and preventive dietetic and nutrition interventions

    Directory of Open Access Journals (Sweden)

    Aritz Urdampilleta

    2013-12-01

    Full Text Available Iron deficiency anemia in athletes is a very common condition that leads to reduced physical performance. Athletes are susceptible of falling iron deposits, mainly by an increase in its use, by its loss, or by insufficient intake. The present review aims to establish the basis of current knowledge environment: sports-athletes who have increased risk of anemia, etiology of iron deficiency anemia in the sporting group, providing dietary and nutritional guidelines for its prevention. The databases searched were Pubmed, Scirus and Scielo, as well as the official pages of prestigious organizations, recovering items by keywords: “iron-deficiency anemia”, “sports”, “athletic performance”, “iron intake “or Spanish counterparts. Iron deficiency anemia affects mainly endurance athletes (especially women and marathon and the members of team sports with high impact (volleyball and handball. Usually secondary anemias from hemolysis and oxidative stress resulting from the practice of sport, but it cases have also been documented by increased iron losses associated with exercise. Dietary and nutritional practices to prevent iron deficiency anemia in athletes should aim to ensure: carbohydrate intake between 60-65% of total energy daily minimum intake of 1.4 g of protein per day and a consumption of 20-40 mg iron daily, separating the intake of the main absorption inhibitors (phytate, tanetos and calcium. You need assessed by analytical iron status of the athlete every 2-3 months.

  7. Hereditary sideroblastic anemia: pathophysiology and gene mutations.

    Science.gov (United States)

    Harigae, Hideo; Furuyama, Kazumichi

    2010-10-01

    Sideroblastic anemia is characterized by anemia with the emergence of ring sideroblasts in the bone marrow. Ring sideroblasts are erythroblasts characterized by iron accumulation in perinuclear mitochondria due to impaired iron utilization. There are two forms of sideroblastic anemia, i.e., inherited and acquired sideroblastic anemia. Inherited sideroblastic anemia is a rare and heterogeneous disease caused by mutations of genes involved in heme biosynthesis, iron-sulfur (Fe-S) cluster biogenesis, or Fe-S cluster transport, and mitochondrial metabolism. The most common inherited sideroblastic anemia is X-linked sideroblastic anemia (XLSA) caused by mutations of the erythroid-specific δ-aminolevulinate synthase gene (ALAS2), which is the first enzyme of heme biosynthesis in erythroid cells. Sideroblastic anemia due to SLC25A38 gene mutations, which is a mitochondrial transporter, is the next most common inherited sideroblastic anemia. Other forms of inherited sideroblastic anemia are very rare, and accompanied by impaired function of organs other than hematopoietic tissue, such as the nervous system, muscle, or exocrine glands due to impaired mitochondrial metabolism. Moreover, there are still significant numbers of cases with genetically undefined inherited sideroblastic anemia. Molecular analysis of these cases will contribute not only to the development of effective treatment, but also to the understanding of mitochondrial iron metabolism.

  8. Sickle Cell Anemia (For Teens)

    Science.gov (United States)

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Sickle Cell Disease KidsHealth > For Teens > Sickle Cell Disease Print ... Stay Well? en español Anemia falciforme What Is Sickle Cell Disease? Sickle cell disease is a blood disorder ...

  9. Cooley's Anemia: A Psychosocial Directory.

    Science.gov (United States)

    National Center for Education in Maternal and Child Health, Washington, DC.

    The directory is intended to aid patients and their families who are coping with the genetic disorder of Cooley's anemia. A brief review of the disease covers background, genetics, symptoms, effect on the patient, treatment, and current research. The next section looks at psychosocial needs at various times (time of diagnosis, infancy and toddler…

  10. Acquired aplastic anemia in children.

    Science.gov (United States)

    Hartung, Helge D; Olson, Timothy S; Bessler, Monica

    2013-12-01

    This article provides a practice-based and concise review of the etiology, diagnosis, and management of acquired aplastic anemia in children. Bone marrow transplantation, immunosuppressive therapy, and supportive care are discussed in detail. The aim is to provide the clinician with a better understanding of the disease and to offer guidelines for the management of children with this uncommon yet serious disorder.

  11. Management of Iron Deficiency Anemia

    Science.gov (United States)

    Jimenez, Kristine; Kulnigg-Dabsch, Stefanie

    2015-01-01

    Anemia affects one-fourth of the world’s population, and iron deficiency is the predominant cause. Anemia is associated with chronic fatigue, impaired cognitive function, and diminished well-being. Patients with iron deficiency anemia of unknown etiology are frequently referred to a gastroenterologist because in the majority of cases the condition has a gastrointestinal origin. Proper management improves quality of life, alleviates the symptoms of iron deficiency, and reduces the need for blood transfusions. Treatment options include oral and intravenous iron therapy; however, the efficacy of oral iron is limited in certain gastrointestinal conditions, such as inflammatory bowel disease, celiac disease, and autoimmune gastritis. This article provides a critical summary of the diagnosis and treatment of iron deficiency anemia. In addition, it includes a management algorithm that can help the clinician determine which patients are in need of further gastrointestinal evaluation. This facilitates the identification and treatment of the underlying condition and avoids the unnecessary use of invasive methods and their associated risks. PMID:27099596

  12. Iron deficiency anemia in children

    OpenAIRE

    Pochinok, T. V.

    2016-01-01

    In the article the role of iron in the human body is highlighted. The mechanism of development of iron deficiency states, their consequences and the basic principles of diagnosis and correction of children of different ages are shown.Key words: children, iron deficiency anemia, treatment.

  13. [Neuropsychiatric manifestations ushering pernicious anemia].

    Science.gov (United States)

    Mrabet, S; Ellouze, F; Ellini, S; Mrad, M F

    2015-12-01

    Biermer disease or pernicious anemia is an autoimmune atrophic gastritis characterized by the lack of secretion of gastric intrinsic factor. This leads to an insufficient absorption of vitamin B12 in the ileum. Clinical manifestations are mainly hematologic. Neuropsychiatric manifestations are known but are less frequent especially early in the disease. Inaugural neuropsychiatric arrays are rare and various thus making diagnosis difficult. In this article, we report through two clinical cases different neuropsychiatric manifestations revealing pernicious anemia. Mrs. C.O., aged 56, presented after surgery for gallstones, an acute psychiatric array associated with gait disorders. She had no history of neurological or psychiatric problems. The psychiatric interview revealed delirious syndrome, depressive symptoms and anxiety. Neurological examination noted a flaccid paraplegia with peripheral neuropathic syndrome and myoclonus in the upper limbs. At the full blood count, a macrocytosis (VGM: 112.2fl) without anemia was found. The level of vitamin B12 in the blood was low. Cerebro-spinal MRI was suggestive of a neuro-Biermer and showed hyper signal in the cervical cord on T2-weighted sagittal section. In axial section, hyper signal appears at the posterior columns in the form of V. There were no brain abnormalities. A sensorimotor axonal polyneuropathy was diagnosed. The patient received vitamin B12 intramuscularly for ten days associated with neuroleptic treatment. Mrs. R.M., aged 40, was brought to the psychiatry consultation for acute behavioral disorders progressively worsening over a month. An anxiety syndrome, depressive syndrome and delirious syndrome were identified. Neurological examination showed a posterior cordonal syndrome with quadripyramidal syndrome. Full blood count showed a macrocytic anemia. Serum B12 level was collapsed. Cerebro-spinal MRI was normal. She received vitamin B12 with clinical and biological improvement. Features of pernicious anemia

  14. Matrix metalloproteinase 13 (MMP13) and tissue inhibitor of matrix metalloproteinase 1 (TIMP1), regulated by the MAPK pathway, are both necessary for Madin-Darby canine kidney tubulogenesis.

    Science.gov (United States)

    Hellman, Nathan E; Spector, June; Robinson, Jonathan; Zuo, Xiaofeng; Saunier, Sophie; Antignac, Corinne; Tobias, John W; Lipschutz, Joshua H

    2008-02-15

    A classic model of tubulogenesis utilizes Madin-Darby canine kidney (MDCK) cells. MDCK cells form monoclonal cysts in three-dimensional collagen and tubulate in response to hepatocyte growth factor, which activates multiple signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway. It was shown previously that MAPK activation is necessary and sufficient to induce the first stage of tubulogenesis, the partial epithelial to mesenchymal transition (p-EMT), whereas matrix metalloproteinases (MMPs) are necessary for the second redifferentiation stage. To identify specific MMP genes, their regulators, tissue inhibitors of matrix metalloproteinases (TIMPs), and the molecular pathways by which they are activated, we used two distinct MAPK inhibitors and a technique we have termed subtraction pathway microarray analysis. Of the 19 MMPs and 3 TIMPs present on the Canine Genome 2.0 Array, MMP13 and TIMP1 were up-regulated 198- and 169-fold, respectively, via the MAPK pathway. This was confirmed by two-dimensional and three-dimensional real time PCR, as well as in MDCK cells inducible for the MAPK gene Raf. Knockdown of MMP13 using short hairpin RNA prevented progression past the initial phase of p-EMT. Knockdown of TIMP1 prevented normal cystogenesis, although the initial phase of p-EMT did occasionally occur. The MMP13 knockdown phenotype is likely because of decreased collagenase activity, whereas the TIMP1 knockdown phenotype appears due to increased apoptosis. These data suggest a model, which may also be important for development of other branched organs, whereby the MAPK pathway controls both MDCK p-EMT and redifferentiation, in part by activating MMP13 and TIMP1.

  15. DNA replication arrest in XP variant cells after UV exposure is diverted into an Mre11-dependent recombination pathway by the kinase inhibitor wortmannin

    Energy Technology Data Exchange (ETDEWEB)

    Limoli, C.L.; Laposa, R.; Cleaver, J.E

    2002-12-29

    Ultraviolet (UV) irradiation produces DNA photoproducts that are blocks to DNA replication by normal replicative polymerases. A specialized, damage-specific, distributive polymerase, Pol H or Pol h, that is the product of the hRad30A gene, is required for replication past these photoproducts. This polymerase is absent from XP variant (XP-V) cells that must employ other mechanisms to negotiate blocks to DNA replication. These mechanisms include the use of alternative polymerases or recombination between sister chromatids. Replication forks arrested by UV damage in virus transformed XP-V cells degrade into DNA double strand breaks that are sites for recombination, but in normal cells arrested forks may be protected from degradation by p53 protein. These breaks are sites for binding a protein complex, hMre11/hRad50/Nbs1, that colocalizes with H2AX and PCNA, and can be visualized as immunofluorescent foci. The protein complexes need phosphorylation to activate their DNA binding capacity. Incubation of UV irradiated XP-V cells with the irreversible kinase inhibitor wortmannin, however, increased the yield of Mre11 focus-positive cells. One interpretation of this observation is that two classes of kinases are involved after UV irradiation. One would be a wortmannin-resistant kinase that phosphorylates the Mre11 complex. The other would be a wortmannin-sensitive kinase that phosphorylates and activates the p53/large T in SV40 transformed XP-V cells. The sensitive class corresponds to the PI3-kinases of ATM, ATR, and DNA-PK, but the resistant class remains to be identified. Alternatively, the elevated yield of Mre11 foci positive cells following wortmannin treatment may reflect an overall perturbation to the signaling cascades regulated by wortmannin-sensitive PI3 related kinases. In this scenario, wortmannin could compromise damage inducible-signaling pathways that maintain the stability of stalled forks, resulting in a further destabilization of stalled forks that then

  16. Complement inhibitors to treat IgM-mediated autoimmune hemolysis.

    Science.gov (United States)

    Wouters, Diana; Zeerleder, Sacha

    2015-11-01

    Complement activation in autoimmune hemolytic anemia may exacerbate extravascular hemolysis and may occasionally result in intravascular hemolysis. IgM autoantibodies as characteristically found in cold autoantibody autoimmune hemolytic anemia, in cold agglutinin disease but also in a considerable percentage of patients with warm autoantibodies are very likely to activate complement in vivo. Therapy of IgM-mediated autoimmune hemolytic anemia mainly aims to decrease autoantibody production. However, most of these treatments require time to become effective and will not stop immediate ongoing complement-mediated hemolysis nor prevent hemolysis of transfused red blood cells. Therefore pharmacological inhibition of the complement system might be a suitable approach to halt or at least attenuate ongoing hemolysis and improve the recovery of red blood cell transfusion in autoimmune hemolytic anemia. In recent years, several complement inhibitors have become available in the clinic, some of them with proven efficacy in autoimmune hemolytic anemia. In the present review, we give a short introduction on the pathogenesis of autoimmune hemolytic anemia, followed by an overview on the complement system with a special focus on its regulation. Finally, we will discuss complement inhibitors with regard to their potential efficacy to halt or attenuate hemolysis in complement-mediated autoimmune hemolytic anemia.

  17. Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria.

    Science.gov (United States)

    Blouin, Jean-Marc; Duchartre, Yann; Costet, Pierre; Lalanne, Magalie; Ged, Cécile; Lain, Ana; Millet, Oscar; de Verneuil, Hubert; Richard, Emmanuel

    2013-11-05

    Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder characterized by uroporphyrinogen III synthase (UROS) deficiency resulting in massive porphyrin accumulation in blood cells, which is responsible for hemolytic anemia and skin photosensitivity. Among the missense mutations actually described up to now in CEP patients, the C73R and the P248Q mutations lead to a profound UROS deficiency and are usually associated with a severe clinical phenotype. We previously demonstrated that the UROS(C73R) mutant protein conserves intrinsic enzymatic activity but triggers premature degradation in cellular systems that could be prevented by proteasome inhibitors. We show evidence that the reduced kinetic stability of the UROS(P248Q) mutant is also responsible for increased protein turnover in human erythroid cells. Through the analysis of EGFP-tagged versions of UROS enzyme, we demonstrate that both UROS(C73R) and UROS(P248Q) are equally destabilized in mammalian cells and targeted to the proteasomal pathway for degradation. We show that a treatment with proteasomal inhibitors, but not with lysosomal inhibitors, could rescue the expression of both EGFP-UROS mutants. Finally, in CEP mice (Uros(P248Q/P248Q)) treated with bortezomib (Velcade), a clinically approved proteasome inhibitor, we observed reduced porphyrin accumulation in circulating RBCs and urine, as well as reversion of skin photosensitivity on bortezomib treatment. These results of medical importance pave the way for pharmacologic treatment of CEP disease by preventing certain enzymatically active UROS mutants from early degradation by using proteasome inhibitors or chemical chaperones.

  18. Anemia in peritoneal dialysis patients

    Directory of Open Access Journals (Sweden)

    Laušević Mirjana

    2006-01-01

    Full Text Available A normocytic normochromic anemia is one of the first signs of renal failure. Since anemia increases morbidity and mortality, its elimination is one of the essential objectives of the treatment. Human recombinant erythropoietin (rHuEPO has changed the therapeutical approach to anemia. The aim of the present study was to compare efficacy of anemia correction in peritoneal dialysis patients depending on treatment and dialysis modality. The study is the retrospective analysis of 64 patients who presented to our Clinic in 2003. Eighteen (28.13% patients were treated with rHuEPO, 14 (28% underwent continuous ambulatory peritoneal dialysis (CAPD, 2 (100% - automated peritoneal dialysis (APD and 2 (33.3% - intermittent peritoneal dialysis (IPD. Mean hemoglobin level was 98.6±17.82 g/l in patients treated with rHuEPO versus 98.81±15.14 g/I in patients without rHuEPO treatment. Erythropoietin requirements were 3392.85±1211.77 IU/week. AII patients received iron supplementation during rHuEPO therapy. Mean serum ferritin levels were 463.41 ±360 μg/l. Transferrin saturation (TSAT was 0.35±0.16%. No difference of serum iron and TSAT levels was found between CAPD and IPD patients. The degree of anemia significantly differed between CAPD and IPD patients. A total of 17.11% of PD patients were given blood transfusions, most frequently during the first three months after the onset of dialysis. Our conclusion is that the number of patients receiving rHuEPO should be increased, as 50% of our patients should be substituted, while only 28% are being treated. As 50% of patients receiving rHuEPO failed to reach target Hgb levels, higher EPO doses should be considered. Iron stores should be continuously monitored, particularly in patients receiving rHuEPO, since iron deficiency is an important problem for patients undergoing peritoneal dialysis, especially during erythropoietin therapy. Oral iron supplementation is satisfactory in the majority of patients, and

  19. Research progress of Sonic Hedgehog signaling pathway and its targeted inhibitors in ;medulloblastoma%髓母细胞瘤SHH信号通路及靶向抑制剂研究进展

    Institute of Scientific and Technical Information of China (English)

    林中啸; 蔡铭; 盛汉松; 张弩

    2014-01-01

    SHH信号通路在小脑的发育形成过程中发挥着重要作用,能够调控小脑细胞正常发育周期及细胞增殖,维持小脑正常的功能和结构。SHH信号通路异常激活会出现小脑细胞异常增殖而导致髓母细胞瘤(MB)发生,是MB形成过程中最具有特异性的通路之一。针对SHH信号通路靶向抑制剂治疗将成为治疗MB的新方法,能特异性地阻断特定信号转导途径,靶向于肿瘤细胞的微环境及分子表达从而抑制肿瘤生长和转移。本文就MB发病机制中的SHH信号通路和基于该信号通路靶向抑制剂的研究进展作一综述。%Sonic Hedgehog (SHH) signaling pathway plays an important role in the formation process in the development of the cerebellum. It can regulate the normal development of the cerebellum cell cycle and cell proliferation to maintain normal function and structure of the cerebellum. Aberrant SHH signaling pathway causes severe cerebellar development and medulloblastoma (MB). Targeted for SHH signaling pathway inhibitor treatment will become a new treatment for MB, specificity to block certain signal transduction pathways, targeted to the microenvironment of tumor cells and molecules expression to inhibit tumor growth and metastasis. This review summarized the research progress of SHH signaling pathway and its targeted inhibitors in MB.

  20. PERBEDAAN TINGKAT PENGETAHUAN ANEMIA REMAJA PUTRI SEKOLAH MENENGAH UMUM ANEMIA DAN NON ANEMIA DI ENAM DATI II PROPINSI JAWA BARAT

    OpenAIRE

    Edwi Saraswati; Iman Sumarno

    2012-01-01

    Telah dilakukan survei cepat tentang prevalensi anemia dan pengetahuan anemia pada remaja putri SMU di enam Dati II di Propinsi Jawa Barat. Remaja putri merupakan generasi penerus yang perlu diperhatikan, karena kelak menjadi ibu dan atau tenaga pekerja. Terhadap remaja putri sampel dilakukan pemeriksaan Hb dan pengumpulan data mengenai pengetahuan remaja putri tentang anemia. Informasi ini sangat berguna sebagai dasar penetapan prioritas program kesehatan dan gizi pada kelompok remaja putri ...

  1. Inborn anemias in mice. Comprehensive progress report, 1 August 1979-1 June 1982, to accompany twenty-seventh renewal proposal

    Energy Technology Data Exchange (ETDEWEB)

    Bernstein, S.E.; Russell, E.S.; Barker, J.E.

    1982-07-01

    Hereditary anemias of mice have been investigated including four macrocytic anemias, three hemolytic anemias, nonhemolytic microcytic anemia, transitory siderocytic anemia, sex-linked iron-transport anemia, an ..cap alpha..-thalassemia, and a new target-cell anemia. Each of these blood dyscrasias is caused by the action of a unique mutant gene, which determines the structure of different intracellular molecules controlling a different metabolic process. Thus the wide range of different hereditary anemias has considerable potential for uncovering many different aspects of hemopoietic homeostatic mechanisms in the mouse and by extension to man from an understanding of mammalian mechanisms utilized in the control of erythropoiesis. Each of the different anemias is studied through: (a) biochemical and biophysical characterization of peripheral blood cells; (b) determinations of cellular and organismic radiosensitivity under a variety of conditions; (c) measurements of iron metabolism and heme biosynthesis; (d) morphological and biochemical study of blood-forming tissue; (e) functional tests of the stem cell component; (f) examination of responses to erythroid stimuli and inhibitors; and (g) physiological complementation analysis via transplantation of tissue between individuals of differently affected genotypes.

  2. Fetal Outcome pada Kehamilan Aterm Anemia dan Tidak Anemia di RS Achmad Mochtar Bukittinggi

    Directory of Open Access Journals (Sweden)

    Daulat Azhari

    2016-01-01

    Full Text Available AbstrakAnemia pada kehamilan merupakan faktor resiko gangguan pada fetal outcome dan memiliki komplikasi yang meningkatkan maternal dan perinatal mortality. Tujuan penelitian ini adalah menentukan perbedaan fetal outcome pada kehamilan aterm dengan anemia dan tidak anemia..Penelitian ini menggunakan data sekunder dengan rancangan cross sectional. Total sampel adalah 110 yang terdiri dari 55 ibu hamil aterm dengan anemia dan 55 ibu hamil aterm tidak anemia. Tekhnik pengambilan sampel adalah consecutive sampling dan analisis data menggunakan tes Mann- Whitney. Hasil uji diperoleh rerata berat badan lahir bayi pada ibu hamil aterm anemia adalah 3097,27 gr± 366,93 gr, yang sedikit lebh rendah dibandingkan pada ibu hamil aterm tidak anemia 3200,55 gr± 343,02 gr dengan nilai p= 0,214. Rerata APGAR skor pada menit pertama pada kelompok anemia adalah 7,04± 1,39, yang sedikit lebih rendah jika dibandingkan pada ibu hamil aterm tidak anemia 7.36± 0,65 dengan nilai p= 0,480. Rerata APGAR skor pada menit kelima pada kelompok anemia 8,11± 1,20 sedikit lebih rendah dibandingkan ibu hamil aterm tidak anemia 8,40± 0,62 dengan nilai p= 0,483. Rerata panjang badan lahir pada kelompok anemia adalah 48,58 cm± 1,52 cm hampir tidak memiliki perbedaan dibandingkan ibu hamil aterm tidak anemia 48,89 cm± 1,56 cm  dengan nilai p=0,310. Disimpulkan bahwa tidak ada perbedaan berat badan lahir, APGAR skor menit pertama dan kelima, dan panjang badan lahir pada kehamilan aterm dengan anemia dan tidak anemia.Kata kunci: berat badan lahir, APGAR skor, panjang badan lahir,  wanita hamil aterm dengan anemia AbstractAnemia in pregnancy is a risk factor of fetal outcome disorder and it have complication that increase of matenal and perinatal mortality. The objective of this study was to determine the differences of fetal outcome between aterm pregnant women with anemia and non anemia.This research uses secondary data by using cross sectional study design. Total sample is

  3. Anemias Hereditárias

    OpenAIRE

    Ferreira, Fátima; Carvalho, Fernanda; Costa, Vítor; Farinha, Nuno; Gil-da-Costa, M.ª João; Norton, Lucília; Reis, Ilidia Lima

    2014-01-01

    Os autores efectuam a revisão das anemias hereditárias da consulta de hematologia pediátrica do Hospital S. João no período compreendido entre 1982 e 1995. Dividem-nas em três grandes grupos: Hemoglobinopatias, Doenças da Membrana do glóbulo rubro e Enzimopatias. Calculam a sua frequência relativa, os parâmetros clínicos e analíticos relevantes no diagnóstico, a abordagem terapêutica e respectiva evolução.Destacam a especificidade desta consulta em que as anemias hereditárias correspondem a 4...

  4. Fanconi anemia - learning from children

    Directory of Open Access Journals (Sweden)

    Johanna Svahn

    2011-06-01

    Full Text Available Fanconi Anemia (FA is a rare autosomic recessive and X-linked disease with chromosomal instability after exposure to crosslinking agents as the hallmark. Clinical features of FA are somatic malformations, progressive bone marrow failure and cancer proneness, however there is wide clinical heterogeneity. The symptom most frequently and early associated with morbidity and mortality is progressive pancytopenia in the first decade of life although acute myelogenous leukemia (AML or myelodysplastic syndrome (MDS can appear before aplastic anemia. Squamous cell carcinoma (SCC of the head-neck, intestinal or genital tract has a very high incidence in FA and can appear at young age. This paper will focus on treatment of bone marrow failure in FA.

  5. Thymoma with Autoimmune Hemolytic Anemia

    OpenAIRE

    Kensuke Suzuki; Minehiko Inomata; Shiori Shiraishi; Ryuji Hayashi; Kazuyuki Tobe

    2014-01-01

    A 38-year-old Japanese male was referred to our hospital with abnormal chest X-ray results and severe Coombs-positive hemolytic anemia. He was diagnosed with a stage IV, WHO type A thymoma and was treated with oral prednisolone (1 mg/kg/day) and subsequent chemotherapy. After chemotherapy, the patient underwent surgical resection of the thymoma. Hemolysis rapidly disappeared and did not return after the discontinuation of oral corticosteroids. Corticosteroid therapy may be preferable to chemo...

  6. Iron, Anemia, and Iron Deficiency Anemia among Young Children in the United States

    OpenAIRE

    Gupta, Priya M.; Perrine, Cria G.; Zuguo Mei; Scanlon, Kelley S.

    2016-01-01

    Iron deficiency and anemia are associated with impaired neurocognitive development and immune function in young children. Total body iron, calculated from serum ferritin and soluble transferrin receptor concentrations, and hemoglobin allow for monitoring of the iron and anemia status of children in the United States. The purpose of this analysis is to describe the prevalence of iron deficiency (ID), anemia, and iron deficiency anemia (IDA) among children 1–5 years using data from the 2007–201...

  7. Estimated red blood cell thickness in microcytic anemia due to iron deficiency anemia and thalassemia

    Directory of Open Access Journals (Sweden)

    Viroj Wiwanitkit

    2009-05-01

    Full Text Available "nAnemia is one of the most common hematological disorders that are still the present in all countries around the world. Microcytic anemia is a specific kind of anemia presenting with small red blood cell. In this paper, the author discusses on the estimated red blood cell thickness, a new proposed parameter, comparing between that of iron deficiency anemia and thalassemia and further extrapolate on the clinical implication.

  8. Diamond-Blackfan anemia and nutritional deficiency-induced anemia in children.

    Science.gov (United States)

    Gelbart, David

    2014-04-01

    Diamond-Blackfan anemia is a rare, inherited disease that characteristically presents as a chronic, normochromic macrocytosis due to red cell lineage bone marrow failure. Although studies are elaborating on the genetic basis for its associated comorbidities, little has been published comparing this anemia to other chronic anemias that have similar laboratory results in children. This article offers a global perspective of the disease and compares it with anemia due to vitamin B12 and folate deficiency in children.

  9. Role of Complement in Autoimmune Hemolytic Anemia

    OpenAIRE

    Berentsen, Sigbjørn

    2015-01-01

    Summary The classification of autoimmune hemolytic anemias and the complement system are reviewed. In autoimmune hemolytic anemia of the warm antibody type, complement-mediated cell lysis is clinically relevant in a proportion of the patients but is hardly essential for hemolysis in most patients. Cold antibody-mediated autoimmune hemolytic anemias (primary cold agglutinin disease, secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria) are entirely complement-mediated disorder...

  10. The Clinical Pictures of Autoimmune Hemolytic Anemia

    OpenAIRE

    Packman, Charles H.

    2015-01-01

    Summary Autoimmune hemolytic anemia is characterized by shortened red blood cell survival and a positive Coombs test. The responsible autoantibodies may be either warm reactive or cold reactive. The rate of hemolysis and the severity of the anemia may vary from mild to severe and life-threatening. Diagnosis is made in the laboratory by the findings of anemia, reticulocytosis, a positive Coombs test, and specific serologic tests. The prognosis is generally good but renal failure and death some...

  11. Anemia in children with chronic kidney disease

    OpenAIRE

    Koshy, Susan M.; Geary, Denis F.

    2007-01-01

    Anemia is a common feature of chronic kidney disease, but the management of anemia in children is complex. Erythropoietin and supplemental iron are used to maintain hemoglobin levels. The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) clinical practice guidelines for the management of anemia specifically in children were recently published. Pediatric nephrologists are encouraged to use current clinical practice guidelines and best evidence in conjunction wit...

  12. Anemia and iron deficiency in heart failure.

    Science.gov (United States)

    Gil, Victor M; Ferreira, Jorge S

    2014-01-01

    Heart failure is a common problem and a major cause of mortality, morbidity and impaired quality of life. Anemia is a frequent comorbidity in heart failure and further worsens prognosis and disability. Regardless of anemia status, iron deficiency is a common and usually unidentified problem in patients with heart failure. This article reviews the mechanisms, impact on outcomes and treatment of anemia and iron deficiency in patients with heart failure.

  13. Child with aplastic anemia: Anesthetic management

    OpenAIRE

    Manpreet Kaur; Babita Gupta; Aanchal Sharma; Sanjeev Sharma

    2012-01-01

    Aplastic anemia is a rare heterogeneous disorder of hematopoietic stem cells causing pancytopenia and marrow hypoplasia with the depletion of all types of blood cells. This results in anemia, neutropenia and thrombocytopenia, which pose a challenge to both surgical and anesthetic management of such cases. We report a child with aplastic anemia who sustained traumatic ulcer on the arm and underwent split-thickness skin grafting under general anesthesia. There are only two case reports on anest...

  14. An unusual cause of anemia and encephalopathy

    OpenAIRE

    Sanjeev Kumar Sharma; Dharma Choudhary; Anil Handoo; Gaurav Dhamija; Gaurav Kharya; Vipin Khandelwal; Mayank Dhamija; Sweta Kothari

    2015-01-01

    The authors present here an interesting case of recent onset anemia that was associated with an encephalopathy of the unusual cause.Although severe anemia can theoretically result in anemic hypoxia and can then lead to hypoxic encephalopathy, it is not a primary cause of encephalopathy. More frequently anemia can contribute together with other multiple causes of encephalopathy, such as infections, metabolic abnormalities, trauma, hepatic dysfunction, hypertension, toxins.

  15. Genetics Home Reference: X-linked sideroblastic anemia and ataxia

    Science.gov (United States)

    ... linked sideroblastic anemia and ataxia X-linked sideroblastic anemia and ataxia Enable Javascript to view the expand/ ... Open All Close All Description X-linked sideroblastic anemia and ataxia is a rare condition characterized by ...

  16. Genetics Home Reference: X-linked sideroblastic anemia

    Science.gov (United States)

    ... Conditions X-linked sideroblastic anemia X-linked sideroblastic anemia Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description X-linked sideroblastic anemia is an inherited disorder that prevents developing red ...

  17. Do You Know about Sickle Cell Anemia? (For Kids)

    Science.gov (United States)

    ... X-ray Do You Know About Sickle Cell Anemia? KidsHealth > For Kids > Do You Know About Sickle ... stay in the hospital. What Causes Sickle Cell Anemia? Sickle cell anemia is an inherited (say: in- ...

  18. Do You Know about Sickle Cell Anemia? (For Kids)

    Science.gov (United States)

    ... Operating Room? Do You Know About Sickle Cell Anemia? KidsHealth > For Kids > Do You Know About Sickle ... stay in the hospital. What Causes Sickle Cell Anemia? Sickle cell anemia is an inherited (say: in- ...

  19. Ubiquitin-SUMO Circuitry Controls Activated Fanconi Anemia ID Complex Dosage in Response to DNA Damage

    DEFF Research Database (Denmark)

    Gibbs-Seymour, Ian; Oka, Yasuyoshi; Rajendra, Eeson

    2015-01-01

    We show that central components of the Fanconi anemia (FA) DNA repair pathway, the tumor suppressor proteins FANCI and FANCD2 (the ID complex), are SUMOylated in response to replication fork stalling. The ID complex is SUMOylated in a manner that depends on the ATR kinase, the FA ubiquitin ligase...

  20. [Anemia in patients with rheumatoid arthritis].

    Science.gov (United States)

    Wahle, M

    2012-12-01

    One of the most frequent extra-articular organ manifestations in rheumatoid arthritis (RA) is anemia. As anemia in RA patients may result in severe symptoms and aggravation of other disease manifestations (e.g. arteriosclerosis), the influence on the course of RA is profound. However, the importance of anemia in RA patients is frequently underestimated. The etiology of anemia in RA is complex. Anemia of inflammation (AI) and iron deficiency anemia, alone or in combination are the most frequent forms of anemia in RA. Changes in iron metabolism are the leading causes of anemia in RA patients and mainly induced by the altered synthesis and function of hepcidin and ferroportin. Hepcidin, a peptide produced in the liver and immunocompetent cells, impairs the expression of ferroportin on iron-secreting cells, thus reducing iron bioavailability. The typical changes of iron metabolism and hepcidin synthesis in RA are induced by proinflammatory cytokines, primarily interleukin-6. Hence, the treatment of RA with cytokine antagonists has significant therapeutic implications on anemia in the context of inflammation and impaired iron metabolism.

  1. Child with aplastic anemia: Anesthetic management

    Directory of Open Access Journals (Sweden)

    Manpreet Kaur

    2012-01-01

    Full Text Available Aplastic anemia is a rare heterogeneous disorder of hematopoietic stem cells causing pancytopenia and marrow hypoplasia with the depletion of all types of blood cells. This results in anemia, neutropenia and thrombocytopenia, which pose a challenge to both surgical and anesthetic management of such cases. We report a child with aplastic anemia who sustained traumatic ulcer on the arm and underwent split-thickness skin grafting under general anesthesia. There are only two case reports on anesthetic considerations in aplastic anemia patients in the literature. The anesthetic management is challenging because of the rarity of the disease, associated pancytopenia and immunosuppression.

  2. Dependence on phosphoinositide 3-kinase and RAS-RAF pathways drive the activity of RAF265, a novel RAF/VEGFR2 inhibitor, and RAD001 (Everolimus) in combination.

    Science.gov (United States)

    Mordant, Pierre; Loriot, Yohann; Leteur, Céline; Calderaro, Julien; Bourhis, Jean; Wislez, Marie; Soria, Jean-Charles; Deutsch, Eric

    2010-02-01

    Activation of phosphatidylinositol-3-kinase (PI3K)-AKT and Kirsten rat sarcoma viral oncogene homologue (KRAS) can induce cellular immortalization, proliferation, and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy. This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of KRAS, PI3K-AKT, or both. We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor, RAF265, with a mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), could lead to enhanced antitumoral effects in vitro and in vivo. To address this question, we used cell lines with different status regarding KRAS, PIK3CA, and BRAF mutations, using immunoblotting to evaluate the inhibitors, and MTT and clonogenic assays for effects on cell viability and proliferation. Subcutaneous xenografts were used to assess the activity of the combination in vivo. RAD001 inhibited mTOR downstream signaling in all cell lines, whereas RAF265 inhibited RAF downstream signaling only in BRAF mutant cells. In vitro, addition of RAF265 to RAD001 led to decreased AKT, S6, and Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation in HCT116 cells. In vitro and in vivo, RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells (both KRAS mut, PIK3CA mut); in contrast, the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells. The combination of RAF and mTOR inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both RAS-RAF and PI3K, possibly through the cross-inhibition of 4E binding protein 1 and S6 protein.

  3. Comparison of MEK/ERK pathway inhibitors on the upregulation of vascular G-protein coupled receptors in rat cerebral arteries

    DEFF Research Database (Denmark)

    Sandhu, Hardip; Ansar, Saema; Edvinsson, Lars

    2010-01-01

    on translational level and increased respective contractions. The prostanoid TP receptor mediated contraction curve was left-wards shifted by organ culture. Organ culture was associated with elevated pERK1/2 in the vascular smooth muscle cells: the MEK1/2 inhibitor U0126 attenuated the endothelin ET(B) receptor......Organ culture is an in vitro method for investigating cellular mechanisms involved in upregulation of vasocontractile G-protein coupled receptors. We hypothesize that mitogen-activated-protein kinase (MEK) and/or extracellular-signal-regulated kinase (ERK) specific inhibitors will attenuate the G......-protein coupled receptor expression following organ culture. Rat cerebral arteries were incubated 48h in the presence of MEK/ERK specific inhibitors U0126, PD98059, SL327, or AG126 for different time periods. Contractile responses by activation of endothelin receptor type A and type B, serotonin receptor 5-HT(1B...

  4. Treatment of anemia with darbepoetin alfa in systolic heart failure

    DEFF Research Database (Denmark)

    Swedberg, Karl; Young, James B; Anand, Inder S

    2013-01-01

    Patients with systolic heart failure and anemia have worse symptoms, functional capacity, and outcomes than those without anemia. We evaluated the effects of darbepoetin alfa on clinical outcomes in patients with systolic heart failure and anemia.......Patients with systolic heart failure and anemia have worse symptoms, functional capacity, and outcomes than those without anemia. We evaluated the effects of darbepoetin alfa on clinical outcomes in patients with systolic heart failure and anemia....

  5. Comparison of MEK/ERK pathway inhibitors on the upregulation of vascular G-protein coupled receptors in rat cerebral arteries

    DEFF Research Database (Denmark)

    Sandhu, Hardip; Ansar, Saema; Edvinsson, Lars

    2010-01-01

    on translational level and increased respective contractions. The prostanoid TP receptor mediated contraction curve was left-wards shifted by organ culture. Organ culture was associated with elevated pERK1/2 in the vascular smooth muscle cells: the MEK1/2 inhibitor U0126 attenuated the endothelin ET(B) receptor...

  6. Enhanced cerebrovascular expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 via the MEK/ERK pathway during cerebral ischemia in the rat

    DEFF Research Database (Denmark)

    Maddahi, Aida; Chen, Qingwen; Edvinsson, Lars

    2009-01-01

    of metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). RESULTS: Here, we found an infarct volume of 24.8 +/- 2% and a reduced neurological function after two hours of middle cerebral artery occlusion (MCAO), followed by 48 hours of recirculation in rat. Immunocytochemistry and confocal...

  7. [Prevention of iron deficiency and iron deficiency anemia in tropical areas].

    Science.gov (United States)

    Dillon, J C

    2000-01-01

    Iron deficiency is the most widespread nutritional disease in the World. It is prevalent in tropical areas especially in pregnant women and children. The main cause in these areas is consumption of foods containing inhibitors of iron absorption resulting in insufficient bioavailability. In advanced stages of iron deficiency, low hemoglobin levels lead to anemia. Functional consequences of anemia depend on age including mental and physical retardation in children and work disability in adults. Although other disorders including parasitic, infectious, genetic, and nutritional diseases may be involved in anemia in tropical areas, iron deficiency is always a factor because of nutritional conditions. The WHO has proposed laboratory criteria for use in establishing the incidence of iron deficiency and related anemia in a given population. Based on several surveys, four preventive strategies have been developed, i.e., dietary diversification, iron supplementation, general public health measures, and food fortification. Each of these strategies has advantages and disadvantages. The prevailing consensus is that coordinated use of these approaches holds forth the only hope of impacting the incidence of iron-deficiency anemia in tropical regions.

  8. Nicotinic and muscarinic agonists and acetylcholinesterase inhibitors stimulate a common pathway to enhance GluN2B-NMDAR responses

    OpenAIRE

    Ishibashi, Masaru; Yamazaki, Yoshihiko; Miledi, Ricardo; Sumikawa, Katumi

    2014-01-01

    The cellular mechanisms by which nicotinic and muscarinic cholinergic systems facilitate learning and memory largely remain to be elucidated. This study identified a common signaling pathway stimulated by cognitive-enhancing drugs targeted to nicotinic and m1 muscarinic receptors and acetylcholinesterase. Stimulation of this signaling pathway induces significant increases in glutamate receptor, ionotropic, N-methyl D-aspartate 2B (GluN2B)-containing NMDA receptor (NMDAR)-mediated responses at...

  9. Risk factors associated with anemia, iron deficiency and iron deficiency anemia in rural Nepali pregnant women.

    Science.gov (United States)

    Makhoul, Zeina; Taren, Douglas; Duncan, Burris; Pandey, Pooja; Thomson, Cynthia; Winzerling, Joy; Muramoto, Myra; Shrestha, Ram

    2012-05-01

    We conducted a cross sectional study to investigate risk factors associated with severe anemia [hemoglobin (Hb) iron status among Nepali pregnant women. Socio-demographic, anthropometric, health and dietary data were collected from 3,531 women living in the southeastern plains of Nepal. Stool samples were analyzed for intestinal helminthes. Dark adaptation was assessed using the Night Vision Threshold Test (NVTT). Hb levels were measured in all subjects to detect anemia and the soluble transferrin receptor (sTfR) was measured among a subsample of 479 women. The iron status categories were: 1) normal (Hb> or = 11.0 g/dl and sTfR anemia without iron deficiency (Hbiron deficiency without anemia (Hb > or = 11.0 g/dl and sTfR>8.5 mg/l); and 4) iron deficiency anemia (IDA): (Hb8.5 mg/l). Factors associated with severe anemia and poor iron status were determined using logistic regression. Hookworm infection increased the risk for developing severe anemia [adjusted odds ratio (AOR): 4.26; 95% CI 1.67-10.89; piron deficiency with and without anemia. Intake of iron supplements as tablets and/or tonic was protective against severe anemia, anemia without iron deficiency and IDA. Dietary heme iron was significantly associated with iron deficiency without anemia (RRR: 0.1; 95% CI 0.02-0.47; panemia and associated nutrient deficiencies.

  10. 促红细胞生成素通过 BMP/SMAD 通路对肾性贫血大鼠肾脏的保护作用及其机制%Renoprotective action by erythropoietin via BMP/SMAD signaling pathway in renal anemia in rats and its mechanism

    Institute of Scientific and Technical Information of China (English)

    张妍; 李银岚; 陈孟华

    2015-01-01

    ),blood urea nitrogen (Bun),hemoglobin (Hb),hematocrit (Hct),and hepcidin were measured with automated hematology analyzer.The expressions of bone morphogenetic protein-6 (BMP-6 ),a serine/threonine kinase receptor-1 (SMAD-1 )and serine/threonine kinase receptor-4 (SMAD-4)in the kidney were detected by immunohistochemistry and Western blot.Results ①The results of general indicators:BUN and Scr in IR + EPO group and EPO group were lower than those in SA group (P <0.01).Hb and Hct in IR + EPO group and EPO group were increased significantly compared with those in SA group (P <0.01).Hepcidin was significantly increased in simple anemia group (P <0.01).② ELISA results showed that Hepcidin was lower in IR + EPO group and EPO group than in SA group (P <0.01).③ The results of pathological observation indicated that EPO could reduce rat renal pathology and function.④ Immunohistochemistry revealed that SMAD-4,SMAD-1 and BMP-6 were expressed in the rat glomerular cells and renal tubular epithelial cells.⑤ Western blot further indicated that the expression of SMAD-4 was significantly decreased in IR + EPO group and EPO group (P < 0.01 ).The expression of SMAD-1 in IR+EPO group and EPO group was decreased (P <0.05)while that of BMP-6 was elevated in IR+EPO group and EPO group (P <0.01 ).Conclusion The expression and secretion of hepcidin were inhibited by EPO via the BMP/SMAD pathway,which further corrects anemia and exerts a renal protective effect.

  11. Case 40. Misdiagnosis of refractory macrocytic anemia.

    Science.gov (United States)

    Stringaris, Kate; Bain, Barbara

    2008-11-01

    A diagnosis of myelodysplastic syndrome, refractory anemia subtype, was made in an elderly Indian woman on the basis of a refractory macrocytic anemia with normal vitamin B(12) and folate assays, normal thyroid function, essentially normal liver function and normal cytogenetic analysis. Disease evolution revealed that the diagnosis was erroneous.

  12. Silent Infarcts with Sickle Cell Anemia

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2002-01-01

    Full Text Available The effect of transfusion therapy on the risk for new silent infarct or stroke in children with sickle cell anemia and abnormal transcranial Doppler (TCD ultrasonography was determined at the University of Miami, FL, and other centers in the STOP trial (Stroke Prevention in Sickle Cell Anemia.

  13. The Student with Sickle Cell Anemia.

    Science.gov (United States)

    Tetrault, Sylvia M.

    1981-01-01

    Sickle cell anemia is the most common and severe of inherited chronic blood disorders. In the United States, sickle cell anemia is most common among the Black population. Among the most commonly occurring symptoms are: an enlarged spleen, episodes of severe pain, easily contracted infections, skin ulcers, and frequent urination. (JN)

  14. 9 CFR 311.34 - Anemia.

    Science.gov (United States)

    2010-01-01

    ... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Anemia. 311.34 Section 311.34 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY ORGANIZATION... CERTIFICATION DISPOSAL OF DISEASED OR OTHERWISE ADULTERATED CARCASSES AND PARTS § 311.34 Anemia. Carcasses...

  15. Anemia and survival in human immunodeficiency virus

    DEFF Research Database (Denmark)

    Lundgren, Jens Dilling; Mocroft, Amanda

    2003-01-01

    The prospective, multicenter cohort study EuroSIDA has previously reported on predictors and outcomes of anemia in patients infected with human immunodeficiency virus. In a Cox proportional-hazards model with serial measures of CD4+ cell count, plasma viral load, and degrees of anemia fitted...

  16. Anemia in pregnancy:laboratory diagnostic procedures

    OpenAIRE

    Panova, Gordana

    2010-01-01

    Anemia is common condition in pregnancy and laboratory diagnostic procedures are essential for its detection and categorization. Complete blood count, serum iron, TIBC and ferritin are basic clinical laboratory parameters that provide information about iron status of mother’s body and possible presence of anemia.

  17. Salmonella osteomyelitis by sickle cell anemia

    Energy Technology Data Exchange (ETDEWEB)

    Rausch, H.; Tran, V.T.; Boeckmann, U.

    1985-10-01

    Case report of a 28 year old black sickle cell anemia patient with salmonella osteomyelitis of the radius. Aside from sickle cell anemia patients this skeletal complication of enteric salmonellosis is an extreme rarity. Description of the typical roentgenological features includes intracortical fissures and sequestration.

  18. Duodenal Amyloidosis Masquerading as Iron Deficiency Anemia

    Science.gov (United States)

    Hurairah, Abu

    2016-01-01

    The present study is a unique illustration of duodenal amyloidosis initially manifesting with iron deficiency anemia. It underscores the importance of clinical suspicion of amyloidosis while performing upper gastrointestinal endoscopy with a biopsy to establish the definite diagnosis in patients with unexplained iron deficiency anemia. PMID:27625911

  19. Fanconi anemia proteins and endogenous stresses

    Energy Technology Data Exchange (ETDEWEB)

    Pang Qishen [Division of Experimental Hematology and Cancer Biology, Cincinnati Children' s Research Foundation, Cincinnati, OH (United States); Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH (United States); Andreassen, Paul R., E-mail: Paul.Andreassen@cchmc.org [Division of Experimental Hematology and Cancer Biology, Cincinnati Children' s Research Foundation, Cincinnati, OH (United States); Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH (United States)

    2009-07-31

    Each of the thirteen identified Fanconi anemia (FA) genes is required for resistance to DNA interstrand crosslinking agents, such as mitomycin C, cisplatin, and melphalan. While these agents are excellent tools for understanding the function of FA proteins in DNA repair, it is uncertain whether a defect in the removal of DNA interstrand crosslinks (ICLs) is the basis for the pathophysiology of FA. For example, DNA interstrand crosslinking agents induce other types of DNA damage, in addition to ICLs. Further, other DNA-damaging agents, such as ionizing or ultraviolet radiation, activate the FA pathway, leading to monoubiquitination of FANCD2 and FANCI. Also, FA patients display congenital abnormalities, hematologic deficiencies, and a predisposition to cancer in the absence of an environmental source of ICLs that is external to cells. Here we consider potential sources of endogenous DNA damage, or endogenous stresses, to which FA proteins may respond. These include ICLs formed by products of lipid peroxidation, and other forms of oxidative DNA damage. FA proteins may also potentially respond to telomere shortening or replication stress. Defining these endogenous sources of DNA damage or stresses is critical for understanding the pathogenesis of deficiencies for FA proteins. We propose that FA proteins are centrally involved in the response to replication stress, including replication stress arising from oxidative DNA damage.

  20. Transplante renal na anemia falciforme

    OpenAIRE

    Friedrisch, Joao Ricardo; Barros, Elvino José Guardão; Manfro, Roberto Ceratti; Bittar,Christina Matzenbacher; Silla, Lucia Mariano da Rocha

    2003-01-01

    Embora a anemia falciforme e as síndromes falciformes freqüentemente causem várias alterações funcionais renais, não é comum a insuficiência renal terminal. Nestes casos, o transplante renal é uma alternativa que se acompanha de resultados comparáveis aos obtidos em receptores sem hemoglobinopatias. Esta estratégia terapêutica tem sido, no entanto, pouco relatada para portadores de hemoglobinopatia SC. Este relato descreve a evolução de dois pacientes portadores de hemoglobinopatia SC que for...

  1. Colonic lymphangiomatosis associated with anemia

    Institute of Scientific and Technical Information of China (English)

    Woo Chul Chung; Hye-Kang Kim; Jin Young Yoo; Jeong Rok Lee; Kang-Moon Lee; Chang Nyol Paik; U-Im Jang; Jin Mo Yang

    2008-01-01

    lymphangioma is an uncommon malformation of lymphatic system.Multiple colonic lymphangioma named as lymphangiomatosis is considered an extremely rare disease.Although lymphangioma is a benign tumor and most colonic lymphangiomas do not cause symptoms and do not require treatment,resection of lymphangioma is necessary in the presence of symptoms such as abdominal pain,bleeding,intussusceptions.We report a case of colonic lymphangiomatosis in a man who presented with abdominal discomfort and anemia,which was diagnosed and treated with endoscopic snare polyperctomy.

  2. Unexplained Aspects of Anemia of Inflammation

    Directory of Open Access Journals (Sweden)

    Elizabeth A. Price

    2010-01-01

    Full Text Available Anemia of inflammation (AI, also known as anemia of chronic inflammation or anemia of chronic disease was described over 50 years ago as anemia in association with clinically overt inflammatory disease, and the findings of low plasma iron, decreased bone marrow sideroblasts and increased reticuloendothelial iron. Pathogenic features underlying AI include a mild shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the marrow to erythropoietin, and impaired iron metabolism mediated by inflammatory cytokines and the iron regulatory peptide, hepcidin. Despite marked recent advances in understanding AI, gaps remain, including understanding of the pathogenesis of AI associated with “noninflammatory” or mildly inflammatory diseases, the challenge of excluding iron deficiency anemia in the context of concomitant inflammation, and understanding more precisely the contributory role of hepcidin in the development of AI in human inflammatory diseases.

  3. TW-37, a Small-Molecule Inhibitor of Bcl-2, Inhibits Cell Growth and Induces Apoptosis in Pancreatic Cancer: Involvement of Notch-1 Signaling Pathway

    OpenAIRE

    2009-01-01

    Overexpression of Bcl-2 family proteins has been found in a variety of aggressive human carcinomas, including pancreatic cancer, suggesting that specific agents targeting Bcl-2 family proteins would be valuable for pancreatic cancer therapy. We have previously reported that TW-37, a small-molecule inhibitor of Bcl-2 family proteins, inhibited cell growth and induced apoptosis in pancreatic cancer. However, the precise role and the molecular mechanism of action of TW-37 have not been fully elu...

  4. Gamma-Secretase Inhibitors Abrogate Oxaliplatin-Induced Activation of the Notch-1 Signaling Pathway in Colon Cancer Cells Resulting in Enhanced Chemosensitivity

    OpenAIRE

    Meng, Raymond D.; Shelton, Christopher C.; Li, Yue-Ming; Qin, Li-Xuan; Paty, Philip B.; Schwartz, Gary K.

    2009-01-01

    Because Notch signaling is implicated in colon cancer tumorigenesis and protects from apoptosis by inducing pro-survival targets, it was hypothesized that inhibition of Notch signaling with gamma-secretase inhibitors (GSIs) may enhance the chemosensitivity of colon cancer cells. We first show that the Notch-1 receptor and its downstream target Hes-1 is upregulated with colon cancer progression, similar to other genes involved in chemoresistance. We then report that chemotherapy induces Notch-...

  5. MiR-21 inhibitor suppressed the progression of retinoblastoma via the modulation of PTEN/PI3K/AKT pathway.

    Science.gov (United States)

    Gui, Fu; Hong, Zhengdong; You, Zhipeng; Wu, Hongxi; Zhang, Yulan

    2016-12-01

    MicroRNA-21 (miR-21) was reported to act as an oncogene during the development of many human tumors. However, little was revealed about the function of miR-21 in retinoblastoma (RB). In this study, we examined the expression of miR-21 in RB tissues and explored the relationship between miR-21 and phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-OH kinase (PI3K)/AKT signal. Quantitative real-time PCR (qRT-PCR) results showed that the level of miR-21 in RB tissues was higher than that in retinal normal tissues. In Weri-Rb-1 cells, miR-21 inhibitor suppressed the expression of miR-21 and cell viability, but improved cell apoptotic rates by modulating the levels of PDCD4, Bax, and Bcl-2. Meanwhile, miR-21 inhibitor suppressed cell migration and invasion via inhibiting the protein levels of MMP2 and MMP9 and significantly affected the expression of PTEN, PI3K, and p-AKT. Taken together, miR-21 inhibitor suppressed cell proliferation, migration, and invasion via the PTEN/PI3K/AKT signal. These findings revealed the molecular basis of miR-21 functioning in the progression of RB and provided a new means for cell therapy in RB.

  6. A novel zwitterionic inhibitor of aldose reductase interferes with polyol pathway in ex vivo and in vivo models of diabetic complications.

    Science.gov (United States)

    Karasova, M Juskova; Prnova, M Soltesova; Stefek, M

    2014-10-01

    Recently a zwitterionic principle has been suggested as an alternative to bioisosteric replacement for increasing low bioavailability of aldose reductase inhibitors bearing an acidic function. In the present work we studied the effect of a novel zwitterionic inhibitor of aldose reductase [(2-benzyl-2,3,4,5-tetrahydro-1 H-pyrido[4,3-b]indole-8-yl)-acetic acid, compound 1] on sorbitol accumulation in ex vivo and in vivo models of diabetic complications. The effect of 1 on sorbitol accumulation in isolated rat eye lenses incubated with high glucose and in selected organs of streptozotocin-induced diabetic rats was evaluated. Significantly increased sorbitol levels were recorded in the lenses incubated with 50 mM glucose in comparison with controls. Sorbitol production was inhibited by 1 at concentrations of 25 and 100 μM. Under in vivo conditions in diabetic rats, significant elevation of sorbitol levels in selected organs was recorded. Compound 1 administered i.g. for five consecutive days (twice a day 25 mg/kg) inhibited sorbitol accumulation in erythrocytes and the sciatic nerve, yet it was without effect in eye lenses. A similar picture of inhibition was observed after i.p. administration of 1. To conclude, the results suggest that the zwitterionic principle may represent a practicable way of improving bioavailability of aldose reductase inhibitors bearing an acidic function.

  7. Inhibitors of second messenger pathways and Ca(2+)-induced exposure of phosphatidylserine in red blood cells of patients with sickle cell disease.

    Science.gov (United States)

    Gbotosho, O T; Cytlak, U M; Hannemann, A; Rees, D C; Tewari, S; Gibson, J S

    2014-07-01

    The present work investigates the contribution of various second messenger systems to Ca(2+)-induced phosphatidylserine (PS) exposure in red blood cells (RBCs) from sickle cell disease (SCD) patients. The Ca(2+) dependence of PS exposure was confirmed using the Ca(2+) ionophore bromo-A23187 to clamp intracellular Ca(2+) over 4 orders of magnitude in high or low potassium-containing (HK or LK) saline. The percentage of RBCs showing PS exposure was significantly increased in LK over HK saline. This effect was reduced by the Gardos channel inhibitors, clotrimazole and charybdotoxin. Nevertheless, although Ca(2+) loading in the presence of an outwardly directed electrochemical gradient for K(+) stimulated PS exposure, substantial exposure still occurred in HK saline. Under the conditions used inhibitors of other second messenger systems (ABT491, quinacrine, acetylsalicylic acid, 3,4-dichloroisocoumarin, GW4869 and zVAD-fmk) did not inhibit the relationship between [Ca(2+)] and PS exposure. Inhibitors of phospholipase A2, cyclooxygenase, platelet-activating factor, sphingomyelinase and caspases, therefore, were without effect on Ca(2+)-induced PS exposure in RBCs, incubated in either HK or LK saline.

  8. Development of an image-based screening system for inhibitors of the plastidial MEP pathway and of protein geranylgeranylation [v2; ref status: indexed, http://f1000r.es/5p9

    Directory of Open Access Journals (Sweden)

    Michael Hartmann

    2015-08-01

    Full Text Available In a preceding study we have recently established an in vivo visualization system for the geranylgeranylation of proteins in a stably transformed tobacco BY-2 cell line, which involves expressing a dexamethasone-inducible GFP fused to the prenylable, carboxy-terminal basic domain of the rice calmodulin CaM61, which naturally bears a CaaL geranylgeranylation motif (GFP-BD-CVIL. By using pathway-specific inhibitors it was there demonstrated that inhibition of the methylerythritol phosphate (MEP pathway with oxoclomazone and fosmidomycin, as well as inhibition of protein geranylgeranyl transferase type 1 (PGGT-1, shifted the localization of the GFP-BD-CVIL protein from the membrane to the nucleus. In contrast, the inhibition of the mevalonate (MVA pathway with mevinolin did not affect this localization. Furthermore, in this initial study complementation assays with pathway-specific intermediates confirmed that the precursors for the cytosolic isoprenylation of this fusion protein are predominantly provided by the MEP pathway. In order to optimize this visualization system from a more qualitative assay to a statistically trustable medium or a high-throughput screening system, we established now new conditions that permit culture and analysis in 96-well microtiter plates, followed by fluorescence microscopy. For further refinement, the existing GFP-BD-CVIL cell line was transformed with an estradiol-inducible vector driving the expression of a RFP protein, C-terminally fused to a nuclear localization signal (NLS-RFP. We are thus able to quantify the total number of viable cells versus the number of inhibited cells after various treatments. This approach also includes a semi-automatic counting system, based on the freely available image processing software. As a result, the time of image analysis as well as the risk of user-generated bias is reduced to a minimum. Moreover, there is no cross-induction of gene expression by dexamethasone and estradiol

  9. Development of an image-based screening system for inhibitors of the plastidial MEP pathway and of protein geranylgeranylation [v1; ref status: indexed, http://f1000r.es/4vt

    Directory of Open Access Journals (Sweden)

    Michael Hartmann

    2015-01-01

    Full Text Available We have recently established an in vivo visualization system for the geranylgeranylation of proteins in a stably transformed tobacco BY-2 cell line, which involves expressing a dexamethasone-inducible GFP fused to the prenylable, carboxy-terminal basic domain of the rice calmodulin CaM61, which naturally bears a CaaL geranylgeranylation motif (GFP-BD-CVIL. By using pathway-specific inhibitors it was demonstrated that inhibition of the methylerythritol phosphate (MEP pathway with oxoclomazone and fosmidomycin, as well as inhibition of protein geranylgeranyl transferase type 1 (PGGT-1, shifted the localization of the GFP-BD-CVIL protein from the membrane to the nucleus. In contrast, the inhibition of the mevalonate (MVA pathway with mevinolin did not affect this localization. Furthermore, complementation assays with pathway-specific intermediates confirmed that the precursors for the cytosolic isoprenylation of this fusion protein are predominantly provided by the MEP pathway. In order to optimize this visualization system from a more qualitative assay to a statistically trustable medium or a high-throughput screening system, we established new conditions that permit culture and analysis in 96-well microtiter plates, followed by fluorescence microscopy. For further refinement, the existing GFP-BD-CVIL cell line was transformed with an estradiol-inducible vector driving the expression of a RFP protein, C-terminally fused to a nuclear localization signal (NLS-RFP. We are thus able to quantify the total number of viable cells versus the number of inhibited cells after various treatments. This approach also includes a semi-automatic counting system, based on the freely available image processing software. As a result, the time of image analysis as well as the risk of user-generated bias is reduced to a minimum. Moreover, there is no cross-induction of gene expression by dexamethasone and estradiol, which is an important prerequisite for this test

  10. Delayed globin synthesis leads to excess heme and the macrocytic anemia of Diamond Blackfan anemia and del(5q) myelodysplastic syndrome.

    Science.gov (United States)

    Yang, Zhantao; Keel, Siobán B; Shimamura, Akiko; Liu, Li; Gerds, Aaron T; Li, Henry Y; Wood, Brent L; Scott, Bart L; Abkowitz, Janis L

    2016-05-11

    Diamond Blackfan anemia (DBA) and myelodysplastic syndrome (MDS) with isolated del(5q) are severe macrocytic anemias; although both are associated with impaired ribosome assembly, why the anemia occurs is not known. We cultured marrow cells from DBA (n = 3) and del(5q) MDS (n = 6) patients and determined how heme (a toxic chemical) and globin (a protein) are coordinated. We show that globin translation initiates slowly, whereas heme synthesis proceeds normally. This results in insufficient globin protein, excess heme and excess reactive oxygen species in early erythroid precursors, and CFU-E (colony-forming unit-erythroid)/proerythroblast cell death. The cells that can more rapidly and effectively export heme or can slow heme synthesis preferentially survive and appropriately mature. Consistent with these observations, treatment with 10 μM succinylacetone, a specific inhibitor of heme synthesis, improved the erythroid cell output of DBA and del(5q) MDS marrow cultures by 68 to 95% (P = 0.03 to 0.05), whereas the erythroid cell output of concurrent control marrow cultures decreased by 4 to 13%. Our studies demonstrate that erythropoiesis fails when heme exceeds globin. Our data further suggest that therapies that decrease heme synthesis (or facilitate heme export) could improve the red blood cell production of persons with DBA, del(5q) MDS, and perhaps other macrocytic anemias.

  11. Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

    OpenAIRE

    Čolović, Mirjana B.; Krstić, Danijela Z; Lazarević-Pašti, Tamara D; Bondžić, Aleksandra M; Vasić, Vesna M

    2013-01-01

    Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are appl...

  12. Anemia of Chronic Disease and Iron Deficiency Anemia in Inflammatory Bowel Diseases: Pathophysiology, Diagnosis, and Treatment.

    Science.gov (United States)

    Murawska, Natalia; Fabisiak, Adam; Fichna, Jakub

    2016-05-01

    Anemia coexists with inflammatory bowel disease (IBD) in up to two-thirds of patients, significantly impairing quality of life. The most common types of anemia in patients with IBD are iron deficiency anemia and anemia of chronic disease, which often overlap. In most cases, available laboratory tests allow successful diagnosis of iron deficiency, where difficulties appear, recently established indices such as soluble transferrin-ferritin ratio or percentage of hypochromic red cells are used. In this review, we discuss the management of the most common types of anemia in respect of the latest available data. Thus, we provide the mechanisms underlying pathophysiology of these entities; furthermore, we discuss the role of hepcidin in developing anemia in IBD. Next, we present the treatment options for each type of anemia and highlight the importance of individual choice of action. We also focus on newly developed intravenous iron preparations and novel, promising drug candidates targeting hepcidin. Concurrently, we talk about difficulties in differentiating between the true and functional iron deficiency, and discuss tools facilitating the process. Finally, we emphasize the importance of proper diagnosis and treatment of anemia in IBD. We conclude that management of anemia in patients with IBD is tricky, and appropriate screening of patients regarding anemia is substantial.

  13. Iron Deficiency, Anemia and Mortality in Renal Transplant Recipients

    NARCIS (Netherlands)

    Eisenga, Michele F.; Minovic, Isidor; Berger, Stefan P.; Kootstra-Ros, Jenny E.; van den Berg, Else; Riphagen, Ineke J.; Navis, Gerjan; van der Meer, Peter; Bakker, Stephan J. L.; Gaillard, Carlo A. J. M.

    2016-01-01

    Anemia, iron deficiency anemia (IDA), and iron deficiency (ID) are highly prevalent in renal transplant recipients (RTR). Anemia is associated with poor outcome, but the role of ID is unknown. Therefore, we aimed to investigate the association of ID, irrespective of anemia, with all-cause mortality

  14. Iron Deficiency, Anemia and Mortality in Renal Transplant Recipients

    NARCIS (Netherlands)

    Eisenga, Michele F; Minovic, Isidor; Berger, Stefan P; Kootstra-Ros, Jenny E; van den Berg, Else; Riphagen, Ineke J; Navis, Gerjan; van der Meer, Peter; Bakker, Stephan J L; Gaillard, Carlo A J M

    2016-01-01

    Anemia, iron deficiency anemia (IDA) and iron deficiency (ID) are highly prevalent in renal transplant recipients (RTR). Anemia is associated with poor outcome, but the role of ID is unknown. Therefore, we aimed to investigate the association of ID, irrespective of anemia, with all-cause mortality i

  15. Novel bioassay for the discovery of inhibitors of the 2-C-Methyl-D-Erythritol 4-Phosphate (MEP) and terpenoid pathways leading to carotenoid biosynthesis

    Science.gov (United States)

    The 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway leads to the synthesis of isopentenyl-phosphate (IPP) in plastids. It is a major branch point providing precursors for the synthesis of carotenoids, tocopherols, plastoquinone and the phytyl chain of chlorophylls, as well as the hormones abscisi...

  16. Red blood cell abnormalities and the pathogenesis of anemia in end-stage renal disease.

    Science.gov (United States)

    Georgatzakou, Hara T; Antonelou, Marianna H; Papassideri, Issidora S; Kriebardis, Anastasios G

    2016-08-01

    Anemia is the most common hematologic complication in end-stage renal disease (ESRD). It is ascribed to decreased erythropoietin production, shortened red blood cell (RBC) lifespan, and inflammation. Uremic toxins severely affect RBC lifespan; however, the implicated molecular pathways are poorly understood. Moreover, current management of anemia in ESRD is controversial due to the "anemia paradox" phenomenon, which underlines the need for a more individualized approach to therapy. RBCs imprint the adverse effects of uremic, inflammatory, and oxidative stresses in a context of structural and functional deterioration that is associated with RBC removal signaling and morbidity risk. RBCs circulate in hostile plasma by raising elegant homeostatic defenses. Variability in primary defect, co-morbidity, and therapeutic approaches add complexity to the pathophysiological background of the anemic ESRD patient. Several blood components have been suggested as biomarkers of anemia-related morbidity and mortality risk in ESRD. However, a holistic view of blood cell and plasma modifications through integrated omics approaches and high-throughput studies might assist the development of new diagnostic tests and therapies that will target the underlying pathophysiologic processes of ESRD anemia.

  17. Interleukin-27 is a potent inhibitor of cis HIV-1 replication in monocyte-derived dendritic cells via a type I interferon-independent pathway.

    Directory of Open Access Journals (Sweden)

    Qian Chen

    Full Text Available IL-27, a member of the IL-12 family of cytokines, plays an important and diverse role in the function of the immune system. Whilst generally recognized as an anti-inflammatory cytokine, in addition IL-27 has been found to have broad anti-viral effects. Recently, IL-27 has been shown to be a potent inhibitor of HIV-1 infection in CD4+ T cells and macrophages. The main objective of this study was to see whether IL-27 has a similar inhibitory effect on HIV-1 replication in dendritic cells (DCs. Monocytes were differentiated into immature DCs (iDCs and mature DCs (mDCs with standard techniques using a combination of GM-CSF, IL-4 and LPS. Following differentiation, iDCs were infected with HIV-1 and co-cultured in the presence or absence of IL-27. IL-27 treated DCs were shown to be highly potent inhibitors of cis HIV-1, particularly of CCR5 tropic strains. Of note, other IL-12 family members (IL-12, IL-23 and IL-35 had no effect on HIV-1 replication. Microarray studies of IL-27 treated DCs showed no up-regulation of Type I (IFN gene expression. Neutralization of the Type-I IFN receptor had no impact on the HIV inhibition. Lastly, IL-27 mediated inhibition was shown to act post-viral entry and prior to completion of reverse transcription. These results show for the first time that IL-27 is a potent inhibitor of cis HIV-1 infection in DCs by a Type I IFN independent mechanism. IL-27 has previously been reported to inhibit HIV-1 replication in CD4+ T cells and macrophages, thus taken together, this cytokine is a potent anti-HIV agent against all major cell types targeted by the HIV-1 virus and may have a therapeutic role in the future.

  18. The cardio-renal anemia syndrome

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    Dimković Siniša

    2007-01-01

    Full Text Available Introduction. The problem of anemia in congestive heart failure and chronic kidney disease was thought to be insignificant for a long period of time. Recent investigations pointed out that the problem of anemia should be defined in the context of the cardio-renal anemia syndrome. A positive feedback mechanism indicates that cardio-renal anemia syndrome is due to an interaction between congestive heart failure, chronic renal failure and anemia. The aim of the study was to present the possible pathophysiological mechanisms of this syndrome, epidemiological characteristics and therapeutic results of the former investigations. Results. The results of the retrospective and prospective controlled trails have shown that management of anemia with subcutaneous administration of recombinant human erythropoietin together with intravenous iron infusion for at least 3-6 months lead to: relief of symptoms (improved NYHA functional class; increased left ventricular ejection fraction; reduced cardiovascular morbidity and mortality; reduced number of rehospitalizations; reduced requirements for usual therapeutic agents (especially diuretics; and improved renal function. Conclusion. In patients with heart and kidney disease anemia should be routinely identified and appropriately treated. Subcutaneous recombinant erythropoietin and intravenous iron may significantly improve overall survival and quality of life of these patients. .

  19. [Sideropenic anemia in infants and toddlers].

    Science.gov (United States)

    Jakovljević, G; Votava-Raić, A; Tjesić-Drinković, D; Rajić, L; Femenić-Kes, R; Konja, J; Goluza, I; Bilić, E; Leskovar, V

    2001-01-01

    Iron-deficiency anemia is the most common anemia in infants. In the routine pediatric care this problem is encountered every day. Numerous factors in infancy (low birth weight, rapid growth, insufficient nutrition) are involved in the development of iron-deficiency anemia, and they must be considered when establishing diagnosis, counselling parents, and prescribing oral iron preparations. Data on 119 patients aged up to two years treated in the Division of Gastroenterology and Nutrition, Pediatric Department, University Hospital Centre Zagreb Salata between 1994 and 1999, were analyzed. We were prompted to do so because of great frequency of iron-deficiency anemia as one of associated diagnoses, and unfortunately often the only diagnosis requiring hospitalization. Out of 119 patients with iron-deficiency anemia, nine (7.7%) patients (four premature newborns and three from twin pregnancy) had to receive transfusion of erythrocyte concentrate due to very bad general condition and low red blood count, accompanied by clinical signs of anemic hypoxia. We also analyzed prenatal and perinatal history, socioeconomic living conditions of these children, i.e. their nutrition, and if they had previously received oral iron preparations. Some of the results, such as inadequate alimentation with flour, as well as insufficient prophylaxis of iron deficiency, which were found in most cases of severe anemia, point to the need of paying greater attention to this problem, better parents education, and more adequate screening for iron deficiency anemia.

  20. Iron deficiency anemia in the elderly

    Directory of Open Access Journals (Sweden)

    Indra Kurniawan

    2011-02-01

    Full Text Available The numbers of older people in the world have been growing rapidly. Anemia is the most common hematologic problem encountered in older adults. However, anemia should not be accepted as an inevitable consequence of aging. Anemia in the elderly signifies an underlying disease. Iron Defi ciency Anemia (IDA is being one of the most common causes of anemia in older people. IDA in the elderly is often associated with such non specific symptoms. The diagnosis of IDA is typically based on laboratory results. Hence, the utilization of the various laboratory tests plays an important role for the diagnosis of IDA. The presence of IDA in the elderly is usually related with gastrointestinal disorders. Thus,  gastrointestinal evaluation should be contemplated in all patients with IDA unless there is a history of clinically important non gastrointestinal blood loss. Older people with IDA should have iron supplementation both to correct anemia and to replenish body iron stores. However, the underlying cause should always be treated to prevent further iron loss. (Med J Indones 2011; 20:71-7Keywords: anemia, elderly, gastrointestinal, iron deficiency

  1. Inborn anemias in mice: (Annual report, 1981-1982)

    Energy Technology Data Exchange (ETDEWEB)

    Bernstein, S.E.

    1982-07-19

    Hereditary anemias of mice are the chief objects of investigation, specificially four macrocytic anemias, 3 types of hemolytic anemia, nonhemolytic microcytic anemia, transitory siderocytic anemia, sex-linked iron-transport anemia, the autoimmune hemolytic anemia of NZB mice, an ..cap alpha..-thalassemia and a new hypochromic anemia with hemochromatosis. New types of anemia may be analyzed as new mutations appear. Three new mutations have been identified during the past 18 months. These anemias are studied through characterization of peripheral blood values, determinations of radiosensitivity under a variety of conditions, measurements of iron metabolism and heme synthesis, study of normal and abnormal erythrocyte membrane proteins, histological and biochemical characterization of blood-forming tissue, functional tests of the stem-cell component, examination of responses to erythroid stimuli, and transplantation of tissue and parabiosis between individuals of differently affected genotypes. 31 refs.

  2. Iron deficiency and iron deficiency anemia in women.

    Science.gov (United States)

    Coad, Jane; Pedley, Kevin

    2014-01-01

    Iron deficiency is one of the most common nutritional problems in the world and disproportionately affects women and children. Stages of iron deficiency can be characterized as mild deficiency where iron stores become depleted, marginal deficiency where the production of many iron-dependent proteins is compromised but hemoglobin levels are normal and iron deficiency anemia where synthesis of hemoglobin is decreased and oxygen transport to the tissues is reduced. Iron deficiency anemia is usually assessed by measuring hemoglobin levels but this approach lacks both specificity and sensitivity. Failure to identify and treat earlier stages of iron deficiency is concerning given the neurocognitive implications of iron deficiency without anemia. Most of the daily iron requirement is derived from recycling of senescent erythrocytes by macrophages; only 5-10 % comes from the diet. Iron absorption is affected by inhibitors and enhancers of iron absorption and by the physiological state. Inflammatory conditions, including obesity, can result in iron being retained in the enterocytes and macrophages causing hypoferremia as a strategic defense mechanism to restrict iron availability to pathogens. Premenopausal women usually have low iron status because of iron loss in menstrual blood. Conditions which further increase iron loss, compromise absorption or increase demand, such as frequent blood donation, gastrointestinal lesions, athletic activity and pregnancy, can exceed the capacity of the gastrointestinal tract to upregulate iron absorption. Women of reproductive age are at particularly high risk of iron deficiency and its consequences however there is a controversial argument that evolutionary pressures have resulted in an iron deficient phenotype which protects against infection.

  3. Consumo de leite de vaca e anemia na infância no Município de São Paulo Cow's milk consumption and childhood anemia in the city of São Paulo, southern Brazil

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    Renata Bertazzi Levy-Costa

    2004-12-01

    Full Text Available OBJETIVO: Avaliar a influência de consumo de leite de vaca sobre o risco de anemia em menores de cinco anos. MÉTODOS: Estudou-se amostra domiciliar de menores de cinco anos do Município de São Paulo (n=584 em 1995 e 1996. O diagnóstico de anemia (hemoglobina OBJECTIVE: To evaluate the influence of the consumption of cow's milk on the risk of anemia during childhood in the city of São Paulo. METHODS: We have studied a probabilistic sample (n=584 of underfive children living in the city of São Paulo, southeastern Brazil, between 1995 and 1996. Anemia (hemoglobin <11g/dl was diagnosed using capillary blood obtained by fingertip puncture. The cow's milk content and the density of heme and nonheme iron in the child's diet were obtained using 24-hour recall questionnaires. Multiple linear and logistic regression models were used to study the association between cow's milk content in the diet and hemoglobin concentration or risk of anemia, and included statistical control for potential confounders (age, sex, birthweight, presence of intestinal parasites, family income, and mother's schooling. RESULTS: The prevalence of anemia was 45.2% and the mean contribution of milk to the total caloric content of the children's diets was 22.0%. The association between milk consumption and risk of anemia remained significant, even after considering the dilutive effect of milk consumption on the density of iron in the diet, thus indicating a possible inhibitor effect of milk on the absorption of the iron present in the other foods ingested by the child. CONCLUSIONS: The relative participation of cow's milk in the child's diet showed a significant positive association with risk of anemia in children between ages six and 60 months, regardless of the density of iron in the diet.

  4. Towards a Molecular Understanding of the Fanconi Anemia Core Complex

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    Charlotte Hodson

    2012-01-01

    Full Text Available Fanconi Anemia (FA is a genetic disorder characterized by the inability of patient cells to repair DNA damage caused by interstrand crosslinking agents. There are currently 14 verified FA genes, where mutation of any single gene prevents repair of DNA interstrand crosslinks (ICLs. The accumulation of ICL damage results in genome instability and patients having a high predisposition to cancers. The key event of the FA pathway is dependent on an eight-protein core complex (CC, required for the monoubiquitination of each member of the FANCD2-FANCI complex. Interestingly, the majority of patient mutations reside in the CC. The molecular mechanisms underlying the requirement for such a large complex to carry out a monoubiquitination event remain a mystery. This paper documents the extensive efforts of researchers so far to understand the molecular roles of the CC proteins with regard to its main function in the FA pathway, the monoubiquitination of FANCD2 and FANCI.

  5. Anemia

    Science.gov (United States)

    ... B-12 (meat and dairy), and folic acid (citrus juices, dark green leafy vegetables, legumes, and fortified ... ASH Meeting on Lymphoma Biology ASH Workshop on Genome Editing Publications Blood The Hematologist ASH Clinical News ...

  6. Correlates of anemia in pregnant women

    Directory of Open Access Journals (Sweden)

    Ranjana Singh

    2015-09-01

    Full Text Available Background: Anemia during pregnancy is a global public health challenge facing the world today. Prevalence of anemia in pregnancy in all the age groups is higher in India as compared to other developing countries. Objective: This study is aimed at determining the magnitude and to explore the socio-demographic and other correlates of anemia among pregnant women. Methodology: This descriptive study with cross-sectional design was conducted in a tertiary care hospital. Pregnant who were attending antenatal clinic for a period of one year were comprised the study material. Correlation between variables was analyzed using the chi-square and odd ratio. Results: Three hundred and thirty eight pregnant women were registered for the present study, whose age ranged from 16 to 45 years with a mean age of 26.08 years. Majority (81.95% participants were found to be anemic. It was observed that anemia was more prevalent in pregnant women age groups i.e. 25-29 years and 30+years i.e. 86.67% and 86.21% respectively. Anemia was 82.92% in women were belonging to Hindu and others religion and 82.24% in women having vegetarian diet. Maximum prevalence (83.93% of anemia was observed in women who were booked for antenatal care in the 3rd trimester of pregnancy. The prevalence of anemia is higher (>85% in women having parity two or more, but this association was not statistically significant. Very few (6.21% were found to be severely anemic as compared to women who were moderately anemic (43.19%. Multiple logistic regression analysis of these factors showed that possibility of anemia is less in women who belong to rural area and it is highly significant. Analysis further showed significant association between anemia and type of diet and other factors like women having parity 1 and 4. Conclusion: The prevalence of anemia amongst the pregnant participants was very high. The socio-demographic and obstetrics factors were found to be associated with anemia. To prevent

  7. The effect of MEP pathway and other inhibitors on the intracellular localization of a plasma membrane-targeted, isoprenylable GFP reporter protein in tobacco BY-2 cells [v2; ref status: indexed, http://f1000r.es/2af

    Directory of Open Access Journals (Sweden)

    Michael Hartmann

    2013-11-01

    Full Text Available We have established an in vivo visualization system for the geranylgeranylation of proteins in a stably transformed tobacco BY-2 cell line, based on the expression of a dexamethasone-inducible GFP fused to the carboxy-terminal basic domain of the rice calmodulin CaM61, which naturally bears a CaaL geranylgeranylation motif (GFP-BD-CVIL. By using pathway-specific inhibitors it was demonstrated that inhibition of the methylerythritol phosphate (MEP pathway with known inhibitors like oxoclomazone and fosmidomycin, as well as inhibition of the protein geranylgeranyltransferase type 1 (PGGT-1, shifted the localization of the GFP-BD-CVIL protein from the membrane to the nucleus. In contrast, the inhibition of the mevalonate (MVA pathway with mevinolin did not affect the localization. During the present work, this test system has been used to examine the effect of newly designed inhibitors of the MEP pathway and inhibitors of sterol biosynthesis such as squalestatin, terbinafine and Ro48-8071. In addition, we also studied the impact of different post-prenylation inhibitors or those suspected to affect the transport of proteins to the plasma membrane on the localization of the geranylgeranylable fusion protein GFP-BD-CVIL.

  8. Prevalence of pernicious anemia in patients with macrocytic anemia and low serum B12

    OpenAIRE

    2014-01-01

    Objective: The current research evaluated the prevalence of pernicious anemia (PA) in patients with macrocytic anemia (high MCV) and low serum B12 in Riyadh. Methods: Blood testing was done in 77 patients (males: 45.5%, females: 54.5%) with macrocytic anemia; 84 patients; (males: 23.8%, females: 76.2%) with low serum B12 and 30 healthy subjects. Complete blood count, differential count, folic acid, vitamin B12, intrinsic factor, gastric parietal cell antibodies and holotranscobalamin II were ...

  9. Differential Inhibition of the TGF-β Signaling Pathway in HCC Cells Using the Small Molecule Inhibitor LY2157299 and the D10 Monoclonal Antibody against TGF-β Receptor Type II.

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    Francesco Dituri

    Full Text Available We investigated blocking the TGF-β signaling pathway in HCC using two small molecule inhibitors (LY2157299, LY2109761 and a neutralizing humanized antibody (D10 against TGF-βRII. LY2157299 and LY2109761 inhibited HCC cell migration on Laminin-5, Fibronectin, Vitronectin, Fibrinogen and Collagen-I and de novo phosphorylation of pSMAD2. LY2157299 inhibited HCC migration and cell growth independently of the expression levels of TGF-βRII. In contrast to LY2157299, D10 showed a reduction in pSMAD2 only after a short exposure. This study supports the use of LY2157299 in clinical trials, and presents new insights into TGF-β receptor cycling in cancer cells.

  10. Immune-mediated hemolytic anemia.

    Science.gov (United States)

    Rosse, Wendell F; Hillmen, Peter; Schreiber, Alan D

    2004-01-01

    Hemolytic anemia due to immune function is one of the major causes of acquired hemolytic anemia. In recent years, as more is known about the immune system, these entities have become better understood and their treatment improved. In this section, we will discuss three areas in which this progress has been apparent. In Section I, Dr. Peter Hillmen outlines the recent findings in the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH), relating the biochemical defect (the lack of glycosylphosphatidylinositol [GPI]-linked proteins on the cell surface) to the clinical manifestations, particularly hemolysis (and its effects) and thrombosis. He discusses the pathogenesis of the disorder in the face of marrow dysfunction insofar as it is known. His major emphasis is on innovative therapies that are designed to decrease the effectiveness of complement activation, since the lack of cellular modulation of this system is the primary cause of the pathology of the disease. He recounts his considerable experience with a humanized monoclonal antibody against C5, which has a remarkable effect in controlling the manifestations of the disease. Other means of controlling the action of complement include replacing the missing modulatory proteins on the cell surface; these studies are not as developed as the former agent. In Section II, Dr. Alan Schreiber describes the biochemistry, genetics, and function of the Fc gamma receptors and their role in the pathobiology of autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura due to IgG antibodies. He outlines the complex varieties of these molecules, showing how they vary in genetic origin and in function. These variations can be related to three-dimensional topography, which is known in some detail. Liganding IgG results in the transduction of a signal through the tyrosine-based activation motif and Syk signaling. The role of these receptors in the pathogenesis of hematological diseases due to IgG antibodies is

  11. [A simple algorithm for anemia].

    Science.gov (United States)

    Egyed, Miklós

    2014-03-09

    The author presents a novel algorithm for anaemia based on the erythrocyte haemoglobin content. The scheme is based on the aberrations of erythropoiesis and not on the pathophysiology of anaemia. The hemoglobin content of one erytrocyte is between 28-35 picogram. Any disturbance in hemoglobin synthesis can lead to a lower than 28 picogram hemoglobin content of the erythrocyte which will lead to hypochromic anaemia. In contrary, disturbances of nucleic acid metabolism will result in a hemoglobin content greater than 36 picogram, and this will result in hyperchromic anaemia. Normochromic anemia, characterised by hemoglobin content of erythrocytes between 28 and 35 picogram, is the result of alteration in the proliferation of erythropoeisis. Based on these three categories of anaemia, a unique system can be constructed, which can be used as a model for basic laboratory investigations and work-up of anaemic patients.

  12. Sideroblastic anemias: variations on imprecision in diagnostic criteria, proposal for an extended classification of sideroblastic anemias.

    Science.gov (United States)

    Koc, S; Harris, J W

    1998-01-01

    Sideroblastic anemias are caused by a diversity of hereditary, congenital, or acquired disorders. Criteria used in describing sideroblastic anemias vary widely among standard medical textbooks and even so have been imprecisely applied in the literature. Recent discoveries concerning the basic pathophysiologic mechanisms involving the molecular biology of nuclear and mitochondrial DNA, erythroid ALA synthase (ALAS-2), and iron transport have made the classification of sideroblastic anemias very complex. We recommend a more precise evaluation and documentation of the components that characterize the sideroblastic abnormality and propose an extended classification of the sideroblastic anemias.

  13. Curcumin, a Potential Inhibitor of Up-regulation of TNF-alpha and IL-6 Induced by Palmitate in 3T3-L1 Adipocytes through NF-kappaB and JNK Pathway

    Institute of Scientific and Technical Information of China (English)

    SHAO-LING WANG; YING EI; YING WEN; YAN-FENG CHEN; LI-XIN NA; SONG-TAO LI; CHANG-HAO SUN

    2009-01-01

    Objective To investigate the attenuating effect of curcumin, an anti-inflammatory compound derived from dietary spice turmeric (Curcuma longa) on the pro-inflammatory insulin-resistant state in 3T3-L1 adipocytes. Methods Glucose uptake rate was determined with the [3H] 2-deoxyglucose uptake method. Expressions of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured by quantitative RT-PCR analysis and ELISA. Nuclear transcription factor kappaB p65 (NF-κB p65) and mitogen-activated protein kinase (MAPKs) were detected by Western blot assay. Results The basal glucose uptake was not altered, and curcumin increased the insulin-stimulated glucose uptake in 3T3-L1 cells. Curcumin suppressed the transcription and secretion of TNF-α and IL-6 induced by palmitate in a concentration-dependent manner. Palmitate induced nuclear translocation of NF-kB. The activities of Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase1/2 (ERK1/2) and p38MAPK decreased in the presence of curcumin. Moreover, pretreatment with SP600125 (inhibitor of JNK) instead of PD98059 or SB203580 (inhibitor of ERK 1/2 or p38MAPK, respectively) decreased the up-regulation of TNF-α induced by palmitate. Conclusion Curcumin reverses palmitate-induced insulin resistance state in 3T3-L1 adipocytes through the NF-kB and JNK pathway.

  14. Signaling Pathways in Pathogenesis of Diamond Blackfan Anemia

    Science.gov (United States)

    2014-10-01

    morphant phenotype employed in this paper has been previously published, confirmation of the phenotype using CRISPR -based technology is now readily...particular morphant phenotype employed in this paper has been previously published, confirmation of the phenotype using CRISPR -based technology is

  15. Signaling Pathways in Pathogenesis of Diamond Blackfan Anemia

    Science.gov (United States)

    2013-10-01

    erythropoiesis through upregulation of p53 and miR34a. To more rigorously test this hypothesis and identify new downstream targets and microRNAs...pending. Applied for a Leukemia & Lymphoma Society Specialized Centers of Research ( SCOR ) – P.I. Beverly Mitchell, M.D. – not funded. 10

  16. Anemia of Inflammation and Chronic Disease

    Science.gov (United States)

    ... and Prevention website. www.cdc.gov/chronicdisease/overview/index.htm . Updated August 13, 2012. Accessed July 24, 2013. [3] Besarab A, Coyne DW. Iron supplementation to treat anemia in patients with chronic kidney disease. Nature Reviews ...

  17. Iron-Deficiency Anemia and Stroke

    OpenAIRE

    J Gordon Millichap

    2007-01-01

    The prevalence of iron-deficiency anemia (IDA) in young children at the time of stroke and in age-matched healthy controls was compared in a case-control study conducted at the Hospital for Sick Children, Toronto, Canada.

  18. Role of Complement in Autoimmune Hemolytic Anemia.

    Science.gov (United States)

    Berentsen, Sigbjørn

    2015-09-01

    The classification of autoimmune hemolytic anemias and the complement system are reviewed. In autoimmune hemolytic anemia of the warm antibody type, complement-mediated cell lysis is clinically relevant in a proportion of the patients but is hardly essential for hemolysis in most patients. Cold antibody-mediated autoimmune hemolytic anemias (primary cold agglutinin disease, secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria) are entirely complement-mediated disorders. In cold agglutinin disease, efficient therapies have been developed in order to target the pathogenic B-cell clone, but complement modulation remains promising in some clinical situations. No established therapy exists for secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria, and the possibility of therapeutic complement inhibition is interesting. Currently, complement modulation is not clinically documented in any autoimmune hemolytic anemia. The most relevant candidate drugs and possible target levels of action are discussed.

  19. CHRONIC HEART FAILURE AND IRON-DEFICIENT ANEMIA

    Directory of Open Access Journals (Sweden)

    M. V. Melnik

    2015-12-01

    Full Text Available 62 chronic heart failure (CHF patients with iron-deficient anemia (IDA were studied. Standard CHF therapy (angiotensin converting enzyme inhibitors, β-blockers, diuretics, cardiac glycosides was accompanied with the correction of iron deficiency by intravenous injection of Venofer and subsequent Ferro-Folgamma prescription (average daily dose of iron 137,75±5mg. After treatment serum iron level increased by 95,5% and hemoglobin level – by 9,8%. Left ventricular ejection fraction increased by 32,2% and physical activity tolerance – by 47,6%. Before treatment 32 CHF patients with IDA (51,6% had III functional class (FC of CHF according to NYHA and 16 patients (25,8% – IV FC. After treatment I FC was observed in 18 CHF patients (29%, II FC – in 26 patients and only 18 patients demonstrated III FC of CHF.

  20. CHRONIC HEART FAILURE AND IRON-DEFICIENT ANEMIA

    Directory of Open Access Journals (Sweden)

    M. V. Melnik

    2007-01-01

    Full Text Available 62 chronic heart failure (CHF patients with iron-deficient anemia (IDA were studied. Standard CHF therapy (angiotensin converting enzyme inhibitors, β-blockers, diuretics, cardiac glycosides was accompanied with the correction of iron deficiency by intravenous injection of Venofer and subsequent Ferro-Folgamma prescription (average daily dose of iron 137,75±5mg. After treatment serum iron level increased by 95,5% and hemoglobin level – by 9,8%. Left ventricular ejection fraction increased by 32,2% and physical activity tolerance – by 47,6%. Before treatment 32 CHF patients with IDA (51,6% had III functional class (FC of CHF according to NYHA and 16 patients (25,8% – IV FC. After treatment I FC was observed in 18 CHF patients (29%, II FC – in 26 patients and only 18 patients demonstrated III FC of CHF.

  1. [Anemia in obstetrics and gynecological surgery].

    Science.gov (United States)

    Gredilla Díaz, E

    2015-06-01

    Iron deficiency is more common in women due to uterine bleeding, which affects them throughout their fertile life. Additionally, iron needs increase physiologically during pregnancy and breastfeeding. Pregnant women therefore constitute one of the risk groups for iron deficiency. During the postpartum period, iron deficiency is the most common cause of anemia. Longer hospital stays and greater susceptibility to infections are potential consequences of postpartum anemia.

  2. Iron deficiency or anemia of inflammation?

    OpenAIRE

    Nairz, Manfred; Theurl, Igor; Wolf, Dominik; Weiss, Günter

    2016-01-01

    Summary Iron deficiency and immune activation are the two most frequent causes of anemia, both of which are based on disturbances of iron homeostasis. Iron deficiency anemia results from a reduction of the body’s iron content due to blood loss, inadequate dietary iron intake, its malabsorption, or increased iron demand. Immune activation drives a diversion of iron fluxes from the erythropoietic bone marrow, where hemoglobinization takes place, to storage sites, particularly the mononuclear ph...

  3. Doubling Down on the PI3K-AKT-mTOR Pathway Enhances the Antitumor Efficacy of PARP Inhibitor in Triple Negative Breast Cancer Model beyond BRCA-ness

    Directory of Open Access Journals (Sweden)

    Pradip De

    2014-01-01

    Full Text Available Phosphoinositide 3-kinase (PI3K pathway, in addition to its pro-proliferative and antiapoptotic effects on tumor cells, contributes to DNA damage repair (DDR. We hypothesized that GDC-0980, a dual PI3K-mammalian target of rapamycin (mTOR inhibitor, would induce an efficient antitumor effect in BRCA-competent triple negative breast cancer (TNBC model when combined with ABT888 and carboplatin. Mechanism-based in vitro studies demonstrated that GDC-0980 treatment alone or in combination led to DNA damage (increased pγH2AXS139; Western blot, immunofluorescence, gain in poly ADP-ribose (PAR, and a subsequent sensitization of BRCA-competent TNBC cells to ABT888 plus carboplatin with a time-dependent 1 decrease in proliferation signals (pAKTT308/S473, pP70S6KT421/S424, pS6RPS235/236, PAR/poly(ADP-ribose polymerase (PARP ratios, PAR/pγH2AX ratios, live/dead cell ratios, cell cycle progression, and three-dimensional clonogenic growths and 2 increase in apoptosis markers (cleaved caspases 3 and 9, a pro-apoptotic BH3-only of Bcl-2 family (BIM, cleaved PARP, annexin V. The combination was effective in vitro in BRCA-wild-type PIK3CA-H1047R-mutated BT20 and PTEN-null HCC70 cells. The combination blocked the growth of established xenograft tumors by 80% to 90% with a concomitant decrease in tumor Ki67, CD31, phosphorylated vascular endothelial growth factor receptor, pS6RPS235/236, and p4EBP1T37/46 as well as an increase in cleaved caspase 3 immunohistochemistry (IHC levels. Interestingly, a combination with GDC-0941, a pan-PI3K inhibitor, failed to block the tumor growth in MDA-MB231. Results demonstrate that the dual inhibition of PI3K and mTOR regulates DDR. In a BRCA-competent model, GDC-0980 enhanced the antitumor activity of ABT888 plus carboplatin by inhibiting both tumor cell proliferation and tumor-induced angiogenesis along with an increase in the tumor cell apoptosis. This is the first mechanism-based study to demonstrate the integral role of the

  4. Mouse models of anemia of cancer.

    Directory of Open Access Journals (Sweden)

    Airie Kim

    Full Text Available Anemia of cancer (AC may contribute to cancer-related fatigue and impair quality of life. Improved understanding of the pathogenesis of AC could facilitate better treatment, but animal models to study AC are lacking. We characterized four syngeneic C57BL/6 mouse cancers that cause AC. Mice with two different rapidly-growing metastatic lung cancers developed the characteristic findings of anemia of inflammation (AI, with dramatically different degrees of anemia. Mice with rapidly-growing metastatic melanoma also developed a severe anemia by 14 days, with hematologic and inflammatory parameters similar to AI. Mice with a slow-growing peritoneal ovarian cancer developed an iron-deficiency anemia, likely secondary to chronically impaired nutrition and bleeding into the peritoneal cavity. Of the four models, hepcidin mRNA levels were increased only in the milder lung cancer model. Unlike in our model of systemic inflammation induced by heat-killed Brucella abortus, ablation of hepcidin in the ovarian cancer and the milder lung cancer mouse models did not affect the severity of anemia. Hepcidin-independent mechanisms play an important role in these murine models of AC.

  5. An Approach to Iron-Deficiency Anemia

    Directory of Open Access Journals (Sweden)

    Imran Rasul

    2001-01-01

    Full Text Available Iron-deficiency anemia is a common reason for referral to a gastroenterologist. In adult men and postmenopausal women, gastrointestinal tract pathology is often the cause of iron-deficiency anemia, so patients are frequently referred for endoscopic evaluation. Endoscopy may be costly and at times difficult for the patient. Therefore, physicians need to know what lesions can be identified reliably and, more importantly, the importance of ruling out life-threatening conditions such as occult malignancy. Over the past decade, a number of prospective studies have been completed that examined the yield of endoscopy in the investigation of iron-deficiency anemia. The present article provides a broad overview of iron-deficiency anemia, with particular emphasis on hematological diagnosis, etiology, the use of endoscopy in identifying lesions and iron-repletion therapy. Other clinical scenarios, including assessment of patients on anti-inflammatory or anticoagulation therapy and patients with bleeding of obscure origin, are also addressed. The present article provides a diagnostic algorithm to iron-deficiency anemia, which describes a more systematic manner in which to approach iron-deficiency anemia.

  6. Myocardial disease,anemia and heart failure

    Institute of Scientific and Technical Information of China (English)

    Donald S Silverberg; Dov Wexler; Adrian Iaina; Doron Schwartz

    2005-01-01

    Abstract Many patients with congestive heart failure (CHF) fail to respond to maximal CHF therapy and progress to end stage CHF with many hospitalizations, very poor quality of life, end stage renal failure, or die of cardiovascular complications within a short time. One factor that has generally been ignored in many of these patients is the fact that they are often anemic.The anemia is due mainly to renal failure but also to the inhibitory effects of cytokines on the bone marrow. Anemia itself may further worsen the cardiac function and make the patients resistant to standard CHF therapies. Indeed anemia has been associated with increased severity of CHF, increased hospitalization, worse cardiac function and functional class, higher doses of diuretics,worsening of renal function and reduced quality of life. In both controlled and uncontrolled studies the correction of the anemia with erythropoietin (EPO) and oral or Ⅳ iron is associated with improvement in all these parameters. EPO itself may also play a direct role in improving the heart unrelated to the improvement of the anemia. Anemia may also play a role in the worsening of coronary heart disease even without CHF.

  7. Mitochondrial iron metabolism and sideroblastic anemia.

    Science.gov (United States)

    Sheftel, Alex D; Richardson, Des R; Prchal, Josef; Ponka, Prem

    2009-01-01

    Sideroblastic anemias are a heterogeneous group of disorders, characterized by mitochondrial iron overload in developing red blood cells. The unifying characteristic of all sideroblastic anemias is the ring sideroblast, which is a pathological erythroid precursor containing excessive deposits of non-heme iron in mitochondria with perinuclear distribution creating a ring appearance. Sideroblastic anemias may be hereditary or acquired. Hereditary sideroblastic anemias are caused by defects in genes present on the X chromosome (mutations in the ALAS2, ABCB7, or GRLX5 gene), genes on autosomal chromosomes, or mitochondrial genes. Acquired sideroblastic anemias are either primary (refractory anemia with ring sideroblasts, RARS, representing one subtype of the myelodysplastic syndrome) or secondary due to some drugs, toxins, copper deficiency, or chronic neoplastic disease. The pathogenesis of mitochondrial iron loading in developing erythroblasts is diverse. Ring sideroblasts can develop as a result of a heme synthesis defect in erythroblasts (ALAS2 mutations), a defect in iron-sulfur cluster assembly, iron-sulfur protein precursor release from mitochondria (ABCB7 mutations), or by a defect in intracellular iron metabolism in erythroid cells (e.g. RARS).

  8. Iron deficiency anemia in celiac disease.

    Science.gov (United States)

    Freeman, Hugh James

    2015-08-21

    Iron is an important micronutrient that may be depleted in celiac disease. Iron deficiency and anemia may complicate well-established celiac disease, but may also be the presenting clinical feature in the absence of diarrhea or weight loss. If iron deficiency anemia occurs, it should be thoroughly evaluated, even if celiac disease has been defined since other superimposed causes of iron deficiency anemia may be present. Most often, impaired duodenal mucosal uptake of iron is evident since surface absorptive area in the duodenum is reduced, in large part, because celiac disease is an immune-mediated disorder largely focused in the proximal small intestinal mucosa. Some studies have also suggested that blood loss may occur in celiac disease, sometimes from superimposed small intestinal disorders, including ulceration or neoplastic diseases, particularly lymphoma. In addition, other associated gastric or colonic disorders may be responsible for blood loss. Rarely, an immune-mediated hemolytic disorder with increased urine iron loss may occur that may respond to a gluten-free diet. Reduced expression of different regulatory proteins critical in iron uptake has also been defined in the presence and absence of anemia. Finally, other rare causes of microcytic anemia may occur in celiac disease, including a sideroblastic form of anemia reported to have responded to a gluten-free diet.

  9. Iron deficiency anemia in celiac disease

    Science.gov (United States)

    Freeman, Hugh James

    2015-01-01

    Iron is an important micronutrient that may be depleted in celiac disease. Iron deficiency and anemia may complicate well-established celiac disease, but may also be the presenting clinical feature in the absence of diarrhea or weight loss. If iron deficiency anemia occurs, it should be thoroughly evaluated, even if celiac disease has been defined since other superimposed causes of iron deficiency anemia may be present. Most often, impaired duodenal mucosal uptake of iron is evident since surface absorptive area in the duodenum is reduced, in large part, because celiac disease is an immune-mediated disorder largely focused in the proximal small intestinal mucosa. Some studies have also suggested that blood loss may occur in celiac disease, sometimes from superimposed small intestinal disorders, including ulceration or neoplastic diseases, particularly lymphoma. In addition, other associated gastric or colonic disorders may be responsible for blood loss. Rarely, an immune-mediated hemolytic disorder with increased urine iron loss may occur that may respond to a gluten-free diet. Reduced expression of different regulatory proteins critical in iron uptake has also been defined in the presence and absence of anemia. Finally, other rare causes of microcytic anemia may occur in celiac disease, including a sideroblastic form of anemia reported to have responded to a gluten-free diet. PMID:26309349

  10. Cardio-renal-anemia syndrome: A report of three cases

    Directory of Open Access Journals (Sweden)

    U H Okafor

    2012-01-01

    Full Text Available Patients with chronic kidney diseases (CKDs and cardiovascular diseases (CVDs present with various degree of anemia. Anemia has been associated with poor outcome in patients with CKD and CVD. CVD is the commonest cause of morbidity and mortality in patients with CKD. CKD causes anemia and CVD, and this rapidly deteriorates when anemia is not corrected. This triad of CVD, CKD, and anemia has been termed cardio-renal-anemia syndrome. The objec-tive of this study is to highlight the importance of cardio-renal-anemia syndrome, their relation-ship, and management. Three patients with various stages of CKD who presented with anemia and cardiovascular abnormalities are reported. The patients responded well to various interventional measures, with improvement in their clinical and laboratory parameters. Cardio-renal-anemia syndrome is an entity that should be identified. Early and appropriate intervention leads to better outcome.

  11. ANEMIA IN INFLAMMATORY BOWEL DISEASE MORE THAN AN EXTRAINTESTINAL COMPLICATION.

    Science.gov (United States)

    Nemeş, Roxana Maria; Pop, Corina Silvia; Calagiu, Dorina; Dobrin, Denisa; Chetroiu, Diana; Jantea, Petruta; Postolache, Paraschiva

    2016-01-01

    The most common hematologic complication of inflammatory bowel disease (IBD)--ulcerative colitis and Crohn's Disease is anemia. Anemia in patients with IBD may be a result of iron, vitamin B12 or folate deficiency; anemia of chronic disease and hemolytic anemia are other causes in these patients. Factors contributing to the development of anemia include chronic gastrointestinal blood loss, vitamin B12 malabsorption secondary to terminal ileitis, folate deficiency as a result of sulfasalazine therapy. Approximately 30% of patients with IBD have hemoglobin levels below 12 g/dl. The risk of developing anemia relates to disease activity, given that blood loss and inflammatory anemia are triggered by intestinal inflammation. In the management strategy of IBD patients with anemia it is important to distinguish between the different types of anemia in order to decide an appropriate manner of treatment.

  12. Methods to identify molecular expression of mTOR pathway: a rationale approach to stratify patients affected by clear cell renal cell carcinoma for more likely response to mTOR inhibitors

    Science.gov (United States)

    Fiorini, Claudia; Massari, Francesco; Pedron, Serena; Sanavio, Sara; Ciccarese, Chiara; Porcaro, Antonio Benito; Artibani, Walter; Bertoldo, Francesco; Zampini, Claudia; Sava, Teodoro; Ficial, Miriam; Caliò, Anna; Chilosi, Marco; D’Amuri, Alessandro; Sanguedolce, Francesca; Tortora, Giampaolo; Scarpa, Aldo; Delahunt, Brett; Porta, Camillo; Martignoni, Guido; Brunelli, Matteo

    2014-01-01

    Since target therapy with mTOR inhibitors plays an important role in the current management of clear cell renal cell carcinoma (RCC), there is an increasing demand for predictive biomarkers, which may help to select patients that are most likely to benefit from personalized treatment. When dealing with formalin-fixed paraffin-embedded (FFPE) cancer tissue specimens, several techniques may be used to identify potential molecular markers, yielding different outcome in terms of accuracy. We sought to investigate and compare the capability of three main techniques to detect molecules performing an active function in mTOR pathway in RCC. Immunohistochemistry (IHC), Western blot (WB) and immunofluorescence (IF) analyses were performed on FFPE RCC tissue specimens from 16 patients by using the following mTOR pathway-related: mTOR (Ser235/236), phospho-mTOR (p-mTOR/Ser2448), phospho-p70S6k (p-p70S6k/Thr389), both monoclonal and polyclonal, phospho-S6Rb (p-S6Rb) and phospho-4EBP1 (p-4EBP1/Thr37/46). No single molecule was simultaneously revealed by all three techniques. Only p-p70S6k was detected by two methods (IHC and IF) using a monoclonal antibody. The other molecules were detected exclusively by one technique, as follows: p-mTOR and polyclonal p-p70S6K by IHC, p70S6K, p-S6Rb and p-4EBP1 by WB, and, finally, mTOR by IF. We found significant differences in detecting mTOR pathway-related active biomarkers by using three common techniques such as IHC, WB and IF on RCC samples. Such results have important implications in terms of predictive biomarker testing, and need to be related to clinical end-points such as responsiveness to targeted drugs by prospective studies. PMID:25520878

  13. Differential effects of MAPK pathway inhibitors on migration and invasiveness of BRAF(V600E) mutant thyroid cancer cells in 2D and 3D culture.

    Science.gov (United States)

    Ingeson-Carlsson, Camilla; Martinez-Monleon, Angela; Nilsson, Mikael

    2015-11-01

    Tumor microenvironment influences targeted drug therapy. In this study we compared drug responses to RAF and MEK inhibitors on tumor cell migration in 2D and 3D culture of BRAF(V600E) mutant cell lines derived from human papillary (BCPAP) and anaplastic (SW1736) thyroid carcinomas. Scratch wounding was compared to a double-layered collagen gel model developed for analysis of directed tumor cell invasion during prolonged culture. In BCPAP both PLX4720 and U0126 inhibited growth and migration in 2D and decreased tumor cell survival in 3D. In SW1736 drugs had no effect on migration in 2D but decreased invasion in 3D, however this related to reduced growth. Dual inhibition of BRAF(V600E) and MEK reduced but did not prevent SW1736 invasion although rebound phosphorylation of ERK in response to PLX4720 was blocked by U0126. These findings indicate that anti-tumor drug effects in vitro differ depending on culture conditions (2D vs. 3D) and that the invasive features of anaplastic thyroid cancer depend on non-MEK mechanism(s).

  14. Fanconi Anemia — Case Report of Rare Aplastic Anemia at Child

    Directory of Open Access Journals (Sweden)

    Deaconu Alina

    2014-06-01

    Full Text Available Introduction: Fanconi anemia is an autosomal recessive disease characterized by congenital abnormalities, defective haematopoiesis, and a high risk of developing acute myeloid leukaemia, myelodysplastic syndrome and cancers. FA was first described in 1927 by the Swiss pediatrician Guido Fanconi. The diagnosis is based on morphological abnormalities, hematologic abnormalities (pancytopenia, macrocytic anemia and progressive bone marrow failure and genetic tests (cariograma.

  15. Iron, Anemia, and Iron Deficiency Anemia among Young Children in the United States

    Science.gov (United States)

    Gupta, Priya M.; Perrine, Cria G.; Mei, Zuguo; Scanlon, Kelley S.

    2016-01-01

    Iron deficiency and anemia are associated with impaired neurocognitive development and immune function in young children. Total body iron, calculated from serum ferritin and soluble transferrin receptor concentrations, and hemoglobin allow for monitoring of the iron and anemia status of children in the United States. The purpose of this analysis is to describe the prevalence of iron deficiency (ID), anemia, and iron deficiency anemia (IDA) among children 1–5 years using data from the 2007–2010 National Health and Nutrition Examination Survey (NHANES). Prevalence of ID, anemia, and IDA among children 1–5 years was 7.1% (5.5, 8.7), 3.2% (2.0, 4.3), and 1.1% (0.6, 1.7), respectively. The prevalence of both ID and anemia were higher among children 1–2 years (p < 0.05). In addition, 50% of anemic children 1–2 years were iron deficient. This analysis provides an update on the prevalence of ID, anemia, and IDA for a representative sample of US children. Our results suggest little change in these indicators over the past decade. Monitoring of ID and anemia is critical and prevention of ID in early childhood should remain a public health priority. PMID:27249004

  16. Biologics beyond TNF-α inhibitors and the effect of targeting the homologues TL1A-DR3 pathway in chronic inflammatory disorders

    DEFF Research Database (Denmark)

    Tougaard, Peter; Zervides, Kristoffer Alexander; Skov, Søren

    2016-01-01

    A number of anti-tumor necrosis factor alpha (TNF-α) biologics have been developed in recent years, such as adalimumab, etanercept, and infliximab for the treatment of chronic inflammatory disorders like rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis and several other...... novel drugs that target TNF-α signaling are still being developed. Indeed, blockade of this pathway seems so important amongst immune-targets that TNF-α targeted therapies will continue to have a significant role in the treatment of chronic inflammation. However, up to 40% of RA and IBD patients do...... concentrations of TL1A has been demonstrated in patients with various chronic inflammatory disorders. Here, we describe the current knowledge of TL1As immunobiology and present results from human disease, animal models, and pre-clinical intervention studies that point toward development of anti-TL1A therapy...

  17. Fanconi's Anemia Effect or Sickle Cell Anemia Effect: That is the Question.

    Science.gov (United States)

    Unal, Sule; Chui, David H K; Gumruk, Fatma

    2015-01-01

    A 16-year-old boy who was diagnosed to have sickle cell anemia was referred to our center. The parental consanguinity, growth retardation and dysmorphic features prompted a search for possible Fanconi's Anemia (FA). The diepoxybutane (DEB) test was positive, confirming FA. The interaction of both diseases might account for his relatively mild phenotype in terms of both sickle cell anemia (or Hb S, HBB: c.20A > T) and FA. The high Hb F level that might be related to concomitant FA, may have caused a milder phenotype of sickle cell anemia, whereas nitric oxide (NO) depletion as a consequence of sickle cell anemia, may have caused a delay in the bone marrow failure of FA.

  18. Anemia in patients with diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Dimković Nada

    2007-01-01

    Full Text Available Introduction: Anemia is more common and pronounced in patients with diabetic, than in patients with non-diabetic renal disease. While several factors contribute to its pathogenesis, the failure of the kidney to increase erythropoietin in response to falling hemoglobin appears to be the dominant factor. The most frequent complications of anemia in diabetic patients include decreased quality of life and work capacity and increased cardiovascular morbidity and mortality. Material and Methods: This cross-sectional multicenter study included a total of 539 patients with type I (~20% and type II diabetes (~80% classified into five stages according to the glomerular filtration rate. Results Diabetic nephropathy appears in stage I, and progresses in all patients to the stage V (p=0.045. The presence of anemia progressively increased from stage I to stage V (from 60% to 100%, p=0.008. Only 62% of patients with anemia were treated (mainly with iron and only 3.4% received erythropoietin treatment. Hypertension was present in 90% of patients in stage I and in 100% of patients in stage V nephropathy. The presence of heart failure increased from 0% (stage I to 51% (stage IV, p=0.03. Around 62% of patients were referred to a nephrologist, and according to the logistic regression model, renal failure and presence of anemia were significant predictors of patients' referral to nephrologist. Conclusion: In a primary care setting, anemia is a frequent finding, even in the very beginning of diabetic renal disease. Currently available guidelines for management of anemia are not followed; this may explain high percentage of patients with heart failure in pre-dialysis stage. Early referral to a nephrologist and regular follow-up by an endocrinologist and cardiologist are the best way for the prevention of diabetic complications and comorbidity.

  19. Aspectos moleculares da anemia falciforme

    Directory of Open Access Journals (Sweden)

    Galiza Neto Gentil Claudino de

    2003-01-01

    Full Text Available No presente artigo abordaram-se vários aspectos relacionados à natureza molecular da anemia falciforme, desordem hematológica de caráter hereditário que acomete expressivo número de indivíduos em várias regiões do mundo. As pesquisas realizadas em torno desta patologia da hemácia, ao longo de quase um século, a partir de 1910, cooperaram para a criação de um novo e importante segmento da ciência, denominado biologia molecular. A descoberta dos polimorfismos da mutação (GAT->GTG no gene que codifica a cadeia beta da hemoglobina, originando diferentes haplótipos da doença, permitiu um melhor e mais amplo conhecimento em torno da heterogeneidade clínica nos pacientes falcêmicos. Analisando a hemoglobina na sua estrutura normal e mutante, sua produção e evolução, pode-se ter um entendimento mais completo da fisiopatologia desta doença e da sua complexidade clínica.

  20. Effects of Secondary Hyperparathyroidism Treatment on Improvement in Anemia: Results from the MBD-5D Study

    Science.gov (United States)

    Tanaka, Motoko; Yoshida, Kazuki; Fukuma, Shingo; Ito, Kazuko; Matsushita, Kazutaka; Fukagawa, Masafumi; Fukuhara, Shunichi; Akizawa, Tadao

    2016-01-01

    Objectives Anemia is an important prognostic factor in hemodialysis patients. It has been reported that parathyroidectomy ameliorates anemia and reduces the requirement of postoperative erythropoiesis-stimulating agents. The objective of this study was to assess the effect of cinacalcet, which is considered as a pharmacological parathyroidectomy, on anemia in hemodialysis patients. Methods We used data from a prospective cohort of Japanese hemodialysis patients with secondary hyperparathyroidism; the criteria were: intact parathyroid hormone concentrations ≥ 180 pg/mL or use of an intravenous or oral vitamin D receptor activator. All patients were cinacalcet-naïve at study enrollment. The main outcome measure was achievement of the target hemoglobin level (≥10.0 g/dL), which was measured repeatedly every 6 months. Cinacalcet exposure was defined as cumulative time since initiation. Both conventional longitudinal models and marginal structural models were adjusted for confounding factors. Results Among 3,201 cinacalcet-naïve individuals at baseline, cinacalcet was initiated in 1,337 individuals during the follow up. Cinacalcet users were slightly younger; included more patients with chronic glomerulonephritis and fewer with diabetes; were more likely to have a history of parathyroidectomy; and were more often on activated vitamin D agents, phosphate binders, and iron supplements. After adjusting for both time-invariant and time-varying potential confounders, including demographics, comorbidities, comedications, and laboratory values, each additional 6-month duration on cinacalcet was associated with a 1.1-fold increase in the odds of achieving the target hemoglobin level. Conclusions Cinacalcet may improve anemia in chronic hemodialysis patients with secondary hyperparathyroidism, possibly through pathways both within and outside the parathyroid hormone pathways. Further investigations are warranted to delineate the roles of cinacalcet not only in the

  1. STUDY OF RBC HISTOGRAM IN VARIOUS ANEMIAS

    Directory of Open Access Journals (Sweden)

    Sandhya

    2014-12-01

    Full Text Available Over the past few years complete blood count (CBC by the automated hematology analyzers and microscopic examination of peripheral smear have complemented each other to provide a comprehensive report on patients’ blood sample. Numerous classifications for anemia have been established and the important parameters involved in the classifications are Hb, HCT, MCV, RDW, MCH, MCHC, reticulocytes and IRF. Many of these values are obtained only by automated heamatology analyzers. One histogram graph is worth 1000 numbers. A large collection of data, displayed as a visual image, can convey information with far more impact than the numbers alone. In hematology, these data take on several forms, one of which is the RBC histogram. Therefore a study of variation in RBC histograms in various anemias. Many times it is seen that histogram patterns show varying features when a simultaneous peripheral smear is reported. It is also seen that there are many limitations when manual peripheral smears reporting is done for example: peripheral smear reports are subjective, labor intensive and statistically unreliable. However microscopic peripheral smear examination also has their advantages. This study intends to create a guide to laboratory personnel and clinicians with sufficient accuracy to presumptively diagnose morphological classes of anemia directly from the automated hematology cell counter forms and correlate with morphological features of peripheral smear examination. OBJECTIVE: 1. The objective of the study is to know the utility and advantage of red cell histograms. 2. To study the automated histogram patterns along with morphological features noticed on peripheral smear examination. SOURCE OF DATA: All anemic patients from Central Diagnostic Laboratory of A.J.IMS. METHOD OF COLLECTION OF DATA: A total of about 100 patients were included in the study. Complete blood count including HB, TC, DC, Platelet count hematocrit value, RBC indices was obtained

  2. Differential effect of the expression of TGF-β pathway inhibitors, Smad-7 and Ski, on invasive breast carcinomas: relation to biologic behavior.

    Science.gov (United States)

    Theohari, Irini; Giannopoulou, Ioanna; Magkou, Christina; Nomikos, Alexandros; Melissaris, Savvas; Nakopoulou, Lydia

    2012-02-01

    The aim of our study was to investigate the expression of Smad-7 and Ski proteins in invasive breast carcinomas, to determine their clinicopathological value and their influence on carcinomas biologic behavior. Immunohistochemistry was applied on 150 invasive breast carcinomas to detect the expression of Smad-7 and Ski. Their correlation to clinicopathologic parameters and markers of metastasis was statistically processed using chi-squared test. Overall and disease-free survival was assessed using Kaplan-Meier test and log-rank statistics. Smad-7 was immunodetected in the cytoplasm of cancer cells in 60%, whereas Ski was immunodetected in the cytoplasm and nuclei in 44.5% and 17.6% of the cases, respectively. Smad-7 expression was positively correlated with tumor size, stage, matrix metalloproteinase (MMP)-9, and MMP-14. Cytoplasmic Ski expression was negatively associated with tumor size, stage, and lymph node status, and its nuclear expression was negatively related to histologic grade. Cytoplasmic Ski expression was associated with longer overall and disease-free survival. It appears that two negative regulators of the transforming growth factor-β pathway, Smad-7 and Ski, behave differentially in invasive breast carcinomas. Smad-7 appears to be related with an aggressive phenotype, whereas Ski expression is related to a less aggressive behavior and positively influences patients' survival.

  3. Inhibitor of p53-p21 pathway induces the differentiation of human umbilical cord derived mesenchymal stem cells into cardiomyogenic cells.

    Science.gov (United States)

    Ruan, Zhong-Bao; Zhu, Li; Yin, Yi-Gang; Chen, Ge-Cai

    2016-08-01

    P53 is shown recently to play an important role in the proliferation and differentiation of mesenchymal stem cells. In this study, human umbilical cord derived mesenchymal stem cells (hUCMSCs) were isolated and purified from the umbilical cords of normal or cesarean term deliveries, after treatment with 20 μmol/L PFT-α for 24 h, hUCMSCs were continued to be cultured for 4 weeks, cardiac-specific protein expression of cTnI, Desmin and Nkx2.5 was determined using immunofluorescence assay and RT-PCR. The expression of p53 and p21 was detected by western blot. Results showed that no expression of cTnI, Desmin or Nkx2.5 was observed in the control and the PFT-α group at 1 week after induction. However, after 4 weeks, while control group still had little expression of cTnI, Desmin and Nkx2.5, the PFT-α group demonstrated strong expression of cTnI, Desmin and Nkx2.5 (P cells in the PFT-α group (36.98 %) was significantly higher than that in the control group (4.41 %) (P p21 was seen in the PFT-α group at 4 weeks. The difference compared with the control group was statistically significant (P cells by modulating the p53-p21 pathway.

  4. Pro-Inflammatory Cytokine-Mediated Anemia: Regarding Molecular Mechanisms of Erythropoiesis

    Directory of Open Access Journals (Sweden)

    F. Morceau

    2009-01-01

    Full Text Available Anemia of cancer and chronic inflammatory diseases is a frequent complication affecting quality of life. For cancer patients it represents a particularly bad prognostic. Low level of erythropoietin is considered as one of the causes of anemia in these pathologies. The deficiency in erythropoietin production results from pro-inflammatory cytokines effect. However, few data is available concerning molecular mechanisms involved in cytokine-mediated anemia. Some recent publications have demonstrated the direct effect of pro-inflammatory cytokines on cell differentiation towards erythroid pathway, without erythropoietin defect. This suggested that pro-inflammatory cytokine-mediated signaling pathways affect erythropoietin activity. They could interfere with erythropoietin-mediated signaling pathways, inducing early apoptosis and perturbing the expression and regulation of specific transcription factors involved in the control of erythroid differentiation. In this review we summarize the effect of tumor necrosis factor (TNFα, TNF-related apoptosis-inducing ligand (TRAIL, and interferon (IFN-γ on erythropoiesis with a particular interest for molecular feature.

  5. HEMOLYTIC ANEMIA IMUNNE-MEDIATED IN DOGS

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    R. C. Castilho

    2016-11-01

    Full Text Available Due to the reduction in the number of red blood cells, caused by the immune system, the immune-mediated hemolytic anemia (IMHA is the most common disease among the hemolytic anemias and occurs more frequently in dogs (Nelson & Couto, 2010, wherein the most affected breeds are Cocker Spaniel, Poodle, Doberman and Collie (ETTINGER; FELDMAN 2004; THRALL et al 2007.. There is no pathognomonic sign for the diagnosis of the immune-mediated hemolytic anemia; however, laboratory findings show regenerative anemia, spherocytosis, positive results in Coombs' test and rarely, monocytes with hemosiderin or erythrocytes phagocytosis, but even with these findings, the primary and secondary IMHA can not be differentiate from each other. Differentiation can only be achieved when there is a deep investigation into the cause of the anemia. The IMHA therapeutics starts with the support treatment and follows with an immunosuppressive therapy. In relation to IMHA Mortality rates, the numbers range from 25% to 50% (Thrall, 2007, or above 70% (CARR; Panciera; Kidd, 2002.

  6. Reticulocyte maturity indices in iron deficiency anemia

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    Muriel Wollmann

    2014-01-01

    Full Text Available Objective: The aim of this study was to analyze the reticulocyte maturity indices (low, medium, and high fluorescence ratios in iron deficient 1- to 6-year-old children, and identify the prevalence of iron deficiency anemia in this population. Methods: The present study included 39 subjects, divided into two groups: control subjects (n = 33, and subjects with iron deficiency anemia (n = 6. The results were analyzed by Student's t-test for comparison of means. Differences were considered significant when two-tailed p-value < 0.05. Results: Subjects with iron deficiency anemia presented increases in the proportion of mean (10.3 ± 4.7% vs. 6.0 ± 3.4%; p-value = 0.003, and high fluorescence reticulocytes (2.3 ± 0.87% vs. 0.9 ± 0.9%; p-value = 0.03 compared to the control group. The prevalence of anemia in this population was 15% (n = 6. Conclusion: The indices related to immaturity of reticulocytes are higher in the presence of iron deficiency, thus demonstrating a deficiency in the raw material to form hemoglobin and are, therefore, possible early markers of iron deficiency and anemia. We emphasize the need to standardize these indices for use in clinical practice and lab test results.

  7. Anemia among school children in eastern Nepal.

    Science.gov (United States)

    Khatiwada, Saroj; Gelal, Basanta; Gautam, Sharad; Tamang, Man Kumar; Shakya, Prem Raj; Lamsal, Madhab; Baral, Nirmal

    2015-06-01

    Anemia is one of the most common public health problems in developing countries like Nepal. This study was done to find the prevalence of anemia among the children aged 4-13 years in eastern Nepal. A cross-sectional study was conducted in 2012 in four districts (Morang, Udayapur, Bhojpur and Ilam) of eastern Nepal to find the prevalence of anemia among the school children of eastern Nepal. Children aged 4-13 years were selected randomly from different schools of above districts and 618 venous blood samples were collected. Hemoglobin level was estimated by using cyanmethemoglobin method. The mean hemoglobin level was 12.2 ± 1.82 gm/dl. About 37.9% (n = 234) children were found anemic. Anemia prevalence was 42.4% (n = 78), 31.6% (n = 60), 45.3% (n = 48) and 34.8% (n = 48) among school children of Morang, Udayapur, Bhojpur and Ilam district, respectively. The study finds anemia as a significant health problem among the school children of eastern Nepal.

  8. Iron-refractory iron deficiency anemia.

    Science.gov (United States)

    Yılmaz Keskin, Ebru; Yenicesu, İdil

    2015-03-05

    Iron is essential for life because it is indispensable for several biological reactions, such as oxygen transport, DNA synthesis, and cell proliferation. Over the past few years, our understanding of iron metabolism and its regulation has changed dramatically. New disorders of iron metabolism have emerged, and the role of iron as a cofactor in other disorders has begun to be recognized. The study of genetic conditions such as hemochromatosis and iron-refractory iron deficiency anemia (IRIDA) has provided crucial insights into the molecular mechanisms controlling iron homeostasis. In the future, these advances may be exploited to improve treatment of both genetic and acquired iron disorders. IRIDA is caused by mutations in TMPRSS6, the gene encoding matriptase-2, which downregulates hepcidin expression under conditions of iron deficiency. The typical features of this disorder are hypochromic, microcytic anemia with a very low mean corpuscular volume of erythrocytes, low transferrin saturation, no (or inadequate) response to oral iron, and only a partial response to parenteral iron. In contrast to classic iron deficiency anemia, serum ferritin levels are usually low-normal, and serum or urinary hepcidin levels are inappropriately high for the degree of anemia. Although the number of cases reported thus far in the literature does not exceed 100, this disorder is considered the most common of the "atypical" microcytic anemias. The aim of this review is to share the current knowledge on IRIDA and increase awareness in this field.

  9. Iron-Refractory Iron Deficiency Anemia

    Science.gov (United States)

    Yılmaz Keskin, Ebru; Yenicesu, İdil

    2015-01-01

    Iron is essential for life because it is indispensable for several biological reactions, such as oxygen transport, DNA synthesis, and cell proliferation. Over the past few years, our understanding of iron metabolism and its regulation has changed dramatically. New disorders of iron metabolism have emerged, and the role of iron as a cofactor in other disorders has begun to be recognized. The study of genetic conditions such as hemochromatosis and iron-refractory iron deficiency anemia (IRIDA) has provided crucial insights into the molecular mechanisms controlling iron homeostasis. In the future, these advances may be exploited to improve treatment of both genetic and acquired iron disorders. IRIDA is caused by mutations in TMPRSS6, the gene encoding matriptase-2, which downregulates hepcidin expression under conditions of iron deficiency. The typical features of this disorder are hypochromic, microcytic anemia with a very low mean corpuscular volume of erythrocytes, low transferrin saturation, no (or inadequate) response to oral iron, and only a partial response to parenteral iron. In contrast to classic iron deficiency anemia, serum ferritin levels are usually low-normal, and serum or urinary hepcidin levels are inappropriately high for the degree of anemia. Although the number of cases reported thus far in the literature does not exceed 100, this disorder is considered the most common of the “atypical” microcytic anemias. The aim of this review is to share the current knowledge on IRIDA and increase awareness in this field. PMID:25805669

  10. Pulmonary functions in pregnancy complicated with anemia

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    Subhalaxmi Dash

    2014-08-01

    Full Text Available Background: The aim of the present study was to find out the variation of pulmonary function parameters in different trimesters of pregnancy as well as variation according to severity of anemia in each trimester. Methods: The present case control study was carried out in the post-graduate department of obstetrics and gynecology, M.K.C.G. medical college and hospital, Berhampur, during the period from October 2012 to October 2013. This study entitled and ldquo;Pulmonary functions in pregnancy complicated with anemia and rdquo;, embodies the pulmonary functions of 60 anemic pregnant females (study group and 100 healthy pregnant females (control in different trimesters of pregnancy. The pulmonary function parameters, which were studied, are FVC, FEV1, FEV1/FVC, FEF25-75%, PEFR and MVV in both the study and control group. Results: Comparing the variation with advancing gestation in study and control, it was seen that FVC, FEV1, FEV1/FVC and FEF25-75% showed no significant alteration. With increasing severity of anemia compared to controls, FVC, FEV1, PEFR and MVV values reduce significantly. As FEF25-75% is not effort dependent, it shows no significant variation. Conclusion: Thus from this study, it can be concluded that moderate to severe anemia in pregnancy can adversely affect pulmonary functions. Hence nutritional anemia in early pregnancy should be provided with iron supplements in order to prevent adverse obstetric outcomes. [Int J Res Med Sci 2014; 2(4.000: 1431-1437

  11. Clinical patterns and hematological spectrum in autoimmune hemolytic anemia

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    Vanamala Alwar

    2010-01-01

    Conclusion :AIHAs have a female predilection and commonly present with symptoms of anemia. AIHA secondary to other diseases (especially connective tissue disorders is more common. Primary AIHAs presented with severe anemia and laboratory evidence of marked hemolysis.

  12. Gene Therapy: a Breakthrough for Sickle Cell Anemia?

    Science.gov (United States)

    ... fullstory_163849.html Gene Therapy: A Breakthrough for Sickle Cell Anemia? But treatment has only been given to ... gene therapy to treat, or even potentially cure, sickle cell anemia. The findings come from just one patient, ...

  13. Craving and Chewing Ice: A Sign of Anemia?

    Science.gov (United States)

    ... constantly craving and chewing ice a sign of anemia? Answers from Ruben A. Mesa, M.D. Possibly. Doctors use the term "pica" ... ice (pagophagia) is often associated with iron deficiency anemia, although the reason is unclear. At least one ...

  14. What Are the Signs and Symptoms of Fanconi Anemia?

    Science.gov (United States)

    ... What Are the Signs and Symptoms of Fanconi Anemia? Major Signs and Symptoms Your doctor may suspect ... sisters also should be tested for the disorder. Anemia The most common symptom of all types of ...

  15. What Are the Signs and Symptoms of Aplastic Anemia?

    Science.gov (United States)

    ... What Are the Signs and Symptoms of Aplastic Anemia? Lower than normal numbers of red blood cells, ... most of the signs and symptoms of aplastic anemia. Signs and Symptoms of Low Blood Cell Counts ...

  16. Effective inhibition of colon cancer cell growth with MgAl-layered double hydroxide (LDH loaded 5-FU and PI3K/mTOR dual inhibitor BEZ-235 through apoptotic pathways

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    Chen J

    2014-07-01

    Full Text Available Jiezhong Chen,1,2 Renfu Shao,3 Li Li,4 Zhi Ping Xu,4 Wenyi Gu4 1School of Biomedical Sciences, University of Queensland, St Lucia, Queensland, 2Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, 3GeneCology Research Centre, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Maroochydore, Queensland, 4Australian Institute of Bioengineering and Nanotechnology, University of Queensland, St Lucia, Queensland, Australia Abstract: Colon cancer is the third most common cancer and the third largest cause of cancer-related death. Fluorouracil (5-FU is the front-line chemotherapeutic agent for colon cancer. However, its response rate is less than 60%, even in combination with other chemotherapeutic agents. The side effects of 5-FU also limit its application. Nanoparticles have been used to deliver 5-FU, to increase its effectiveness and reduce side effects. Another common approach for colon cancer treatment is targeted therapy against the phosphoinositide 3-kinase (PI3K/protein kinase B (Akt pathway. A recently-invented inhibitor of this pathway, BEZ-235, has been tested in several clinical trials and has shown effectiveness and low side effects. Thus, it is a very promising drug for colon cancer treatment. The combination of these two drugs, especially nanoparticle-packed 5-FU and BEZ-235, has not been studied. In the present study, we demonstrated that nanoparticles of layered double hydroxide (LDH loaded with 5-FU were more effective than a free drug at inhibiting colon cancer cell growth, and that a combination treatment with BEZ-235 further increased the sensitivity of colon cancer cells to the treatment of LDH-packed 5-FU (LDH-5-FU. BEZ-235 alone can decrease colon cancer HCT-116 cell viability to 46% of the control, and the addition of LDH-5-FU produced a greater effect, reducing cell survival to 8% of the control. Our data indicate that the combination therapy of

  17. Sobre o diagnostico histologico da anemia drepanocytica On the histologic diagnosis of the drepanocytic anemia

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    A. Penna de Azevedo

    1937-01-01

    Full Text Available No presente trabalho são descriptas as alterações anatomo-pathologicas do baço na anemia drepanocytica (anemia falciforme, Sicklecell anemia A observação refere-se a um menino de 12 annos de edade, de côr preta, o qual veio a fallecer em consequencia de processo de trombo-phlebite cerebral e de leptomeningite. A doença não foi reconhecida durante a vida e sómente pelo exame dos córtes histologicos do baço é que foi estabelecido o diagnostico de anemia drepanocytica, apresentando o baço as alterações peculiares á doença.In the present paper, the pathologico-anatomical changes of spleen in drepanocytic anemia are described (Sickle-cell anemia. In the case history, a 12 years old negro boy is concerned, who died in consequence of a cerebral thrombophlebitis process and leptomeningitis. The disease had not been recognized during life, and only on examination of the histological sections of the spleen the diagnosis of drepanocytic anemia was made, as this organ presented changes which are peculiar of the disease.

  18. Immune Hemolytic Anemia in a Patient with Tuberculous Lymphadenitis

    OpenAIRE

    Manjunath Nandennavar; Sanju Cyriac; Krishnakumar,; T G Sagar

    2011-01-01

    Anemia in tuberculosis is usually anemia of chronic disease. Severe hemolytic anemia is exceedingly rare in tuberculosis patients. We report a patient diagnosed with tubercular lymphadenitis complicated by Coomb′s positive hemolytic anemia. Patient responded well to antituberculous treatment. Hematological parameters improved after initiation of antituberculosis treatment. To the best of our knowledge, this is the first case from India of an adult patient with tuberculous lymphadenitis presen...

  19. Anemia among Primary School Children in Eastern Ethiopia

    OpenAIRE

    Firehiwot Mesfin; Yemane Berhane; Alemayehu Worku

    2015-01-01

    Background Anemia during childhood impairs physical growth, cognitive development and school performance. Identifying the causes of anemia in specific contexts can help efforts to prevent negative consequences of anemia among children. The objective of this study was to assess prevalence and identify correlates of anemia among school children in Eastern Ethiopia. Methods A cross sectional study was conducted from January 2012 to February 2012 in Kersa, Eastern Ethiopia. The study included ran...

  20. Osteopetrosis: A rare cause of anemia - Review of literature

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    Saluja S

    2009-07-01

    Full Text Available Normocytic anaemia is caused either by hypoproliferation of haemopoietic tissue or increased destruction of red cell. Osteopetrosis is a rare cause of anaemia. The leading clinical features are pallor, growth failure, hepatosplenomegaly.On hematological examination, anemia, thrombocytopenia, leucocytosis and myelophthisic anemia are commonly observed in this disease. We are highlighting osteopetrosis as a rare cause of anemia presenting to us for evaluation of anemia