Emerging functions of the Fanconi anemia pathway at a glance.

Science.gov (United States)

Sumpter, Rhea; Levine, Beth

2017-08-15

Fanconi anemia (FA) is a rare disease, in which homozygous or compound heterozygous inactivating mutations in any of 21 genes lead to genomic instability, early-onset bone marrow failure and increased cancer risk. The FA pathway is essential for DNA damage response (DDR) to DNA interstrand crosslinks. However, proteins of the FA pathway have additional cytoprotective functions that may be independent of DDR. We have shown that many FA proteins participate in the selective autophagy pathway that is required for the destruction of unwanted intracellular constituents. In this Cell Science at a Glance and the accompanying poster, we briefly review the role of the FA pathway in DDR and recent findings that link proteins of the FA pathway to selective autophagy of viruses and mitochondria. Finally, we discuss how perturbations in FA protein-mediated selective autophagy may contribute to inflammatory as well as genotoxic stress. © 2017. Published by The Company of Biologists Ltd.

The role of the Fanconi anemia pathway in DNA repair and maintenance of genome stability

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Aleksandra M. Koczorowska

2014-05-01

Full Text Available The Fanconi anemia (FA pathway is one of the DNA repair systems involved in removal of DNA crosslinks. Proteins which belong to this pathway are crucial to the protection of genetic information, whereas disturbances in their function have serious implications for the whole organism. Biallelic mutations in FA genes are the cause of Fanconi anemia – a genetic disease which manifests itself through numerous congenital abnormalities, chromosomal instability and increased predisposition to cancer. The FA pathway is composed of fifteen proteins. Eight of them, in the presence of DNA interstrand crosslinks (ICLs, form a nuclear core complex responsible for monoubiquitination of FANCD2 and FANCI, which is a key step of ICL repair. FA proteins which are not involved in the monoubiquitination step participate in repair of DNA double strand breaks via homologous recombination. Some of the FA proteins, besides having a direct role in the repair of DNA damage, are engaged in replication, cell cycle control and mitosis. The unperturbed course of those processes determines the maintenance of genome stability.

Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway.

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van Twest, Sylvie; Murphy, Vincent J; Hodson, Charlotte; Tan, Winnie; Swuec, Paolo; O'Rourke, Julienne J; Heierhorst, Jörg; Crismani, Wayne; Deans, Andrew J

2017-01-19

Monoubiquitination and deubiquitination of FANCD2:FANCI heterodimer is central to DNA repair in a pathway that is defective in the cancer predisposition syndrome Fanconi anemia (FA). The "FA core complex" contains the RING-E3 ligase FANCL and seven other essential proteins that are mutated in various FA subtypes. Here, we purified recombinant FA core complex to reveal the function of these other proteins. The complex contains two spatially separate FANCL molecules that are dimerized by FANCB and FAAP100. FANCC and FANCE act as substrate receptors and restrict monoubiquitination to the FANCD2:FANCI heterodimer in only a DNA-bound form. FANCA and FANCG are dispensable for maximal in vitro ubiquitination. Finally, we show that the reversal of this reaction by the USP1:UAF1 deubiquitinase only occurs when DNA is disengaged. Our work reveals the mechanistic basis for temporal and spatial control of FANCD2:FANCI monoubiquitination that is critical for chemotherapy responses and prevention of Fanconi anemia. Copyright © 2017 Elsevier Inc. All rights reserved.

Defects in the Fanconi Anemia Pathway and Chromatid Cohesion in Head and Neck Cancer.

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Stoepker, Chantal; Ameziane, Najim; van der Lelij, Petra; Kooi, Irsan E; Oostra, Anneke B; Rooimans, Martin A; van Mil, Saskia E; Brink, Arjen; Dietrich, Ralf; Balk, Jesper A; Ylstra, Bauke; Joenje, Hans; Feller, Stephan M; Brakenhoff, Ruud H

2015-09-01

Failure to repair DNA damage or defective sister chromatid cohesion, a process essential for correct chromosome segregation, can be causative of chromosomal instability (CIN), which is a hallmark of many types of cancers. We investigated how frequent this occurs in head and neck squamous cell carcinoma (HNSCC) and whether specific mechanisms or genes could be linked to these phenotypes. The genomic instability syndrome Fanconi anemia is caused by mutations in any of at least 16 genes regulating DNA interstrand crosslink (ICL) repair. Since patients with Fanconi anemia have a high risk to develop HNSCC, we investigated whether and to which extent Fanconi anemia pathway inactivation underlies CIN in HNSCC of non-Fanconi anemia individuals. We observed ICL-induced chromosomal breakage in 9 of 17 (53%) HNSCC cell lines derived from patients without Fanconi anemia. In addition, defective sister chromatid cohesion was observed in five HNSCC cell lines. Inactivation of FANCM was responsible for chromosomal breakage in one cell line, whereas in two other cell lines, somatic mutations in PDS5A or STAG2 resulted in inadequate sister chromatid cohesion. In addition, FANCF methylation was found in one cell line by screening an additional panel of 39 HNSCC cell lines. Our data demonstrate that CIN in terms of ICL-induced chromosomal breakage and defective chromatid cohesion is frequently observed in HNSCC. Inactivation of known Fanconi anemia and chromatid cohesion genes does explain CIN in the minority of cases. These findings point to phenotypes that may be highly relevant in treatment response of HNSCC. ©2015 American Association for Cancer Research.

Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair.

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Nakanishi, Koji; Yang, Yun-Gui; Pierce, Andrew J; Taniguchi, Toshiyasu; Digweed, Martin; D'Andrea, Alan D; Wang, Zhao-Qi; Jasin, Maria

2005-01-25

Fanconi anemia (FA) is a recessive disorder characterized by congenital abnormalities, progressive bone-marrow failure, and cancer susceptibility. Cells from FA patients are hypersensitive to agents that produce DNA crosslinks and, after treatment with these agents, have pronounced chromosome breakage and other cytogenetic abnormalities. Eight FANC genes have been cloned, and the encoded proteins interact in a common cellular pathway. DNA-damaging agents activate the monoubiquitination of FANCD2, resulting in its targeting to nuclear foci that also contain BRCA1 and BRCA2/FANCD1, proteins involved in homology-directed DNA repair. Given the interaction of the FANC proteins with BRCA1 and BRCA2, we tested whether cells from FA patients (groups A, G, and D2) and mouse Fanca-/- cells with a targeted mutation are impaired for this repair pathway. We find that both the upstream (FANCA and FANCG) and downstream (FANCD2) FA pathway components promote homology-directed repair of chromosomal double-strand breaks (DSBs). The FANCD2 monoubiquitination site is critical for normal levels of repair, whereas the ATM phosphorylation site is not. The defect in these cells, however, is mild, differentiating them from BRCA1 and BRCA2 mutant cells. Surprisingly, we provide evidence that these proteins, like BRCA1 but unlike BRCA2, promote a second DSB repair pathway involving homology, i.e., single-strand annealing. These results suggest an early role for the FANC proteins in homologous DSB repair pathway choice.

Iron-Deficiency Anemia

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Full Text Available ... deficiency anemia. Proton pump inhibitors interfere with iron absorption, and blood thinners increase the likelihood of bleeding ... oranges, strawberries, and tomatoes, may help increase your absorption of iron. If you are pregnant, talk to ...

The fanconi anemia pathway limits human papillomavirus replication.

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Hoskins, Elizabeth E; Morreale, Richard J; Werner, Stephen P; Higginbotham, Jennifer M; Laimins, Laimonis A; Lambert, Paul F; Brown, Darron R; Gillison, Maura L; Nuovo, Gerard J; Witte, David P; Kim, Mi-Ok; Davies, Stella M; Mehta, Parinda A; Butsch Kovacic, Melinda; Wikenheiser-Brokamp, Kathryn A; Wells, Susanne I

2012-08-01

High-risk human papillomaviruses (HPVs) deregulate epidermal differentiation and cause anogenital and head and neck squamous cell carcinomas (SCCs). The E7 gene is considered the predominant viral oncogene and drives proliferation and genome instability. While the implementation of routine screens has greatly reduced the incidence of cervical cancers which are almost exclusively HPV positive, the proportion of HPV-positive head and neck SCCs is on the rise. High levels of HPV oncogene expression and genome load are linked to disease progression, but genetic risk factors that regulate oncogene abundance and/or genome amplification remain poorly understood. Fanconi anemia (FA) is a genome instability syndrome characterized at least in part by extreme susceptibility to SCCs. FA results from mutations in one of 15 genes in the FA pathway, whose protein products assemble in the nucleus and play important roles in DNA damage repair. We report here that loss of FA pathway components FANCA and FANCD2 stimulates E7 protein accumulation in human keratinocytes and causes increased epithelial proliferation and basal cell layer expansion in the HPV-positive epidermis. Additionally, FANCD2 loss stimulates HPV genome amplification in differentiating cells, demonstrating that the intact FA pathway functions to restrict the HPV life cycle. These findings raise the possibility that FA genes suppress HPV infection and disease and suggest possible mechanism(s) for reported associations of HPV with an FA cohort in Brazil and for allelic variation of FA genes with HPV persistence in the general population.

Stress and DNA repair biology of the Fanconi anemia pathway

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Longerich, Simonne; Li, Jian; Xiong, Yong; Sung, Patrick

2014-01-01

Fanconi anemia (FA) represents a paradigm of rare genetic diseases, where the quest for cause and cure has led to seminal discoveries in cancer biology. Although a total of 16 FA genes have been identified thus far, the biochemical function of many of the FA proteins remains to be elucidated. FA is rare, yet the fact that 5 FA genes are in fact familial breast cancer genes and FA gene mutations are found frequently in sporadic cancers suggest wider applicability in hematopoiesis and oncology. Establishing the interaction network involving the FA proteins and their associated partners has revealed an intersection of FA with several DNA repair pathways, including homologous recombination, DNA mismatch repair, nucleotide excision repair, and translesion DNA synthesis. Importantly, recent studies have shown a major involvement of the FA pathway in the tolerance of reactive aldehydes. Moreover, despite improved outcomes in stem cell transplantation in the treatment of FA, many challenges remain in patient care. PMID:25237197

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

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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.

Evidence for subcomplexes in the Fanconi anemia pathway.

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Medhurst, Annette L; Laghmani, El Houari; Steltenpool, Jurgen; Ferrer, Miriam; Fontaine, Chantal; de Groot, Jan; Rooimans, Martin A; Scheper, Rik J; Meetei, Amom Ruhikanta; Wang, Weidong; Joenje, Hans; de Winter, Johan P

2006-09-15

Fanconi anemia (FA) is a genomic instability disorder, clinically characterized by congenital abnormalities, progressive bone marrow failure, and predisposition to malignancy. Cells derived from patients with FA display a marked sensitivity to DNA cross-linking agents, such as mitomycin C (MMC). This observation has led to the hypothesis that the proteins defective in FA are involved in the sensing or repair of interstrand cross-link lesions of the DNA. A nuclear complex consisting of a majority of the FA proteins plays a crucial role in this process and is required for the monoubiquitination of a downstream target, FANCD2. Two new FA genes, FANCB and FANCL, have recently been identified, and their discovery has allowed a more detailed study into the molecular architecture of the FA pathway. We demonstrate a direct interaction between FANCB and FANCL and that a complex of these proteins binds FANCA. The interaction between FANCA and FANCL is dependent on FANCB, FANCG, and FANCM, but independent of FANCC, FANCE, and FANCF. These findings provide a framework for the protein interactions that occur "upstream" in the FA pathway and suggest that besides the FA core complex different subcomplexes exist that may have specific functions other than the monoubiquitination of FANCD2.

RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway.

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Xie, Jenny; Kim, Hyungjin; Moreau, Lisa A; Puhalla, Shannon; Garber, Judy; Al Abo, Muthana; Takeda, Shunichi; D'Andrea, Alan D

2015-04-01

The Fanconi anemia/BRCA (FA/BRCA) pathway is a DNA repair pathway that is required for excision of DNA interstrand cross-links. The 17 known FA proteins, along with several FA-associated proteins (FAAPs), cooperate in this pathway to detect, unhook, and excise DNA cross-links and to subsequently repair the double-strand breaks generated in the process. In the current study, we identified a patient with FA with a point mutation in FANCA, which encodes a mutant FANCA protein (FANCAI939S). FANCAI939S failed to bind to the FAAP20 subunit of the FA core complex, leading to decreased stability. Loss of FAAP20 binding exposed a SUMOylation site on FANCA at amino acid residue K921, resulting in E2 SUMO-conjugating enzyme UBC9-mediated SUMOylation, RING finger protein 4-mediated (RNF4-mediated) polyubiquitination, and proteasome-mediated degradation of FANCA. Mutation of the SUMOylation site of FANCA rescued the expression of the mutant protein. Wild-type FANCA was also subject to SUMOylation, RNF4-mediated polyubiquitination, and degradation, suggesting that regulated release of FAAP20 from FANCA is a critical step in the normal FA pathway. Consistent with this model, cells lacking RNF4 exhibited interstrand cross-linker hypersensitivity, and the gene encoding RNF4 was epistatic with the other genes encoding members of the FA/BRCA pathway. Together, the results from our study underscore the importance of analyzing unique patient-derived mutations for dissecting complex DNA repair processes.

Replication Protein A (RPA) deficiency activates the Fanconi anemia DNA repair pathway.

Science.gov (United States)

Jang, Seok-Won; Jung, Jin Ki; Kim, Jung Min

2016-09-01

The Fanconi anemia (FA) pathway regulates DNA inter-strand crosslink (ICL) repair. Despite our greater understanding of the role of FA in ICL repair, its function in the preventing spontaneous genome instability is not well understood. Here, we show that depletion of replication protein A (RPA) activates the FA pathway. RPA1 deficiency increases chromatin recruitment of FA core complex, leading to FANCD2 monoubiquitination (FANCD2-Ub) and foci formation in the absence of DNA damaging agents. Importantly, ATR depletion, but not ATM, abolished RPA1 depletion-induced FANCD2-Ub, suggesting that ATR activation mediated FANCD2-Ub. Interestingly, we found that depletion of hSSB1/2-INTS3, a single-stranded DNA-binding protein complex, induces FANCD2-Ub, like RPA1 depletion. More interestingly, depletion of either RPA1 or INTS3 caused increased accumulation of DNA damage in FA pathway deficient cell lines. Taken together, these results indicate that RPA deficiency induces activation of the FA pathway in an ATR-dependent manner, which may play a role in the genome maintenance.

Phase 1 Study of the E-Selectin Inhibitor GMI 1070 in Patients with Sickle Cell Anemia

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Wun, Ted; Styles, Lori; DeCastro, Laura; Telen, Marilyn J.; Kuypers, Frans; Cheung, Anthony; Kramer, William; Flanner, Henry; Rhee, Seungshin; Magnani, John L.; Thackray, Helen

2014-01-01

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 PMID:24988449

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

Directory of Open Access Journals (Sweden)

Ted Wun

Full Text Available 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.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.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.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.ClinicalTrials.gov NCT00911495.

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

Science.gov (United States)

Wun, Ted; Styles, Lori; DeCastro, Laura; Telen, Marilyn J; Kuypers, Frans; Cheung, Anthony; Kramer, William; Flanner, Henry; Rhee, Seungshin; Magnani, John L; Thackray, Helen

2014-01-01

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. 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. 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. 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. ClinicalTrials.gov NCT00911495.

Developmental defects in zebrafish for classification of EGF pathway inhibitors

Energy Technology Data Exchange (ETDEWEB)

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.

Developmental defects in zebrafish for classification of EGF pathway inhibitors

International Nuclear Information System (INIS)

Pruvot, Benoist; Curé, Yoann; Djiotsa, Joachim; Voncken, Audrey; Muller, Marc

2014-01-01

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

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

International Nuclear Information System (INIS)

Romick-Rosendale, Lindsey E.; Lui, Vivian W.Y.; Grandis, Jennifer R.; Wells, Susanne I.

2013-01-01

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

The Fanconi Anemia Pathway: Repairing the Link Between DNA Damage and Squamous Cell Carcinoma

Science.gov (United States)

Romick-Rosendale, Lindsey E.; Lui, Vivian W. Y.; Grandis, Jennifer R.; Wells, Susanne I.

2013-01-01

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. PMID:23333482

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.

Signaling Pathways in Pathogenesis of Diamond Blackfan Anemia

Science.gov (United States)

2014-10-01

Allergy and Infectious Diseases. This research was funded by NIH National Heart , Lung, and Blood Institute grant R01 HL097561, a St. Baldrick’s Foundation...with anemia, congenital malformations and cancer. p53 mediates many features of DBA, but the mechanism of p53 activation remains unclear. Another...frequently mutated RP in DBA (Boria et al., 2010; Draptchinskaia et al., 1999; Farrar et al., 2011). DBA is associated with anemia, malformations and

SnapShot: Fanconi anemia and associated proteins.

Science.gov (United States)

Wang, Anderson T; Smogorzewska, Agata

2015-01-15

Fanconi anemia is a genetic disorder resulting from biallelic mutations in one of the 17 FANC genes. It is characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. The underlying cause is genomic instability resulting from the deficiency in replication-dependent DNA interstrand crosslink repair pathway commonly referred to as the Fanconi anemia-BRCA pathway. This SnapShot presents the key factors involved. Copyright © 2015 Elsevier Inc. All rights reserved.

Pathway-based identification of biomarkers for targeted therapeutics: personalized oncology with PI3K pathway inhibitors.

Science.gov (United States)

Andersen, Jannik N; Sathyanarayanan, Sriram; Di Bacco, Alessandra; Chi, An; Zhang, Theresa; Chen, Albert H; Dolinski, Brian; Kraus, Manfred; Roberts, Brian; Arthur, William; Klinghoffer, Rich A; Gargano, Diana; Li, Lixia; Feldman, Igor; Lynch, Bethany; Rush, John; Hendrickson, Ronald C; Blume-Jensen, Peter; Paweletz, Cloud P

2010-08-04

Although we have made great progress in understanding the complex genetic alterations that underlie human cancer, it has proven difficult to identify which molecularly targeted therapeutics will benefit which patients. Drug-specific modulation of oncogenic signaling pathways in specific patient subpopulations can predict responsiveness to targeted therapy. Here, we report a pathway-based phosphoprofiling approach to identify and quantify clinically relevant, drug-specific biomarkers for phosphatidylinositol 3-kinase (PI3K) pathway inhibitors that target AKT, phosphoinositide-dependent kinase 1 (PDK1), and PI3K-mammalian target of rapamycin (mTOR). We quantified 375 nonredundant PI3K pathway-relevant phosphopeptides, all containing AKT, PDK1, or mitogen-activated protein kinase substrate recognition motifs. Of these phosphopeptides, 71 were drug-regulated, 11 of them by all three inhibitors. Drug-modulated phosphoproteins were enriched for involvement in cytoskeletal reorganization (filamin, stathmin, dynamin, PAK4, and PTPN14), vesicle transport (LARP1, VPS13D, and SLC20A1), and protein translation (S6RP and PRAS40). We then generated phosphospecific antibodies against selected, drug-regulated phosphorylation sites that would be suitable as biomarker tools for PI3K pathway inhibitors. As proof of concept, we show clinical translation feasibility for an antibody against phospho-PRAS40(Thr246). Evaluation of binding of this antibody in human cancer cell lines, a PTEN (phosphatase and tensin homolog deleted from chromosome 10)-deficient mouse prostate tumor model, and triple-negative breast tumor tissues showed that phospho-PRAS40(Thr246) positively correlates with PI3K pathway activation and predicts AKT inhibitor sensitivity. In contrast to phosphorylation of AKT(Thr308), the phospho-PRAS40(Thr246) epitope is highly stable in tissue samples and thus is ideal for immunohistochemistry. In summary, our study illustrates a rational approach for discovery of drug

Blockade of the ERK pathway markedly sensitizes tumor cells to HDAC inhibitor-induced cell death

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Ozaki, Kei-ichi; Minoda, Ai; Kishikawa, Futaba; Kohno, Michiaki

2006-01-01

Constitutive activation of the extracellular signal-regulated kinase (ERK) pathway is associated with the neoplastic phenotype of a large number of human tumor cells. Although specific blockade of the ERK pathway by treating such tumor cells with potent mitogen-activated protein kinase/ERK kinase (MEK) inhibitors completely suppresses their proliferation, it by itself shows only a modest effect on the induction of apoptotic cell death. However, these MEK inhibitors markedly enhance the efficacy of histone deacetylase (HDAC) inhibitors to induce apoptotic cell death: such an enhanced cell death is observed only in tumor cells in which the ERK pathway is constitutively activated. Co-administration of MEK inhibitor markedly sensitizes tumor cells to HDAC inhibitor-induced generation of reactive oxygen species, which appears to mediate the enhanced cell death induced by the combination of these agents. These results suggest that the combination of MEK inhibitors and HDAC inhibitors provides an efficient chemotherapeutic strategy for the treatment of tumor cells in which the ERK pathway is constitutively activated

Variation in cisplatinum sensitivity is not associated with Fanconi Anemia/BRCA pathway inactivation in head and neck squamous cell carcinoma cell lines.

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Snyder, Eric R; Ricker, Justin L; Chen, Zhong; Waes, Carter Van

2007-01-08

Fanconi Anemia has recently been associated with a high risk of head and neck squamous cell carcinoma (HNSCC). Inactivation of the Fanconi Anemia (FANC-BRCA) pathway via promoter methylation of the FANCF gene has been proposed to be responsible for variation in cisplatinum (CDDP) sensitivity seen in ovarian and HNSCCs. Promoter methylation of the FANCF gene has been observed in 15% of HNSCC specimens, but the relationship to FANC pathway activation and CDDP sensitivity has not been reported. In the present study, 10 HNSCC cell lines were examined for expression of nine genes involved in the FANC-BRCA pathway by RT-PCR: FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, BRCA1 and BRCA2. FANC pathway function was evaluated by western blotting for FANCD2 mono-ubiquitination. All of the cell lines were also analyzed for variation in CDDP cytotoxicity. While significant differences were found in CDDP cytotoxicity, Fanconi pathway defects are an infrequent cause, as no evidence of transcriptional down-regulation of FANCF or other FANC mRNAs, or functional FANC-BRCA pathway defects were observed. These findings suggest that the variation in CDDP sensitivity of many HNSCCs is most frequently due to factors other than FANC-BRCA pathway inactivation.

Genetic/metabolic effect of iron metabolism and rare anemias

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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

Anemia, tumor hypoxemia, and the cancer patient

International Nuclear Information System (INIS)

Varlotto, John; Stevenson, Mary Ann

2005-01-01

sensitization has met with limited success via the use of hyperbaric oxygen, electron-affinic radiosensitizers, and mitomycin. Improvements in tumor oxygenation via the use of carbogen and nicotinamide, RSR13, and tirapazamine have shown promising clinical results and are all currently being tested in Phase III trials. The National Comprehensive Cancer Network (NCCN) guidelines recommend transfusion or erythropoietin for symptomatic patients with a hemoglobin of 10-11 g/dl and state that erythropoietin should strongly be considered if hemoglobin falls to less than 10 g/dl. These recommendations were based on studies that revealed an improvement in the quality of life of cancer patients, but not patient survival with anemia correction. Phase III studies evaluating the correction of anemia via erythropoietin have shown mixed results with some studies reporting a decrease in patient survival despite an improvement in hemoglobin levels. Diverse functions of erythropoietin are reviewed, including its potential to inhibit apoptosis via the JAK2/STAT5/BCL-X pathway. Correction of anemia by the use of blood transfusions has also shown a decrement in patient survival, possibly through inflammatory and/or immunosuppressive pathways. Conclusions: Anemia is a prevalent condition associated with cancer and its therapies. Proper Phase III trials are necessary to find the best way to correct anemia for specific patients. Future studies of erythropoietin must evaluate the possible anti-apoptotic effects by directly assessing the tumor for erythropoietin receptors or the presence of the JAK2/STAT5/BCL-X pathway. Due to the ability of transfusions to cause immunosuppression, most probably through inflammatory pathways, it may be best to study the effects of transfusion with the prolonged use of anti-inflammatory medications

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

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

2015-05-12

Ubiquitin and ubiquitin-like proteins (UBLs) function in a wide array of cellular processes. UBL5 is an atypical UBL that does not form covalent conjugates with cellular proteins and which has a known role in modulating pre-mRNA splicing. Here, we report an unexpected involvement of human UBL5 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 in response to DNA damage and hypersensitivity to ICLs. By mapping the sequence determinants underlying UBL5-FANCI binding, we generated separation-of-function mutants to demonstrate that key aspects of FA pathway function, including FANCI-FANCD2 heterodimerization, FANCD2 and FANCI monoubiquitylation and maintenance of chromosome stability after ICLs, are compromised when the UBL5-FANCI interaction is selectively inhibited by mutations in either protein. Together, our findings establish UBL5 as a factor that promotes the functionality of the FA DNA repair pathway. © 2015 The Authors.

Fanconi anemia proteins in telomere maintenance.

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Sarkar, Jaya; Liu, Yie

2016-07-01

Mammalian chromosome ends are protected by nucleoprotein structures called telomeres. Telomeres ensure genome stability by preventing chromosome termini from being recognized as DNA damage. Telomere length homeostasis is inevitable for telomere maintenance because critical shortening or over-lengthening of telomeres may lead to DNA damage response or delay in DNA replication, and hence genome instability. Due to their repetitive DNA sequence, unique architecture, bound shelterin proteins, and high propensity to form alternate/secondary DNA structures, telomeres are like common fragile sites and pose an inherent challenge to the progression of DNA replication, repair, and recombination apparatus. It is conceivable that longer the telomeres are, greater is the severity of such challenges. Recent studies have linked excessively long telomeres with increased tumorigenesis. Here we discuss telomere abnormalities in a rare recessive chromosomal instability disorder called Fanconi Anemia and the role of the Fanconi Anemia pathway in telomere biology. Reports suggest that Fanconi Anemia proteins play a role in maintaining long telomeres, including processing telomeric joint molecule intermediates. We speculate that ablation of the Fanconi Anemia pathway would lead to inadequate aberrant structural barrier resolution at excessively long telomeres, thereby causing replicative burden on the cell. Published by Elsevier B.V.

Repair pathways independent of the Fanconi anemia nuclear core complex play a predominant role in mitigating formaldehyde-induced DNA damage

International Nuclear Information System (INIS)

Noda, Taichi; Takahashi, Akihisa; Kondo, Natsuko; Mori, Eiichiro; Okamoto, Noritomo; Nakagawa, Yosuke; Ohnishi, Ken; Zdzienicka, Malgorzata Z.; Thompson, Larry H.; Helleday, Thomas; Asada, Hideo

2011-01-01

The role of the Fanconi anemia (FA) repair pathway for DNA damage induced by formaldehyde was examined in the work described here. The following cell types were used: mouse embryonic fibroblast cell lines FANCA -/- , FANCC -/- , FANCA -/- C -/- , FANCD2 -/- and their parental cells, the Chinese hamster cell lines FANCD1 mutant (mt), FANCGmt, their revertant cells, and the corresponding wild-type (wt) cells. Cell survival rates were determined with colony formation assays after formaldehyde treatment. DNA double strand breaks (DSBs) were detected with an immunocytochemical γH2AX-staining assay. Although the sensitivity of FANCA -/- , FANCC -/- and FANCA -/- C -/- cells to formaldehyde was comparable to that of proficient cells, FANCD1mt, FANCGmt and FANCD2 -/- cells were more sensitive to formaldehyde than the corresponding proficient cells. It was found that homologous recombination (HR) repair was induced by formaldehyde. In addition, γH2AX foci in FANCD1mt cells persisted for longer times than in FANCD1wt cells. These findings suggest that formaldehyde-induced DSBs are repaired by HR through the FA repair pathway which is independent of the FA nuclear core complex. -- Research highlights: → We examined to clarify the repair pathways of formaldehyde-induced DNA damage. Formaldehyde induces DNA double strand breaks (DSBs). → DSBs are repaired through the Fanconi anemia (FA) repair pathway. → This pathway is independent of the FA nuclear core complex. → We also found that homologous recombination repair was induced by formaldehyde.

Small molecule inhibitors uncover synthetic genetic interactions of human flap endonuclease 1 (FEN1 with DNA damage response genes.

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Thomas A Ward

Full Text Available Flap endonuclease 1 (FEN1 is a structure selective endonuclease required for proficient DNA replication and the repair of DNA damage. Cellularly active inhibitors of this enzyme have previously been shown to induce a DNA damage response and, ultimately, cell death. High-throughput screens of human cancer cell-lines identify colorectal and gastric cell-lines with microsatellite instability (MSI as enriched for cellular sensitivity to N-hydroxyurea series inhibitors of FEN1, but not the PARP inhibitor olaparib or other inhibitors of the DNA damage response. This sensitivity is due to a synthetic lethal interaction between FEN1 and MRE11A, which is often mutated in MSI cancers through instabilities at a poly(T microsatellite repeat. Disruption of ATM is similarly synthetic lethal with FEN1 inhibition, suggesting that disruption of FEN1 function leads to the accumulation of DNA double-strand breaks. These are likely a result of the accumulation of aberrant replication forks, that accumulate as a consequence of a failure in Okazaki fragment maturation, as inhibition of FEN1 is toxic in cells disrupted for the Fanconi anemia pathway and post-replication repair. Furthermore, RAD51 foci accumulate as a consequence of FEN1 inhibition and the toxicity of FEN1 inhibitors increases in cells disrupted for the homologous recombination pathway, suggesting a role for homologous recombination in the resolution of damage induced by FEN1 inhibition. Finally, FEN1 appears to be required for the repair of damage induced by olaparib and cisplatin within the Fanconi anemia pathway, and may play a role in the repair of damage associated with its own disruption.

Fanca-/- hematopoietic stem cells demonstrate a mobilization defect which can be overcome by administration of the Rac inhibitor NSC23766.

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Milsom, Michael D; Lee, Andrew W; Zheng, Yi; Cancelas, Jose A

2009-07-01

Fanconi anemia is a severe bone marrow failure syndrome resulting from inactivating mutations of Fanconi anemia pathway genes. Gene and cell therapy trials using hematopoietic stem cells and progenitors have been hampered by poor mobilization of HSC to peripheral blood in response to G-CSF. Using a murine model of Fanconi anemia (Fanca(-/-) mice), we found that the Fanca deficiency was associated with a profound defect in hematopoietic stem cells and progenitors mobilization in response to G-CSF in absence of bone marrow failure, which correlates with the findings of clinical trials in Fanconi anemia patients. This mobilization defect was overcome by co-administration of the Rac inhibitor NSC23766, suggesting that Rac signaling is implicated in the retention of Fanca(-/-) hematopoietic stem cells and progenitors in the bone marrow. In view of these data, we propose that targeting Rac signaling may enhance G-CSF-induced HSC mobilization in Fanconi anemia.

Chickens treated with a nitric oxide inhibitor became more resistant to Plasmodium gallinaceum infection due to reduced anemia, thrombocytopenia and inflammation

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2013-01-01

Malaria is a serious infectious disease caused by parasites of the Plasmodium genus that affect different vertebrate hosts. Severe malaria leads to host death and involves different pathophysiological phenomena such as anemia, thrombocytopenia and inflammation. Nitric oxide (NO) is an important effector molecule in this disease, but little is known about its role in avian malaria models. Plasmodium gallinaceum- infected chickens were treated with aminoguanidine (AG), an inhibitor of inducible nitric oxide synthase, to observe the role of NO in the pathogenesis of this avian model. AG increased the survival of chickens, but also induced higher parasitemia. Treated chickens demonstrated reduced anemia and thrombocytopenia. Moreover, erythrocytes at different stages of maturation, heterophils, monocytes and thrombocytes were infected by Plasmodium gallinaceum and animals presented a generalized leucopenia. Activated leukocytes and thrombocytes with elongated double nuclei were observed in chickens with higher parasitemia; however, eosinophils were not involved in the infection. AG reduced levels of hemozoin in the spleen and liver, indicating lower inflammation. Taken together, the results suggest that AG reduced anemia, thrombocytopenia and inflammation, explaining the greater survival rate of the treated chickens. PMID:23398940

The Fanconi anemia pathway limits the severity of mutagenesis.

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Hinz, John M; Nham, Peter B; Salazar, Edmund P; Thompson, Larry H

2006-08-13

Fanconi anemia (FA) is a developmental and cancer predisposition disorder in which key, yet unknown, physiological events promoting chromosome stability are compromised. FA cells exhibit excess metaphase chromatid breaks and are universally hypersensitive to DNA interstrand crosslinking agents. Published mutagenesis data from single-gene mutation assays show both increased and decreased mutation frequencies in FA cells. In this review we discuss the data from the literature and from our isogenic fancg knockout hamster CHO cells, and interpret these data within the framework of a molecular model that accommodates these seemingly divergent observations. In FA cells, reduced rates of recovery of viable X-linked hypoxanthine phosphoribosyltransferase (hprt) mutants are characteristically observed for diverse mutagenic agents, but also in untreated cultures, indicating the relevance of the FA pathway for processing assorted DNA lesions. We ascribe these reductions to: (1) impaired mutagenic translesion synthesis within hprt during DNA replication and (2) lethality of mutant cells following replication fork breakage on the X chromosome, caused by unrepaired double-strand breaks or large deletions/translocations encompassing essential genes flanking hprt. These findings, along with studies showing increased spontaneous mutability of FA cells at two autosomal loci, support a model in which FA proteins promote both translesion synthesis at replication-blocking lesions and repair of broken replication forks by homologous recombination and DNA end joining. The essence of this model is that the FANC protein pathway serves to restrict the severity of mutational outcome by favoring base substitutions and small deletions over larger deletions and chromosomal rearrangements.

Repair pathways independent of the Fanconi anemia nuclear core complex play a predominant role in mitigating formaldehyde-induced DNA damage

Energy Technology Data Exchange (ETDEWEB)

Noda, Taichi [Department of Biology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Department of Dermatology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Takahashi, Akihisa [Department of Biology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Kondo, Natsuko [Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, Kumatori-cho, Sennan-gun, Osaka 590-0494 (Japan); Mori, Eiichiro [Department of Biology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Okamoto, Noritomo [Department of Otorhinolaryngology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Nakagawa, Yosuke [Department of Oral and Maxillofacial Surgery, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Ohnishi, Ken [Department of Biology, Ibaraki Prefectual University of Health Sciences, 4669-2 Ami, Ami-mati, Inasiki-gun, Ibaraki 300-0394 (Japan); Zdzienicka, Malgorzata Z. [Department of Molecular Cell Genetics, Collegium Medicum in Bydgoszcz, Nicolaus-Copernicus-University in Torun, ul. Sklodowskiej-Curie 9, 85-094 Bydgoszcz (Poland); Thompson, Larry H. [Biosciences and Biotechnology Division, L452, Lawrence Livermore National Laboratory, P.O. Box 808, Livermore, CA 94551-0808 (United States); Helleday, Thomas [Gray Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ (United Kingdom); Department of Genetics, Microbiology and Toxicology Stockholm University, SE-106 91 Stockholm (Sweden); Asada, Hideo [Department of Dermatology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); and others

2011-01-07

The role of the Fanconi anemia (FA) repair pathway for DNA damage induced by formaldehyde was examined in the work described here. The following cell types were used: mouse embryonic fibroblast cell lines FANCA{sup -/-}, FANCC{sup -/-}, FANCA{sup -/-}C{sup -/-}, FANCD2{sup -/-} and their parental cells, the Chinese hamster cell lines FANCD1 mutant (mt), FANCGmt, their revertant cells, and the corresponding wild-type (wt) cells. Cell survival rates were determined with colony formation assays after formaldehyde treatment. DNA double strand breaks (DSBs) were detected with an immunocytochemical {gamma}H2AX-staining assay. Although the sensitivity of FANCA{sup -/-}, FANCC{sup -/-} and FANCA{sup -/-}C{sup -/-} cells to formaldehyde was comparable to that of proficient cells, FANCD1mt, FANCGmt and FANCD2{sup -/-} cells were more sensitive to formaldehyde than the corresponding proficient cells. It was found that homologous recombination (HR) repair was induced by formaldehyde. In addition, {gamma}H2AX foci in FANCD1mt cells persisted for longer times than in FANCD1wt cells. These findings suggest that formaldehyde-induced DSBs are repaired by HR through the FA repair pathway which is independent of the FA nuclear core complex. -- Research highlights: {yields} We examined to clarify the repair pathways of formaldehyde-induced DNA damage. Formaldehyde induces DNA double strand breaks (DSBs). {yields} DSBs are repaired through the Fanconi anemia (FA) repair pathway. {yields} This pathway is independent of the FA nuclear core complex. {yields} We also found that homologous recombination repair was induced by formaldehyde.

Functional analyses of ATM, ATR and Fanconi anemia proteins in lung carcinoma

International Nuclear Information System (INIS)

Beumer, Jan H.; Fu, Katherine Y.; Anyang, Bean N.; Siegfried, Jill M.; Bakkenist, Christopher J.

2015-01-01

ATM and ATR are kinases implicated in a myriad of DNA-damage responses. ATM kinase inhibition radiosensitizes cells and selectively kills cells with Fanconi anemia (FA) gene mutations. ATR kinase inhibition sensitizes cells to agents that induce replication stress and selectively kills cells with ATM and TP53 mutations. ATM mutations and FANCF promoter-methylation are reported in lung carcinomas. We undertook functional analyses of ATM, ATR, Chk1 and FA proteins in lung cancer cell lines. We included Calu6 that is reported to be FANCL-deficient. In addition, the cancer genome atlas (TCGA) database was interrogated for alterations in: 1) ATM, MRE11A, RAD50 and NBN; 2) ATR, ATRIP and TOPBP1; and 3) 15 FA genes. No defects in ATM, ATR or Chk1 kinase activation, or FANCD2 monoubiquitination were identified in the lung cancer cell lines examined, including Calu6, and major alterations in these pathways were not identified in the TCGA database. Cell lines were radiosensitized by ATM kinase inhibitor KU60019, but no cell killing by ATM kinase inhibitor alone was observed. While no synergy between gemcitabine or carboplatin and ATR kinase inhibitor ETP-46464 was observed, synergy between gemcitabine and Chk1 kinase inhibitor UCN-01 was observed in 54 T, 201 T and H460, and synergy between carboplatin and Chk1 kinase inhibitor was identified in 201 T and 239 T. No interactions between ATM, ATR and FA activation were observed by either ATM or ATR kinase inhibition in the lung cancer cell lines. Analyses of ATM serine 1981 and Chk1 serine 345 phosphorylation, and FANCD2 monoubiquitination revealed that ATM and ATR kinase activation and FA pathway signaling are intact in the lung cancer cell lines examined. As such, these posttranslational modifications may have utility as biomarkers for the integrity of DNA damage signaling pathways in lung cancer. Different sensitization profiles between gemcitabine and carboplatin and ATR kinase inhibitor ETP-46464 and Chk1 kinase inhibitor

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

2016-01-13

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.

Recent advances in understanding hematopoiesis in Fanconi Anemia

Science.gov (United States)

Bagby, Grover

2018-01-01

Fanconi anemia is an inherited disease characterized by genomic instability, hypersensitivity to DNA cross-linking agents, bone marrow failure, short stature, skeletal abnormalities, and a high relative risk of myeloid leukemia and epithelial malignancies. The 21 Fanconi anemia genes encode proteins involved in multiple nuclear biochemical pathways that effect DNA interstrand crosslink repair. In the past, bone marrow failure was attributed solely to the failure of stem cells to repair DNA. Recently, non-canonical functions of many of the Fanconi anemia proteins have been described, including modulating responses to oxidative stress, viral infection, and inflammation as well as facilitating mitophagic responses and enhancing signals that promote stem cell function and survival. Some of these functions take place in non-nuclear sites and do not depend on the DNA damage response functions of the proteins. Dysfunctions of the canonical and non-canonical pathways that drive stem cell exhaustion and neoplastic clonal selection are reviewed, and the potential therapeutic importance of fully investigating the scope and interdependences of the canonical and non-canonical pathways is emphasized. PMID:29399332

Autoimmune Hemolytic Anemia as a Complication of Nivolumab Therapy.

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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.

Autoimmune Hemolytic Anemia as a Complication of Nivolumab Therapy

Directory of Open Access Journals (Sweden)

Amruth R. Palla

2016-11-01

Full Text Available 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.

Fanca−/− hematopoietic stem cells demonstrate a mobilization defect which can be overcome by administration of the Rac inhibitor NSC23766

Science.gov (United States)

Milsom, Michael D.; Lee, Andrew W.; Zheng, Yi; Cancelas, Jose A.

2009-01-01

Fanconi anemia is a severe bone marrow failure syndrome resulting from inactivating mutations of Fanconi anemia pathway genes. Gene and cell therapy trials using hematopoietic stem cells and progenitors have been hampered by poor mobilization of HSC to peripheral blood in response to G-CSF. Using a murine model of Fanconi anemia (Fanca−/− mice), we found that the Fanca deficiency was associated with a profound defect in hematopoietic stem cells and progenitors mobilization in response to G-CSF in absence of bone marrow failure, which correlates with the findings of clinical trials in Fanconi anemia patients. This mobilization defect was overcome by co-administration of the Rac inhibitor NSC23766, suggesting that Rac signaling is implicated in the retention of Fanca−/− hematopoietic stem cells and progenitors in the bone marrow. In view of these data, we propose that targeting Rac signaling may enhance G-CSF-induced HSC mobilization in Fanconi anemia. PMID:19491337

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

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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.

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

OpenAIRE

Viviana P. Ferreira; Vladimir Fazito Vale; Michael K. Pangburn; Maha Abdeladhim; Antonio Ferreira Mendes-Sousa; Iliano V. Coutinho-Abreu; Manoochehr Rasouli; Elizabeth A. Brandt; Claudio Meneses; Kolyvan Ferreira Lima; Ricardo Nascimento Araújo; Marcos Horácio Pereira; Michalis Kotsyfakis; Fabiano Oliveira; Shaden Kamhawi

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 sa...

Hypoxia disrupts the Fanconi anemia pathway and sensitizes cells to chemotherapy through regulation of UBE2T

International Nuclear Information System (INIS)

Ramaekers, Chantal H.M.A.; Beucken, Twan van den; Meng, Alice; Kassam, Shaqil; Thoms, John; Bristow, Robert G.; Wouters, Bradly G.

2011-01-01

Background and purpose: Hypoxia is a common feature of the microenvironment of solid tumors which has been shown to promote malignancy and poor patient outcome through multiple mechanisms. The association of hypoxia with more aggressive disease may be due in part to recently identified links between hypoxia and genetic instability. For example, hypoxia has been demonstrated to impede DNA repair by down-regulating the homologous recombination protein RAD51. Here we investigated hypoxic regulation of UBE2T, a ubiquitin ligase required in the Fanconi anemia (FA) DNA repair pathway. Materials and methods: We analysed UBE2T expression by microarray, quantitative PCR and western blot analysis in a panel of cancer cell lines as a function of oxygen concentration. The importance of this regulation was assessed by measuring cell survival in response to DNA damaging agents under normoxia or hypoxia. Finally, HIF dependency was determined using knockdown cell lines and RCC4 cells which constitutively express HIF1α. Results: Hypoxia results in rapid and potent reductions in mRNA levels of UBE2T in a panel of cancer cell lines. Reduced UBE2T mRNA expression is HIF independent and was not due to changes in mRNA or protein stability, but rather reflected reduced promoter activity. Exposure of tumor cells to hypoxia greatly increased their sensitivity to treatment with the interstrand crosslinking (ICL) agent mitomycin C. Conclusions: Exposure to hypoxic conditions down-regulates UBE2T expression which correlates with an increased sensitivity to crosslinking agents consistent with a defective Fanconi anemia pathway. This pathway can potentially be exploited to target hypoxic cells in tumors.

Predictors of early treatment discontinuation and severe anemia in a Brazilian cohort of hepatitis C patients treated with first-generation protease inhibitors

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N. Miotto

2016-01-01

Full Text Available The aim of this study was to determine risk factors for adverse events (AE-related treatment discontinuation and severe anemia among patients with chronic hepatitis C virus (HCV genotype 1 infection, treated with first-generation protease inhibitor (PI-based therapy. We included all patients who initiated treatment with PI-based therapy at a Brazilian university hospital between November 2013 and December 2014. We prospectively collected data from medical records using standardized questionnaires and used Epi Info 6.0 for analysis. Severe anemia was defined as hemoglobin ≤8.5 mg/dL. We included 203 patients: 132 treated with telaprevir (TVR and 71 treated with boceprevir (BOC. AE-related treatment discontinuation rate was 19.2% and anemia was the main reason (38.5%. Risk factors for treatment discontinuation were higher comorbidity index (OR=1.85, CI=1.05-3.25 for BOC, and higher bilirubin count (OR=1.02, CI=1.01-1.04 and lower BMI (OR=0.98, CI=0.96-0.99 for TVR. Severe anemia occurred in 35 (17.2% patients. Risk factors for this outcome were lower estimated glomerular filtration rate (eGFR; OR=0.95, CI=0.91-0.98 for patients treated with TVR, and higher comorbidity index (OR=2.21, CI=1.04-4.67 and ribavirin dosage (OR=0.84, CI=0.72-0.99 for those treated with BOC. Fifty-five (57.3% patients treated with TVR and 15 (27.3% patients treated with BOC achieved sustained virological response (SVR. Among patients who received TVR and interrupted treatment due to AE (n=19, only 26.3% (n=5 achieved SVR (P=0.003. Higher number of comorbidities, lower eGFR and advanced liver disease are associated with severe anemia and early treatment cessation, which may compromise SVR achievement.

Chemosensitizing tumor cells by targeting the Fanconi anemia pathway with an adenovirus overexpressing dominant-negative FANCA.

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Ferrer, Miriam; de Winter, Johan P; Mastenbroek, D C Jeroen; Curiel, David T; Gerritsen, Winald R; Giaccone, Giuseppe; Kruyt, Frank A E

2004-08-01

Fanconi anemia (FA) is a rare genetic disorder characterized by bone-marrow failure and cellular hypersensitivity to crosslinking agents, including cisplatin. Here, we studied the use of the FA pathway as a possible target for cancer gene therapy with the aim to sensitize tumor cells for cisplatin by interfering with the FA pathway. As proof-of-principle, FA and non-FA lymphoblast-derived tumors were grown subcutaneously in scid mice and treated with two different concentrations of cisplatin. As predicted, the antitumor response was considerably improved in FA tumors. An adenoviral vector encoding a dominant-negative form of FANCA, FANCA600DN, was generated that interfered with endogenous FANCA-FANCG interaction resulting in the disruption of the FA pathway as illustrated by disturbed FANCD2 monoubiquitination. A panel of cell lines, including non-small-cell lung cancer cells, could be sensitized approximately two- to three-fold for cisplatin after Ad.CMV.FANCA600DN infection that may increase upon enhanced infection efficiency. In conclusion, targeting the FA pathway may provide a novel strategy for the sensitization of solid tumors for cisplatin and, in addition, provides a tool for examining the role of the FA pathway in determining chemoresistance in different tumor types.

Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors.

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Krishnamurthy, Nithya; Kurzrock, Razelle

2018-01-01

The Wnt/beta-catenin pathway is a family of proteins that is implicated in many vital cellular functions such as stem cell regeneration and organogenesis. Several intra-cellular signal transduction pathways are induced by Wnt, notably the Wnt/beta-catenin dependent pathway or canonical pathway and the non-canonical or beta-catenin-independent pathway; the latter includes the Wnt/Ca2+ and Planar Cell Polarity pathway (PCP). Wnt activation occurs at the intestinal crypt floor, and is critical to optimal maintenance of stem cells. Colorectal cancers show evidence of Wnt signaling pathway activation and this is associated with loss of function of the tumor regulator APC. Wnt activation has been observed in breast, lung, and hematopoietic malignancies and contributes to tumor recurrence. The Wnt pathway cross talks with the Notch and Sonic Hedgehog pathways, which has implications for therapeutic interventions in cancers. There are significant challenges in targeting the Wnt pathway, including finding agents that are efficacious without damaging the system of normal somatic stem cell function in cellular repair and tissue homeostasis. Here, we comprehensively review the Wnt pathway and its interactions with the Notch and Sonic Hedgehog pathways. We present the state of the field in effectors and inhibitors of Wnt signaling, including updates on clinical trials in various cancers with inhibitors of Wnt, Notch, and Sonic Hedgehog. Copyright © 2017 Elsevier Ltd. All rights reserved.

Click Chemistry-based Discovery of [3-Hydroxy-5-(1H-1,2,3-triazol-4-yl)picolinoyl]glycines as Orally Active Hypoxia Inducing Factor Prolyl Hydroxylase Inhibitors with Favorable Safety Profiles for the Treatment of Anemia.

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Wu, Yue; Jiang, Zhensheng; Li, Zhihong; Gu, Jing; You, Qi-Dong; Zhang, Xiaojin

2018-06-01

As a gene associated with anemia, the erythropoiesis gene is physiologically expressed under hypoxia regulated by hypoxia-inducing factor-α (HIF-α). Thus, stabilizing HIF-α is a potent strategy to stimulate the expression and secretion of erythropoiesis. In this study we applied click chemistry to the discovery of HIF prolyl hydroxylase 2 (HIF-PHD2) inhibitors for the first time and a series of triazole compounds showed preferable inhibitory activity in fluorescence polarization assay. Of particular note was the orally active HIF-PHD inhibitor 15i (IC50 = 62.23 nM), which was almost ten times more active than the phase III drug FG-4592 (IC50 = 591.4 nM). Furthermore, it can upregulate the hemoglobin of cisplatin induced anemia mice (120 g/L) to normal levels (160 g/L) with no apparent toxicity observed in vivo. These results confirm that triazole compound 15i is a promising candidate for the treatment of renal anemia.

Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity

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Wynn Michelle L

2011-10-01

Full Text Available Abstract Background It has been shown in experimental and theoretical work that covalently modified signaling cascades naturally exhibit bidirectional signal propagation via a phenomenon known as retroactivity. An important consequence of retroactivity, which arises due to enzyme sequestration in covalently modified signaling cascades, is that a downstream perturbation can produce a response in a component upstream of the perturbation without the need for explicit feedback connections. Retroactivity may, therefore, play an important role in the cellular response to a targeted therapy. Kinase inhibitors are a class of targeted therapies designed to interfere with a specific kinase molecule in a dysregulated signaling pathway. While extremely promising as anti-cancer agents, kinase inhibitors may produce undesirable off-target effects by non-specific interactions or pathway cross-talk. We hypothesize that targeted therapies such as kinase inhibitors can produce off-target effects as a consequence of retroactivity alone. Results We used a computational model and a series of simple signaling motifs to test the hypothesis. Our results indicate that within physiologically and therapeutically relevant ranges for all parameters, a targeted inhibitor can naturally induce an off-target effect via retroactivity. The kinetics governing covalent modification cycles in a signaling network were more important for propagating an upstream off-target effect in our models than the kinetics governing the targeted therapy itself. Our results also reveal the surprising and crucial result that kinase inhibitors have the capacity to turn "on" an otherwise "off" parallel cascade when two cascades share an upstream activator. Conclusions A proper and detailed characterization of a pathway's structure is important for identifying the optimal protein to target as well as what concentration of the targeted therapy is required to modulate the pathway in a safe and effective

Prevalence and association of post-renal transplant anemia

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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.

Acquisition of Relative Interstrand Crosslinker Resistance and PARP Inhibitor Sensitivity in Fanconi Anemia Head and Neck Cancers.

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Lombardi, Anne J; Hoskins, Elizabeth E; Foglesong, Grant D; Wikenheiser-Brokamp, Kathryn A; Wiesmüller, Lisa; Hanenberg, Helmut; Andreassen, Paul R; Jacobs, Allison J; Olson, Susan B; Keeble, Winifred W; Hays, Laura E; Wells, Susanne I

2015-04-15

Fanconi anemia is an inherited disorder associated with a constitutional defect in the Fanconi anemia DNA repair machinery that is essential for resolution of DNA interstrand crosslinks. Individuals with Fanconi anemia are predisposed to formation of head and neck squamous cell carcinomas (HNSCC) at a young age. Prognosis is poor, partly due to patient intolerance of chemotherapy and radiation requiring dose reduction, which may lead to early recurrence of disease. Using HNSCC cell lines derived from the tumors of patients with Fanconi anemia, and murine HNSCC cell lines derived from the tumors of wild-type and Fancc(-/-) mice, we sought to define Fanconi anemia-dependent chemosensitivity and DNA repair characteristics. We utilized DNA repair reporter assays to explore the preference of Fanconi anemia HNSCC cells for non-homologous end joining (NHEJ). Surprisingly, interstrand crosslinker (ICL) sensitivity was not necessarily Fanconi anemia-dependent in human or murine cell systems. Our results suggest that the increased Ku-dependent NHEJ that is expected in Fanconi anemia cells did not mediate relative ICL resistance. ICL exposure resulted in increased DNA damage sensing and repair by PARP in Fanconi anemia-deficient cells. Moreover, human and murine Fanconi anemia HNSCC cells were sensitive to PARP inhibition, and sensitivity of human cells was attenuated by Fanconi anemia gene complementation. The observed reliance upon PARP-mediated mechanisms reveals a means by which Fanconi anemia HNSCCs can acquire relative resistance to the ICL-based chemotherapy that is a foundation of HNSCC treatment, as well as a potential target for overcoming chemoresistance in the chemosensitive individual. ©2015 American Association for Cancer Research.

AMP-activated protein kinase is involved in the activation of the Fanconi anemia/BRCA pathway in response to DNA interstrand crosslinks.

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Chun, Min Jeong; Kim, Sunshin; Hwang, Soo Kyung; Kim, Bong Sub; Kim, Hyoun Geun; Choi, Hae In; Kim, Jong Heon; Goh, Sung Ho; Lee, Chang-Hun

2016-08-16

Fanconi anemia complementation group (FANC) proteins constitute the Fanconi Anemia (FA)/BRCA pathway that is activated in response to DNA interstrand crosslinks (ICLs). We previously performed yeast two-hybrid screening to identify novel FANC-interacting proteins and discovered that the alpha subunit of AMP-activated protein kinase (AMPKα1) was a candidate binding partner of the FANCG protein, which is a component of the FA nuclear core complex. We confirmed the interaction between AMPKα and both FANCG using co-immunoprecipitation experiments. Additionally, we showed that AMPKα interacted with FANCA, another component of the FA nuclear core complex. AMPKα knockdown in U2OS cells decreased FANCD2 monoubiquitination and nuclear foci formation upon mitomycin C-induced ICLs. Furthermore, AMPKα knockdown enhanced cellular sensitivity to MMC. MMC treatment resulted in an increase in AMPKα phosphorylation/activation, indicating AMPK is involved in the cellular response to ICLs. FANCA was phosphorylated by AMPK at S347 and phosphorylation increased with MMC treatment. MMC-induced FANCD2 monoubiquitination and nuclear foci formation were compromised in a U2OS cell line that stably overexpressed the S347A mutant form of FANCA compared to wild-type FANCA-overexpressing cells, indicating a requirement for FANCA phosphorylation at S347 for proper activation of the FA/BRCA pathway. Our data suggest AMPK is involved in the activation of the FA/BRCA pathway.

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

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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. 

Integrated QSAR study for inhibitors of Hedgehog Signal Pathway against multiple cell lines:a collaborative filtering method.

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Gao, Jun; Che, Dongsheng; Zheng, Vincent W; Zhu, Ruixin; Liu, Qi

2012-07-31

The Hedgehog Signaling Pathway is one of signaling pathways that are very important to embryonic development. The participation of inhibitors in the Hedgehog Signal Pathway can control cell growth and death, and searching novel inhibitors to the functioning of the pathway are in a great demand. As the matter of fact, effective inhibitors could provide efficient therapies for a wide range of malignancies, and targeting such pathway in cells represents a promising new paradigm for cell growth and death control. Current research mainly focuses on the syntheses of the inhibitors of cyclopamine derivatives, which bind specifically to the Smo protein, and can be used for cancer therapy. While quantitatively structure-activity relationship (QSAR) studies have been performed for these compounds among different cell lines, none of them have achieved acceptable results in the prediction of activity values of new compounds. In this study, we proposed a novel collaborative QSAR model for inhibitors of the Hedgehog Signaling Pathway by integration the information from multiple cell lines. Such a model is expected to substantially improve the QSAR ability from single cell lines, and provide useful clues in developing clinically effective inhibitors and modifications of parent lead compounds for target on the Hedgehog Signaling Pathway. In this study, we have presented: (1) a collaborative QSAR model, which is used to integrate information among multiple cell lines to boost the QSAR results, rather than only a single cell line QSAR modeling. Our experiments have shown that the performance of our model is significantly better than single cell line QSAR methods; and (2) an efficient feature selection strategy under such collaborative environment, which can derive the commonly important features related to the entire given cell lines, while simultaneously showing their specific contributions to a specific cell-line. Based on feature selection results, we have proposed several

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

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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.

GDC-0449-a potent inhibitor of the hedgehog pathway.

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Robarge, Kirk D; Brunton, Shirley A; Castanedo, Georgette M; Cui, Yong; Dina, Michael S; Goldsmith, Richard; Gould, Stephen E; Guichert, Oivin; Gunzner, Janet L; Halladay, Jason; Jia, Wei; Khojasteh, Cyrus; Koehler, Michael F T; Kotkow, Karen; La, Hank; Lalonde, Rebecca L; Lau, Kevin; Lee, Leslie; Marshall, Derek; Marsters, James C; Murray, Lesley J; Qian, Changgeng; Rubin, Lee L; Salphati, Laurent; Stanley, Mark S; Stibbard, John H A; Sutherlin, Daniel P; Ubhayaker, Savita; Wang, Shumei; Wong, Susan; Xie, Minli

2009-10-01

SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.

ERK mutations confer resistance to mitogen-activated protein kinase pathway inhibitors.

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Goetz, Eva M; Ghandi, Mahmoud; Treacy, Daniel J; Wagle, Nikhil; Garraway, Levi A

2014-12-01

The use of targeted therapeutics directed against BRAF(V600)-mutant metastatic melanoma improves progression-free survival in many patients; however, acquired drug resistance remains a major medical challenge. By far, the most common clinical resistance mechanism involves reactivation of the MAPK (RAF/MEK/ERK) pathway by a variety of mechanisms. Thus, targeting ERK itself has emerged as an attractive therapeutic concept, and several ERK inhibitors have entered clinical trials. We sought to preemptively determine mutations in ERK1/2 that confer resistance to either ERK inhibitors or combined RAF/MEK inhibition in BRAF(V600)-mutant melanoma. Using a random mutagenesis screen, we identified multiple point mutations in ERK1 (MAPK3) and ERK2 (MAPK1) that could confer resistance to ERK or RAF/MEK inhibitors. ERK inhibitor-resistant alleles were sensitive to RAF/MEK inhibitors and vice versa, suggesting that the future development of alternating RAF/MEK and ERK inhibitor regimens might help circumvent resistance to these agents. ©2014 American Association for Cancer Research.

The Fanconi anemia pathway sensitizes to DNA alkylating agents by inducing JNK-p53-dependent mitochondrial apoptosis in breast cancer cells.

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Zhao, Lin; Li, Yanlin; He, Miao; Song, Zhiguo; Lin, Shu; Yu, Zhaojin; Bai, Xuefeng; Wang, Enhua; Wei, Minjie

2014-07-01

The Fanconi anemia/BRCA (FA/BRCA) DNA damage repair pathway plays a pivotal role in the cellular response to DNA alkylating agents and greatly influences drug response in cancer treatment. However, the molecular mechanisms underlying the FA/BRCA pathway reversed resistance have received limited attention. In the present study, we investigated the effect of Fanconi anemia complementation group F protein (FANCF), a critical factor of the FA/BRCA pathway, on cancer cell apoptosis induced by DNA alkylating agents such as mitomycin c (MMC). We found that FANCF shRNA potentiated MMC-induced cytotoxicity and apoptosis in MCF-7 and MDA-MB-231 breast cancer cells. At a mechanistic level, FANCF shRNA downregulated the anti-apoptotic protein Bcl-2 and upregulated the pro-apoptotic protein Bax, accompanied by release of cyt-c and smac into the cytosol in MMC-treated cells. Furthermore, activation of caspase-3 and -9, other than caspase-8, cleavage of poly(ADP ribose) polymerase (PARP), and a decrease of mitochondrial membrane potential (MMP) indicated that involvement of the mitochondrial apoptotic pathway in FANCF silencing of MMC-treated breast cancer cells. A decrease in IAP family proteins XIAP and survivin were also observed following FANCF silencing in MMC-treated breast cancer cells. Notably, FANCF shRNA was able to increase p53 levels through activation of the JNK pathway in MMC-treated breast cancer cells. Furthermore, p53 inhibition using pifithrin-α abolished the induction of caspase-3 and PARP by FANCF shRNA and MMC, indicating that MMC-induced apoptosis is substantially enhanced by FANCF shRNA via p53-dependent mechanisms. To our knowledge, we provide new evidence for the potential application of FANCF as a chemosensitizer in breast cancer therapy.

Faktor Risiko yang Berhubungan dengan Kejadian Anemia pada Remaja Putri

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Mahmut Jaelani

2017-11-01

Full Text Available Teenage girls are one of the groups who are prone to anemia. Anemia in teenage girls is still a big public health problem because the prevalence is still ≥20% that is equal to 21,7%. This study aimed to examine the dominant factors associated with the incidence of anemia and determinants in teenage girls in MTsN 02 Kota Bengkulu with a cross-sectional design. The population was all female adolescents in MTsN 02 Kota Bengkulu and the sample was taken by using simple random sampling as much as 100 respondents taken from class VII and class VIII. The results showed that the anemia was 33.0% and there was a relationship between menstrual period (p=0,028, nutritional status (p=0,000, breakfast habits (p=0,000, iron intake (p=0,000, intake protein (p=0,017, consumption pattern of iron absorption inhibitor (p=0,045 and there was no significant correlation between maternal education level (p=0,265 with incidence of anemia in Young women at MTsN 02 Kota Bengkulu. Variable nutritional status is the most dominant associated anemia in young women.

Tissue factor pathway inhibitor for prediction of placenta-mediated adverse pregnancy outcomes in high-risk women: AngioPred study.

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Aurélie Di Bartolomeo

Full Text Available The study aimed to evaluate if the rate of tissue factor pathway inhibitor during pregnancy and following delivery could be a predictive factor for placenta-mediated adverse pregnancy outcomes in high-risk women.This was a prospective multicentre cohort study of 200 patients at a high risk of occurrence or recurrence of placenta-mediated adverse pregnancy outcomes conducted between June 2008 and October 2010. Measurements of tissue factor pathway inhibitor resistance (normalized ratio and tissue factor pathway inhibitor activity were performed for the last 72 patients at 20, 24, 28, 32, and 36 weeks of gestation and during the postpartum period.Overall, 15 patients presented a placenta-mediated adverse pregnancy outcome. There was no difference in normalized tissue factor pathway inhibitor ratios between patients with and without placenta-mediated adverse pregnancy outcomes during pregnancy and in the post-partum period. Patients with placenta-mediated adverse pregnancy outcomes had tissue factor pathway inhibitor activity rates that were significantly higher than those in patients without at as early as 24 weeks of gestation. The same results were observed following delivery.Among high-risk women, the tissue factor pathway inhibitor activity of patients with gestational vascular complications is higher than that in other patients. Hence, these markers could augment a screening strategy that includes an analysis of angiogenic factors as well as clinical and ultrasound imaging with Doppler measurement of the uterine arteries.

Blockade of the ERK pathway enhances the therapeutic efficacy of the histone deacetylase inhibitor MS-275 in human tumor xenograft models

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Sakamoto, Toshiaki; Ozaki, Kei-ichi; Fujio, Kohsuke; Kajikawa, Shu-hei [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Uesato, Shin-ichi [Department of Biotechnology, Faculty of Engineering, Kansai University, Osaka 564-8680 (Japan); Watanabe, Kazushi [Proubase Technology Inc., Kanagawa 211-0063 (Japan); Tanimura, Susumu [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Koji, Takehiko [Department of Histology and Cell Biology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan); Kohno, Michiaki, E-mail: kohnom@nagasaki-u.ac.jp [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Proubase Technology Inc., Kanagawa 211-0063 (Japan); Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto 606-8501 (Japan)

2013-04-19

Highlights: •Blockade of the ERK pathway enhances the anticancer efficacy of HDAC inhibitors. •MEK inhibitors sensitize human tumor xenografts to HDAC inhibitor cytotoxicity. •Such the enhanced efficacy is achieved by a transient blockade of the ERK pathway. •This drug combination provides a promising therapeutic strategy for cancer patients. -- Abstract: The ERK pathway is up-regulated in various human cancers and represents a prime target for mechanism-based approaches to cancer treatment. Specific blockade of the ERK pathway alone induces mostly cytostatic rather than pro-apoptotic effects, however, resulting in a limited therapeutic efficacy of the ERK kinase (MEK) inhibitors. We previously showed that MEK inhibitors markedly enhance the ability of histone deacetylase (HDAC) inhibitors to induce apoptosis in tumor cells with constitutive ERK pathway activation in vitro. To evaluate the therapeutic efficacy of such drug combinations, we administered the MEK inhibitor PD184352 or AZD6244 together with the HDAC inhibitor MS-275 in nude mice harboring HT-29 or H1650 xenografts. Co-administration of the MEK inhibitor markedly sensitized the human xenografts to MS-275 cytotoxicity. A dose of MS-275 that alone showed only moderate cytotoxicity thus suppressed the growth of tumor xenografts almost completely as well as induced a marked reduction in tumor cellularity when administered with PD184352 or AZD6244. The combination of the two types of inhibitor also induced marked oxidative stress, which appeared to result in DNA damage and massive cell death, specifically in the tumor xenografts. The enhanced therapeutic efficacy of the drug combination was achieved by a relatively transient blockade of the ERK pathway. Administration of both MEK and HDAC inhibitors represents a promising chemotherapeutic strategy with improved safety for cancer patients.

Expression and localization of tissue factor pathway inhibitor-2 in normal and atherosclerotic human vessels

NARCIS (Netherlands)

Crawley, James T. B.; Goulding, David A.; Ferreira, Valérie; Severs, Nicholas J.; Lupu, Florea

2002-01-01

Tissue factor pathway inhibitor-2 (TFPI-2) is a Kunitz-type, serine protease inhibitor with inhibitory activity toward activated factor XI, plasma kallikrein, plasmin, certain matrix metalloproteinases, and the tissue factor:activated factor VII complex. In this study, we investigated TFPI-2

Update of the human and mouse Fanconi anemia genes.

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Dong, Hongbin; Nebert, Daniel W; Bruford, Elspeth A; Thompson, David C; Joenje, Hans; Vasiliou, Vasilis

2015-11-24

Fanconi anemia (FA) is a recessively inherited disease manifesting developmental abnormalities, bone marrow failure, and increased risk of malignancies. Whereas FA has been studied for nearly 90 years, only in the last 20 years have increasing numbers of genes been implicated in the pathogenesis associated with this genetic disease. To date, 19 genes have been identified that encode Fanconi anemia complementation group proteins, all of which are named or aliased, using the root symbol "FANC." Fanconi anemia subtype (FANC) proteins function in a common DNA repair pathway called "the FA pathway," which is essential for maintaining genomic integrity. The various FANC mutant proteins contribute to distinct steps associated with FA pathogenesis. Herein, we provide a review update of the 19 human FANC and their mouse orthologs, an evolutionary perspective on the FANC genes, and the functional significance of the FA DNA repair pathway in association with clinical disorders. This is an example of a set of genes--known to exist in vertebrates, invertebrates, plants, and yeast--that are grouped together on the basis of shared biochemical and physiological functions, rather than evolutionary phylogeny, and have been named on this basis by the HUGO Gene Nomenclature Committee (HGNC).

Multiple TPR motifs characterize the Fanconi anemia FANCG protein.

NARCIS (Netherlands)

Blom, E.; Vrugt, van der H.J.; Vries, de Y.; Winter, de J.P.; Arwert, F.; Joenje, H.

2004-01-01

The genome protection pathway that is defective in patients with Fanconi anemia (FA) is controlled by at least eight genes, including BRCA2. A key step in the pathway involves the monoubiquitylation of FANCD2, which critically depends on a multi-subunit nuclear 'core complex' of at least six FANC

Impaired TIP60-mediated H4K16 acetylation accounts for the aberrant chromatin accumulation of 53BP1 and RAP80 in Fanconi anemia pathway-deficient cells.

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Renaud, Emilie; Barascu, Aurelia; Rosselli, Filippo

2016-01-29

To rescue collapsed replication forks cells utilize homologous recombination (HR)-mediated mechanisms to avoid the induction of gross chromosomal abnormalities that would be generated by non-homologous end joining (NHEJ). Using DNA interstrand crosslinks as a replication barrier, we investigated how the Fanconi anemia (FA) pathway promotes HR at stalled replication forks. FA pathway inactivation results in Fanconi anemia, which is associated with a predisposition to cancer. FANCD2 monoubiquitination and assembly in subnuclear foci appear to be involved in TIP60 relocalization to the chromatin to acetylates histone H4K16 and prevents the binding of 53BP1 to its docking site, H4K20Me2. Thus, FA pathway loss-of-function results in accumulation of 53BP1, RIF1 and RAP80 at damaged chromatin, which impair DNA resection at stalled replication fork-associated DNA breaks and impede HR. Consequently, DNA repair in FA cells proceeds through the NHEJ pathway, which is likely responsible for the accumulation of chromosome abnormalities. We demonstrate that the inhibition of NHEJ or deacetylase activity rescue HR in FA cells. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Pernicious anemia

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... 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 ...

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

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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

2016-10-01

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.

DNA interstrand cross-link repair: understanding role of Fanconi anemia pathway and therapeutic implications.

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Shukla, Pallavi; Solanki, Avani; Ghosh, Kanjaksha; Vundinti, Babu Rao

2013-11-01

Interstrand cross-links (ICLs) are extremely toxic DNA lesions that prevent DNA double-helix separation due to the irreversible covalent linkage binding of some agents on DNA strands. Agents that induce these ICLs are thus widely used as chemotherapeutic drugs but may also lead to tumor growth. Fanconi anemia (FA) is a rare genetic disorder that leads to ICL sensitivity. This review provides update on current understanding of the role of FA proteins in repairing ICLs at various stages of cell cycle. We also discuss link between DNA cross-link genotoxicity caused by aldehydes in FA pathway. Besides this, we summarize various ICL agents that act as drugs to treat different types of tumors and highlight strategies for modulating ICL sensitivity for therapeutic interventions that may be helpful in controlling cancer and life-threatening disease, FA. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

BLM promotes the activation of Fanconi Anemia signaling pathway.

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Panneerselvam, Jayabal; Wang, Hong; Zhang, Jun; Che, Raymond; Yu, Herbert; Fei, Peiwen

2016-05-31

Mutations in the human RecQ helicase, BLM, causes Bloom Syndrome, which is a rare autosomal recessive disorder and characterized by genomic instability and an increased risk of cancer. Fanconi Anemia (FA), resulting from mutations in any of the 19 known FA genes and those yet to be known, is also characterized by chromosomal instability and a high incidence of cancer. BLM helicase and FA proteins, therefore, may work in a common tumor-suppressor signaling pathway. To date, it remains largely unclear as to how BLM and FA proteins work concurrently in the maintenance of genome stability. Here we report that BLM is involved in the early activation of FA group D2 protein (FANCD2). We found that FANCD2 activation is substantially delayed and attenuated in crosslinking agent-treated cells harboring deficient Blm compared to similarly treated control cells with sufficient BLM. We also identified that the domain VI of BLM plays an essential role in promoting FANCD2 activation in cells treated with DNA crosslinking agents, especially ultraviolet B. The similar biological effects performed by ΔVI-BLM and inactivated FANCD2 further confirm the relationship between BLM and FANCD2. Mutations within the domain VI of BLM detected in human cancer samples demonstrate the functional importance of this domain, suggesting human tumorigenicity resulting from mtBLM may be at least partly attributed to mitigated FANCD2 activation. Collectively, our data show a previously unknown regulatory liaison in advancing our understanding of how the cancer susceptibility gene products act in concert to maintain genome stability.

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

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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.

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

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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. © Society for Leukocyte Biology.

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

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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.

In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor.

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van der Heijden, Michiel S; Brody, Jonathan R; Dezentje, David A; Gallmeier, Eike; Cunningham, Steven C; Swartz, Michael J; DeMarzo, Angelo M; Offerhaus, G Johan A; Isacoff, William H; Hruban, Ralph H; Kern, Scott E

2005-10-15

BRCA2, FANCC, and FANCG gene mutations are present in a subset of pancreatic cancer. Defects in these genes could lead to hypersensitivity to interstrand cross-linkers in vivo and a more optimal treatment of pancreatic cancer patients based on the genetic profile of the tumor. Two retrovirally complemented pancreatic cancer cell lines having defects in the Fanconi anemia pathway, PL11 (FANCC-mutated) and Hs766T (FANCG-mutated), as well as several parental pancreatic cancer cell lines with or without mutations in the Fanconi anemia/BRCA2 pathway, were assayed for in vitro and in vivo sensitivities to various chemotherapeutic agents. A distinct dichotomy of drug responses was observed. Fanconi anemia-defective cancer cells were hypersensitive to the cross-linking agents mitomycin C (MMC), cisplatin, chlorambucil, and melphalan but not to 5-fluorouracil, gemcitabine, doxorubicin, etoposide, vinblastine, or paclitaxel. Hypersensitivity to cross-linking agents was confirmed in vivo; FANCC-deficient xenografts of PL11 and BRCA2-deficient xenografts of CAPAN1 regressed on treatment with two different regimens of MMC whereas Fanconi anemia-proficient xenografts did not. The MMC response comprised cell cycle arrest, apoptosis, and necrosis. Xenografts of PL11 also regressed after a single dose of cyclophosphamide whereas xenografts of genetically complemented PL11(FANCC) did not. MMC or other cross-linking agents as a clinical therapy for pancreatic cancer patients with tumors harboring defects in the Fanconi anemia/BRCA2 pathway should be specifically investigated.

Preclinical rationale for PI3K/Akt/mTOR pathway inhibitors as therapy for epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer.

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Gadgeel, Shirish M; Wozniak, Antoinette

2013-07-01

Mutations in the epidermal growth factor receptor gene (EGFR) are frequently observed in non-small-cell lung cancer (NSCLC), occurring in about 40% to 60% of never-smokers and in about 17% of patients with adenocarcinomas. EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have transformed therapy for patients with EGFR-mutant NSCLC and have proved superior to chemotherapy as first-line treatment for this patient group. Despite these benefits, there are currently 2 key challenges associated with EGFR inhibitor therapy for patients with NSCLC. First, only 85% to 90% of patients with the EGFR mutation derive clinical benefit from EGFR TKIs, with the remainder demonstrating innate resistance to therapy. Second, acquired resistance to EGFR TKIs inevitably occurs in patients who initially respond to therapy, with a median duration of response of about 10 months. Mutant EGFR activates various subcellular signaling cascades, including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which demonstrates maintained activity in a variety of TKI-resistant cancers. Given the fundamental role of the PI3K/Akt/mTOR pathway in tumor oncogenesis, proliferation, and survival, PI3K pathway inhibitors have emerged as a possible solution to the problem of EGFR TKI resistance. However resistance to EGFR TKIs is associated with considerable heterogeneity and complexity. Preclinical experiments investigating these phenomena suggest that in some patients, PI3K inhibitors will have to be paired with other targeted agents if they are to be effective. This review discusses the preclinical data supporting PI3K/Akt/mTOR pathway inhibitor combinations in EGFR TKI-resistant NSCLC from the perspective of the various agents currently being investigated in clinical trials. Copyright © 2013 Elsevier Inc. All rights reserved.

Pregnancy Complications: Anemia

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... online community 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 ...

Recent advances in understanding hematopoiesis in Fanconi Anemia [version 1; referees: 4 approved

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Grover Bagby

2018-01-01

Full Text Available Fanconi anemia is an inherited disease characterized by genomic instability, hypersensitivity to DNA cross-linking agents, bone marrow failure, short stature, skeletal abnormalities, and a high relative risk of myeloid leukemia and epithelial malignancies. The 21 Fanconi anemia genes encode proteins involved in multiple nuclear biochemical pathways that effect DNA interstrand crosslink repair. In the past, bone marrow failure was attributed solely to the failure of stem cells to repair DNA. Recently, non-canonical functions of many of the Fanconi anemia proteins have been described, including modulating responses to oxidative stress, viral infection, and inflammation as well as facilitating mitophagic responses and enhancing signals that promote stem cell function and survival. Some of these functions take place in non-nuclear sites and do not depend on the DNA damage response functions of the proteins. Dysfunctions of the canonical and non-canonical pathways that drive stem cell exhaustion and neoplastic clonal selection are reviewed, and the potential therapeutic importance of fully investigating the scope and interdependences of the canonical and non-canonical pathways is emphasized.

Iron-Deficiency Anemia

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... To Health Topics / Iron-Deficiency Anemia Iron-Deficiency Anemia Also known as Leer en español Iron-deficiency ... anemia. Blood tests to screen for iron-deficiency anemia To screen for iron-deficiency anemia, your doctor ...

Anemia (For Parents)

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... Staying Safe Videos for Educators Search English Español Anemia KidsHealth / For Parents / Anemia What's in this article? ... Deficiency Anemia in My Kids? Print What Is Anemia? Anemia is when the level of healthy red ...

Oral human papillomavirus is common in individuals with Fanconi anemia.

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Sauter, Sharon L; Wells, Susanne I; Zhang, Xue; Hoskins, Elizabeth E; Davies, Stella M; Myers, Kasiani C; Mueller, Robin; Panicker, Gitika; Unger, Elizabeth R; Sivaprasad, Umasundari; Brown, Darron R; Mehta, Parinda A; Butsch Kovacic, Melinda

2015-05-01

Fanconi anemia is a rare genetic disorder resulting in a loss of function of the Fanconi anemia-related DNA repair pathway. Individuals with Fanconi anemia are predisposed to some cancers, including oropharyngeal and gynecologic cancers, with known associations with human papillomavirus (HPV) in the general population. As individuals with Fanconi anemia respond poorly to chemotherapy and radiation, prevention of cancer is critical. To determine whether individuals with Fanconi anemia are particularly susceptible to oral HPV infection, we analyzed survey-based risk factor data and tested DNA isolated from oral rinses from 126 individuals with Fanconi anemia and 162 unaffected first-degree family members for 37 HPV types. Fourteen individuals (11.1%) with Fanconi anemia tested positive, significantly more (P = 0.003) than family members (2.5%). While HPV prevalence was even higher for sexually active individuals with Fanconi anemia (17.7% vs. 2.4% in family; P = 0.003), HPV positivity also tended to be higher in the sexually inactive (8.7% in Fanconi anemia vs. 2.9% in siblings). Indeed, having Fanconi anemia increased HPV positivity 4.9-fold (95% CI, 1.6-15.4) considering age and sexual experience, but did not differ by other potential risk factors. Our studies suggest that oral HPV is more common in individuals with Fanconi anemia. It will be essential to continue to explore associations between risk factors and immune dysfunction on HPV incidence and persistence over time. HPV vaccination should be emphasized in those with Fanconi anemia as a first step to prevent oropharyngeal cancers, although additional studies are needed to determine whether the level of protection it offers in this population is adequate. ©2015 American Association for Cancer Research.

Iron-Deficiency Anemia

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Full Text Available ... To Health Topics / Iron-Deficiency Anemia Iron-Deficiency Anemia Also known as Leer en español Iron-deficiency ... anemia. Blood tests to screen for iron-deficiency anemia To screen for iron-deficiency anemia, your doctor ...

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

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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.

Iron-Deficiency Anemia

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Full Text Available ... Research Home / < Back To Health Topics / Iron-Deficiency Anemia Iron-Deficiency Anemia Also known as Leer en español Iron-deficiency ... iron-deficiency anemia. Blood tests to screen for iron-deficiency anemia To screen for iron-deficiency anemia, your doctor ...

Hemolytic anemia

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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: ...

Identification of novel target genes involved in Indian Fanconi anemia patients using microarray.

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Shyamsunder, Pavithra; Ganesh, Kripa S; Vidyasekar, Prasanna; Mohan, Sheila; Verma, Rama Shanker

2013-12-01

Fanconi anemia (FA) is a genetic disorder characterized by progressive bone marrow failure and a predisposition to cancers. Mutations have been documented in 15 FA genes that participate in the FA-BRCA DNA repair pathway, a fundamental pathway in the development of the disease and the presentation of its characteristic symptoms. Certain symptoms such as oxygen sensitivity, hematological abnormalities and impaired immunity suggest that FA proteins could participate in or independently control other pathways as well. In this study, we identified 9 DNA repair genes that were down regulated in a genome wide analysis of 6 Indian Fanconi anemia patients. Functional clustering of a total of 233 dysregulated genes identified key biological processes that included regulation of transcription, DNA repair, cell cycle and chromosomal organization. Microarray data revealed the down regulation of ATXN3, ARID4A and ETS-1, which were validated by RTPCR in a subsequent sample set of 9 Indian FA patients. Here we report for the first time a gene expression profile of Fanconi anemia patients from the Indian population and a pool of genes that might aid in the acquisition and progression of the FA phenotype. © 2013 Elsevier B.V. All rights reserved.

Delayed globin synthesis leads to excess heme and the macrocytic anemia of Diamond Blackfan anemia and del(5q) myelodysplastic syndrome.

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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. Copyright © 2016, American Association for the Advancement of Science.

Iron-Deficiency Anemia

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Full Text Available ... en español Iron-deficiency anemia is a common type of anemia that occurs if you do not ... iron-deficiency anemia and help rule out other types of anemia. Treatment will explain treatment-related complications ...

Anemia (For Teens)

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... Staying Safe Videos for Educators Search English Español Anemia KidsHealth / For Teens / Anemia What's in this article? ... Enough Iron Print en español Anemia What Is Anemia? Lots of teens are tired. With all the ...

Fanconi anemia

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... possibly given through a vein) to treat infections Blood transfusions to treat symptoms due to low blood counts ... have regular check-ups to screen for cancer. Alternative Names Fanconi's anemia; Anemia - Fanconi's Images Formed elements of blood References Bagby GC. Aplastic anemia and related bone ...

Hemolytic Anemia

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... worsen your condition or lead to complications. Hemolytic Anemia and Children Parents of children who have hemolytic anemia usually ... members, friends, and your child's classmates about hemolytic anemia. You also may want to tell your child's teachers or other caregivers about the condition. Let ...

Iron-Deficiency Anemia

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Full Text Available ... anemia, your doctor may order the following blood tests to diagnose iron-deficiency anemia: Complete blood count (CBC) to ... than normal when viewed under a microscope. Different tests help your doctor diagnose iron-deficiency anemia. In iron-deficiency anemia, blood ...

The participation of the Fanconi anemia pathway in the replication of UV-damage DNA

International Nuclear Information System (INIS)

Federico, M.B.; Vallerga, M.B.; Mansilla, S.F.; Speroni, J.; Habif, M.; D'Alessio, C.; Gottifredi, V.

2011-01-01

When cells are challenged with genotoxic agents, replicating cells must use damaged DNA as templates. In this way, active replication forks do not collapse and cell viability is protected. After UV irradiation a specialized DNA polymerase pol eta uses UV damaged DNA as template. Intriguingly, Pol eta lost in human cells does not steeply increase UV sensitivity. This suggests that compensatory mechanisms promote cell survival when pol eta is absent. We have found an increase and sustained FANCD2 ubiquitination and focal formation after UV irradiation when pol eta is lost. FANCD2 is a key marker of the activation of the FANCONI ANEMIA (FA) pathway. While there is limited information regarding a role of the FA pathway after UV irradiation, it is well established that FANCD2 ubiquitination is linked to the recruitment of homologous recombination (HR) specific markers to other lesions. We therefore thought that cell viability in the absence of pol eta might result from the activation of FANDC2-dependent HR at collapsed replication forks. We are currently analyzing markers of damage such as γH2AX phosphorylation, markers of HR such as Rad51, markers of double strand breaks accumulation such as 53BP1 and setting up viability assays. This information might allow us to predict if FANCD2 can trigger HR after UV and if this contributes to cell viability when pol eta is absent. (authors)

Iron deficiency anemia in sports and preventive dietetic and nutrition interventions

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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.

What Is Aplastic Anemia?

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... Home / Anemia Aplastic Anemia Also known as What Is 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 ...

[Fanconi anemia: cellular and molecular features].

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Macé, G; Briot, D; Guervilly, J-H; Rosselli, F

2007-02-01

Fanconi anemia (FA) is a recessive human cancer prone syndrome featuring bone marrow failure, developmental abnormalities and hypersensitivity to DNA crosslinking agents exposure. 11 among 12 FA gene have been isolated. The biochemical functions of the FANC proteins remain poorly understood. Anyhow, to cope with DNA crosslinks a cell needs a functional FANC pathway. Moreover, the FANC proteins appear to be involved in cell protection against oxidative damage and in the control of TNF-alpha activity. In this review, we describe the current understanding of the FANC pathway and we present how it may be integrated in the complex networks of proteins involved in maintaining the cellular homeostasis.

Iron-Deficiency Anemia

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Full Text Available ... Blood Transfusion Heart-Healthy Lifestyle Changes Heart Failure Hemolytic Anemia Hemophilia Pernicious Anemia Restless Legs Syndrome Von Willebrand Disease Other Resources NHLBI resources Your Guide to Anemia [ ...

What Is Anemia?

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... Intramural Research Home / Anemia Anemia Also known as Iron-poor blood , Low blood , ... you or your child diagnosed with Diamond-Blackfan anemia? The registry is collecting information from people with ...

Anemia

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... child might have anemia. They will do a physical exam and review your health history and symptoms. To diagnose anemia, your doctor ... and Wellness Staying Healthy Healthy Living Travel Occupational Health First Aid and ... Pets and Animals myhealthfinder Food and Nutrition Healthy Food ...

DPP4 inhibitors promote biological functions of human endothelial progenitor cells by targeting the SDF-1/CXCR4 signaling pathway

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Liu Feng

2016-01-01

Full Text Available Dipeptidyl peptidase 4 (DPP4 inhibitors(oral hypoglycemic agentshave beneficial effects during the early stages of diabetes. In this study, we evaluated the role of DPP4inhibitorsonthe biological functions of cultured human endothelial progenitor cells (EPCs. After treating EPCs with the DPP4 inhibitors sitagliptin and vildagliptin, we examined the mRNA expression of DPP4, vascular endothelial growth factor (VEGF,VEGF receptor 2 (VEGFR-2,endothelial nitric oxide synthase (eNOS, caspase-3,stromal cell-derived factor-1 (SDF-1, chemokine (C-X-C motif receptor 4 (CXCR4 were measured by RT-PCR. The protein expression of SDF-1 and CXCR4 was determined by Western blot; cell proliferation was tested by the MTT method, and DPP4 activity was determined by a DPP4 assay. Our results revealed that DPP4 expression and activity were inhibited following the treatment with various doses of DPP4 inhibitors. Cell proliferation and the expression of VEGF, VEGFR-2andeNOS were up regulated, while cell apoptosis was inhibited by DPP4 inhibitors in a dose-dependent manner. DPP4 inhibitors activated the SDF-1/CXCR4 signaling pathway, shown by the elevated expression of SDF-1/CXCR4. This further proved that after the SDF-1/CXCR4 signaling pathway was blocked by its inhibitor ADM3100, the effects of DPP4 inhibitors on the proliferation and apoptosis, and the expression of VEGF, VEGFR-2and eNOS of EPCs were significantly reduced. These findings suggest that DPP4 inhibitors promote the biological functions of human EPCs by up regulating the SDF-1/CXCR4 signaling pathway.

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

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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.

Anemia and Pregnancy

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... 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 ...

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

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Nur Handayani Utami

2015-03-01

Full Text Available 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. Analisis ini merupakan analisa dari data studi kohor Tumbuh Kembang anak pada tahun pertama, yang dilaksanakan di Kelurahan Kebon Kalapa dan Ciwaringin, Kota Bogor yang dianalisa menggunakan disainkasus kontrol. Sebanyak 47 ibu hamil menjadi sampel dalam analisa ini. Kategori untuk anemia yaitu apabila kadar hemoglobin (Hb ibu hamil ≤11 g/dL. Kekurangan gizi besi dikategorikan apabila kadar serum transferrin reseptor (sTfR diatas 4.4 mg/L. Sedangkan Anemia Gizi Besi dikategorikan apabila memiliki kadar Hb < 11 g/dL dan sTfr > 4.4 mg/L. Tes one way anova digunakan untuk menganalisa adanya perbedaan asupan energi, protein dan zat gizi mikro antara ibu hamil yang mengalami anemia, anemia gizi besi maupun yang normal. Odd ratio dianalisa dengan menggunakan uji chi square. Nilai signifikan ditentukan apabila nilai p value < 0.05 dan perhitungan OR> 1. 27.7% dari ibu hamil di lokasi studi mengalami anemia, 14.9% tergolong dalam anemia ringan, 10.6% anemia sedang dan 2.1% anemia berat. Anemia gizi besi dialami oleh 17% dari wanita hamil. Terdapat hubungan yang signifikan antara keparahan anemia dan terjadinya anemia gizi besi. Tidak ditemukan perbedaan antara asupan protein, besi, folate dan zink pada wanita yang mengalami anemia, anemia gizi besi maupun yang normal. Akan tetapi terdapat kecenderungan bahwa asupan zat besi dan seng pada ibu yang anemia dan anemia gizi besi lebih rendah daripada ibu yang normal. Anemia masih menjadi permasalahan kesehatan pada ibu

Inborn anemias in mice

International Nuclear Information System (INIS)

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 α-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

Anemia Due to Excessive Bleeding

Science.gov (United States)

... Hemolytic Anemia Hemoglobin C, S-C, and E Diseases Iron Deficiency Anemia Sickle Cell Disease Thalassemias Vitamin Deficiency Anemia (See ... Hemolytic Anemia Hemoglobin C, S-C, and E Diseases Iron Deficiency Anemia Sickle Cell Disease Thalassemias Vitamin Deficiency Anemia NOTE: ...

From Bad to Worse: Anemia on Admission and Hospital-Acquired Anemia.

Science.gov (United States)

Koch, Colleen G; Li, Liang; Sun, Zhiyuan; Hixson, Eric D; Tang, Anne S; Phillips, Shannon C; Blackstone, Eugene H; Henderson, J Michael

2017-12-01

Anemia at hospitalization is often treated as an accompaniment to an underlying illness, without active investigation, despite its association with morbidity. Development of hospital-acquired anemia (HAA) has also been associated with increased risk for poor outcomes. Together, they may further heighten morbidity risk from bad to worse. The aims of this study were to (1) examine mortality, length of stay, and total charges in patients with present-on-admission (POA) anemia and (2) determine whether these are exacerbated by development of HAA. In this cohort investigation, from January 1, 2009, to August 31, 2011, a total of 44,483 patients with POA anemia were admitted to a single health system compared with a reference group of 48,640 without POA anemia or HAA. Data sources included the University HealthSystem Consortium database and electronic medical records. Risk-adjustment methods included logistic and linear regression models for mortality, length of stay, and total charges. Present-on-admission anemia was defined by administrative coding. Hospital-acquired anemia was determined by changes in hemoglobin values from the electronic medical record. Approximately one-half of the patients experienced worsening of anemia with development of HAA. Risk for death and resource use increased with increasing severity of HAA. Those who developed severe HAA had 2-fold greater odds for death; that is, mild POA anemia with development of severe HAA resulted in greater mortality (odds ratio, 2.57; 95% confidence interval, 2.08-3.18; P < 0.001), increased length of stay (2.23; 2.16-2.31; P < 0.001), and higher charges (2.09; 2.03-2.15; P < 0.001). Present-on-admission anemia is associated with increased mortality and resource use. This risk is further increased from bad to worse when patients develop HAA. Efforts to address POA anemia and HAA deserve attention.

Your Guide to Anemia

Science.gov (United States)

... Inherited Causes l Folate or iron deficiency l Fanconi anemia from poor diet l Shwachman-Diamond l Demand ... cells, leading to aplastic anemia. These conditions include Fanconi anemia, Shwachman-Diamond syndrome, dyskeratosis congenita, Diamond- Blackfan anemia, ...

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... to moderate iron-deficiency anemia, or red blood cell transfusion for severe iron-deficiency anemia. You may ... body needs iron to make healthy red blood cells. Iron-deficiency anemia usually develops over time because ...

Iron-Deficiency Anemia

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Full Text Available ... view the colon directly. What if my doctor thinks something else is causing my iron-deficiency anemia? ... deficiency anemia early in life affects later behavior, thinking, and mood during adolescence. Treating anemia in premature ...

Iron-Deficiency Anemia

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Full Text Available ... you are diagnosed with iron-deficiency anemia. Risk Factors You may have an increased risk for iron- ... iron-deficiency anemia if you have certain risk factors , including pregnancy. To prevent iron-deficiency anemia, your ...

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... detect signs of iron-deficiency anemia and help rule out other types of anemia. Treatment will explain ... your blood. More testing may be needed to rule out other types of anemia. Tests for gastrointestinal ...

About Anemia (For Kids)

Science.gov (United States)

... Safe Videos for Educators Search English Español About Anemia KidsHealth / For Kids / About Anemia What's in this ... to every cell in your body. What Is Anemia? Anemia happens when a person doesn't have ...

Management of Anemia in Patients with Inflammatory Bowel Disease (IBD).

Science.gov (United States)

Patel, Dhruvan; Trivedi, Chinmay; Khan, Nabeel

2018-03-01

Anemia is the most common complication as well as an extra intestinal manifestation of inflammatory bowel disease (IBD). It is associated with a significant impact on patient's quality of life (QoL); as well it represents a common cause of frequent hospitalization, delay of hospital inpatient discharge and overall increased healthcare burden. In spite of all these, anemia is still often underdiagnosed and undertreated. Our aim in this review is to provide a pathway for physicians to help them achieve early diagnosis as well as timely and appropriate treatment of anemia which in turn would hopefully reduce the prevalence and subsequent complications of this condition among IBD patients. The etiology of anemia among IBD patients is most commonly due to iron deficiency anemia (IDA) followed by anemia of chronic disease. Despite this, more than a third of anemic ulcerative colitis (UC) patients are not tested for IDA and among those tested and diagnosed with IDA, a quarter are not treated with iron replacement therapy. A new algorithm has been validated to predict who will develop moderate to severe anemia at the time of UC diagnosis. While oral iron is effective for the treatment of mild iron deficiency-related anemia, the absorption of iron is influenced by chronic inflammatory states as a consequence of the presence of elevated levels of hepcidin. Also, it is important to recognize that ferritin is elevated in chronic inflammatory states and among patients with active IBD, ferritin levels less than 100 are considered to be diagnostic of iron deficiency. Newer formulations of intra-venous (IV) iron have a good safety profile and can be used for replenishment of iron stores and prevention of iron deficiency in the future. Routine screening for anemia is important among patients with IBD. The cornerstone for the accurate management of anemia in IBD patients lies in accurately diagnosing the type of anemia. All IBD patients with IDA should be considered appropriate for

Prevention of Bronchial Hyperplasia by EGFR Pathway Inhibitors in an Organotypic Culture Model

Science.gov (United States)

Lee, Jangsoon; Ryu, Seung-Hee; Kang, Shin Myung; Chung, Wen-Cheng; Gold, Kathryn Ann; Kim, Edward S.; Hittelman, Walter N.; Hong, Waun Ki; Koo, Ja Seok

2011-01-01

Lung cancer is the leading cause of cancer-related mortality worldwide. Early detection or prevention strategies are urgently needed to increase survival. Hyperplasia is the first morphologic change that occurs in the bronchial epithelium during lung cancer development, followed by squamous metaplasia, dysplasia, carcinoma in situ, and invasive tumor. The current study was designed to determine the molecular mechanisms that control bronchial epithelium hyperplasia. Using primary normal human tracheobronchial epithelial (NHTBE) cells cultured using the 3-dimensional organotypic method, we found that the epidermal growth factor receptor (EGFR) ligands EGF, transforming growth factor-alpha, and amphiregulin induced hyperplasia, as determined by cell proliferation and multilayered epithelium formation. We also found that EGF induced increased cyclin D1 expression, which plays a critical role in bronchial hyperplasia; this overexpression was mediated by activating the mitogen-activated protein kinase pathway but not the phosphoinositide 3-kinase/Akt signaling pathway. Erlotinib, an EGFR tyrosine kinase inhibitor, and U0126, a MEK inhibitor, completely inhibited EGF-induced hyperplasia. Furthermore, a promoter analysis revealed that the activator protein-1 transcription factor regulates EGF-induced cyclin D1 overexpression. Activator protein-1 depletion using siRNA targeting its c-Jun component completely abrogated EGF-induced cyclin D1 expression. In conclusion, we demonstrated that bronchial hyperplasia can be modeled in vitro using primary NHTBE cells maintained in a 3-dimensional (3-D) organotypic culture. EGFR and MEK inhibitors completely blocked EGF-induced bronchial hyperplasia, suggesting that they have a chemopreventive role. PMID:21505178

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... for iron-deficiency anemia if you have certain risk factors , including pregnancy. To prevent iron-deficiency anemia, your doctor may recommend you eat heart-healthy foods or control other conditions that can cause iron-deficiency anemia. ...

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... Home / < Back To Health Topics / Iron-Deficiency Anemia Iron-Deficiency Anemia Also known as Leer en español ... bleeding Consuming less than recommended daily amounts of iron Iron-deficiency anemia can be caused by getting ...

Iron-Deficiency Anemia

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Full Text Available ... may require intravenous (IV) iron therapy or a blood transfusion . Iron supplements Your doctor may recommend that you ... Anemia Aplastic Anemia Arrhythmia Blood Donation Blood Tests Blood Transfusion Heart-Healthy Lifestyle Changes Heart Failure Hemolytic Anemia ...

Iron-Deficiency Anemia

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Full Text Available ... Iron-Deficiency Anemia Iron-Deficiency Anemia Also known as Leer en español Iron-deficiency anemia is a ... address the cause of your iron deficiency, such as any underlying bleeding. If undiagnosed or untreated, iron- ...

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... Medicine (TOPMed) Program Non-NHLBI resources Anemia (National Library of Medicine, MedlinePlus) Anemia in Chronic Kidney Disease ( ... Supplement Fact Sheet (NIH) Iron-Deficiency Anemia (National Library of Medicine, MedlinePlus) Building 31 31 Center Drive ...

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... anemia if you have certain risk factors , including pregnancy. To prevent iron-deficiency anemia, your doctor may recommend you eat heart-healthy foods or control other conditions that can cause iron-deficiency anemia. Blood tests to screen for ...

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 ...

Treatment of renal anemia: Erythropoiesis stimulating agents and beyond

Directory of Open Access Journals (Sweden)

Patrick Biggar

2017-09-01

Full Text Available Anemia, complicating the course of chronic kidney disease, is a significant parameter, whether interpreted as subjective impairment or an objective prognostic marker. Renal anemia is predominantly due to relative erythropoietin (EPO deficiency. EPO inhibits apoptosis of erythrocyte precursors. Studies using EPO substitution have shown that increasing hemoglobin (Hb levels up to 10-11 g/dL is associated with clinical improvement. However, it has not been unequivocally proven that further intensification of erythropoiesis stimulating agent (ESA therapy actually leads to a comprehensive benefit for the patient, especially as ESAs are potentially associated with increased cerebro-cardiovascular events. Recently, new developments offer interesting options not only via stimulating erythropoeisis but also by employing additional mechanisms. The inhibition of activin, a member of the transforming growth factor superfamily, has the potential to correct anemia by stimulating liberation of mature erythrocyte forms and also to mitigate disturbed mineral and bone metabolism as well. Hypoxia-inducible factor prolyl hydroxylase inhibitors also show pleiotropic effects, which are at the focus of present research and have the potential of reducing mortality. However, conventional ESAs offer an extensive body of safety evidence, against which the newer substances should be measured. Carbamylated EPO is devoid of Hb augmenting effects whilst exerting promising tissue protective properties. Additionally, the role of hepcidin antagonists is discussed. An innovative new hemodialysis blood tube system, reducing blood contact with air, conveys a totally different and innocuous option to improve renal anemia by reducing mechanical hemolysis.

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... Topics News & Resources Intramural Research Home / < Back To Health Topics / Iron-Deficiency Anemia Iron-Deficiency Anemia Also known as Leer ... and symptoms as well as complications from iron-deficiency anemia. Research for Your Health The NHLBI is part of the U.S. Department ...

International Climate Migration: Evidence for the Climate Inhibitor Mechanism and the Agricultural Pathway.

Science.gov (United States)

Nawrotzki, Raphael J; Bakhtsiyarava, Maryia

2017-05-01

Research often assumes that, in rural areas of developing countries, adverse climatic conditions increase (climate driver mechanism) rather than reduce (climate inhibitor mechanism) migration, and that the impact of climate on migration is moderated by changes in agricultural productivity (agricultural pathway). Using representative census data in combination with high-resolution climate data derived from the novel Terra Populus system, we explore the climate-migration relationship in rural Burkina Faso and Senegal. We construct four threshold-based climate measures to investigate the effect of heat waves, cold snaps, droughts and excessive precipitation on the likelihood of household-level international outmigration. Results from multi-level logit models show that excessive precipitation increases international migration from Senegal while heat waves decrease international mobility in Burkina Faso, providing evidence for the climate inhibitor mechanism. Consistent with the agricultural pathway, interaction models and results from a geographically weighted regression (GWR) reveal a conditional effect of droughts on international outmigration from Senegal, which becomes stronger in areas with high levels of groundnut production. Moreover, climate change effects show a clear seasonal pattern, with the strongest effects appearing when heat waves overlap with the growing season and when excessive precipitation occurs prior to the growing season.

Anemia in Chronic Kidney Disease

Science.gov (United States)

... artérielle Heart Disease Mineral & Bone Disorder Anemia in Chronic Kidney Disease What is anemia? Anemia is a condition in ... as they should. How is anemia related to chronic kidney disease? Anemia commonly occurs in people with chronic kidney ...

Anemia in Chronic Kidney Disease

Science.gov (United States)

... Cysts Solitary Kidney Your Kidneys & How They Work 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 ...

Evaluation of WO2014207069 A1: Multitarget Hedgehog pathway inhibitors and uses thereof.

Science.gov (United States)

Manetti, Fabrizio; Petricci, Elena

2016-01-01

In recent years, the involvement of the Hedgehog (Hh) signaling pathway in various human diseases and dysfunctions has been clearly demonstrated. Smoothened (Smo), one of the upstream signal transducers, has been the most druggable target of the Hh pathway. However, the emergence of resistance to Smo inhibitors and the identification of Smo-independent activation of the Hh pathway led to the need to find new chemical entities able to interfere with downstream components, such as Gli. For this purpose, two different computational approaches have been applied to a small-sized library of natural compounds. As a result, an isoflavone derivative that showed ability to inhibit both Smo and Gli1 has been identified; namely, Glabrescione B. A new synthetic approach has been planned for this compound and its derivatives. Biological evaluation demonstrated the mechanism of action and showed a promising preclinical profile.

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... Topics section only, or the News and Resources section. NHLBI Entire Site NHLBI Entire Site Health ... español Iron-deficiency anemia is a common type of anemia that occurs if you do not have enough iron in your body. People with mild or moderate iron-deficiency anemia ...

Predictors of anemia in preschool children: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project

Science.gov (United States)

Aaron, Grant J; Huang, Jin; Varadhan, Ravi; Temple, Victor; Rayco-Solon, Pura; Macdonald, Barbara

2017-01-01

Background: A lack of information on the etiology of anemia has hampered the design and monitoring of anemia-control efforts. Objective: We aimed to evaluate predictors of anemia in preschool children (PSC) (age range: 6–59 mo) by country and infection-burden category. Design: Cross-sectional data from 16 surveys (n = 29,293) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed separately and pooled by category of infection burden. We assessed relations between anemia (hemoglobin concentration anemia (hemoglobin concentration anemia with concomitant iron deficiency (defined as an inflammation-adjusted ferritin concentration anemia in >50% of surveys. Associations between breastfeeding and anemia were attenuated by controlling for child age, which was negatively associated with anemia. The most consistent predictors of severe anemia were malaria, poor sanitation, and underweight. In multivariable pooled models, child age, iron deficiency, and stunting independently predicted anemia and severe anemia. Inflammation was generally associated with anemia in the high- and very high–infection groups but not in the low- and medium-infection groups. In PSC with anemia, 50%, 30%, 55%, and 58% of children had concomitant iron deficiency in low-, medium-, high-, and very high–infection categories, respectively. Conclusions: Although causal inference is limited by cross-sectional survey data, results suggest anemia-control programs should address both iron deficiency and infections. The relative importance of factors that are associated with anemia varies by setting, and thus, country-specific data are needed to guide programs. PMID:28615260

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, ...

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.

An Ixodes ricinus Tick Salivary Lectin Pathway Inhibitor Protects Borrelia burgdorferi sensu lato from Human Complement

NARCIS (Netherlands)

Wagemakers, Alex; Coumou, Jeroen; Schuijt, Tim J.; Oei, Anneke; Nijhof, Ard M.; van 't Veer, Cornelis; van der Poll, Tom; Bins, Adriaan D.; Hovius, Joppe W. R.

2016-01-01

We previously identified tick salivary lectin pathway inhibitor (TSLPI) in Ixodes scapularis, a vector for Borrelia burgdorferi sensu stricto (s.s.) in North America. TSLPI is a salivary protein facilitating B. burgdorferi s.s. transmission and acquisition by inhibiting the host lectin complement

Severe Aplastic Anemia (SAA)

Science.gov (United States)

... page Print this page My Cart Severe aplastic anemia (SAA) Severe aplastic anemia (SAA) is a disease ... leukemia (ALL) Other diseases What is severe aplastic anemia (SAA)? SAA is a bone marrow disease. The ...

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.

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

The Prevalence of Anemia and Moderate-Severe Anemia in the US Population (NHANES 2003-2012)

Science.gov (United States)

2016-01-01

Since anemia is associated with poor health outcomes, the prevalence of anemia is a significant public health indicator. Even though anemia is primarily caused by iron deficiency, low oxygen-carrying capacity may result from other conditions such as chronic diseases, which remain a relevant health concern in the United States. However, studies examining current rates of anemia in the total US population and in more specific subgroups are limited. Data from five National Health and Nutrition Examination Surveys (NHANES) from 2003 to 2012 were analyzed to assess two outcomes: anemia and moderate-severe anemia, which were based upon serum hemoglobin levels (Hb) as per World Health Organization (WHO) definitions. Statistical analysis using SAS examined temporal trends and the prevalence of anemia among sexes, age groups, and races/ethnicities. The study estimated that an average of 5.6% of the U.S. population met the criteria for anemia and 1.5% for moderate-severe anemia during this 10-year period. High-risk groups such as pregnant women, elderly persons, women of reproductive age, non-Hispanic blacks, and Hispanics were identified, and relationships between multiple risk factors were examined. Rates of anemia in men increased monotonically with age, while that of women increased bimodally with peaks in age group 40–49 years and 80–85 years. The effect of risk factors was observed to compound. For instance, the prevalence of anemia in black women aged 80–85 years was 35.6%, 6.4 times higher than the population average. Moreover, anemia is a growing problem because of the increased prevalence of anemia (4.0% to 7.1%) and moderate-severe anemia (1.0% to 1.9%), which nearly doubled from 2003–2004 to 2011–2012. Thus, these results augment the current knowledge on anemia prevalence, severity, and distribution among subgroups in the US and raised anemia as an issue that requires urgent public health intervention. PMID:27846276

International Climate Migration: Evidence for the Climate Inhibitor Mechanism and the Agricultural Pathway

Science.gov (United States)

Nawrotzki, Raphael J.; Bakhtsiyarava, Maryia

2016-01-01

Research often assumes that, in rural areas of developing countries, adverse climatic conditions increase (climate driver mechanism) rather than reduce (climate inhibitor mechanism) migration, and that the impact of climate on migration is moderated by changes in agricultural productivity (agricultural pathway). Using representative census data in combination with high-resolution climate data derived from the novel Terra Populus system, we explore the climate-migration relationship in rural Burkina Faso and Senegal. We construct four threshold-based climate measures to investigate the effect of heat waves, cold snaps, droughts and excessive precipitation on the likelihood of household-level international outmigration. Results from multi-level logit models show that excessive precipitation increases international migration from Senegal while heat waves decrease international mobility in Burkina Faso, providing evidence for the climate inhibitor mechanism. Consistent with the agricultural pathway, interaction models and results from a geographically weighted regression (GWR) reveal a conditional effect of droughts on international outmigration from Senegal, which becomes stronger in areas with high levels of groundnut production. Moreover, climate change effects show a clear seasonal pattern, with the strongest effects appearing when heat waves overlap with the growing season and when excessive precipitation occurs prior to the growing season. PMID:28943813

Cytotoxicity and activation of the Wnt/beta-catenin pathway in mouse embryonic stem cells treated with four GSK3 inhibitors.

Science.gov (United States)

Naujok, Ortwin; Lentes, Jana; Diekmann, Ulf; Davenport, Claudia; Lenzen, Sigurd

2014-04-29

Small membrane-permeable molecules are now widely used during maintenance and differentiation of embryonic stem cells of different species. In particular the glycogen synthase kinase 3 (GSK3) is an interesting target, since its chemical inhibition activates the Wnt/beta-catenin pathway. In the present comparative study four GSK3 inhibitors were characterized. Cytotoxicity and potential to activate the Wnt/beta-catenin pathway were tested using the commonly used GSK3 inhibitors BIO, SB-216763, CHIR-99021, and CHIR-98014. Wnt/beta-catenin-dependent target genes were measured by quantitative PCR to confirm the Wnt-reporter assay and finally EC50-values were calculated. CHIR-99021 and SB-216763 had the lowest toxicities in mouse embryonic stem cells and CHIR-98014 and BIO the highest toxicities. Only CHIR-99021 and CHIR-98014 lead to a strong induction of the Wnt/beta-catenin pathway, whereas BIO and SB-216763 showed a minor or no increase in activation of the Wnt/beta-catenin pathway over the natural ligand Wnt3a. The data from the Wnt-reporter assay were confirmed by gene expression analysis of the TCF/LEF regulated gene T. Out of the four tested GSK3 inhibitors, only CHIR-99021 and CHIR-98014 proved to be potent pharmacological activators of the Wnt/beta-catenin signaling pathway. But only in the case of CHIR-99021 high potency was combined with very low toxicity.

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 ...

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

Science.gov (United States)

Bach, Thomas J

2013-01-01

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. PMID:24555083

Iron deficiency anemia and megaloblastic anemia in obese patients.

Science.gov (United States)

Arshad, Mahmoud; Jaberian, Sara; Pazouki, Abdolreza; Riazi, Sajedeh; Rangraz, Maryam Aghababa; Mokhber, Somayyeh

2017-03-01

The association between obesity and different types of anemia remained uncertain. The present study aimed to assess the relation between obesity parameters and the occurrence of iron deficiency anemia and also megaloblastic anemia among Iranian population. This cross-sectional study was performed on 1252 patients with morbid obesity that randomly selected from all patients referred to Clinic of obesity at Rasoul-e-Akram Hospital in 2014. The morbid obesity was defined according to the guideline as body mass index (BMI) equal to or higher than 40 kg/m2. Various laboratory parameters including serum levels of hemoglobin, iron, ferritin, folic acid, and vitamin B12 were assessed using the standard laboratory techniques. BMI was adversely associated with serum vitamin B12, but not associated with other hematologic parameters. The overall prevalence of iron deficiency anemia was 9.8%. The prevalence of iron deficiency anemia was independent to patients' age and also to body mass index. The prevalence of vitamin B12 deficiency was totally 20.9%. According to the multivariable logistic regression model, no association was revealed between BMI and the occurrence of iron deficiency anemia adjusting gender and age. A similar regression model showed that higher BMI could predict occurrence of vitamin B12 deficiency in morbid obese patients. Although iron deficiency is a common finding among obese patients, vitamin B12 deficiency is more frequent so about one-fifth of these patients suffer vitamin B12 deficiency. In fact, the exacerbation of obesity can result in exacerbation of vitamin B12 deficiency.

Fanconi anemia and the development of leukemia.

Science.gov (United States)

Alter, Blanche P

2014-01-01

Fanconi anemia (FA) is a rare autosomal recessive cancer-prone inherited bone marrow failure syndrome, due to mutations in 16 genes, whose protein products collaborate in a DNA repair pathway. The major complications are aplastic anemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and specific solid tumors. A severe subset, due to mutations in FANCD1/BRCA2, has a cumulative incidence of cancer of 97% by age 7 years; the cancers are AML, brain tumors, and Wilms tumor; several patients have multiple events. Patients with the other genotypes (FANCA through FANCQ) have cumulative risks of more than 50% of marrow failure, 20% of AML, and 30% of solid tumors (usually head and neck or gynecologic squamous cell carcinoma), by age 40, and they too are at risk of multiple adverse events. Hematopoietic stem cell transplant may cure AML and MDS, and preemptive transplant may be appropriate, but its use is a complicated decision. Published by Elsevier Ltd.

[The clinical significance of hepcidin detection in the patients with anemia and rheumatoid arthritis].

Science.gov (United States)

Galushko, E A

2014-01-01

The prevalence of anemia in patients with rheumatoid arthritis (RA) varies from 30 to 70%. 25% of the cases are diagnosed within 1 year after onset of the disease. On the whole, anemia in RA is described as anemia of a chronic disease (ACD). Pathogenesis ofACD is a multifactor process underlain by an immune mechanism: cytokines and cells ofthe reticuloendothelial system cause changes in iron homeostasis, proliferation of erythroid precursors, erythropoietin production and lifespan of erythrocytes. The key pathogenetic factor is disordered iron metabolism. IL-6 increasing hepatic production acute-phase protein (hepcidin) is the most important cytokine involved in ACD pathogenesis. Hence the necessity to measure its serum level for differential diagnostics of anemic syndrome in patients with RA and the choice of effective basal therapy. Recent data on the therapeutic potency of tocilizumab (IL-6 receptor inhibitor) demonstrate not its safety and sustainable beneficial clinical effect in combination with the favourable action on hemoglobin profile and reduction offatigue.

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

OpenAIRE

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 2007–201...

Recombinant human tissue factor pathway inhibitor exerts anticoagulant, anti-inflammatory and antimicrobial effects in murine pneumococcal pneumonia

NARCIS (Netherlands)

van den Boogaard, F. E.; Brands, X.; Schultz, M. J.; Levi, M. [=Marcel M.; Roelofs, J. J. T. H.; van 't Veer, C.; van der Poll, T.

2011-01-01

Background: Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia and a major cause of sepsis. Recombinant human tissue factor pathway inhibitor (rh-TFPI) attenuates sepsis-induced coagulation and has been evaluated in clinical trials involving patients

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

Directory of Open Access Journals (Sweden)

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.

Human pluripotent stem cell-derived erythropoietin-producing cells ameliorate renal anemia in mice.

Science.gov (United States)

Hitomi, Hirofumi; Kasahara, Tomoko; Katagiri, Naoko; Hoshina, Azusa; Mae, Shin-Ichi; Kotaka, Maki; Toyohara, Takafumi; Rahman, Asadur; Nakano, Daisuke; Niwa, Akira; Saito, Megumu K; Nakahata, Tatsutoshi; Nishiyama, Akira; Osafune, Kenji

2017-09-27

The production of erythropoietin (EPO) by the kidneys, a principal hormone for the hematopoietic system, is reduced in patients with chronic kidney disease (CKD), eventually resulting in severe anemia. Although recombinant human EPO treatment improves anemia in patients with CKD, returning to full red blood cell production without fluctuations does not always occur. We established a method to generate EPO-producing cells from human induced pluripotent stem cells (hiPSCs) by modifying previously reported hepatic differentiation protocols. These cells showed increased EPO expression and secretion in response to low oxygen conditions, prolyl hydroxylase domain-containing enzyme inhibitors, and insulin-like growth factor 1. The EPO protein secreted from hiPSC-derived EPO-producing (hiPSC-EPO) cells induced the erythropoietic differentiation of human umbilical cord blood progenitor cells in vitro. Furthermore, transplantation of hiPSC-EPO cells into mice with CKD induced by adenine treatment improved renal anemia. Thus, hiPSC-EPO cells may be a useful tool for clarifying the mechanisms of EPO production and may be useful as a therapeutic strategy for treating renal anemia. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Inhibitors of the 5-lipoxygenase arachidonic acid pathway induce ATP release and ATP-dependent organic cation transport in macrophages.

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da Silva-Souza, Hercules Antônio; Lira, Maria Nathalia de; Costa-Junior, Helio Miranda; da Cruz, Cristiane Monteiro; Vasconcellos, Jorge Silvio Silva; Mendes, Anderson Nogueira; Pimenta-Reis, Gabriela; Alvarez, Cora Lilia; Faccioli, Lucia Helena; Serezani, Carlos Henrique; Schachter, Julieta; Persechini, Pedro Muanis

2014-07-01

We have previously described that arachidonic acid (AA)-5-lipoxygenase (5-LO) metabolism inhibitors such as NDGA and MK886, inhibit cell death by apoptosis, but not by necrosis, induced by extracellular ATP (ATPe) binding to P2X7 receptors in macrophages. ATPe binding to P2X7 also induces large cationic and anionic organic molecules uptake in these cells, a process that involves at least two distinct transport mechanisms: one for cations and another for anions. Here we show that inhibitors of the AA-5-LO pathway do not inhibit P2X7 receptors, as judged by the maintenance of the ATPe-induced uptake of fluorescent anionic dyes. In addition, we describe two new transport phenomena induced by these inhibitors in macrophages: a cation-selective uptake of fluorescent dyes and the release of ATP. The cation uptake requires secreted ATPe, but, differently from the P2X7/ATPe-induced phenomena, it is also present in macrophages derived from mice deficient in the P2X7 gene. Inhibitors of phospholipase A2 and of the AA-cyclooxygenase pathway did not induce the cation uptake. The uptake of non-organic cations was investigated by measuring the free intracellular Ca(2+) concentration ([Ca(2+)]i) by Fura-2 fluorescence. NDGA, but not MK886, induced an increase in [Ca(2+)]i. Chelating Ca(2+) ions in the extracellular medium suppressed the intracellular Ca(2+) signal without interfering in the uptake of cationic dyes. We conclude that inhibitors of the AA-5-LO pathway do not block P2X7 receptors, trigger the release of ATP, and induce an ATP-dependent uptake of organic cations by a Ca(2+)- and P2X7-independent transport mechanism in macrophages. Copyright © 2014 Elsevier B.V. All rights reserved.

Iron-Deficiency Anemia

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Full Text Available ... your doctor may recommend you eat heart-healthy foods or control other conditions that can cause iron-deficiency anemia. Blood tests to screen for iron-deficiency anemia To screen ...

Iron-Deficiency Anemia

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Full Text Available ... from developing iron-deficiency anemia. Foods that are good sources of iron include dried beans, dried fruits, eggs, lean red meat, ... signs of iron-deficiency anemia include: Brittle nails ...

Iron-Deficiency Anemia

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Full Text Available ... for iron-deficiency anemia. Lifestyle habits Certain lifestyle habits may increase your risk for iron-deficiency anemia, including: Vegetarian or vegan eating patterns. Not eating enough iron-rich foods, such ...

Iron-Deficiency Anemia

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Full Text Available ... Hemophilia Pernicious Anemia Restless Legs Syndrome Von Willebrand Disease Other Resources NHLBI resources Your Guide to Anemia [PDF, 1.54MB] Cardiovascular Health Study Recipient Epidemiology Donor Studies (REDS) program ...

Sickle cell anemia

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Anemia - sickle cell; Hemoglobin SS disease (Hb SS); Sickle cell disease ... Sickle cell anemia is caused by an abnormal type of hemoglobin called hemoglobin S. Hemoglobin is a protein inside red blood cells ...

Effect of hypoxia on tissue factor pathway inhibitor expression in breast cancer.

Science.gov (United States)

Cui, X Y; Tinholt, M; Stavik, B; Dahm, A E A; Kanse, S; Jin, Y; Seidl, S; Sahlberg, K K; Iversen, N; Skretting, G; Sandset, P M

2016-02-01

ESSENTIALS: A hypoxic microenvironment is a common feature of tumors that may influence activation of coagulation. MCF-7 and SK-BR-3 breast cancer cells and breast cancer tissue samples were used. The results showed transcriptional repression of tissue factor pathway inhibitor expression in hypoxia. Hypoxia-inducible factor 1α may be a target for the therapy of cancer-related coagulation and thrombosis. Activation of coagulation is a common finding in patients with cancer, and is associated with an increased risk of venous thrombosis. As a hypoxic microenvironment is a common feature of solid tumors, we investigated the role of hypoxia in the regulation of tissue factor (TF) pathway inhibitor (TFPI) expression in breast cancer. To explore the transcriptional regulation of TFPI by hypoxia-inducible factor (HIF)-1α in breast cancer cells and their correlation in breast cancer tissues. MCF-7 and SK-BR-3 breast cancer cells were cultured in 1% oxygen or treated with cobalt chloride (CoCl2 ) to mimic hypoxia. Time-dependent and dose-dependent downregulation of TFPI mRNA (quantitative RT-PCR) and of free TFPI protein (ELISA) were observed in hypoxia. Western blotting showed parallel increases in the levels of HIF-1α protein and TF. HIF-1α inhibitor abolished or attenuated the hypoxia-induced downregulation of TFPI. Luciferase reporter assay showed that both hypoxia and HIF-1α overexpression caused strong repression of TFPI promoter activity. Subsequent chromatin immunoprecipitation and mutagenesis analysis demonstrated a functional hypoxia response element within the TFPI promoter, located at -1065 to -1060 relative to the transcriptional start point. In breast cancer tissue samples, gene expression analyses showed a positive correlation between the mRNA expression of TFPI and that of HIF-1α. This study demonstrates that HIF-1α is involved in the transcriptional regulation of the TFPI gene, and suggests that a hypoxic microenvironment inside a breast tumor may

PTP1B inhibitor promotes endothelial cell motility by activating the DOCK180/Rac1 pathway.

Science.gov (United States)

Wang, Yuan; Yan, Feng; Ye, Qing; Wu, Xiao; Jiang, Fan

2016-04-07

Promoting endothelial cell (EC) migration is important not only for therapeutic angiogenesis, but also for accelerating re-endothelialization after vessel injury. Several recent studies have shown that inhibition of protein tyrosine phosphatase 1B (PTP1B) may promote EC migration and angiogenesis by enhancing the vascular endothelial growth factor receptor-2 (VEGFR2) signalling. In the present study, we demonstrated that PTP1B inhibitor could promote EC adhesion, spreading and migration, which were abolished by the inhibitor of Rac1 but not RhoA GTPase. PTP1B inhibitor significantly increased phosphorylation of p130Cas, and the interactions among p130Cas, Crk and DOCK180; whereas the phosphorylation levels of focal adhesion kinase, Src, paxillin, or Vav2 were unchanged. Gene silencing of DOCK180, but not Vav2, abrogated the effects of PTP1B inhibitor on EC motility. The effects of PTP1B inhibitor on EC motility and p130Cas/DOCK180 activation persisted in the presence of the VEGFR2 antagonist. In conclusion, we suggest that stimulation of the DOCK180 pathway represents an alternative mechanism of PTP1B inhibitor-stimulated EC motility, which does not require concomitant VEGFR2 activation as a prerequisite. Therefore, PTP1B inhibitor may be a useful therapeutic strategy for promoting EC migration in cardiovascular patients in which the VEGF/VEGFR functions are compromised.

Vitamin Deficiency Anemia

Science.gov (United States)

... are unique to specific vitamin deficiencies. Folate-deficiency anemia risk factors include: Undergoing hemodialysis for kidney failure. ... the metabolism of folate. Vitamin B-12 deficiency anemia risk factors include: Lack of intrinsic factor. Most ...

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 ...

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.

Genetic variants in fanconi anemia pathway genes BRCA2 and FANCA predict melanoma survival.

Science.gov (United States)

Yin, Jieyun; Liu, Hongliang; Liu, Zhensheng; Wang, Li-E; Chen, Wei V; Zhu, Dakai; Amos, Christopher I; Fang, Shenying; Lee, Jeffrey E; Wei, Qingyi

2015-02-01

Cutaneous melanoma (CM) is the most lethal skin cancer. The Fanconi anemia (FA) pathway involved in DNA crosslink repair may affect CM susceptibility and prognosis. Using data derived from published genome-wide association study, we comprehensively analyzed the associations of 2,339 common single-nucleotide polymorphisms (SNPs) in 14 autosomal FA genes with overall survival (OS) in 858 CM patients. By performing false-positive report probability corrections and stepwise Cox proportional hazards regression analyses, we identified significant associations between CM OS and four putatively functional SNPs: BRCA2 rs10492396 (AG vs. GG: adjusted hazard ratio (adjHR)=1.85, 95% confidence interval (CI)=1.16-2.95, P=0.010), rs206118 (CC vs. TT+TC: adjHR=2.44, 95% CI=1.27-4.67, P=0.007), rs3752447 (CC vs. TT+TC: adjHR=2.10, 95% CI=1.38-3.18, P=0.0005), and FANCA rs62068372 (TT vs. CC+CT: adjHR=1.85, 95% CI=1.27-2.69, P=0.001). Moreover, patients with an increasing number of unfavorable genotypes (NUG) of these loci had markedly reduced OS and melanoma-specific survival (MSS). The final model incorporating with NUG, tumor stage, and Breslow thickness showed an improved discriminatory ability to classify both 5-year OS and 5-year MSS. Additional investigations, preferably prospective studies, are needed to validate our findings.

Iron-Deficiency Anemia

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Full Text Available ... may be diagnosed with iron-deficiency anemia if you have low iron or ferritin levels in your blood. More testing may be needed to rule out other types of anemia. Tests for gastrointestinal ...

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.

Plasmin-dependent proteolysis of tissue factor pathway inhibitor in a mouse model of endotoxemia.

Science.gov (United States)

Lupu, C; Herlea, O; Tang, H; Lijnen, R H; Lupu, F

2013-01-01

The development of a procoagulant state in sepsis, owing to aberrant expression of tissue factor (TF) and a sharp decrease in the level of its major inhibitor, TF pathway inhibitor (TFPI), could lead to microthrombotic organ failure. The mechanism for the decline in TFPI activity in the lung could involve plasmin-mediated cleavage of the inhibitor. To investigate the effect of plasmin generation on lung-associated TFPI activity, in normal conditions and during infusion of endotoxin (lipopolysaccharide [LPS]) in mice. Plasmin generation and TFPI activity were assayed in the lungs of mice deficient in tissue-type plasminogen (Plg) activator (t-PA) or Plg, at 2 h after LPS or saline injection. The sharp loss of lung-associated TFPI activity at 2 h after LPS challenge paralleled the abrupt increase in plasmin generation. TFPI activity was significantly retained in both t-PA(-/-) and Plg(-/-) mice, which are unable to generate plasmin. The increased plasmin generation during the early stages of sepsis could cleave/inactivate TFPI and thus lead to thrombotic complications. © 2012 International Society on Thrombosis and Haemostasis.

Anemia of Chronic Liver Diseases

International Nuclear Information System (INIS)

Shin, Hyun Chung; Lee, Jhung Sang; Koh, Chang Soon; Lee, Mun Ho

1971-01-01

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 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.

Iron-Deficiency Anemia

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Full Text Available ... deficiency anemia can cause serious complications, including heart failure and development delays in children. Explore this Health ... to iron-deficiency anemia include: End-stage kidney failure, where there is blood loss during dialysis. People ...

Iron-Deficiency Anemia

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Full Text Available ... deficiency anemia can cause serious complications, including heart failure and development delays in children. Explore this Health ... lead to iron-deficiency anemia include: End-stage kidney failure, where there is blood loss during dialysis. ...

Iron-Deficiency Anemia

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Full Text Available ... iron-deficiency anemia early in life affects later behavior, thinking, and mood during adolescence. Treating anemia in ... Visit Children and Clinical Studies to hear experts, parents, and children talk about their experiences with clinical ...

Iron-Deficiency Anemia

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Full Text Available ... contribute to differences in disease severity and how patients respond to treatment. The NHLBI Strategic Vision highlights ... Anemia in Chronic Kidney Disease (National Institute of Diabetes and Digestive and Kidney Diseases) Avoiding Anemia (National ...

Iron-Deficiency Anemia

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Full Text Available ... to improve health through research and scientific discovery. Improving health with current research Learn about the following ... deficiency anemia early in life affects later behavior, thinking, and mood during adolescence. Treating anemia in premature ...

Iron-Deficiency Anemia

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Full Text Available ... with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, we are investigating how ... Anemia in Chronic Kidney Disease (National Institute of Diabetes and Digestive and Kidney Diseases) Avoiding Anemia (National ...

Iron-Deficiency Anemia

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Full Text Available ... iron-deficiency anemia. These conditions include: Intestinal and digestive conditions, such as celiac disease; inflammatory bowel diseases, ... iron-deficiency anemia , such as bleeding in the digestive or urinary tract or heavy menstrual bleeding, your ...

Iron-Deficiency Anemia

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Full Text Available ... mg and women need 18 mg. After age 51, both men and women need 8 mg. Pregnant ... for iron-deficiency anemia. Learn about exciting research areas that NHLBI is exploring about iron-deficiency anemia. ...

Iron-Deficiency Anemia

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Full Text Available ... heart failure . Increased risk of infections Motor or cognitive development delays in children Pregnancy complications, such as ... for iron-deficiency anemia. Learn about exciting research areas that NHLBI is exploring about iron-deficiency anemia. ...

Iron-Deficiency Anemia

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Full Text Available ... heavy menstrual periods. Individuals with a gene for hemophilia, including symptomatic female carriers who have heavy menstrual ... Heart-Healthy Lifestyle Changes Heart Failure Hemolytic Anemia Hemophilia Pernicious Anemia Restless Legs Syndrome Von Willebrand Disease ...

Iron-Deficiency Anemia

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Full Text Available ... conditions that can cause iron-deficiency anemia. Blood tests to screen for iron-deficiency anemia To screen ... the size of your liver and spleen. Blood tests Based on results from blood tests to screen ...

Iron-Deficiency Anemia

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Full Text Available ... less than 12 g/dl for women is diagnostic of anemia. In iron-deficiency anemia, red blood ... both full-term and preterm infants. Look for Diagnosis will explain tests and procedures that your doctor ...

Iron-Deficiency Anemia

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Full Text Available ... iron-fortified foods that have iron added. Vegetarian diets can provide enough iron if you choose nonmeat ... Anemia in Chronic Kidney Disease (National Institute of Diabetes and Digestive and Kidney Diseases) Avoiding Anemia (National ...

Iron-Deficiency Anemia

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Full Text Available ... less than 12 g/dl for women is diagnostic of anemia. In iron-deficiency anemia, red blood ... physical exam, or order blood tests or other diagnostic tests. Physical exam Your doctor may ask about ...

Iron-Deficiency Anemia

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Full Text Available ... and pregnancy. Good sources of iron are meat, poultry, fish, and iron-fortified foods that have iron ... Anemia Restless Legs Syndrome Von Willebrand Disease Other Resources NHLBI resources Your Guide to Anemia [PDF, 1. ...

Iron-Deficiency Anemia

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Full Text Available ... learning how having iron-deficiency anemia early in life affects later behavior, thinking, and mood during adolescence. ... iron-deficiency anemia in blood donors affects the quality of donated red blood cells, such as how ...

Side Effects: Anemia

Science.gov (United States)

Anemia is a side effect of cancer treatments, including chemotherapy and radiation therapy. It can make women and men feel fatigued, dizzy, and short of breath. Learn how to manage fatigue caused by anemia during cancer treatment.

Iron-Deficiency Anemia

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Full Text Available ... endoscopy or colonoscopy, to stop bleeding. Healthy lifestyle changes To help you meet your daily recommended iron ... iron-deficiency anemia early in life affects later behavior, thinking, and mood during adolescence. Treating anemia in ...

Iron-Deficiency Anemia

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Full Text Available ... leaving cells where it is stored or from being absorbed in the duodenum, the first part of ... treatments for iron-deficiency anemia. Living With After being diagnosed with iron-deficiency anemia, it is important ...

Iron-Deficiency Anemia

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Full Text Available ... iron-deficiency anemia. Search the NIH Research Portfolio Online Reporting Tools (RePORT) to learn about research that ... iron-deficiency anemia in blood donors affects the quality of donated red blood cells, such as how ...

Cancer-related anemia

International Nuclear Information System (INIS)

Abdel-Rzaeq, Hikmat N.

2004-01-01

Anemia is the most common hematological abnormality in cancer patients is often under-recognized and undertreated. The pathogenesis of cancer anemia is complex and most of time multifactorial; involving factors related to the tumor itself or its therapy. While anemia can be present in a wide range of symptoms, involing almost every organ, it is beleived that it contributes much to cancer-related-fatigue, one of the most common symptoms in cancer patients. In addition there is increasing evidence to suggest that anemia is an independent factor adversely affecting tumor reponse and patient survival. While blood transfusion was the only option to treat cancer related anemia, the use of recombinant human erythropoietin (rHuEPO) is becomig the new standard of care, more so with the recent studies demonstrating the feasibility of a sigle weekly injection .Things are even getting better with the recent approval of a new form of rHuEPO; Darbepoetin an analogue with a 3-fold longer half-life. In addition to its effects in raising homoglobin, several well controlled studies demonstrated decrease in transfusion requirementsand better qualify of life assessed objectively using standard assesments scales. (author)

Iron deficiency or anemia of inflammation? : Differential diagnosis and mechanisms of anemia of inflammation.

Science.gov (United States)

Nairz, Manfred; Theurl, Igor; Wolf, Dominik; Weiss, Günter

2016-10-01

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 phagocytes system in liver and spleen. This results in iron-limited erythropoiesis and anemia. This review summarizes current diagnostic and pathophysiological concepts of iron deficiency anemia and anemia of inflammation, as well as combined conditions, and provides a brief outlook on novel therapeutic options.

Iron-Deficiency Anemia

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Full Text Available ... other conditions that can cause iron-deficiency anemia. Blood tests to screen for iron-deficiency anemia To screen ... check the size of your liver and spleen. Blood tests Based on results from blood tests to screen ...

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.

Tissue Factor Pathway Inhibitor: Multiple Anticoagulant Activities for a Single Protein.

Science.gov (United States)

Mast, Alan E

2016-01-01

Tissue factor (TF) pathway inhibitor (TFPI) is an anticoagulant protein that inhibits early phases of the procoagulant response. Alternatively spliced isoforms of TFPI are differentially expressed by endothelial cells and human platelets and plasma. The TFPIβ isoform localizes to the endothelium surface where it is a potent inhibitor of TF-factor VIIa complexes that initiate blood coagulation. The TFPIα isoform is present in platelets. TFPIα contains a stretch of 9 amino acids nearly identical to those found in the B-domain of factor V that are well conserved in mammals. These amino acids provide exosite binding to activated factor V, which allows for TFPIα to inhibit prothrombinase during the initiation phase of blood coagulation. Endogenous inhibition at this point in the coagulation cascade was only recently recognized and has provided a biochemical rationale to explain the pathophysiological mechanisms underlying several clinical disorders. These include the east Texas bleeding disorder that is caused by production of an altered form of factor V with high affinity for TFPI and a paradoxical procoagulant effect of heparins. In addition, these findings have led to ideas for pharmacological targeting of TFPI that may reduce bleeding in hemophilia patients. © 2015 American Heart Association, Inc.

Aerobic, Metal-Free, and Catalytic Dehydrogenative Coupling of Heterocycles: En Route to Hedgehog Signaling Pathway Inhibitors.

Science.gov (United States)

Bering, Luis; Paulussen, Felix M; Antonchick, Andrey P

2018-04-06

The nitrosonium ion-catalyzed dehydrogenative coupling of heteroarenes under mild reaction conditions is reported. The developed method utilizes ambient molecular oxygen as a terminal oxidant, and only water is produced as byproduct. Dehydrogenative coupling of heteroarenes translated into the rapid discovery of novel hedgehog signaling pathway inhibitors, emphasizing the importance of the developed methodology.

Iron-Deficiency Anemia

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Full Text Available ... blocks the intestine from taking up iron. Other medical conditions Other medical conditions that may lead to iron-deficiency anemia ... daily amount of iron. If you have other medical conditions that cause iron-deficiency anemia , such as ...

Iron-Deficiency Anemia

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Full Text Available ... hemoglobin levels. This was associated with a greater risk of death even with mild anemia. Now, anemia in older adults is recognized as an important condition. NHLBI Small Business Program. Through the NHLBI Small Business Program , we ...

Iron-Deficiency Anemia

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Full Text Available ... loss and lead to iron-deficiency anemia. Common causes of blood loss that lead to iron-deficiency anemia include: Bleeding in your GI tract, from an ulcer, colon cancer, or regular use of medicines such as aspirin ...

Iron-Deficiency Anemia

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Full Text Available ... for iron-deficiency anemia. Lifestyle habits Certain lifestyle habits may increase your risk for iron-deficiency anemia, including: Vegetarian or vegan eating patterns. Not eating enough iron-rich foods, such as meat and fish, may result in ...

Iron-Deficiency Anemia

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Full Text Available ... even with mild anemia. Now, anemia in older adults is recognized as an important condition. NHLBI Small Business Program. Through the NHLBI Small Business Program , we fund research and development for domestic small businesses that have strong potential ...

Iron-Deficiency Anemia

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Full Text Available ... anemia. Return to Signs, Symptoms, and Complications to review signs and symptoms as well as complications from iron-deficiency ... NIH]) Heavy Menstrual Bleeding (Centers for Disease Control and ... Dietary Supplement Fact Sheet (NIH) Iron-Deficiency Anemia (National Library ...

Iron-Deficiency Anemia

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Full Text Available ... be at risk for iron-deficiency anemia. Lifestyle habits Certain lifestyle habits may increase your risk for iron-deficiency anemia, ... you are experiencing side effects such as a bad metallic taste, vomiting, diarrhea, constipation, or upset stomach. ...

Iron-Deficiency Anemia

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Full Text Available ... how we are using current research and advancing research to prevent iron-deficiency anemia. Participate in NHLBI Clinical Trials will explain our ongoing clinical studies that are investigating prevention strategies for iron-deficiency anemia. Signs, Symptoms, and Complications ...

Iron-Deficiency Anemia (For Parents)

Science.gov (United States)

... Videos for Educators Search English Español Iron-Deficiency Anemia KidsHealth / For Parents / Iron-Deficiency Anemia What's in ... common nutritional deficiency in children. About Iron-Deficiency Anemia Every red blood cell in the body contains ...

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.

A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors.

Science.gov (United States)

Loboda, Andrey; Nebozhyn, Michael; Klinghoffer, Rich; Frazier, Jason; Chastain, Michael; Arthur, William; Roberts, Brian; Zhang, Theresa; Chenard, Melissa; Haines, Brian; Andersen, Jannik; Nagashima, Kumiko; Paweletz, Cloud; Lynch, Bethany; Feldman, Igor; Dai, Hongyue; Huang, Pearl; Watters, James

2010-06-30

Hyperactivation of the Ras signaling pathway is a driver of many cancers, and RAS pathway activation can predict response to targeted therapies. Therefore, optimal methods for measuring Ras pathway activation are critical. The main focus of our work was to develop a gene expression signature that is predictive of RAS pathway dependence. We used the coherent expression of RAS pathway-related genes across multiple datasets to derive a RAS pathway gene expression signature and generate RAS pathway activation scores in pre-clinical cancer models and human tumors. We then related this signature to KRAS mutation status and drug response data in pre-clinical and clinical datasets. The RAS signature score is predictive of KRAS mutation status in lung tumors and cell lines with high (> 90%) sensitivity but relatively low (50%) specificity due to samples that have apparent RAS pathway activation in the absence of a KRAS mutation. In lung and breast cancer cell line panels, the RAS pathway signature score correlates with pMEK and pERK expression, and predicts resistance to AKT inhibition and sensitivity to MEK inhibition within both KRAS mutant and KRAS wild-type groups. The RAS pathway signature is upregulated in breast cancer cell lines that have acquired resistance to AKT inhibition, and is downregulated by inhibition of MEK. In lung cancer cell lines knockdown of KRAS using siRNA demonstrates that the RAS pathway signature is a better measure of dependence on RAS compared to KRAS mutation status. In human tumors, the RAS pathway signature is elevated in ER negative breast tumors and lung adenocarcinomas, and predicts resistance to cetuximab in metastatic colorectal cancer. These data demonstrate that the RAS pathway signature is superior to KRAS mutation status for the prediction of dependence on RAS signaling, can predict response to PI3K and RAS pathway inhibitors, and is likely to have the most clinical utility in lung and breast tumors.

A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors

Directory of Open Access Journals (Sweden)

Paweletz Cloud

2010-06-01

Full Text Available Abstract Background Hyperactivation of the Ras signaling pathway is a driver of many cancers, and RAS pathway activation can predict response to targeted therapies. Therefore, optimal methods for measuring Ras pathway activation are critical. The main focus of our work was to develop a gene expression signature that is predictive of RAS pathway dependence. Methods We used the coherent expression of RAS pathway-related genes across multiple datasets to derive a RAS pathway gene expression signature and generate RAS pathway activation scores in pre-clinical cancer models and human tumors. We then related this signature to KRAS mutation status and drug response data in pre-clinical and clinical datasets. Results The RAS signature score is predictive of KRAS mutation status in lung tumors and cell lines with high (> 90% sensitivity but relatively low (50% specificity due to samples that have apparent RAS pathway activation in the absence of a KRAS mutation. In lung and breast cancer cell line panels, the RAS pathway signature score correlates with pMEK and pERK expression, and predicts resistance to AKT inhibition and sensitivity to MEK inhibition within both KRAS mutant and KRAS wild-type groups. The RAS pathway signature is upregulated in breast cancer cell lines that have acquired resistance to AKT inhibition, and is downregulated by inhibition of MEK. In lung cancer cell lines knockdown of KRAS using siRNA demonstrates that the RAS pathway signature is a better measure of dependence on RAS compared to KRAS mutation status. In human tumors, the RAS pathway signature is elevated in ER negative breast tumors and lung adenocarcinomas, and predicts resistance to cetuximab in metastatic colorectal cancer. Conclusions These data demonstrate that the RAS pathway signature is superior to KRAS mutation status for the prediction of dependence on RAS signaling, can predict response to PI3K and RAS pathway inhibitors, and is likely to have the most clinical

Concurrent epigenetic silencing of wnt/β-catenin pathway inhibitor genes in B cell chronic lymphocytic leukaemia

International Nuclear Information System (INIS)

Moskalev, Evgeny A; Pötz, Oliver; Joos, Thomas O; Hoheisel, Jörg D; Luckert, Katrin; Vorobjev, Ivan A; Mastitsky, Sergey E; Gladkikh, Aleena A; Stephan, Achim; Schrenk, Marita; Kaplanov, Kamil D; Kalashnikova, Olga B

2012-01-01

The Wnt/β-catenin signalling is aberrantly activated in primary B cell chronic lymphocytic leukaemia (CLL). Epigenetic silencing of pathway inhibitor genes may be a mechanism for its activation. In this study, we investigated systematically and quantitatively the methylation status of 12 Wnt/β-catenin pathway inhibitor genes – CDH1, DACT1, DKK1, DKK2, DKK3, DKK4, SFRP1, SFRP2, SFRP3, SFRP4, SFRP5 and WIF1 – in the cell lines EHEB and MEC-1 as well as patient samples. Quantification of DNA methylation was performed by means of bisulphite pyrosequencing and confirmed by bisulphite Sanger sequencing. Gene expression was analysed by qPCR using GAPDH as internal control. E-cadherin and β-catenin protein quantification was carried out by microsphere-based immunoassays. Methylation differences observed between the patient and control groups were tested using generalised least squares models. For 10 genes, a higher methylation level was observed in tumour material. Only DKK4 exhibited similarly high methylation levels in both tumour and normal specimens, while DACT1 was always essentially unmethylated. However, also for these inhibitors, treatment of cells with the demethylating agent 5-aza-2´-deoxycytidine resulted in an induction of their expression, as shown by quantitative PCR, suggesting an indirect epigenetic control of activity. While the degree of demethylation and its transcriptional consequences differed between the genes, there was an overall high correlation of demethylation and increased activity. Protein expression studies revealed that no constitutive Wnt/β-catenin signalling occurred in the cell lines, which is in discrepancy with results from primary CLL. However, treatment with 5-aza-2´-deoxycytidine caused accumulation of β-catenin. Simultaneously, E-cadherin expression was strongly induced, leading to the formation of a complex with β-catenin and thus demonstrating its epigenetically regulated inhibition effect. The results suggest an

Iron-Deficiency Anemia

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Full Text Available ... if you are diagnosed with iron-deficiency anemia. Risk Factors You may have an increased risk for iron-deficiency anemia because of your age, ... or sex. Age You may be at increased risk for iron deficiency at certain ages: Infants between ...

Iron-Deficiency Anemia

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Full Text Available ... Are you curious about how inflammation from chronic diseases can cause iron-deficiency anemia? Read more When there is ... DBDR) is a leader in research on the causes, prevention, and treatment of blood diseases, including iron-deficiency anemia. Search the NIH Research ...

Iron-Deficiency Anemia

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Full Text Available ... iron-deficiency anemia early in life affects later behavior, thinking, and mood during adolescence. Treating anemia in premature or very small newborns . In collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, we are investigating how ...

Iron-Deficiency Anemia

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Full Text Available ... iron supplements work best to treat iron-deficiency anemia in children who do not consume the daily recommended amount ... and Clinical Studies to hear experts, parents, and children talk about their experiences with clinical ... Anemia Arrhythmia Blood Donation Blood Tests Blood ...

Iron-Deficiency Anemia

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Full Text Available ... stores are developed during the third trimester of pregnancy. Children between ages 1 and 2, especially if they drink a lot ... Resources NHLBI resources Your Guide to Anemia [PDF, ... (National Institute of Diabetes and Digestive and Kidney Diseases) Avoiding Anemia (National ...

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,

Anemia in the general population

DEFF Research Database (Denmark)

Martinsson, Andreas; Andersson, Charlotte; Andell, Pontus

2014-01-01

predictor of mortality, with the highest mortality observed for macrocytic anemia, which was less prevalent than microcytic and normocytic anemia. Dietary intake of iron and vitamin B12 were significantly lower and use of antithrombotic medications was significantly higher in subjects with anemia. The World...

Iron-Deficiency Anemia

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Full Text Available ... how having iron-deficiency anemia early in life affects later behavior, thinking, and mood during adolescence. Treating anemia in premature or very small newborns . In collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, we are investigating how ...

Iron-Deficiency Anemia

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Full Text Available ... anemia, including: Vegetarian or vegan eating patterns. Not eating enough iron-rich foods, such as meat and fish, may result in ... deficiency anemia, your doctor may recommend heart-healthy eating and choosing iron-rich foods, especially during certain stages of life when more ...

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... iron-deficiency anemia early in life affects later behavior, thinking, and mood during adolescence. Treating anemia in premature or very small newborns . In collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, we are investigating how best to treat ...

Iron-Deficiency Anemia

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Full Text Available ... over 65 years of age had low hemoglobin levels. This was associated with a greater risk of death even with mild anemia. Now, anemia in older adults is recognized as an important condition. NHLBI Small Business Program. Through the NHLBI Small Business Program , we ...

Anemia: An approach to evaluation, 2014

Directory of Open Access Journals (Sweden)

Philip Kuriakose

2015-01-01

Full Text Available Anemia is very commonly encountered in general clinical practice among all age groups. The more commonly used way to classify anemia has been to categorize it as being microcytic (mean corpuscular volume [MCV] 100 fL, which in turn allows for a more practical way to attempt to come up with a cause for any decrease in hemoglobin. Microcytic anemias are usually due to iron deficiency (in turn, a result of a number of different etiologies ranging from decreased intake, malabsorption, or blood loss, hemoglobinopathies (thalassemic syndromes, and some cases of severe anemia resulting from chronic disease. Normocytic anemia is often a result of anemia of chronic disease, hemolysis, or secondary to bone marrow failure. Macrocytic anemias are frequently caused by deficiencies of folic acid and/or Vitamin B12, exposure to toxic agents like drugs that interfere with DNA metabolism and alcohol, as also bone marrow failure states, such as from myelodysplastic syndrome. A comprehensive history, physical examination, and directed laboratory evaluation will help to identify a specific cause for anemia.

Severe anemia in Malawian children

NARCIS (Netherlands)

Calis, Job C. J.; Phiri, Kamija S.; Faragher, E. Brian; Brabin, Bernard J.; Bates, Imelda; Cuevas, Luis E.; de Haan, Rob J.; Phiri, Ajib I.; Malange, Pelani; Khoka, Mirriam; Hulshof, Paul J. M.; van Lieshout, Lisette; Beld, Marcel G. H. M.; teo, Yik Y.; Rockett, Kirk A.; Richardson, Anna; Kwiatkowski, Dominic P.; Molyneux, Malcolm E.; Boele van Hensbroek, Michael

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, <5.0 g per deciliter) and

Severe anemia in Malawian children

NARCIS (Netherlands)

Calis, Job Cj; Phiri, Kamija S.; Faragher, E. Brian; Brabin, Bernard J.; Bates, Imelda; Cuevas, Luis E.; de Haan, Rob J.; Phiri, Ajib I.; Malange, Pelani; Khoka, Mirriam; Hulshof, Paul Jm; van Lieshout, Lisette; Beld, Marcel Ghm; teo, Yik Y.; Rockett, Kirk A.; Richardson, Anna; Kwiatkowski, Dominic P.; Molyneux, Malcolm E.; van Hensbroek, Michaël Boele

2016-01-01

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. We conducted a case-control study of 381 preschool children with severe anemia (hemoglobin concentration, <5.0 g per deciliter) and 757 preschool

Overcoming reprogramming resistance of Fanconi anemia cells

Science.gov (United States)

Müller, Lars U. W.; Milsom, Michael D.; Harris, Chad E.; Vyas, Rutesh; Brumme, Kristina M.; Parmar, Kalindi; Moreau, Lisa A.; Schambach, Axel; Park, In-Hyun; London, Wendy B.; Strait, Kelly; Schlaeger, Thorsten; DeVine, Alexander L.; Grassman, Elke; D'Andrea, Alan; Daley, George Q.

2012-01-01

Fanconi anemia (FA) is a recessive syndrome characterized by progressive fatal BM failure and chromosomal instability. FA cells have inactivating mutations in a signaling pathway that is critical for maintaining genomic integrity and protecting cells from the DNA damage caused by cross-linking agents. Transgenic expression of the implicated genes corrects the phenotype of hematopoietic cells, but previous attempts at gene therapy have failed largely because of inadequate numbers of hematopoietic stem cells available for gene correction. Induced pluripotent stem cells (iPSCs) constitute an alternate source of autologous cells that are amenable to ex vivo expansion, genetic correction, and molecular characterization. In the present study, we demonstrate that reprogramming leads to activation of the FA pathway, increased DNA double-strand breaks, and senescence. We also demonstrate that defects in the FA DNA-repair pathway decrease the reprogramming efficiency of murine and human primary cells. FA pathway complementation reduces senescence and restores the reprogramming efficiency of somatic FA cells to normal levels. Disease-specific iPSCs derived in this fashion maintain a normal karyotype and are capable of hematopoietic differentiation. These data define the role of the FA pathway in reprogramming and provide a strategy for future translational applications of patient-specific FA iPSCs. PMID:22371882

Iron-Deficiency Anemia

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Full Text Available ... also are hoping to determine which iron supplements work best to treat iron-deficiency anemia in children who do not consume the daily recommended amount of iron. Read less Participate in NHLBI Clinical Trials We lead or sponsor many studies related to iron-deficiency anemia. See if you ...

Iron-Deficiency Anemia

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Full Text Available ... Precision Medicine Activities Obesity, Nutrition, and Physical Activity Population and Epidemiology Studies Women’s Health All Science A- ... to help your body absorb iron. Avoid drinking black tea, which reduces iron ... was associated with a greater risk of death even with mild anemia. Now, anemia in older ...

Effects of Secondary Hyperparathyroidism Treatment on Improvement in Anemia: Results from the MBD-5D Study.

Directory of Open Access Journals (Sweden)

Motoko Tanaka

Full Text Available 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.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.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.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 management of chronic kidney

Severe anemia in Malawian children.

Science.gov (United States)

Calis, Job Cj; Phiri, Kamija S; Faragher, E Brian; Brabin, Bernard J; Bates, Imelda; Cuevas, Luis E; de Haan, Rob J; Phiri, Ajib I; Malange, Pelani; Khoka, Mirriam; Hulshof, Paul Jm; van Lieshout, Lisette; Beld, Marcel Ghm; Teo, Yik Y; Rockett, Kirk A; Richardson, Anna; Kwiatkowski, Dominic P; Molyneux, Malcolm E; van Hensbroek, Michaël Boele

2016-09-01

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. We conducted a case-control study of 381 preschool children with severe anemia (hemoglobin concentration, <5.0 g per deciliter) and 757 preschool children without severe anemia in urban and rural settings in Malawi. Causal factors previously associated with severe anemia were studied. The data were examined by multivariate analysis and structural equation modeling. Bacteremia (adjusted odds ratio, 5.3; 95% confidence interval [CI], 2.6 to 10.9), malaria (adjusted odds ratio, 2.3; 95% CI, 1.6 to 3.3), hookworm (adjusted odds ratio, 4.8; 95% CI, 2.0 to 11.8), human immunodeficiency virus infection (adjusted odds ratio, 2.0; 95% CI, 1.0 to 3.8), the G6PD -202/-376 genetic disorder (adjusted odds ratio, 2.4; 95% CI, 1.3 to 4.4), vitamin A deficiency (adjusted odds ratio, 2.8; 95% CI, 1.3 to 5.8), and vitamin B 12 deficiency (adjusted odds ratio, 2.2; 95% CI, 1.4 to 3.6) were associated with severe anemia. Folate deficiency, sickle cell disease, and laboratory signs of an abnormal inflammatory response were uncommon. Iron deficiency was not prevalent in case patients (adjusted odds ratio, 0.37; 95% CI, 0.22 to 0.60) and was negatively associated with bacteremia. Malaria was associated with severe anemia in the urban site (with seasonal transmission) but not in the rural site (where malaria was holoendemic). Seventy-six percent of hookworm infections were found in children under 2 years of age. There are multiple causes of severe anemia in Malawian preschool children, but folate and iron deficiencies are not prominent among them. Even in the presence of malaria parasites, additional or alternative causes of severe anemia should be considered.

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... grams per deciliter (g/dl) for men and less than 12 g/dl for women is diagnostic of anemia. In iron-deficiency anemia, ... blood levels of iron will be low, or less than 10 micromoles per liter (mmol/L) for both men and women. Normal levels are 10 to 30 mmol/L. ...

Anemia in the Newborn

Science.gov (United States)

... Overview of Horseshoe Kidney Additional Content Medical News Anemia in the Newborn By Andrew W. Walter, MS ... for the Professional Version Blood Problems in Newborns Anemia in the Newborn Hemolytic Disease of the Newborn ...

Pharmacoepidemiology of anemia in kidney transplant recipients.

Science.gov (United States)

Winkelmayer, Wolfgang C; Kewalramani, Reshma; Rutstein, Mark; Gabardi, Steven; Vonvisger, Tania; Chandraker, Anil

2004-05-01

ABSTRACT. Anemia has long been known to be a complication of end-stage renal disease (ESRD), and it has been linked to cardiovascular morbidity and mortality. Although kidney transplant recipients (KTR) are prone to experiencing cardiovascular outcomes, little is known about the epidemiology of anemia in this population. With few exceptions, studies to date have not fully evaluated the associations between posttransplant anemia (PTA) and medications commonly used in KTR, particularly immunosuppressant drugs, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB). The authors aimed to specifically investigate possible associations between these drugs and PTA. Detailed medical information was retrospectively collected on 374 consecutive KTR from our transplant clinic. Univariate/multivariate linear regression models were used to test for associations between hematocrit (HCT) and other covariates, and logistic regression models were used to detect independent predictors of PTA, defined as HCT <33%. The mean time since transplantation was 7.7 yr, and mean creatinine was 2.2 mg/dl. The prevalence of PTA was 28.6%. Ten percent of all patients were on erythropoietin therapy, but only 41.6% of patients whose HCT was <30 received this treatment. From multivariate analyses, the authors found that female gender and lower renal function were associated with lower HCT (both P < 0.001). Patients on ACEI had significantly lower HCT (P = 0.005) compared with patients without such treatment. In addition, a significant curvilinear dose-response relationship was found between ACEI dose and HCT. Among the immunosuppressant drugs, mycophenolate mofetil (P = 0.05) and tacrolimus (P = 0.02) were associated with a lower HCT. The authors conclude that PTA is prevalent and undertreated in KTR. Several medications that are possibly modifiable correlates of PTR deserve further study.

Genetics Home Reference: Diamond-Blackfan anemia

Science.gov (United States)

... Home Health Conditions Diamond-Blackfan anemia Diamond-Blackfan anemia Printable PDF Open All Close All Enable Javascript ... view the expand/collapse boxes. Description Diamond-Blackfan anemia is a disorder of the bone marrow . The ...

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. Copyright © 2014 Elsevier Ltd. All rights reserved.

Anemia of Inflammation and Chronic Disease

Science.gov (United States)

... AI/ACD. AI/ACD is easily confused with iron- deficiency anemia because in both forms of anemia levels of ... cell production. Low blood iron levels occur in iron-deficiency anemia because levels of the iron stored in the ...

Predictors of anemia in women of reproductive age: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project.

Science.gov (United States)

Wirth, James P; Woodruff, Bradley A; Engle-Stone, Reina; Namaste, Sorrel Ml; Temple, Victor J; Petry, Nicolai; Macdonald, Barbara; Suchdev, Parminder S; Rohner, Fabian; Aaron, Grant J

2017-07-01

Background: Anemia in women of reproductive age (WRA) (age range: 15-49 y) remains a public health problem globally, and reducing anemia in women by 50% by 2025 is a goal of the World Health Assembly. Objective: We assessed the associations between anemia and multiple proximal risk factors (e.g., iron and vitamin A deficiencies, inflammation, malaria, and body mass index) and distal risk factors (e.g., education status, household sanitation and hygiene, and urban or rural residence) in nonpregnant WRA. Design: Cross-sectional, nationally representative data from 10 surveys ( n = 27,018) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed individually and pooled by the infection burden and risk in the country. We examined the severity of anemia and measured the bivariate associations between anemia and factors at the country level and by infection burden, which we classified with the use of the national prevalences of malaria, HIV, schistosomiasis, sanitation, and water-quality indicators. Pooled multivariate logistic regression models were constructed for each infection-burden category to identify independent determinants of anemia (hemoglobin concertation <120 g/L). Results: Anemia prevalence was ∼40% in countries with a high infection burden and 12% and 7% in countries with moderate and low infection burdens, respectively. Iron deficiency was consistently associated with anemia in multivariate models, but the proportion of anemic women who were iron deficient was considerably lower in the high-infection group (35%) than in the moderate- and low-infection groups (65% and 71%, respectively). In the multivariate analysis, inflammation, vitamin A insufficiency, socioeconomic status, and age were also significantly associated with anemia, but malaria and vitamin B-12 and folate deficiencies were not. Conclusions: The contribution of iron deficiency to anemia varies according to a country's infection

Predictors of anemia in women of reproductive age: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project

Science.gov (United States)

Woodruff, Bradley A; Petry, Nicolai; Macdonald, Barbara; Aaron, Grant J

2017-01-01

Background: Anemia in women of reproductive age (WRA) (age range: 15–49 y) remains a public health problem globally, and reducing anemia in women by 50% by 2025 is a goal of the World Health Assembly. Objective: We assessed the associations between anemia and multiple proximal risk factors (e.g., iron and vitamin A deficiencies, inflammation, malaria, and body mass index) and distal risk factors (e.g., education status, household sanitation and hygiene, and urban or rural residence) in nonpregnant WRA. Design: Cross-sectional, nationally representative data from 10 surveys (n = 27,018) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed individually and pooled by the infection burden and risk in the country. We examined the severity of anemia and measured the bivariate associations between anemia and factors at the country level and by infection burden, which we classified with the use of the national prevalences of malaria, HIV, schistosomiasis, sanitation, and water-quality indicators. Pooled multivariate logistic regression models were constructed for each infection-burden category to identify independent determinants of anemia (hemoglobin concertation Anemia prevalence was ∼40% in countries with a high infection burden and 12% and 7% in countries with moderate and low infection burdens, respectively. Iron deficiency was consistently associated with anemia in multivariate models, but the proportion of anemic women who were iron deficient was considerably lower in the high-infection group (35%) than in the moderate- and low-infection groups (65% and 71%, respectively). In the multivariate analysis, inflammation, vitamin A insufficiency, socioeconomic status, and age were also significantly associated with anemia, but malaria and vitamin B-12 and folate deficiencies were not. Conclusions: The contribution of iron deficiency to anemia varies according to a country’s infection burden. Anemia

Fanconi Anemia Mesenchymal Stromal Cells-Derived Glycerophospholipids Skew Hematopoietic Stem Cell Differentiation Through Toll-Like Receptor Signaling.

Science.gov (United States)

Amarachintha, Surya; Sertorio, Mathieu; Wilson, Andrew; Li, Xiaoli; Pang, Qishen

2015-11-01

Fanconi anemia (FA) patients develop bone marrow (BM) failure or leukemia. One standard care for these devastating complications is hematopoietic stem cell transplantation. We identified a group of mesenchymal stromal cells (MSCs)-derived metabolites, glycerophospholipids, and their endogenous inhibitor, 5-(tetradecyloxy)-2-furoic acid (TOFA), as regulators of donor hematopoietic stem and progenitor cells. We provided two pieces of evidence that TOFA could improve hematopoiesis-supporting function of FA MSCs: (a) limiting-dilution cobblestone area-forming cell assay revealed that TOFA significantly increased cobblestone colonies in Fanca-/- or Fancd2-/- cocultures compared to untreated cocultures. (b) Competitive repopulating assay using output cells collected from cocultures showed that TOFA greatly alleviated the abnormal expansion of the donor myeloid (CD45.2+Gr1+Mac1+) compartment in both peripheral blood and BM of recipient mice transplanted with cells from Fanca-/- or Fancd2-/- cocultures. Furthermore, mechanistic studies identified Tlr4 signaling as the responsible pathway mediating the effect of glycerophospholipids. Thus, targeting glycerophospholipid biosynthesis in FA MSCs could be a therapeutic strategy to improve hematopoiesis and stem cell transplantation. © 2015 AlphaMed Press.

APLASTIC ANEMIA

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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;}

Transcriptome analysis of the zebrafish model of Diamond-Blackfan anemia from RPS19 deficiency via p53-dependent and -independent pathways.

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Qiong Jia

Full Text Available Diamond-Blackfan anemia (DBA is a rare inherited bone marrow failure syndrome that is characterized by pure red-cell aplasia and associated physical deformities. It has been proven that defects of ribosomal proteins can lead to this disease and that RPS19 is the most frequently mutated gene in DBA patients. Previous studies suggest that p53-dependent genes and pathways play important roles in RPS19-deficient embryos. However, whether there are other vital factors linked to DBA has not been fully clarified. In this study, we compared the whole genome RNA-Seq data of zebrafish embryos injected with RPS19 morpholino (RPS19 MO, RPS19 and p53 morpholino simultaneously (RPS19+p53 MO and control morpholino (control. We found that genes enriched in the functions of hematological systems, nervous system development and skeletal and muscular disorders had significant differential expression in RPS19 MO embryos compared with controls. Co-inhibition of p53 partially alleviates the abnormalities for RPS19-deficient embryos. However, the hematopoietic genes, which were down-regulated significantly in RPS19 MO embryos, were not completely recovered by the co-inhibition of p53. Furthermore, we identified the genome-wide p53-dependent and -independent genes and pathways. These results indicate that not only p53 family members but also other factors have important impacts on RPS19-deficient embryos. The detection of potential pathogenic genes and pathways provides us a new paradigm for future research on DBA, which is a systematic and complex hereditary disease.

Fanconi Anemia — Case Report of Rare Aplastic Anemia at Child

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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.

Hedgehog Pathway Inhibitor HhAntag691 Is a Potent Inhibitor of ABCG2/BCRP and ABCB1/Pgp

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Yimao Zhang

2009-01-01

Full Text Available HhAntag691 (GDC-0449, a low-molecular weight inhibitor of the tumor-promoting hedgehog (Hh signaling pathway, has been used to treat medulloblastoma in animal models and has recently entered clinical trials for a variety of solid tumors. Here, we show that HhAntag691 inhibits multiple ATP-binding cassette (ABC transporters. ATP-binding cassette transporters are within a family of membrane proteins, the overexpression of which is associated with multidrug resistance, a major impediment to successful cancer treatment. HhAntag691 is a potent inhibitor of two ABC transporters, ABCG2/BCRP and ABCB1/Pgp, and is a mild inhibitor of ABCC1/MRP1. In ABCG2-overexpressing HEK293 cells, HhAntag691 increased retention of the fluorescent ABCG2 substrate BODIPY-prazosin and resensitized these cells to mitoxantrone, an antineoplastic ABCG2 substrate. In Madin-Darby canine kidney II cells engineered to overexpress Pgp or MRP1, HhAntag691 increased the retention of calcein-AM and resensitized them to colchicine. HhAntag691 also resensitized human non-small cell lung carcinoma cells NCI-H460/par and NCI-H460/MX20, which overexpress ABCG2 in response to mitoxantrone, to mitoxantrone, and to topotecan or SN-38. The IC50 values of HhAntag691 for inhibition of ABCG2 and Pgp were ∼1.4 and ∼3.0 µM, respectively. Because ABC transporters are highly expressed at the blood-brain barrier and on many tumor cells, they contribute significantly to treatment failure of many types of cancer, particularly of those within the neuraxis. In addition to its effect on Hh signaling, the ability of HhAntag691 and related compounds to inhibit two key ABC transporters could contribute to their effectiveness in treating malignancies.

Genetic diagnosis for congenital hemolytic anemia.

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Ohga, Shouichi

2016-01-01

Congenital hemolytic anemia is a group of monogenic diseases presenting with anemia due to increased destruction of circulating erythrocytes. The etiology of inherited anemia accounts for germline mutations of the responsible genes coding for the structural components of erythrocytes and extra-erythrocytes. The erythrocyte abnormalities are classified into three major disorders of red cell membrane defects, hemoglobinopathies, and red cell enzymopathies. The extra-erythrocyte abnormalities, typified by consumption coagulopathy and intravascular hemolysis, include Upshaw-Schulman syndrome and atypical hemolytic uremic syndrome. The clinical manifestations of congenital hemolytic anemia are anemia, jaundice, cholelithiasis and splenomegaly, while the onset mode and severity are both variable. Genetic overlapping of red cell membrane protein disorders, and distinct frequency and mutation spectra differing among races make it difficult to understand this disease entity. On the other hand, genetic modifiers for the phenotype of β-globin diseases provide useful information for selecting the optimal treatment and for long-term management. Recently, next generation sequencing techniques have enabled us to determine the novel causative genes in patients with undiagnosed hemolytic anemias. We herein review the concept and strategy for genetic diagnosis of inherited hemolytic anemias.

FANCD2 Western blot as a diagnostic tool for Brazilian patients with Fanconi anemia

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D.V. Pilonetto

2009-03-01

Full Text Available Fanconi anemia is a rare hereditary disease showing genetic heterogeneity due to a variety of mutations in genes involved in DNA repair pathways, which may lead to different clinical manifestations. Phenotypic variability makes diagnosis difficult based only on clinical manifestations, therefore laboratory tests are necessary. New advances in molecular pathogenesis of this disease led researchers to develop a diagnostic test based on Western blot for FANCD2. The objective of the present study was to determine the efficacy of this method for the diagnosis of 84 Brazilian patients with Fanconi anemia, all of whom tested positive for the diepoxybutane test, and 98 healthy controls. The FANCD2 monoubiquitinated isoform (FANCDS+/FANCD2L- was not detected in 77 patients (91.7%. In 2 patients (2.4%, there was an absence of both the monoubiquitinated and the non-ubiquitinated proteins (FANCD2S-/FANCD2L- and 5 patients (5.9% had both isoforms (FANCD2S+/FANCD2L+. This last phenotype suggests downstream subtypes or mosaicism. All controls were diepoxybutane negative and were also negative on the FANCD2 Western blot. The Western blot for FANCD2 presented a sensitivity of 94% (79/84 and specificity of 100% (98/98. This method was confirmed as an efficient approach to screen Brazilian patients with deleterious mutations on FANCD2 (FANCD2S-/FANCD2L- or other upstream genes of the FA/BRCA pathway (FANCDS+/FANCD2L-, to confirm the chromosome breakage test and to classify patients according to the level of FA/BRCA pathway defects. However, patients showing both FANCD2 isoforms (FANCD2S+/FANCD2L+ require additional studies to confirm mutations on downstream Fanconi anemia genes or the presence of mosaicism.

High-content screening in zebrafish embryos identifies butafenacil as a potent inducer of anemia.

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Jessica K Leet

Full Text Available Using transgenic zebrafish (fli1:egfp that stably express enhanced green fluorescent protein (eGFP within vascular endothelial cells, we recently developed and optimized a 384-well high-content screening (HCS assay that enables us to screen and identify chemicals affecting cardiovascular development and function at non-teratogenic concentrations. Within this assay, automated image acquisition procedures and custom image analysis protocols are used to quantify body length, heart rate, circulation, pericardial area, and intersegmental vessel area within individual live embryos exposed from 5 to 72 hours post-fertilization. After ranking developmental toxicity data generated from the U.S. Environmental Protection Agency's (EPA's zebrafish teratogenesis assay, we screened 26 of the most acutely toxic chemicals within EPA's ToxCast Phase-I library in concentration-response format (0.05-50 µM using this HCS assay. Based on this screen, we identified butafenacil as a potent inducer of anemia, as exposure from 0.39 to 3.125 µM butafenacil completely abolished arterial circulation in the absence of effects on all other endpoints evaluated. Butafenacil is an herbicide that inhibits protoporphyrinogen oxidase (PPO--an enzyme necessary for heme production in vertebrates. Using o-dianisidine staining, we then revealed that severe butafenacil-induced anemia in zebrafish was due to a complete loss of hemoglobin following exposure during early development. Therefore, six additional PPO inhibitors within the ToxCast Phase-I library were screened to determine whether anemia represents a common adverse outcome for these herbicides. Embryonic exposure to only one of these PPO inhibitors--flumioxazin--resulted in a similar phenotype as butafenacil, albeit not as severe as butafenacil. Overall, this study highlights the potential utility of this assay for (1 screening chemicals for cardiovascular toxicity and (2 prioritizing chemicals for future hypothesis

Anemias hemolíticas

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Ricardo Cediel Ángel

1957-04-01

Full Text Available Hayem (1898 y más tarde Widal (1907 señalaron que, al paso que la forma congénita clásica de anemia hemolítica de Minkowski y Chauffard a menudo causaba pocos síntomas, otro tipo que ellos clasificaron como adquirido, con frecuencia' se asociaba con anemia severa y acentuada incapacidad. Incluyeron allí casos de excesiva destrucción de sangre asociada a diversas infecciones ó intoxicaciones lo mismo que casos de etiología desconocida. Chauffard fue capaz de demostrar autohemolisinas en el suero de unos pocos casos de anemia hemolítica aguda adquirida y se refirió a ellos como "ictericias hemolisínicas". Sin embargo por muchos años existió la duda de que hubiera un verdadero tipo de anemia hemolítica adquirida y muy poco fue tenida en cuenta la posibilidad de que pudiera jugar papel en estos casos una reacción inmunológica.

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...

Genetics Home Reference: iron-refractory iron deficiency anemia

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... refractory iron deficiency anemia Iron-refractory iron deficiency anemia Printable PDF Open All Close All Enable Javascript ... expand/collapse boxes. Description Iron-refractory iron deficiency anemia is one of many types of anemia , which ...

The Simple Chordate Ciona intestinalis Has a Reduced Complement of Genes Associated with Fanconi Anemia

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Stanley, Edward C.; Azzinaro, Paul A.; Vierra, David A.; Howlett, Niall G.; Irvine, Steven Q.

2016-01-01

Fanconi anemia (FA) is a human genetic disease characterized by congenital defects, bone marrow failure, and increased cancer risk. FA is associated with mutation in one of 24 genes. The protein products of these genes function cooperatively in the FA pathway to orchestrate the repair of DNA interstrand cross-links. Few model organisms exist for the study of FA. Seeking a model organism with a simpler version of the FA pathway, we searched the genome of the simple chordate Ciona intestinalis ...

Activation of mPTP-dependent mitochondrial apoptosis pathway by a novel pan HDAC inhibitor resminostat in hepatocellular carcinoma cells

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Fu, Meili [Department of Infectious Disease, Linyi People’s Hospital, Linyi (China); Shi, Wenhong [Department of Radiotherapy, Linyi Tumor Hospital, Linyi (China); Li, Zhengling [Department of Nursing, Tengzhou Central People’s Hospital, Tengzhou (China); Liu, Haiyan, E-mail: liuhaiyanlinyi5@sina.com [Department of Nursing, Linyi People’s Hospital, No. 27 Jiefang Road, Linyi 276000, Shandong (China)

2016-09-02

Over-expression and aberrant activation of histone deacetylases (HDACs) are often associated with poor prognosis of hepatocellular carcinoma (HCC). Here, we evaluated the potential anti-hepatocellular carcinoma (HCC) cell activity by resminostat, a novel pan HDAC inhibitor (HDACi). We demonstrated that resminostat induced potent cytotoxic and anti-proliferative activity against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, resminostat treatment in HCC cells activated mitochondrial permeability transition pore (mPTP)-dependent apoptosis pathway, which was evidenced by physical association of cyclophilin-D and adenine nucleotide translocator 1 (ANT-1), mitochondrial depolarization, cytochrome C release and caspase-9 activation. Intriguingly, the mPTP blockers (sanglifehrin A and cyclosporine A), shRNA knockdown of cyclophilin-D or the caspase-9 inhibitor dramatically attenuated resminostat-induced HCC cell apoptosis and cytotoxicity. Reversely, HCC cells with exogenous cyclophilin-D over-expression were hyper-sensitive to resminostat. Intriguingly, a low concentration of resminostat remarkably potentiated sorafenib-induced mitochondrial apoptosis pathway activation, leading to a profound cytotoxicity in HCC cells. The results of this preclinical study indicate that resminostat (or plus sorafenib) could be further investigated as a valuable anti-HCC strategy. - Highlights: • Resminostat inhibits human HCC cell survival and proliferation. • Resminostat activates mPTP-dependent mitochondrial apoptosis pathway in HCC cells. • Resminostat potentiates sorafenib-induced mitochondrial apoptosis pathway activation. • mPTP or caspase-9 inhibition attenuates apoptosis by resminostat or plus sorafenib.

Identification of an inhibitor of the MurC enzyme, which catalyzes an essential step in the peptidoglycan precursor synthesis pathway.

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Zawadzke, Laura E; Norcia, Michael; Desbonnet, Charlene R; Wang, Hong; Freeman-Cook, Kevin; Dougherty, Thomas J

2008-02-01

The pathway for synthesis of the peptidoglycan precursor UDP-N-acetylmuramyl pentapeptide is essential in Gram-positive and Gram-negative bacteria. This pathway has been exploited in the recent past to identify potential new antibiotics as inhibitors of one or more of the Mur enzymes. In the present study, a high-throughput screen was employed to identify potential inhibitors of the Escherichia coli MurC (UDP-N-acetylmuramic acid:L-alanine ligase), the first of four paralogous amino acid-adding enzymes. Inhibition of ATP consumed during the MurC reaction, using an adaptation of a kinase assay format, identified a number of potential inhibitory chemotypes. After nonspecific inhibition testing and chemical attractiveness were assessed, C-1 emerged as a compound for further characterization. The inhibition of MurC by this compound was confirmed in both a kinetic-coupled enzyme assay and a direct nuclear magnetic resonance product detection assay. C-1 was found to be a low micromolar inhibitor of the E. coli MurC reaction, with preferential inhibition by one of two enantiomeric forms. Experiments indicated that it was a competitive inhibitor of ATP binding to the MurC enzyme. Further work with MurC enzymes from several bacterial sources revealed that while the compound was equally effective at inhibiting MurC from genera (Proteus mirabilis and Klebsiella pneumoniae) closely related to E. coli, MurC enzymes from more distant Gram-negative species such as Haemophilus influenzae, Acinetobacter baylyi, and Pseudomonas aeruginosa were not inhibited.

The challenge of microangiopathic hemolytic anemia

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Hassanain Hani Hassan

2017-01-01

Full Text Available Microangiopathic hemolytic anemia (MAHA is a Coomb's-negative hemolytic anemia characterized by red cell fragmentation (schistocytes. Thrombotic microangiopathy anemia, including thrombotic thrombocytopenia and hemolytic-uremic syndrome, malignant hypertension, preeclampsia are among the most common causes. We present a case of MAHA presenting with thrombocytopenia initially diagnosed as MAHA secondary to thrombotic thrombocytopenic purpura and received five sessions plasmapheresis without improvement but with worsening of anemia and thrombocytopenia. On further inquiry, glucose-6-phosphate dehydrogenase deficiency was identified, and the patient showed dramatic recovery after the trial of B12 and folate.

Metformin Therapy for Fanconis Anemia

Science.gov (United States)

2017-08-01

AWARD NUMBER: W81XWH-16-1-0300 TITLE: Metformin Therapy for Fanconis Anemia PRINCIPAL INVESTIGATOR: Markus Grompe CONTRACTING ORGANIZATION... Anemia 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-1-0300 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Markus Grompe 5d. PROJECT NUMBER 5e. TASK...298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 This award pertains to the treatment of the inherited bone marrow failure syndrome Fanconi’s Anemia

Therapeutic effect of a novel Wnt pathway inhibitor on cardiac regeneration after myocardial infarction.

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Yang, Dezhong; Fu, Wenbin; Li, Liangpeng; Xia, Xuewei; Liao, Qiao; Yue, Rongchuan; Chen, Hongmei; Chen, Xiongwen; An, Songzhu; Zeng, Chunyu; Wang, Wei Eric

2017-12-15

After myocardial infarction (MI), the heart is difficult to repair because of great loss of cardiomyoctyes and lack of cardiac regeneration. Novel drug candidates that aim at reducing pathological remodeling and stimulating cardiac regeneration are highly desirable. In the present study, we identified if and how a novel porcupine inhibitor CGX1321 influenced MI and cardiac regeneration. Permanent ligation of left anterior descending (LAD) coronary artery was performed in mice to induce MI injury. Cardiac function was measured by echocardiography, infarct size was examined by TTC staining. Fibrosis was evaluated with Masson's trichrome staining and vimentin staining. As a result, CGX1321 administration blocked the secretion of Wnt proteins, and inhibited both canonical and non-canonical Wnt signaling pathways. CGX1321 improved cardiac function, reduced myocardial infarct size, and fibrosis of post-MI hearts. CGX1321 significantly increased newly formed cardiomyocytes in infarct border zone of post-MI hearts, evidenced by the increased EdU + cardiomyocytes. Meanwhile, CGX1321 increased Ki67 + and phosphohistone H3 (PH3 + ) cardiomyocytes in culture, indicating enhanced cardiomyocyte proliferation. The mRNA microarray showed that CGX1321 up-regulated cell cycle regulating genes such as Ccnb1 and Ccne1 CGX1321 did not alter YAP protein phosphorylation and nuclear translocation in cardiomyocytes. In conclusion, porcupine inhibitor CGX1321 reduces MI injury by limiting fibrosis and promoting regeneration. It promotes cardiomyocyte proliferation by stimulating cell cycle regulating genes with a Hippo/YAP-independent pathway. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Anemia and survival in human immunodeficiency virus

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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...

Genetics Home Reference: X-linked sideroblastic anemia

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... Conditions X-linked sideroblastic anemia X-linked sideroblastic anemia Printable PDF Open All Close All Enable Javascript ... the expand/collapse boxes. Description X-linked sideroblastic anemia is an inherited disorder that prevents developing red ...

Special Issues for People with Aplastic Anemia

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... 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 ...

Ginger Stimulates Hematopoiesis via Bmp Pathway in Zebrafish

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Ferri-Lagneau, Karine F.; Moshal, Karni S.; Grimes, Matthew; Zahora, Braden; Lv, Lishuang; Sang, Shengmin; Leung, TinChung

2012-01-01

Background Anemia is a hematologic disorder with decreased number of erythrocytes. Erythropoiesis, the process by which red blood cells differentiate, are conserved in humans, mice and zebrafish. The only known agents available to treat pathological anemia are erythropoietin and its biologic derivatives. However, erythropoietin therapy elicits unwanted side-effects, high cost and intravenous or subcutaneous injection, warranting the development of a more cost effective and non-peptide alternative. Ginger (Zingiber officinale) has been widely used in traditional medicine; however, to date there is no scientific research documenting the potential of ginger to stimulate hematopoiesis. Methodology/Principal Findings Here, we utilized gata1:dsRed transgenic zebrafish embryos to investigate the effect of ginger extract on hematopoiesis in vivo and we identified its bioactive component, 10-gingerol. We confirmed that ginger and 10-gingerol promote the expression of gata1 in erythroid cells and increase the expression of hematopoietic progenitor markers cmyb and scl. We also demonstrated that ginger and 10-gingerol can promote the hematopoietic recovery from acute hemolytic anemia in zebrafish, by quantifying the number of circulating erythroid cells in the dorsal aorta using video microscopy. We found that ginger and 10-gingerol treatment during gastrulation results in an increase of bmp2b and bmp7a expression, and their downstream effectors, gata2 and eve1. At later stages ginger and 10-gingerol can induce bmp2b/7a, cmyb, scl and lmo2 expression in the caudal hematopoietic tissue area. We further confirmed that Bmp/Smad pathway mediates this hematopoiesis promoting effect of ginger by using the Bmp-activated Bmp type I receptor kinase inhibitors dorsomorphin, LND193189 and DMH1. Conclusions/Significance Our study provides a strong foundation to further evaluate the molecular mechanism of ginger and its bioactive components during hematopoiesis and to investigate their

LAMA HAID DAN KEJADIAN ANEMIA PADA REMAJA PUTRI

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Febrianti Febrianti

2015-04-01

Full Text Available Latar belakang: Madrasah Aliyah Negeri (MAN 2 Bogor adalah sekolah dengan angka  prevalensi anemia tertinggi di kota Bogor. Dari pemeriksaan Puskesmas Bogor Timur pada tahun 2009, ada 65,8 persen  siswi sekolah tersebut yang menderita anemia. Tujuan:  Identifikasi faktor-faktor yang berhubungan dengan kejadian anemia. Metode: Penelitian kuantitatif dengan rancangan potong lintang. Variabel dependen adalah kejadian anemia. Variabel independen terdiri atas lama haid, frekuensi makan, kebiasaan makan buah-buahan, kebiasaan makan protein hewani, kebiasaan makan protein nabati, dan kebiasaan minum teh. Pengumpulan data dilakukan dua tahap yaitu pengisian kuesioner dan pengambilan sampel darah. Data dianalisis univariat dan bivariat. Hasil:  Ditemukan  hubungan  yang  bermakna  antara  lama  haid  dengan  kejadian  anemia remaja  putri  (p value=0.028. Variabel lain tidak memiliki hubungan yang bermakna dengan anemia.  Kesimpulan: Prevalensi anemia di MAN 2 Bogor berhubungan dengan lama haid dan tidak berhubungan dengan variabel lain.  Kata kunci: anemia remaja putri, faktor-faktor anemia, lama haid.

Avoiding Anemia: Boost Your Red Blood Cells

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... Issues Subscribe January 2014 Print this issue Avoiding Anemia Boost Your Red Blood Cells En español Send ... Disease When Blood Cells Bend Wise Choices Preventing Anemia To prevent or treat iron-deficiency anemia: Eat ...

Concepts of anemia among low income Nicaraguan women Conceptos de anemia entre mujeres nicaragüenses de baja renta Conceitos de anemia entre mulheres nicaragüenses de baixa renda

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Rita L. Ailinger

2009-04-01

Full Text Available Anemia is a common health problem among women throughout the world, however, there has been minimal research on women's concepts of anemia. The purpose of this study was to examine concepts of anemia in low income Nicaraguan women. A qualitative design was used. Audio-taped open-ended interviews in Spanish with 14 women were used to obtain data. Tapes were transcribed and content analyzed. The findings indicate that few of the women had biomedically accurate concepts of anemia, such as that it was due to lack of iron from poor eating. Others held folk medical beliefs including home remedies, for example drinking the milk of a mare or beet juice and eating certain foods such as bean soup. Most of the women did not know any symptoms of anemia and a few reported that it can develop into leukemia. These concepts of anemia are instructive for nurses working with patients from Nicaragua and will be useful in developing nursing interventions to alleviate this public health problem.La anemia es un problema de salud común entre las mujeres alrededor del mundo, sin embargo, se han realizado pocas investigaciones sobre los conceptos de anemia entre las mujeres. El propósito de este estudio fue examinar los conceptos de anemia en mujeres Nicaragüenses de bajos ingresos económicos. La investigación fue de orden cualitativa. Para la recolección de datos, se realizaron entrevistas semiestructuradas, grabadas en castellano, con 14 mujeres. Las cintas grabadas fueron transcritas y se realizó un análisis de contenido. Los resultados indican que pocas mujeres poseen conocimientos biomédicos sobre anemia, por ejemplo, la ingestión de alimentos pobres en hierro. Otras expresaron creencias populares, como remedios caseros, ingestión de leche de yegua o jugo de remolacha y ciertos alimentos como sopa de judías. La mayoría de las mujeres no conocía ningún síntoma de anemia y pocas relataron que creían que esta enfermedad podría transformarse en

Transcriptional Responses of Escherichia coli to a Small-Molecule Inhibitor of LolCDE, an Essential Component of the Lipoprotein Transport Pathway

Science.gov (United States)

Lorenz, Christian; Dougherty, Thomas J.

2016-01-01

ABSTRACT In Gram-negative bacteria, a dedicated machinery consisting of LolABCDE components targets lipoproteins to the outer membrane. We used a previously identified small-molecule inhibitor of the LolCDE complex of Escherichia coli to assess the global transcriptional consequences of interference with lipoprotein transport. Exposure of E. coli to the LolCDE inhibitor at concentrations leading to minimal and significant growth inhibition, followed by transcriptome sequencing, identified a small group of genes whose transcript levels were decreased and a larger group whose mRNA levels increased 10- to 100-fold compared to those of untreated cells. The majority of the genes whose mRNA concentrations were reduced were part of the flagellar assembly pathway, which contains an essential lipoprotein component. Most of the genes whose transcript levels were elevated encode proteins involved in selected cell stress pathways. Many of these genes are involved with envelope stress responses induced by the mislocalization of outer membrane lipoproteins. Although several of the genes whose RNAs were induced have previously been shown to be associated with the general perturbation of the cell envelope by antibiotics, a small subset was affected only by LolCDE inhibition. Findings from this work suggest that the efficiency of the Lol system function may be coupled to a specific monitoring system, which could be exploited in the development of reporter constructs suitable for use for screening for additional inhibitors of lipoprotein trafficking. IMPORTANCE Inhibition of the lipoprotein transport pathway leads to E. coli death and subsequent lysis. Early significant changes in the levels of RNA for a subset of genes identified to be associated with some periplasmic and envelope stress responses were observed. Together these findings suggest that disruption of this key pathway can have a severe impact on balanced outer membrane synthesis sufficient to affect viability. PMID

Transcriptional Responses of Escherichia coli to a Small-Molecule Inhibitor of LolCDE, an Essential Component of the Lipoprotein Transport Pathway.

Science.gov (United States)

Lorenz, Christian; Dougherty, Thomas J; Lory, Stephen

2016-12-01

In Gram-negative bacteria, a dedicated machinery consisting of LolABCDE components targets lipoproteins to the outer membrane. We used a previously identified small-molecule inhibitor of the LolCDE complex of Escherichia coli to assess the global transcriptional consequences of interference with lipoprotein transport. Exposure of E. coli to the LolCDE inhibitor at concentrations leading to minimal and significant growth inhibition, followed by transcriptome sequencing, identified a small group of genes whose transcript levels were decreased and a larger group whose mRNA levels increased 10- to 100-fold compared to those of untreated cells. The majority of the genes whose mRNA concentrations were reduced were part of the flagellar assembly pathway, which contains an essential lipoprotein component. Most of the genes whose transcript levels were elevated encode proteins involved in selected cell stress pathways. Many of these genes are involved with envelope stress responses induced by the mislocalization of outer membrane lipoproteins. Although several of the genes whose RNAs were induced have previously been shown to be associated with the general perturbation of the cell envelope by antibiotics, a small subset was affected only by LolCDE inhibition. Findings from this work suggest that the efficiency of the Lol system function may be coupled to a specific monitoring system, which could be exploited in the development of reporter constructs suitable for use for screening for additional inhibitors of lipoprotein trafficking. Inhibition of the lipoprotein transport pathway leads to E. coli death and subsequent lysis. Early significant changes in the levels of RNA for a subset of genes identified to be associated with some periplasmic and envelope stress responses were observed. Together these findings suggest that disruption of this key pathway can have a severe impact on balanced outer membrane synthesis sufficient to affect viability. Copyright © 2016 Lorenz et al.

Socio-economic and demographic determinants of childhood anemia

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Sankar Goswmai

2015-09-01

Full Text Available Objective: To evaluate socio-economic and demographic determinants of anemia among Indian children aged 6–59 months. Methods: Statistical analysis was performed on the cross-sectional weighted sample of 40,885 children from 2005 to 2006 National Family Health Survey by using multinomial logistic regression to assess the significance of some risk factors in different degrees of child anemia. Anemia was diagnosed by World Health Organization (WHO cut-off points on hemoglobin level. Pearson's chi-squared test was applied to justify the associations of anemia with different categories of the study population. Results: The prevalence of anemia was 69.5%; 26.2% mild, 40.4% moderate, and 2.9% severe anemia. Overall prevalence rate, along with mild and moderate cases, showed an increasing trend up to 2 years of age and then decreased. Rural children had a higher prevalence rate. Of 28 Indian states in the study, 10 states showed very high prevalence, the highest being Bihar (77.9%. Higher birth order, high index of poverty, low level of maternal education, mother's anemia, non-intake of iron supplements during pregnancy, and vegetarian mother increased the risks of all types of anemia among children (p < 0.05. Christian population was at lower risk; and Scheduled Caste, Scheduled Tribe, and Other Backward Class categories were at higher risk of anemia. Conclusion: The results suggest a need for proper planning and implementation of preventive measures to combat child anemia. Economically under-privileged groups, maternal nutrition and education, and birth control measures should be priorities in the programs. Resumo: Objetivo: Avaliar os fatores socioeconômicos e demográficos determinantes de anemia em crianças indianas com idade de 6 a 59 meses. Métodos: A análise estatística foi realizada na amostra transversal ponderada de 40885 crianças da Pesquisa Nacional de Saúde da Família de 2005–2006, Governo da Índia, utilizando a técnica de

Anemia Aplástica e Gravidez: Relato de Caso Aplastic Anemia and Pregnancy: A Case Report

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Rosiane Alves de Sousa Teles

2002-06-01

Full Text Available A anemia aplástica é distúrbio caracterizado por pancitopenia e medula óssea hipocelular, com substituição gordurosa dos elementos e sem nenhum sinal de transformação maligna ou doença mieloproliferativa. Acomete geralmente adultos jovens e idosos, sem preferência sexual. A maioria dos casos é adquirida, mas pode ocorrer hereditariamente, por distúrbio molecular (anemia de Fanconi. A associação com gravidez é rara, estando relacionada com alta morbidade e mortalidade materna e fetal. Os autores descrevem o caso de uma paciente com anemia aplástica, diagnosticada previamente, cuja gestação complicou com infecção do trato urinário, doença hipertensiva específica da gestação e restrição de crescimento fetal, com parto prematuro eletivo. Apesar das condições adversas na gravidez e parto, mãe e recém-nascido tiveram evolução clínica satisfatória.Aplastic anemia is characterized by a circulating pancytopenia, hypocellularity, and fatty replacement of cellular marrow elements, without evidence of malignant transformation or myeloproliferative disease. It usually affects young and senior adults, without any sexual preference. Most cases of aplastic anemia are acquired, but the disease may also be inherited due to a molecular disorder (Fanconi's anemia. Aplastic anemia in pregnancy is an extremely rare condition with high maternal and fetal morbidity and mortality rates. The authors describe a case of a patient with previously diagnosed aplastic anemia, whose pregnancy was complicated with urinary tract infection, preeclampsia and fetal growth restriction, with elective preterm birth. In spite of the adverse conditions in pregnancy and delivery, mother and newborn had a satisfactory clinical evolution.

Aplastic anemia in Japanese radiological technicians

International Nuclear Information System (INIS)

Kitabatake, T.; Watanabe, T.; Saito, A.; Nakamura, M.; Shiohama Hospital, Mie

1976-01-01

Among the Japanese radiological technicians, four deaths from aplastic anemia have been reported after 1930. On the other hand, during the period from 1930 to 1960, the population of radiological technicians is estimated to be 74,400 man-years, in which 0.5 aplastic anemias are expected. However, actually three died from aplastic anemia. This difference is statistically significant at the 1% level. While, in the period from 1961 to 1973, the observed value is 1 against 0.7 expected. It is concluded that aplastic anemia had been induced frequently among the Japanese radiological technicians in the era when there was much exposure to occupational radiation. (orig.) [de

The incidence of gastrointestinal pathology and subsequent anemia in young men presenting with iron deficiency without anemia.

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Carter, Dan; Bardan, Eytan; Derazne, Estela; Tzur, Dorit; Avidan, Benjamin

2016-10-01

The etiology of iron deficiency (ID) without anemia in young men is unclear, and there are no evidence-based recommendations for the required gastrointestinal (GI) evaluation. The aims of this study were to examine the incidence of significant GI pathology and the development of anemia during the follow-up of young men presenting with ID, but without anemia. All young men (18-30 years) who served in the Israel Defense Forces during the years 2005-2013 and had at least a single laboratory test indicative of ID without anemia were followed until the diagnosis of significant GI pathology or discharge from military service. The study population included 2061 young men (mean age 20.7±1.8). During follow-up of 3150 person years, significant GI pathologies were diagnosed in 39 patients: inflammatory bowel disease in 25 (1.2%), celiac disease in 8 (0.4%), and peptic disease in 4 (0.1%). No cases of GI-related cancer were diagnosed. ID anemia developed during follow-up in 203 (9.8%). Lower baseline hemoglobin levels, lower ferritin levels, and younger age at diagnosis were more common among those who developed anemia. The development of anemia was a predisposing factor for the diagnosis of GI pathology (risk ratio=3.60, 95% confidence interval 1.34-8.32, P=0.012). Significant GI pathology is very uncommon in young men presenting with ID. Overt anemia developed in close to 10% of the study cohort. Therefore, we advise simple GI evaluation (celiac serology, C-reactive protein or fecal calprotectin, and urease breath test) as well as follow-up in this population.

CHRONIC HEART FAILURE AND IRON-DEFICIENT ANEMIA

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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.

CHRONIC HEART FAILURE AND IRON-DEFICIENT ANEMIA

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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.

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

International Nuclear Information System (INIS)

Liu, Qi; Ghosh, Priyanjali; Magpayo, Nicole; Testa, Mauro; Tang, Shikui; Gheorghiu, Liliana; Biggs, Peter; Paganetti, Harald; Efstathiou, Jason A.; Lu, Hsiao-Ming; Held, Kathryn D.; Willers, Henning

2015-01-01

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 137 Cs γ-rays were used. To estimate the RBE of protons relative to 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

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.

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

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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.

The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL.

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Miles, Jennifer A; Frost, Mark G; Carroll, Eilis; Rowe, Michelle L; Howard, Mark J; Sidhu, Ateesh; Chaugule, Viduth K; Alpi, Arno F; Walden, Helen

2015-08-21

The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL). Inefficient repair of these ICL can lead to leukemia and bone marrow failure. A critical step in the pathway is the monoubiquitination of FANCD2 by the RING E3 ligase FANCL. FANCL comprises 3 domains, a RING domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain. The ELF domain is found in all FANCL homologues, yet the function of the domain remains unknown. We report here that the ELF domain of FANCL is required to mediate a non-covalent interaction between FANCL and ubiquitin. The interaction involves the canonical Ile44 patch on ubiquitin, and a functionally conserved patch on FANCL. We show that the interaction is not necessary for the recognition of the core complex, it does not enhance the interaction between FANCL and Ube2T, and is not required for FANCD2 monoubiquitination in vitro. However, we demonstrate that the ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of ubiquitin binding by FANCL in vivo. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

The Evidence-Based Evaluation of Iron Deficiency Anemia.

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Hempel, Eliana V; Bollard, Edward R

2016-09-01

Anemia is a prevalent disease with multiple possible etiologies and resultant complications. Iron deficiency anemia is a common cause of anemia and is typically due to insufficient intake, poor absorption, or overt or occult blood loss. Distinguishing iron deficiency from other causes of anemia is integral to initiating the appropriate treatment. In addition, identifying the underlying cause of iron deficiency is also necessary to help guide management of these patients. We review the key components to an evidence-based, cost-conscious evaluation of suspected iron deficiency anemia. Copyright © 2016 Elsevier Inc. All rights reserved.

Anemia

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... a hemoglobin value of less than 13.5 gm/dl in a man or less than 12.0 gm/dl in a woman. Normal values for children ... types of anemia cannot be prevented, eating healthy foods can help you avoid both iron-and vitamin- ...

Anemia em adolescentes segundo maturação sexual Anemia among adolescents according to sexual maturation

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Bianca Assunção Iuliano

2004-03-01

Full Text Available OBJETIVO: Verificar a prevalência de anemia em adolescentes (hemoglobina0,05. Observou-se aparente aumento do nível médio de hemoglobina com o desenvolvimento do adolescente. Detectou-se anemia em 11,0% dos adolescentes, a maioria na fase púbere, classificada como ''prevalência leve'' segundo a World Health Organization. Não foi encontrada associação entre indicadores sociais e anemia. CONCLUSÃO: O estudo apontou baixa prevalência de anemia, mas acima do esperado entre púberes de escola particular e indica tendência de aumento dos níveis de hemoglobina com o desenvolvimento sexual dos adolescentes. Devem ser realizados novos estudos de prevalência de anemia para se determinar sua causa entre adolescentes de diferentes níveis socioeconômicos.OBJECTIVE: To assess the prevalence of anemia (hemoglobin level <12g/dL in adolescents, according to their sexual maturation stage. METHODS: A cross-sectional study was conducted with all adolescents enrolled in 5th - 8th grades in a private school in the city of São Paulo. Their hemoglobin level was measured (using Hemocue® and sexual development was self-evaluated (with the aid of pictures of the maturation stages proposed by Tanner. The social indicators evaluated were the per capita family income and maternal schooling. Student t test and non-parametric Kruskal-Wallis test were used for mean comparison and Chi-square-test for associations (p<0.05. RESULTS: We analyzed 118 students, of which 66.9% were females (aged 12.2±1.13 years and 33.1% were males (aged 12.0±1.18 years. The mean hemoglobin level was 13.2±1.08 g/dL for females and 13.3±1.21 g/dL for males, with no significant difference. An apparent increase in the mean hemoglobin level was verified along with sexual development of the adolescents. Anemia was detected in 11% of them, most in the pubertal stage, which is classified by the World Health Organization as ''mild prevalence''. No association was found between social

Hypoxia-Inducible Factor and Its Role in the Management of Anemia in Chronic Kidney Disease

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Joshua M. Kaplan

2018-01-01

Full Text Available Hypoxia-inducible factor (HIF plays a crucial role in the response to hypoxia at the cellular, tissue, and organism level. New agents under development to pharmacologically manipulate HIF may provide new and exciting possibilities in the treatment of anemia of chronic kidney disease (CKD as well as in multiple other disease states involving ischemia–reperfusion injury. This article provides an overview of recent studies describing current standards of care for patients with anemia in CKD and associated clinical issues, and those supporting the clinical potential for targeting HIF stabilization with HIF prolyl-hydroxylase inhibitors (HIF-PHI in these patients. Additionally, articles reporting the clinical potential for HIF-PHIs in ‘other’ putative therapeutic areas, the tissue and intracellular distribution of HIF- and prolyl-hydroxylase domain (PHD isoforms, and HIF isoforms targeted by the different PHDs, were identified. There is increasing uncertainty regarding the optimal treatment for anemia of CKD with poorer outcomes associated with treatment to higher hemoglobin targets, and the increasing use of iron and consequent risk of iron imbalance. Attainment and maintenance of more physiologic erythropoietin levels associated with HIF stabilization may improve the management of patients resistant to treatment with erythropoiesis-stimulating agents and improve outcomes at higher hemoglobin targets.

Management of Anemia of Inflammation in the Elderly

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Antonio Macciò

2012-01-01

Full Text Available Anemia of any degree is recognized as a significant independent contributor to morbidity, mortality, and frailty in elderly patients. Among the broad types of anemia in the elderly a peculiar role seems to be played by the anemia associated with chronic inflammation, which remains the most complex form of anemia to treat. The origin of this nonspecific inflammation in the elderly has not yet been clarified. It seems more plausible that the oxidative stress that accompanies ageing is the real cause of chronic inflammation of the elderly and that the same oxidative stress is actually a major cause of this anemia. The erythropoietic agents have the potential to play a therapeutic role in this patient population. Despite some promising results, rHuEPO does not have a specific indication for the treatment of anemia in the elderly. Moreover, concerns about their side effects have spurred the search for alternatives. Considering the etiopathogenetic mechanisms of anemia of inflammation in the elderly population, an integrated nutritional/dietetic approach with nutraceuticals that can manipulate oxidative stress and related inflammation may prevent the onset of this anemia and its negative impact on patients’ performance and quality of life.

Management of Anemia of Inflammation in the Elderly

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Macciò, Antonio; Madeddu, Clelia

2012-01-01

Anemia of any degree is recognized as a significant independent contributor to morbidity, mortality, and frailty in elderly patients. Among the broad types of anemia in the elderly a peculiar role seems to be played by the anemia associated with chronic inflammation, which remains the most complex form of anemia to treat. The origin of this nonspecific inflammation in the elderly has not yet been clarified. It seems more plausible that the oxidative stress that accompanies ageing is the real cause of chronic inflammation of the elderly and that the same oxidative stress is actually a major cause of this anemia. The erythropoietic agents have the potential to play a therapeutic role in this patient population. Despite some promising results, rHuEPO does not have a specific indication for the treatment of anemia in the elderly. Moreover, concerns about their side effects have spurred the search for alternatives. Considering the etiopathogenetic mechanisms of anemia of inflammation in the elderly population, an integrated nutritional/dietetic approach with nutraceuticals that can manipulate oxidative stress and related inflammation may prevent the onset of this anemia and its negative impact on patients' performance and quality of life. PMID:23091709

A Phase Ib open label, randomized, safety study of SANGUINATE™ in patients with sickle cell anemia

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Hemant Misra

Full Text Available Abstract Background: Treatment of sickle cell anemia is a challenging task and despite the well understood genetic and biochemical pathway of sickle hemoglobin, current therapy continues to be limited to the symptomatic treatment of pain, supplemental oxygen, antibiotics, red blood cell transfusions and hydroxyurea. SANGUINATE is a carbon monoxide releasing molecule and oxygen transfer agent under clinical development for the treatment of sickle cell anemia and comorbidities. Methods: An open-label randomized Phase Ib study was performed in adult sickle cell anemia patients. Two dose levels of SANGUINATE were compared to hydroxyurea in 24 homozygotes for Hb SS. Twelve subjects received either a low dose (160 mg/kg of SANGUINATE or 15 mg/kg hydroxyurea. Another 12 subjects received either a high dose (320 mg/kg of SANGUINATE or 15 mg/kg hydroxyurea. The primary endpoint was the safety of SANGUINATE versus hydroxyurea in sickle cell anemia patients. Secondary endpoints included determination of the plasma pharmacokinetics and assessment of hematologic measurements. Results: Musculoskeletal related adverse events were the most common. Transient troponin I levels increased in three patients, one of whom had an increase in tricuspid regurgitant velocity; however, no clinical signs were noted. Following an assessment of vital signs, tricuspid regurgitant velocity, electrocardiogram, serum biochemistry, hematology, urinalysis, and analysis of reported adverse events, SANGUINATE was found to be safe in stable sickle cell anemia patients. Conclusions: The clinical trial met its primary objective of demonstrating an acceptable safety profile for SANGUINATE in patients with sickle cell anemia. This trial established the safety of SANGUINATE at both dose levels and permitted its advance to Phase II trials.

Socio-economic and demographic determinants of childhood anemia

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Sankar Goswmai

2015-10-01

Full Text Available ABSTRACT OBJECTIVE: To evaluate socio-economic and demographic determinants of anemia among Indian children aged 6-59 months. METHODS: Statistical analysis was performed on the cross-sectional weighted sample of 40,885 children from 2005 to 2006 National Family Health Survey by using multinomial logistic regression to assess the significance of some risk factors in different degrees of child anemia. Anemia was diagnosed by World Health Organization (WHO cut-off points on hemoglobin level. Pearson's chi-squared test was applied to justify the associations of anemia with different categories of the study population. RESULTS: The prevalence of anemia was 69.5%; 26.2% mild, 40.4% moderate, and 2.9% severe anemia. Overall prevalence rate, along with mild and moderate cases, showed an increasing trend up to 2 years of age and then decreased. Rural children had a higher prevalence rate. Of 28 Indian states in the study, 10 states showed very high prevalence, the highest being Bihar (77.9%. Higher birth order, high index of poverty, low level of maternal education, mother's anemia, non-intake of iron supplements during pregnancy, and vegetarian mother increased the risks of all types of anemia among children (p < 0.05. Christian population was at lower risk; and Scheduled Caste, Scheduled Tribe, and Other Backward Class categories were at higher risk of anemia. CONCLUSION: The results suggest a need for proper planning and implementation of preventive measures to combat child anemia. Economically under-privileged groups, maternal nutrition and education, and birth control measures should be priorities in the programs.

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

Unexpected Anemia and Reticulocytopenia in an Adolescent With Sickle Cell Anemia Receiving Chronic Transfusion Therapy.

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Blauel, Emily R; Grossmann, Lily T; Vissa, Madhav; Miller, Scott T

2015-10-01

In a patient with sickle cell disease receiving chronic transfusion, exacerbation of anemia with reticulocytopenia must prompt consideration of a delayed hemolytic transfusion reaction with hyperhemolysis, as further transfusion may worsen this condition; definitive diagnosis is sometimes difficult. Anemia evolving during parvovirus B19-induced erythroid hypoplasia (transient aplastic crisis) should be attenuated in chronic transfusion patients due to superior survival of transfused over endogenous red blood cells. A 16-year-old with sickle cell disease receiving chronic transfusion of modified intensity (goal to maintain hemoglobin S<50%) who developed symptomatic anemia with reticulocytopenia was later shown to have had transient aplastic crisis.

Genetics Home Reference: thiamine-responsive megaloblastic anemia syndrome

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... Thiamine-responsive megaloblastic anemia syndrome Thiamine-responsive megaloblastic anemia syndrome Printable PDF Open All Close All Enable ... the expand/collapse boxes. Description Thiamine-responsive megaloblastic anemia syndrome is a rare condition characterized by hearing ...

TNF-α signaling in Fanconi anemia.

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Du, Wei; Erden, Ozlem; Pang, Qishen

2014-01-01

Tumor necrosis factor-alpha (TNF-α) is a major pro-inflammatory cytokine involved in systemic inflammation and the acute phase reaction. Dysregulation of TNF production has been implicated in a variety of human diseases including Fanconi anemia (FA). FA is a genomic instability syndrome characterized by progressive bone marrow failure and cancer susceptibility. The patients with FA are often found overproducing TNF-α, which may directly affect hematopoietic stem cell (HSC) function by impairing HSC survival, homing and proliferation, or indirectly change the bone marrow microenvironment critical for HSC homeostasis and function, therefore contributing to disease progression in FA. In this brief review, we discuss the link between TNF-α signaling and FA pathway with emphasis on the implication of inflammation in the pathophysiology and abnormal hematopoiesis in FA. © 2013.

Chi-squared Automatic Interaction Detection Decision Tree Analysis of Risk Factors for Infant Anemia in Beijing, China.

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Ye, Fang; Chen, Zhi-Hua; Chen, Jie; Liu, Fang; Zhang, Yong; Fan, Qin-Ying; Wang, Lin

2016-05-20

In the past decades, studies on infant anemia have mainly focused on rural areas of China. With the increasing heterogeneity of population in recent years, available information on infant anemia is inconclusive in large cities of China, especially with comparison between native residents and floating population. This population-based cross-sectional study was implemented to determine the anemic status of infants as well as the risk factors in a representative downtown area of Beijing. As useful methods to build a predictive model, Chi-squared automatic interaction detection (CHAID) decision tree analysis and logistic regression analysis were introduced to explore risk factors of infant anemia. A total of 1091 infants aged 6-12 months together with their parents/caregivers living at Heping Avenue Subdistrict of Beijing were surveyed from January 1, 2013 to December 31, 2014. The prevalence of anemia was 12.60% with a range of 3.47%-40.00% in different subgroup characteristics. The CHAID decision tree model has demonstrated multilevel interaction among risk factors through stepwise pathways to detect anemia. Besides the three predictors identified by logistic regression model including maternal anemia during pregnancy, exclusive breastfeeding in the first 6 months, and floating population, CHAID decision tree analysis also identified the fourth risk factor, the maternal educational level, with higher overall classification accuracy and larger area below the receiver operating characteristic curve. The infant anemic status in metropolis is complex and should be carefully considered by the basic health care practitioners. CHAID decision tree analysis has demonstrated a better performance in hierarchical analysis of population with great heterogeneity. Risk factors identified by this study might be meaningful in the early detection and prompt treatment of infant anemia in large cities.

Fanconi anemia and DNA repair.

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Grompe, M; D'Andrea, A

2001-10-01

Fanconi anemia (FA) is an autosomal recessive disorder caused by defects in at least eight distinct genes FANCA, B, C, D1, D2, E, F and G. The clinical phenotype of all FA complementation groups is similar and is characterized by progressive bone marrow failure, cancer proneness and typical birth defects. The principal cellular phenotype is hypersensitivity to DNA damage, particularly interstrand DNA crosslinks. The FA proteins constitute a multiprotein pathway whose precise biochemical function(s) remain unknown. Five of the FA proteins (FANCA, C, E, F and G) interact in a nuclear complex upstream of FANCD2. FANCB and FANCD1 have not yet been cloned, but it is likely that FANCB is part of the nuclear complex and that FANCD1 acts downstream of FANCD2. The FA nuclear complex regulates the mono-ubiquitination of FANCD2 in response to DNA damage, resulting in targeting of this protein into nuclear foci. These foci also contain BRCA1 and other DNA damage response proteins. In male meiosis, FANCD2 also co-localizes with BRCA1 at synaptonemal complexes. Together, these data suggest that the FA pathway functions primarily as a DNA damage response system, although its exact role (direct involvement in DNA repair versus indirect, facilitating role) has not yet been defined.

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 of...

Family structure and child anemia in Mexico.

Science.gov (United States)

Schmeer, Kammi K

2013-10-01

Utilizing longitudinal data from the nationally-representative Mexico Family Life Survey, this study assesses the association between family structure and iron-deficient anemia among children ages 3-12 in Mexico. The longitudinal models (n = 4649), which control for baseline anemia status and allow for consideration of family structure transitions, suggest that children living in stable-cohabiting and single-mother families and those who have recently experienced a parental union dissolution have higher odds of anemia than those in stable-married, father-present family structures. Interaction effects indicate that unmarried family contexts have stronger associations with anemia in older children (over age five); and, that the negative effects of parental union dissolution are exacerbated in poorer households. Resident maternal grandparents have a significant beneficial effect on child anemia independent of parental family structure. These results highlight the importance of family structure for child micronutrient deficiencies and suggest that understanding social processes within households may be critical to preventing child anemia in Mexico. Copyright © 2012 Elsevier Ltd. All rights reserved.

Tissue Factor and Thrombin in Sickle Cell Anemia

OpenAIRE

Chantrathammachart, Pichika; Pawlinski, Rafal

2012-01-01

Sickle cell anemia is an inherited hematologic disorder associated with hemolytic and vaso-occlusive complications. An activation of coagulation is also a prominent feature of sickle cell anemia. Growing evidence indicates that coagulation may contribute to the inflammation and vascular injury in sickle cell anemia. This review focuses on tissue factor expression and its contribution to the activation of coagulation, thrombosis and vascular inflammation in sickle cell anemia.

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.

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

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 J.; 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

Anemia in Mexican women: results of two national probabilistic surveys Anemia en mujeres mexicanas: resultados de dos encuestas nacionales probabilísticas

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Teresa Shamah-Levy

2009-01-01

Full Text Available OBJECTIVE: To describe the prevalence of anemia in Mexican women and analyze its trends with information from the last two national nutrition surveys. MATERIAL AND METHODS: The prevalence of anemia in women was analyzed. Anemia was adjusted by socioeconomic profile and by potentially explanatory variables. RESULTS: The overall prevalence of anemia for pregnant women was 20.2% (95% CI 15.9, 26.2% and 15.5% for non-pregnant women (95% CI 14.7, 16.4%. The prevalence of anemia in women decreased from 1999 to 2006 in all socioeconomic profiles. Adolescent women living in the northern and in the southern regions had a greater risk of anemia than those in Mexico City (p= 0.05. Significant risk was found among low socioeconomic level (pOBJETIVO: Describir la prevalencia de anemia en mujeres y analizar su tendencia a través de las dos últimas encuestas nacionales de nutrición. MATERIAL Y MÉTODOS: Se analizó la prevalencia de anemia en mujeres. La prevalencia de anemia se ajustó por perfil socioeconómico y por posibles variables que la expliquen. RESULTADOS: La prevalencia global de anemia fue de 20.2% (IC95% 15.9, 26.2% para mujeres embarazadas y de 15.5% (IC95% 14.7, 16.4% para mujeres no embarazadas. La prevalencia de anemia en mujeres disminuyó de 1999 a 2006 en todos los niveles socioeconómicos. Las mujeres adolescentes que viven en las regiones norte y sur tuvieron mayor riesgo de anemia que las que viven en la Ciudad de México (p= 0.05. Se encontró un riesgo significativo asociado con el nivel socioeconómico bajo (p< 0.06. La mayor paridad resultó ser un factor de riesgo significativo (p< 0.05. CONCLUSIONES: Aun cuando la presencia de anemia en mujeres en edad reproductiva en México ha disminuido, continúa siendo un problema de salud pública.

Multidisciplinary approach to anemia

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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.

Factors Associated with Anemia in the Institutionalized Elderly.

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Emanuelle Cruz da Silva

Full Text Available As a common problem in long-term care facilities (LTCFs, anemia affects 25-63% of the elderly. The aim of the present study was to describe the prevalence and characteristics of anemia and its associated factors in the institutionalized elderly. The cross-sectional study was carried out with three hundred thirteen individuals aged ≥ 60 years, of both genders, living in long-term care facilities for the elderly in Salvador, Bahia, Brazil. Poisson regression (PR with robust variance estimates was used to assess the factors related to anemia. The prevalence of anemia was 38%. Mild anemia was predominant in both genders (male: 26.8%; female: 21.1%, as normocytic and normochromic anemia, with no anisocytosis (69.75%. Anemia was associated with thinness (PR: 1.68; 95% CI: 1.04-2.72 and with moderate (PR: 1.98; 95% CI: 1.07-3.63 and total (PR: 2.61; 95% CI: 1.34-5.07 dependence in the final model. Severe dependence exhibited borderline significance (PR: 1.94; 95% CI: 1.00-3.77. The prevalence of anemia was high in the institutionalized elderly in both genders, with characteristics suggesting chronic diseases as the causal factor, and the frequency of occurrence was higher in thinness elderly with moderate to total dependence.

Genetics Home Reference: congenital dyserythropoietic anemia

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

FastStats: Anemia or Iron Deficiency

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... 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: 188,000 ...

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....

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

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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.

Prevalence and Correlates of Maternal Anemia in Rural Sidama ...

African Journals Online (AJOL)

In order to assess the prevalence and correlates of prenatal anemia, a survey was conducted among 700 randomly selected pregnant women in rural Sidama, Southern Ethiopia. The prevalences of anemia, Iron Deficiency (ID) and ID anemia were 31.6%, 17.4% and 8.7%, respectively. The burden of anemia was ...

Correction of anemia in pregnancy

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Analía Cánepa

2015-11-01

Se observó que en el 50% de las pacientes estudiadas no se logró corregir la anemia. Concluimos que existe una dificultad en la corrección de la anemia y una necesidad de realizar futuros estudios que permitan conocer las causas de este problema e implementar acciones en base a ellas.

CLINICO PATHOLOGICAL STUDY OF PATTERNS OF ANEMIA DURING PREGNANCY

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Chamakuri

2015-10-01

Full Text Available INTRODUCTION: Anemia is defined as haemoglobin level in the blood below the lower extreme of the normal range for the age and sex of the individual. According to WHO, in developing countries the prevalence of anemia among pregnant women averages 60%, ranging between 35 to 100% among different regions of the world. A hemoglobin concentration below 11.0g/dl or packed cell volume (PCV of less than 33.0% is regarded as anemia during pregnancy by the WHO. It occurs in 40 - 80% of the pregnant women. Iron and folic acid defici encies, malaria, intestinal parasitic infections and hemoglobinopathies are the principal causes of anemia in pregnancy. Predisposing factors include young age, grand multiparity, low socioeconomic status, illiteracy, ignorance and short intervals of pregn ancy. AIM AND OBJECTIVES: 1. To study various patterns of anemia in pregnant women having haemoglobin level < 11 gm%. 2. To determine the most common pattern of anemia in pregnancy based on red cell morphology. MATERIALS AND METHODS: This study is a prospe ctive study over a period of one year from September 2014 to August 2015 in the department of pathology, Andhra medical college, Visakhapatnam . The study was conducted on 120 pregnant women whose haemoglobin level is < 11 gm/dl. All the haemotological parameters & peripheral blood smear stained by Leishman’s stain were evaluated. Complete clinical & obstetric history was recorded. Socioeconomic status was also noted. RESULTS: Out of 120 cases of anemia, we found 47 patie nts (39.1% having dimorphic anemia, 36(30% – microcytic hypochromic anemia, 23(19.1% - normocytic hypochromic anemia, 11(9.16% - sickle cell anemia and 1(0.83% case of pancytopenia. Maximum cases were seen in the age group of 21 - 30 years. 52 cases (43. 3% were primigravida and remaining 68 cases (56.6% were gravida two to four. 20 cases (16.6% were diagnosed in the first trimester, 38 cases (31.6% in the second trimester & 62 cases (51.6s% in the

Human-gyrovirus-Apoptin triggers mitochondrial death pathway--Nur77 is required for apoptosis triggering.

Science.gov (United States)

Chaabane, Wiem; Cieślar-Pobuda, Artur; El-Gazzah, Mohamed; Jain, Mayur V; Rzeszowska-Wolny, Joanna; Rafat, Mehrdad; Stetefeld, Joerg; Ghavami, Saeid; Los, Marek J

2014-09-01

The human gyrovirus derived protein Apoptin (HGV-Apoptin) a homologue of the chicken anemia virus Apoptin (CAV-Apoptin), a protein with high cancer cells selective toxicity, triggers apoptosis selectively in cancer cells. In this paper, we show that HGV-Apoptin acts independently from the death receptor pathway as it induces apoptosis in similar rates in Jurkat cells deficient in either FADD (fas-associated death domain) function or caspase-8 (key players of the extrinsic pathway) and their parental clones. HGV-Apoptin induces apoptosis via the activation of the mitochondrial intrinsic pathway. It induces both mitochondrial inner and outer membrane permebilization, characterized by the loss of the mitochondrial potential and the release into cytoplasm of the pro-apoptotic molecules including apoptosis inducing factor and cytochrome c. HGV-Apoptin acts via the apoptosome, as lack of expression of apoptotic protease-activating factor 1 in murine embryonic fibroblast strongly protected the cells from HGV-Apoptin-induced apoptosis. Moreover, QVD-oph a broad-spectrum caspase inhibitor delayed HGV-Apoptin-induced death. On the other hand, overexpression of the anti-apoptotic BCL-XL confers resistance to HGV-Apoptin-induced cell death. In contrast, cells that lack the expression of the pro-apoptotic BAX and BAK are protected from HGV-Apoptin induced apoptosis. Furthermore, HGV-Apoptin acts independently from p53 signal but triggers the cytoplasmic translocation of Nur77. Taking together these data indicate that HGV-Apoptin acts through the mitochondrial pathway, in a caspase-dependent manner but independently from the death receptor pathway. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.

Disrupted Signaling through the Fanconi Anemia Pathway Leads to Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies

Science.gov (United States)

Geiselhart, Anja; Lier, Amelie; Walter, Dagmar; Milsom, Michael D.

2012-01-01

Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC). This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients. PMID:22675615

Correlative study on anemia and radiotherapy effects in nasopharyngeal carcinoma

International Nuclear Information System (INIS)

Chen Jinsheng; Jiang Yuanshi; Cao Xibiao; Zhan Yongzhong; Yang Liye; Chen Jianxiu; Chen Chengwu; Li Yang

2003-01-01

Objective: To study the effect of oxygen-carrying ability of blood efficacy of radiotherapy for patients with nasopharyngeal carcinoma. Methods: Altogether 161 cases of patients with nasopharyngeal carcinoma were classified according to severity of anemia, and Hb, RBC, MCH, HCT, MCV, MCHC and RDW were tested before, during and after radiotherapy. The patients were followed-up for up to 5 years, the relationship and mechanism among anemia, radiotherapy effects and survival rate was discussed. Results: The survival rate between anemia group and non-anemia group was different significantly (P<0.05). Anemia before radiotherapy, anemia appearance or anemia deterioration during radiotherapy were sensitive factors affecting radiotherapy results. The anemia more severe, the radiotherapy worse. Conclusion: Anemia-hypohemoglobinemia leads to decrease of oxygen-carrying capacity of blood, resulting in oxygen deficiency of tumor cells and their radiotherapy resistance. Therefore this method is worthy of further studies

The potential roles of hepatocyte growth factor (HGF-MET pathway inhibitors in cancer treatment

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Parikh RA

2014-06-01

Full Text Available Rahul A Parikh,1 Peng Wang,2 Jan H Beumer,3 Edward Chu,1 Leonard J Appleman11Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; 2Division of Medical Oncology, University of Kentucky College of Medicine, Markey Cancer Center, Lexington, KY, USA; 3University of Pittsburgh School of Pharmacy, Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USAAbstract: MET is located on chromosome 7q31 and is a proto-oncogene that encodes for hepatocyte growth factor (HGF receptor, a member of the receptor tyrosine kinase (RTK family. HGF, also known as scatter factor (SF, is the only known ligand for MET. MET is a master regulator of cell growth and division (mitogenesis, mobility (motogenesis, and differentiation (morphogenesis; it plays an important role in normal development and tissue regeneration. The HGF-MET axis is frequently dysregulated in cancer by MET gene amplification, translocation, and mutation, or by MET or HGF protein overexpression. MET dysregulation is associated with an increased propensity for metastatic disease and poor overall prognosis across multiple tumor types. Targeting the dysregulated HGF-MET pathway is an area of active research; a number of monoclonal antibodies to HGF and MET, as well as small molecule inhibitors of MET, are under development. This review summarizes the key biological features of the HGF-MET axis, its dysregulation in cancer, and the therapeutic agents targeting the HGF-MET axis, which are in development.Keywords: MET inhibitor, HGF inhibitor, cancer

Aplastic anemia due to radiation

International Nuclear Information System (INIS)

Sakai, Kunio; Saito, Akira

1978-01-01

The relationship between radiation exposure and aplastic anemia, clarified previously, is discussed. When persons such as radiological technicians receive whole-body irradiation in rather large doses, it is possible that aplastic anemia will result later on. However, this is difficult to determine because the irradiated region is limited despite large doses of radiation. (Bell, E.)

Prevalence of Anemia in Latin America and the Caribbean.

Science.gov (United States)

Mujica-Coopman, María F; Brito, Alex; López de Romaña, Daniel; Ríos-Castillo, Israel; Coris, Héctor; Olivares, Manuel

2015-06-01

In Latin America and the Caribbean, anemia has been a public health problem that affects mainly women of childbearing age and children under 6 years of age. However, the current prevalence of anemia in this region is unknown. To examine the latest available prevalence data on anemia in Latin America and the Caribbean. A systematic review was conducted in 2011 and updated in 2014. Studies determining the prevalence of anemia conducted in apparently healthy populations with national or regional representativeness were included in the review. The lowest prevalence rates of anemia among children under 6 years of age were found in Chile (4.0%), Costa Rica (4.0%), Argentina (7.6%), and Mexico (19.9%). In Nicaragua, Brazil, Ecuador, El Panama, and Honduras, anemia was a moderate public health problem, with prevalence ranging Salvador, Cuba, Colombia, the Dominican Republic, Peru, from 20.1% to 37.3%. Anemia was a severe public health problem in Guatemala, Haiti, and Bolivia. The prevalence of anemia among women of childbearing age was lowest in Chile (5.1%). In Colombia, El Salvador, Costa Rica, Nicaragua, Ecuador, Mexico, Peru, Honduras, and Argentina, anemia was a mild public health problem, with prevalence ranging from 7.6% to 18.7%. In Guatemala, Brazil, the Dominican Republic, and Bolivia, anemia was a moderate public health problem, with prevalence ranging from 21.4% to 38.3%. Panama and Haiti had the highest reported prevalence rates (40.0% and 45.5%, respectively), and anemia was considered a severe public health problem in those countries. Anemia remains a public health problem in children under 6 years of age and women of childbearing age in most Latin America and Caribbean countries for which data are available.

Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport.

NARCIS (Netherlands)

Reuter, TY; Medhurst, A.L. dr.; Waisfisz, Q.; Zhi, Y.; Herterich, S.; Hoehn, H.; Gross, H.J.; Joenje, H.; Hoatlin, M.E.; Mathew, C.G.; Huber, PA

2003-01-01

Mutations in one of at least eight different genes cause bone marrow failure, chromosome instability, and predisposition to cancer associated with the rare genetic syndrome Fanconi anemia (FA). The cloning of seven genes has provided the tools to study the molecular pathway disrupted in Fanconi

Prevalence of high blood pressure, heart disease, thalassemia, sickle-cell anemia, and iron-deficiency anemia among the UAE adolescent population.

Science.gov (United States)

Barakat-Haddad, Caroline

2013-01-01

This study examined the prevalence of high blood pressure, heart disease, and medical diagnoses in relation to blood disorders, among 6,329 adolescent students (age 15 to 18 years) who reside in the United Arab Emirates (UAE). Findings indicated that the overall prevalence of high blood pressure and heart disease was 1.8% and 1.3%, respectively. Overall, the prevalence for thalassemia, sickle-cell anemia, and iron-deficiency anemia was 0.9%, 1.6%, and 5%, respectively. Bivariate analysis revealed statistically significant differences in the prevalence of high blood pressure among the local and expatriate adolescent population in the Emirate of Sharjah. Similarly, statistically significant differences in the prevalence of iron-deficiency anemia were observed among the local and expatriate population in Abu Dhabi city, the western region of Abu Dhabi, and Al-Ain. Multivariate analysis revealed the following significant predictors of high blood pressure: residing in proximity to industry, nonconventional substance abuse, and age when smoking or exposure to smoking began. Ethnicity was a significant predictor of heart disease, thalassemia, sickle-cell anemia, and iron-deficiency anemia. In addition, predictors of thalassemia included gender (female) and participating in physical activity. Participants diagnosed with sickle-cell anemia and iron-deficiency anemia were more likely to experience different physical activities.

The Fanconi anemia ID2 complex: dueling saxes at the crossroads.

Science.gov (United States)

Boisvert, Rebecca A; Howlett, Niall G

2014-01-01

Fanconi anemia (FA) is a rare recessive genetic disease characterized by congenital abnormalities, bone marrow failure and heightened cancer susceptibility in early adulthood. FA is caused by biallelic germ-line mutation of any one of 16 genes. While several functions for the FA proteins have been ascribed, the prevailing hypothesis is that the FA proteins function cooperatively in the FA-BRCA pathway to repair damaged DNA. A pivotal step in the activation of the FA-BRCA pathway is the monoubiquitination of the FANCD2 and FANCI proteins. Despite their importance for DNA repair, the domain structure, regulation, and function of FANCD2 and FANCI remain poorly understood. In this review, we provide an overview of our current understanding of FANCD2 and FANCI, with an emphasis on their posttranslational modification and common and unique functions.

Anemia as a risk factor for childhood asthma

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Ramakrishnan K

2010-01-01

Full Text Available Objective: This prospective-(cohort study was conducted to evaluate whether anemia is a risk factor for childhood asthma. Materials and Methods: Two hundred children in the age group of 2-18 years who attended the Outpatient Department with upper respiratory / lower respiratory tract infections were included in this study. One hundred children with anemia were taken as the study group and another 100, age - and sex-matched children without anemia were taken as the control.They were subjected to complete blood count (CBC C-reactive protein (CRP estimation, Mantoux test and chest X-ray. Pulmonary function tests (PFTs were performed on those above six years showing evidence of asthma. Peripheral smear, serum ferritin and serum iron-binding capacity were estimated for all anemic children. Results: Asthma was present in 74 (74% children in the study group and in 33 (33% children in the control group. Iron-deficiency anemia was present in 85 (85% anemia of chronic infection in 20 (20% and the other five (5% had hemolytic anemia. Anemia was found to be a risk factor for childhood asthma. Conclusion: Anemic children were 5.75 times more susceptible to asthmatic attacks when compared with nonanemic children.

Protrusio acetabuli in sickle-cell anemia

International Nuclear Information System (INIS)

Martinez, S.; Apple, J.S.; Baber, C.; Putman, C.E.; Rosse, W.F.

1984-01-01

Of 155 adults with sickle-cell anemia (SS, SC), radiographs of the pelvis or hip demonstrated protrusio acetabuli on at least one side in 14 (3 men and 11 women), as indicated by projection of the acetabular line medial to the ilio-ischial line. All 14 patients had bone changes attributable to sickle-cell anemia, including marrow hyperplasia and osteonecrosis; however, the severity of femoral or acetabular osteonecrosis did not appear directly related to the protrusion. The authors conclude that sickle-cell anemia can predispose to development of protrusio acetabuli

Acquired factor VIII inhibitor syndrome: A rare cause of hematuria

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Muthuvel Seral Kannan

2015-01-01

Full Text Available A 50-year-old woman presented with gross hematuria for 1 month. Clinical examinations, laboratory investigations, ultrasound and contrast computed tomography were normal, except anemia. Cystoscopy revealed bloody efflux from the right side. Retrograde pyelogram showed filling defect in the renal pelvis and biopsy was inconclusive. Renal angiogram was normal. She developed ecchymosis on the right thigh and arm with elevated activated partial thromboplastin time. The partial thromboplastin time correction study and Bethesda study confirmed the presence of acquired factor VIII inhibitor (acquired hemophilia. With flexible ureterorenoscopy, the mass in the renal pelvis was removed and its histopathology revealed clotted blood. The patient was subsequently managed with steroids and Factor eight inhibitor bypass activity.

Magnitude of Anemia at Discharge Increases 30-Day Hospital Readmissions.

Science.gov (United States)

Koch, Colleen G; Li, Liang; Sun, Zhiyuan; Hixson, Eric D; Tang, Anne; Chagin, Kevin; Kattan, Michael; Phillips, Shannon C; Blackstone, Eugene H; Henderson, J Michael

2017-12-01

Anemia during hospitalization is associated with poor health outcomes. Does anemia at discharge place patients at risk for hospital readmission within 30 days of discharge? Our objectives were to examine the prevalence and magnitude of anemia at hospital discharge and determine whether anemia at discharge was associated with 30-day readmissions among a cohort of hospitalizations in a single health care system. From January 1, 2009, to August 31, 2011, there were 152,757 eligible hospitalizations within a single health care system. The endpoint was any hospitalization within 30 days of discharge. The University HealthSystem Consortium's clinical database was used for demographics and comorbidities; hemoglobin values are from the hospitals' electronic medical records, and readmission status was obtained from the University HealthSystem Consortium administrative data systems. Mild anemia was defined as hemoglobin of greater than 11 to less than 12 g/dl in women and greater than 11 to less than 13 g/dl in men; moderate, greater than 9 to less than or equal to 11 g/dl; and severe, less than or equal to 9 g/dl. Logistic regression was used to assess the association of anemia and 30-day readmissions adjusted for demographics, comorbidity, and hospitalization type. Among 152,757 hospitalizations, 72% of patients were discharged with anemia: 31,903 (21%), mild; 52,971 (35%), moderate; and 25,522 (17%), severe. Discharge anemia was associated with severity-dependent increased odds for 30-day hospital readmission compared with those without anemia: for mild anemia, 1.74 (1.65-1.82); moderate anemia, 2.76 (2.64-2.89); and severe anemia, 3.47 (3.30-3.65), P < 0.001. Anemia at discharge is associated with a severity-dependent increased risk for 30-day readmission. A strategy focusing on anemia treatment care paths during index hospitalization offers an opportunity to influence subsequent readmissions.

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.

CLASSIFICATION AND DIAGNOSTICS OF ANEMIA IN CHILDREN

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A. G. Rumyantsev

2011-01-01

Anemia in children is one of the most frequent somatic diseases. Criteria of anemia diagnosis are strictly regulated as decrease of hemoglobin/erythrocytes level accompanies majority of infectious, inflammatory, autoimmune, hereditary diseases and, in several cases, it is estimated as transitory disease in some periods of children’s growth and development. The article presents main classification and differential diagnostic schemes of anemia. Diagnostics makes accent on laboratory analysis; t...

An unusual cause of anemia and encephalopathy

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Sanjeev Kumar Sharma

2015-04-01

Full Text Available 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.

Fanconi anemia: a disorder defective in the DNA damage response.

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Kitao, Hiroyuki; Takata, Minoru

2011-04-01

Fanconi anemia (FA) is a cancer predisposition disorder characterized by progressive bone marrow failure, congenital developmental defects, chromosomal abnormalities, and cellular hypersensitivity to DNA interstrand crosslink (ICL) agents. So far mutations in 14 FANC genes were identified in FA or FA-like patients. These gene products constitute a common ubiquitin-phosphorylation network called the "FA pathway" and cooperate with other proteins involved in DNA repair and cell cycle control to repair ICL lesions and to maintain genome stability. In this review, we summarize recent exciting discoveries that have expanded our view of the molecular mechanisms operating in DNA repair and DNA damage signaling.

Incidencia y mortalidad por anemia en pacientes gravemente enfermos Incidence and mortality due to anemia in acutely ill patients

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Maicelys Ramírez Zaldívar

2012-09-01

Full Text Available Introducción: la anemia es una de las enfermedades más conocidas y evaluadas en la práctica médica diaria. Objetivo: determinar la morbilidad y mortalidad de pacientes graves con anemia. Métodos: se realizó un estudio prospectivo de 118 pacientes ingresados en la Unidad de Terapia Intensiva del Hospital General Universitario "Vladimir Ilich Lenin" de Holguín, desde agosto hasta diciembre de 2010. Las variables discretas fueron comparadas mediante el test de £i al cuadrado y el de Fisher, y las continuas, por medio de las pruebas de T-Student y Mann-Whitney (la hemoglobina media, para á=0,05. Resultados: la anemia afectó 79,6 % de los integrantes de la serie y aumentó evolutivamente, con el consecuente empeoramiento de estos, de los cuales fallecieron 34,0 %, quienes tenían mayor edad (p=0,0004, necesitaron más transfusiones sanguíneas (p=0,005 y presentaron el trastorno de la hemoglobina más tardíamente (5,1 días. De los pacientes con anemia grave (hemoglobina:0,05. Conclusiones: la anemia en los pacientes graves se relacionó con una mayor mortalidad, estadía, necesidad de transfusiones de glóbulos rojos y causas médicas (neurológicas, en tanto, la edad avanzada y la gravedad de la anemia de aparición tardía se asociaron fundamentalmente a la mortalidad.Introduction: anemia is one of the well-known and evaluated diseases in the daily medical practice. Objective: to determine the morbidity and mortality of acutely ill patients with anemia. Methods: a prospective study of 118 patients admitted in the Intensive Therapy Unit of "Vladimir Ilich Lenin" General University Hospital in Holguín was carried out from August to December, 2010. Discrete variables were compared by means of the X² and Fisher tests, and the continuous variables, by means of the T-Student and Mann-Whitney tests (the mean hemoglobin, for á =0.05. Results: anemia affected 79.6% of the members of the series and it increased progressively, with the

Increasing the effectiveness of hematopoiesis in myelodysplastic syndromes: erythropoiesis-stimulating agents and transforming growth factor-β superfamily inhibitors.

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Mies, Anna; Platzbecker, Uwe

2017-07-01

Patients with lower-risk myelodysplastic syndromes (MDS) are mainly affected by chronic anemia and fatigue. Treatment strategies aim to improve anemia and quality of life, as well as iron overload due to red blood cell transfusion support. To promote proliferation and differentiation of erythropoiesis, erythropoiesis-stimulating agents (ESAs) such as erythropoietin (EPO) and mimetics are applied as first-line therapy in a large fraction of lower-risk MDS patients. In general, ESAs yield favorable responses in about half of the patients, although responses are often short-lived. In fact, many ESA-refractory patients harbor defects in late-stage erythropoiesis downstream of EPO action. Novel transforming growth factor (TGF)-β superfamily inhibitors sotatercept and luspatercept represent a promising approach to alleviate anemia by stimulating erythroid differentiation. Copyright © 2017 Elsevier Inc. All rights reserved.

[Effect of anemia on child development: long-term consequences].

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Zavaleta, Nelly; Astete-Robilliard, Laura

2017-01-01

Anemia in children younger than 3 years is a public health problem in Peru and worldwide. It is believed that one of the primary causes of anemia is iron deficiency. Numerous studies and reviews have reported that iron deficiency limited psychomotor development in children and that, despite the correction of anemia, children with iron deficiency experienced poorer long-term performance in cognitive, social, and emotional functioning. These outcomes were reported in observational studies, follow-up studies, and experimental studies with a control group. Anemia can decrease school performance, productivity in adult life, quality of life, and the general income of affected individuals. Here we describe possible mechanisms underlying the effect of iron deficiency, with or without anemia, on childhood development. The high rate of anemia in this age group is a cause for concern. Moreover, anemia should be prevented in the first year of life to avoid long-term negative effects on individual development.

Transient Ischemic Attack Caused by Iron Deficiency Anemia

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Ufuk Emre

2006-02-01

Full Text Available Transient Ischemic Attack Caused by Iron Deficiency Anemia Transient ischemic attacks are episodes of transient focal ischemia involving the brain or brainstem. They are commonly two to thirty minutes in duration and lasting less than 24 hours. Anemia of iron deficiency isn’t frequently cause for transient ischemic attack. It has been reported as a risk factor for childhood ischemic strokes. In the iron deficiency anemia, T‹A may develop as result of hypercoagulable state and increased viscosity that is caused by anemic hypoxia that is result of reduce hemoglobine level, seconder thrombosis and microcytose As iron deficiency anemia has been reported so rarely in adult patients with transient ischemic attacks as a cause, we aimed to discuss the clinical and outcome features of two cases with iron deficiency anemia and transient ischemic attacks in this study. Materials and methods: Routine neurologic examination, biochemical screen, serological tests, vasculitic markers, thyroid function tests, vitamin B 12 level, cranial imaging, vertebral carotid doppler USG examination was conducted in the two patients. Anemia of iron deficiency was found as the only risk factor for TIA and the two patients were treated with replacement of iron and antiagregan therapy. Neurological examination revealed no abnormality through the two years of follow-up. The iron deficiency anemia may be cause of many neurologic problems such a irritability, lethargy, headache, development retardation except from T‹A. In the iron deficiency anemia, early diagnosis and treatment is important

Thyroid storm and warm autoimmune hemolytic anemia.

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Moore, Joseph A; Gliga, Louise; Nagalla, Srikanth

2017-08-01

Graves' disease is often associated with other autoimmune disorders, including rare associations with autoimmune hemolytic anemia (AIHA). We describe a unique presentation of thyroid storm and warm AIHA diagnosed concurrently in a young female with hyperthyroidism. The patient presented with nausea, vomiting, diarrhea and altered mental status. Laboratory studies revealed hemoglobin 3.9g/dL, platelets 171×10 9 L -1 , haptoglobin storm and warm AIHA. She was started on glucocorticoids to treat both warm AIHA and thyroid storm, as well as antithyroid medications, propranolol and folic acid. Due to profound anemia and hemodynamic instability, the patient was transfused two units of uncrossmatched packed red blood cells slowly and tolerated this well. She was discharged on methimazole as well as a prolonged prednisone taper, and achieved complete resolution of the thyrotoxicosis and anemia at one month. Hyperthyroidism can affect all three blood cell lineages of the hematopoietic system. Anemia can be seen in 10-20% of patients with thyrotoxicosis. Several autoimmune processes can lead to anemia in Graves' disease, including pernicious anemia, celiac disease, and warm AIHA. This case illustrates a rarely described presentation of a patient with Graves' disease presenting with concurrent thyroid storm and warm AIHA. Copyright © 2017 Elsevier Ltd. All rights reserved.

Involvement of HDAC1 and the PI3K/PKC signaling pathways in NF-κB activation by the HDAC inhibitor apicidin

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Kim, Yong Kee; Seo, Dong-Wan; Kang, Dong-Won; Lee, Hoi Young; Han, Jeung-Whan; Kim, Su-Nam

2006-01-01

Histone deacetylase (HDAC) inhibitors are appreciated as one of promising anticancer drugs, but they exert differential responses depending on the cell type. We recently reported the critical role of NF-κB as a modulator in determining cell fate for apoptosis in response to an HDAC inhibitor. In this study, we investigate a possible signaling pathway required for NF-κB activation in response to the HDAC inhibitor apicidin. Treatment of HeLa cells with apicidin leads to an increase in transcriptional activity of NF-κB and the expression of its target genes, IL-8 and TNF-α. TNF-α expression by apicidin is induced at earlier time points than NF-κB activation or IL-8 expression. In addition, our data show that the early expression of TNF-α does not lead to activation of NF-κB, because disruption of TNF-α activity by a neutralizing antibody does not affect nuclear translocation of NF-κB, IκBα degradation or reporter gene activation by apicidin. However, this activation of NF-κB requires the PI3K and PKC signaling pathways, but not ERK or JNK. Furthermore, apicidin activation of NF-κB seems to result from HDAC1 inhibition, as evidenced by the observation that overexpression of HDAC1, but not HDAC2, 3 or 4, dramatically inhibits NF-κB reporter gene activity. Collectively, our results suggest that activation of NF-κB signaling by apicidin requires both the PI3K/PKC signaling pathways and HDAC1, and functions as a critical modulator in determining the cellular effect of apicidin

Pyrexia due to megaloblastic anemia: An Unusual Case

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Singh PS, Vijay Verma, Vidyasagar, Granth Kumar

2014-07-01

Full Text Available Postmenopausal vegetarian female presented with short febrile illness associated with generalized weakness Clinical and investigative findings evidenced megaloblastic anemia Since none of investigations could pinpoint the cause for pyrexia and patient did not respond to empirical antibiotic and conservative antimalarial therapy, megaloblastic anemia itself was suspected to be cause for febrile episode Patient was treated with parenteral B12 and oral folic acid for megaloblastic anemia and she responded to it and became afebrile within 72 hours. Subsequently megaloblastic anemia was correlated to be cause of febrile illness.

Tissue factor pathway inhibitor 2 is found in skin and its C-terminal region encodes for antibacterial activity.

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Papareddy, Praveen; Kalle, Martina; Sørensen, Ole E; Lundqvist, Katarina; Mörgelin, Matthias; Malmsten, Martin; Schmidtchen, Artur

2012-01-01

Tissue factor pathway inhibitor 2 (TFPI-2) is a matrix-associated serine protease inhibitor with an enigmatic function in vivo. Here, we describe that TFPI-2 is present in fibrin of wounds and also expressed in skin, where it is up-regulated upon wounding. Neutrophil elastase cleaved TFPI-2, and a C-terminal fragment was found to bind to bacteria. Similarly, a prototypic peptide representing this C-terminal part, EDC34, bound to bacteria and bacterial lipopolysaccharide, and induced bacterial permeabilization. The peptide also induced leakage in artificial liposomes, and displayed a random coil conformation upon interactions with liposomes as well as lipopolysaccharide. EDC34 was antibacterial against both Gram-negative and Gram-positive bacteria in physiological buffer conditions. The results demonstrate that the C-terminus of TFPI-2 encodes for antimicrobial activity, and may be released during wounding.

Genetics Home Reference: X-linked sideroblastic anemia and ataxia

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... linked sideroblastic anemia and ataxia X-linked sideroblastic anemia and ataxia Printable PDF Open All Close All ... the expand/collapse boxes. Description X-linked sideroblastic anemia and ataxia is a rare condition characterized by ...

[Prevalence of anemia in reproductive-age Mexican women].

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Shamah-Levy, Teresa; Villalpando, Salvador; Mundo-Rosas, Verónica; De la Cruz-Góngora, Vanessa; Mejía-Rodríguez, Fabiola; Méndez Gómez-Humarán, Ignacio

2013-01-01

To update the prevalence of anemia and its trend in Mexican women of childbearing age over the past 13 years using information from the National Health and Nutrition Survey 2012 and 2006 (ENSANUT 2012 and ENSANUT 2006, respectively) and from the National Nutrition Survey 1999 (ENN 99). Data came from three national probabilistic surveys, representative at regional and rural / urban level. Hemoglobin (Hb) in women was measured using a HemoCue photometer and classified as anemia according to the WHO criteria. Frequencies and CI95% were estimated for each survey (ENSANUT 2012, ENSANUT 2006 and ENN 99) as well as percentage changes in anemia prevalence among pregnant and non-pregnant women in this survey sequence. The national prevalence of anemia in 2012 in non-pregnant women was 11.6% and in pregnant women was 17.9%. Between 1999 and 2012, a 10 percentage point (pp) decreasing in anemia prevalence was observed in the first ones and a 13.5 pp in the second ones. Although it has declined in the past 13 years, anemia in women of childbearing age remains as a serious public health problem. It is considered necessary to design strategies to prevent iron deficiency and for the early detection of anemia in women.

Reticulocyte parameters in hemoglobinopathies and iron deficiency anemia

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Cortellazzi Laura C.

2003-01-01

Full Text Available Flow cytometric reticulocyte analysis allows the evaluation of reticulocyte maturity. New reticulocyte parameters have been used in the diagnosis and management of anemias, in the bone marrow transplant setting and in the monitoring of iron replacement or erythropoiet in therapy. Reticulocyte numbers and maturation levels have been studied in different hemoglobinopathies and the results have been correlated with the degree of ineffective erythropoiesis. In order to verify differences in reticulocyte parameters in various types of anemias and to test the absolute number of immature reticulocytes as a possible discriminating factor among various types of anemias, reticulocyte counts were performed on 219 samples from patients with sickle cell anemia (SS (n= 62, hemoglobin S trait (n=9, Sbeta thalassemia (n=7, hemoglobin SC disease (n=11, beta thalassemia trait (n=33 and iron deficiency anemia (n= 47, and non-anemic individuals (n= 50. Mean fluorescence index (MFI was defined as representative of the degree of reticulocyte immaturity and it was evaluated as a percentage and in absolute values. Reticulocyte counts and MFI values were significantly higher in SS, Sbeta thalassemic and SC groups when compared to controls, but not different among the three anemia groups. Patients with hemoglobin S trait, iron deficiency anemia and beta thalassemia trait showed reticulocyte parameters similar to the non-anemic group. There was no difference between the b thalassemic trait and iron deficiency anemia in relation to any parameters. MFI in absolute numbers were significantly higher in anemias that develop with the hemolytic process, although this was not evident in MFI percentage values. Our results showed that the erythoid expansion in sickle cell diseases (SS, SC and Sb thalassemia leads to an enhanced immature reticulocyte release from bone marrow and that the phenomena is more evident by the MFI counting in absolute figures than in percentages. We

Prevalence, severity, and related factors of anemia in HIV/AIDS patients

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Mohsen Meidani

2012-01-01

Full Text Available Objective: The prevalence of anemia in HIV infected patients has not been well characterized in Iran. This study aimed to describe the prevalence of anemia and related factors in HIV positive patients. Materials and Methods: In a cross-sectional study, anemia prevalence and risk factors of 212 HIV positive patients were assessed, at the behavioral disease consulting center in Isfahan. The relationship between anemia, demographic variables, and clinical histories were analyzed. Mild to moderate anemia was defined as hemoglobin 8-13 g/dL for men and 8-12 g/dL for women. Severe anemia was defined as hemoglobin, 8 g/dL. Results: A total of 212 HIV positive patients with a mean±SD age of 36.1 ± 9.1 years were assessed. We found that hemoglobin levels were between 4.7 and 16.5 gr/dL. In this study, the overall prevalence of anemia was 71%, with the majority of patients having mild to moderate anemia. Mild to moderate anemia and severe anemia occurred in 67% and 4% of patients, respectively. The mean absolute CD4 count was 348 ± 267.8 cells/cubic mm. Sixty one of 212 patients were at late stage of HIV infection (males=51 and female=10. Of the 212 HIV positive patients enrolled, 17 (8% had a positive history of tuberculosis. We found a strong association between anemia and death. Conclusion: Normocytic anemia with decreased reticulocyte count was the most common type of anemia in overall. Prevalence of anemia in this study is relatively higher than other similar studies. Such a high prevalence of anemia needs close monitoring of patients on a zidovudine-based regimen. Better screening for anemia and infectious diseases, and modified harm reduction strategy (HRS for injection drug users are primary needs in HIV seropositive patients.

Iron Deficiency and Anemia Predict Mortality in Patients with Tuberculosis123

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Isanaka, Sheila; Mugusi, Ferdinand; Urassa, Willy; Willett, Walter C.; Bosch, Ronald J.; Villamor, Eduardo; Spiegelman, Donna; Duggan, Christopher; Fawzi, Wafaie W.

2012-01-01

Many studies have documented a high prevalence of anemia among tuberculosis (TB) patients and anemia at TB diagnosis has been associated with an increased risk of death. However, little is known about the factors contributing to the development of TB-associated anemia and their importance in TB disease progression. Data from a randomized clinical trial of micronutrient supplementation in patients with pulmonary TB in Tanzania were analyzed. Repeated measures of anemia with iron deficiency, anemia without iron deficiency, and iron deficiency without anemia were assessed as risk factors for treatment failure, TB recurrence, and mortality. The prevalence of anemia (hemoglobin iron deficiency (mean corpuscular volume , 80 fL). We found no evidence of an association between anemia (with or without iron deficiency) or iron deficiency without anemia at baseline and the risk of treatment failure at 1 mo after initiation. Anemia without iron deficiency was associated with an independent, 4-fold increased risk of TB recurrence [adjusted RR = 4.10 (95% CI = 1.88, 8.91); P Iron deficiency and anemia (with and without iron deficiency) were associated with a 2- to nearly 3-fold independent increase in the risk of death [adjusted RR for iron deficiency without anemia = 2.89 (95% CI = 1.53, 5.47); P = 0.001; anemia without iron deficiency = 2.72 (95% CI = 1.50, 4.93); P = 0.001; iron deficiency anemia = 2.13 (95% CI = 1.10, 4.11); P = 0.02]. Efforts to identify and address the conditions contributing to TB-associated anemia, including iron deficiency, could play an important role in reducing morbidity and mortality in areas heavily affected by TB. PMID:22190024

Alpha-fetoprotein and Fanconi Anemia: Relevance to DNA Repair and Breast Cancer Susceptibility.

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Lakhi, Nisha A; Mizejewski, Gerald J

2017-02-01

Elevations of serum alpha-fetoprotein (sAFP) have been reported in fetal and infant states of anemia. Fanconi anemia (FA) belongs to a family of genetic instability disorders which lack the capability to repair DNA breaks. The lesion occurs at a checkpoint regulatory step of the G2 to mitotic transition, allowing FA cells to override cell-cycle arrest. FA DNA repair pathways contain complementation groups known as FANC proteins. FANC proteins form multi-protein complexes with BRCA proteins and are involved in homologous DNA repair. An impaired cascade in these events imparts an increased breast cancer susceptibility to female FA patients. Elevations of sAFP have availed this fetal protein to serve as a biomarker for FA disease. However, the origin of the synthesis of sAFA has not been determined in FA patients. We hypothesize that hematopoietic multipotent progenitor stem cells in the bone marrow are the source of sAFP production in FA patients.

Profilaxia da anemia ancilostomótica: sindrome de carencia Prophylaxis of Hookworm Anemia-carencial syndrome

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W. O. Cruz

1945-04-01

Full Text Available É apresentada uma revisão das recentes aquisições na anemia ancilostomótica, assinalando a importância de alimentação qualitativamente deficiente junto á infestação helmíntica na gênese desta doença. Acentuou-se que a anemia ancilostomótica é uma doença de carência. Profilaxia clássica da Ancilostomose resume-se em evitar a infestação do homem pelos ancilostomídeos. Critica-se a aplicabilidade destas medidas e eficiência das mesmas no que diz respeito á incidência da anemia. O presente trabalho mostra aquisições preliminares sôbre fundamentos de uma profilaxia de carência (tipo profilaxia do bócio endêmico da anemia ancilostomótica, baseada na administração de alimentos contaminados por um sal de ferro. As misturas sulfato ferroso-farinha de mandióca e citrato férrico amoniacal-caldo de feijão, mostraram-se eficientes em prevenir a queda das cifras hemáticas durante largos períodos de tempo em indivíduos maciçamente infestados (6-8 meses. Não foi verificada a dose diária mínima eficiente dêstes sais, obtendo-se resultados satisfatorios mesmo com 0.1 g diária de sulfato ferroso (correspondendo a 0.037 g de ferro metálico. Numerosos alimentos e sais de ferro foram experimentados com resultados infrutíferos por diferentes razões. A influência dos helmintos, pela hemorragias intestinais que acarretam poude ser mais uma vez estudada, nos casos de sais de ferro administrados em doses ineficientes ou em períodos de prova sem medicação marcial. É proposta nova classificação de intensidade de infestação, levando em consideração o conhecido fato de ser a atividade dos helmintos, exclusivamente expoliadora. Em conclusão, nos parece exequível a profilaxia da anemia ancilostomótica mediante ingestão de alimentos contaminados por quantidades eficientes de sais de ferro. Êste método profilático extremamente econômico será na prática, provàvelmente, muito superior aos métodos de profilaxia

Salmonella osteomyelitis by sickle cell anemia

International Nuclear Information System (INIS)

Rausch, H.; Tran, V.T.; Boeckmann, U.; Duesseldorf Univ.

1985-01-01

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. (orig.) [de

Fanconi anemia (cross)linked to DNA repair.

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Niedernhofer, Laura J; Lalai, Astrid S; Hoeijmakers, Jan H J

2005-12-29

Fanconi anemia is characterized by hypersensitivity to DNA interstrand crosslinks (ICLs) and susceptibility to tumor formation. Despite the identification of numerous Fanconi anemia (FANC) genes, the mechanism by which proteins encoded by these genes protect a cell from DNA interstrand crosslinks remains unclear. The recent discovery of two DNA helicases that, when defective, cause Fanconi anemia tips the balance in favor of the direct involvement of the FANC proteins in DNA repair and the bypass of DNA lesions.

Anemia and iron deficiency before and after bariatric surgery.

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Salgado, Wilson; Modotti, Caue; Nonino, Carla Barbosa; Ceneviva, Reginaldo

2014-01-01

Iron deficiency and anemia are changes often associated with obesity. Bariatric surgery is responsible for increasing the iron loss and reducing its absorption. The objective of this study was to evaluate anemia and iron deficiency before and after bariatric surgery and to relate them to possible predisposing factors. A retrospective study was conducted on obese patients submitted to open Roux-en-Y gastric bypass, in which clinical and laboratory data were obtained up to 48 months postoperatively. Patients were divided into groups according to the presence or absence of anemia and to the presence or absence of iron deficiency (even without anemia), and all data were compared between these groups. Preoperatively, 21.5% of patients had anemia and 20% had iron deficiency. The number of patients with anemia did not vary through the 4 years of the study, but ferritin levels significantly decreased with time (Panemia. Female gender was a variable associated with a greater incidence of iron deficiency. Anemia and iron deficiency are frequent in obese patients and must be treated before surgery. Medical and nutritional surveillance is important in the postoperative period of bariatric surgery. Management of each condition must be directed at correcting the 2 major sources of iron deficiency and anemia: food intolerance (mostly meat intolerance) and losses (frequently due to menstruation). These are the factors more related to iron deficient anemia. Copyright © 2014 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Iron deficiency, anemia, and mortality in renal transplant recipients.

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Eisenga, Michele F; Minović, 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

2016-11-01

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 in RTR. Cox regression analyses were used to investigate prospective associations. In 700 RTR, prevalences of anemia, IDA, and ID were 34%, 13%, and 30%, respectively. During follow-up for 3.1 (2.7-3.9) years, 81 (12%) RTR died. In univariable analysis, anemia [HR, 1.72 (95%CI: 1.11-2.66), P = 0.02], IDA [2.44 (1.48-4.01), P anemia with mortality became weaker after adjustment for ID [1.52 (0.97-2.39), P = 0.07] and disappeared after adjustment for proteinuria and eGFR [1.09 (0.67-1.78), P = 0.73]. The association of IDA with mortality attenuated after adjustment for potential confounders. In contrast, the association of ID with mortality remained independent of potential confounders, including anemia [1.77 (1.13-2.78), P = 0.01]. In conclusion, ID is highly prevalent among RTR and is associated with an increased risk of mortality, independent of anemia. As ID is a modifiable factor, correction of ID could be a target to improve survival. © 2016 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.

[Spatial analysis of gestational anemia in Peru, 2015].

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Hernández-Vásquez, Akram; Azañedo, Diego; Antiporta, Daniel A; Cortés, Sandra

2017-01-01

To establish regional prevalences of anemia in pregnant women receiving care at public clinics in Peru in 2015 and identify high-prevalence district conglomerates. An ecological study was carried out on data from pregnant women with anemia registered on the Nutritional Status Information System (SIEN) who received care in 7703 public clinics in 2015. Regional and district prevalences of gestational anemia were calculated. District conglomerates with a high prevalence of gestational anemia were identified using the Moran Index. Information was gathered from 311,521 pregnant women distributed in 1638 districts in Peru. The national prevalence of anemia was 24.2% (95% confidence interval [95% CI]: 24.0-24.3%), the rural prevalence was 30.5%, and the urban prevalence was 22.0%. The regions of Huancavelica (45.5%; 95% CI: 44.2-46.7%), Puno (42.8%; 95% CI: 41.9-43.7%), Pasco (38.5%; 95% CI: 36.9-40.0%), Cusco (36.0%; 95% CI: 35.3-36.8%), and Apurímac (32.0%; 95% CI: 30.8-33.1%) had the highest prevalences of anemia. The local Moran Index identified 202 high-priority districts (hot spots) (12.3% of total; 44 urban and 158 rural) located in Ancash, Apurímac, Arequipa, Ayacucho, Cajamarca, Cusco, Huancavelica, Huánuco, Junín, La Libertad, Lima, Pasco, and Puno containing high-prevalence district conglomerates. Gestational anemia in Peru has its highest prevalence rates in rural and southern mountainous areas. The district conglomerates with high prevalence rates of gestational anemia coincide with the areas of high regional prevalence.

Severe anemia in 3 toddlers with gastric lactobezoar.

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Klein-Franke, A; Kropshofer, G; Gassner, I; Meister, B; Salvador, C; Scholl-Bürgi, S; Mueller, T; Heinz-Erian, P

2013-05-01

Anemia in toddlers may result from many disorders including excessive feeding with cow's milk. Another sequel of age-inadequate cow's milk nutrition may be gastric lactobezoar (GLB), a dense lump of coagulated milk and mucus in the stomach. 3 toddlers presented with a history of excessive intake of full cream cow's milk, abdominal distension, vomiting, dehydration, fatigue, marked pallor and tachycardia. Diagnostic imaging revea-led large GLBs as the likely origin of the abdominal symptoms. Laboratory evaluation showed severe anemia with depleted iron stores and signs of protein catabolism. Non-cow's milk-induced causes of anemia including defects of erythropoiesis, hemoglobin structure, RBC-enzymes and blood coagulation, hemolysis, immune disorders, infection, inflammation, extraintestinal hemorrhage, nephropathy were - according to the available data - unlikely to cause the anemia in our patients. Thus their anemia is thought to be due to age-inadequate cow's milk nutrition leading to 1) low intake, decreased absorption/bioavailability and increased intestinal loss of iron, and 2) GLB which induced blood loss following mechanical irritation of the gastric mucosa and vomiting causing high gastric pH and decrease in duodenal iron absorption. The anemia in our patients is due to both exaggerated feeding with cow's milk and adverse effects of GLBs. This hypothesis is supported by the finding that, after erythrocyte transfusion, iron substitution, age-adapted nutrition and GLB-dissolution, the anemia did not recur. We propose to include GLB in the differential diagnosis of anemia in cow's milk fed small children. © Georg Thieme Verlag KG Stuttgart · New York.

Constitutive role of the Fanconi anemia D2 gene in the replication stress response.

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Tian, Yanyan; Shen, Xi; Wang, Rui; Klages-Mundt, Naeh L; Lynn, Erica J; Martin, Sara K; Ye, Yin; Gao, Min; Chen, Junjie; Schlacher, Katharina; Li, Lei

2017-12-08

In response to DNA cross-linking damage, the Fanconi anemia (FA) core complex activates the FA pathway by monoubiquitinating Fanconi anemia complementation group D2 (FANCD2) for the initiation of the nucleolytic processing of the DNA cross-links and stabilization of stalled replication forks. Given that all the classic FA proteins coordinately monoubiquitinate FANCD2, it is unclear why losses of individual classic FA genes yield varying cellular sensitivities to cross-linking damage. To address this question, we generated cellular knock-out models of FA core complex components and FANCD2 and found that FANCD2-null mutants display higher levels of spontaneous chromosomal damage and hypersensitivity to replication-blocking lesions than Fanconi anemia complementation group L (FANCL)-null mutants, suggesting that FANCD2 provides a basal level of DNA protection countering endogenous lesions in the absence of monoubiquitination. FANCD2's ubiquitination-independent function is likely involved in optimized recruitment of nucleolytic activities for the processing and protection of stressed replication forks. Our results reveal that FANCD2 has a ubiquitination-independent role in countering endogenous levels of replication stress, a function that is critical for the maintenance of genomic stability. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

An Etiologic Profile of Anemia in 405 Geriatric Patients

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Tabea Geisel

2014-01-01

Full Text Available Background. Anemia is a common condition in the elderly and a significant risk factor for increased morbidity and mortality, reducing not only functional capacity and mobility but also quality of life. Currently, few data are available regarding anemia in hospitalized geriatric patients. Our retrospective study investigated epidemiology and causes of anemia in 405 hospitalized geriatric patients. Methods. Data analysis was performed using laboratory parameters determined during routine hospital admission procedures (hemoglobin, ferritin, transferrin saturation, C-reactive protein, vitamin B12, folic acid, and creatinine in addition to medical history and demographics. Results. Anemia affected approximately two-thirds of subjects. Of 386 patients with recorded hemoglobin values, 66.3% were anemic according to WHO criteria, mostly (85.1% in a mild form. Anemia was primarily due to iron deficiency (65%, frequently due to underlying chronic infection (62.1%, or of mixed etiology involving a combination of chronic disease and iron deficiency, with absolute iron deficiency playing a comparatively minor role. Conclusion. Greater awareness of anemia in the elderly is warranted due to its high prevalence and negative effect on outcomes, hospitalization duration, and mortality. Geriatric patients should be routinely screened for anemia and etiological causes of anemia individually assessed to allow timely initiation of appropriate therapy.

The carboxyl terminus of FANCE recruits FANCD2 to the Fanconi Anemia (FA) E3 ligase complex to promote the FA DNA repair pathway.

Science.gov (United States)

Polito, David; Cukras, Scott; Wang, Xiaozhe; Spence, Paige; Moreau, Lisa; D'Andrea, Alan D; Kee, Younghoon

2014-03-07

Fanconi anemia (FA) is a genome instability syndrome characterized by bone marrow failure and cellular hypersensitivity to DNA cross-linking agents. In response to DNA damage, the FA pathway is activated through the cooperation of 16 FA proteins. A central player in the pathway is a multisubunit E3 ubiquitin ligase complex or the FA core complex, which monoubiquitinates its substrates FANCD2 and FANCI. FANCE, a subunit of the FA core complex, plays an essential role by promoting the integrity of the complex and by directly recognizing FANCD2. To delineate its role in substrate ubiquitination from the core complex assembly, we analyzed a series of mutations within FANCE. We report that a phenylalanine located at the highly conserved extreme C terminus, referred to as Phe-522, is a critical residue for mediating the monoubiquitination of the FANCD2-FANCI complex. Using the FANCE mutant that specifically disrupts the FANCE-FANCD2 interaction as a tool, we found that the interaction-deficient mutant conferred cellular sensitivity in reconstituted FANCE-deficient cells to a similar degree as FANCE null cells, suggesting the significance of the FANCE-FANCD2 interaction in promoting cisplatin resistance. Intriguingly, ectopic expression of the FANCE C terminus fragment alone in FA normal cells disrupts DNA repair, consolidating the importance of the FANCE-FANCD2 interaction in the DNA cross-link repair.

The Carboxyl Terminus of FANCE Recruits FANCD2 to the Fanconi Anemia (FA) E3 Ligase Complex to Promote the FA DNA Repair Pathway*

Science.gov (United States)

Polito, David; Cukras, Scott; Wang, Xiaozhe; Spence, Paige; Moreau, Lisa; D'Andrea, Alan D.; Kee, Younghoon

2014-01-01

Fanconi anemia (FA) is a genome instability syndrome characterized by bone marrow failure and cellular hypersensitivity to DNA cross-linking agents. In response to DNA damage, the FA pathway is activated through the cooperation of 16 FA proteins. A central player in the pathway is a multisubunit E3 ubiquitin ligase complex or the FA core complex, which monoubiquitinates its substrates FANCD2 and FANCI. FANCE, a subunit of the FA core complex, plays an essential role by promoting the integrity of the complex and by directly recognizing FANCD2. To delineate its role in substrate ubiquitination from the core complex assembly, we analyzed a series of mutations within FANCE. We report that a phenylalanine located at the highly conserved extreme C terminus, referred to as Phe-522, is a critical residue for mediating the monoubiquitination of the FANCD2-FANCI complex. Using the FANCE mutant that specifically disrupts the FANCE-FANCD2 interaction as a tool, we found that the interaction-deficient mutant conferred cellular sensitivity in reconstituted FANCE-deficient cells to a similar degree as FANCE null cells, suggesting the significance of the FANCE-FANCD2 interaction in promoting cisplatin resistance. Intriguingly, ectopic expression of the FANCE C terminus fragment alone in FA normal cells disrupts DNA repair, consolidating the importance of the FANCE-FANCD2 interaction in the DNA cross-link repair. PMID:24451376

[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.

Frequency of anemia in chronic psychiatry patients

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Korkmaz S

2015-10-01

Full Text Available Sevda Korkmaz,1 Sevler Yildiz,1 Tuba Korucu,1 Burcu Gundogan,1 Zehra Emine Sunbul,1 Hasan Korkmaz,2 Murad Atmaca1 1Department of Psychiatry, 2Department of Cardiology, Faculty of Medicine, Firat University, Elazig, Turkey Purpose: Anemia could cause psychiatric symptoms such as cognitive function disorders and depression or could deteriorate an existing psychiatric condition when it is untreated. The objective of this study is to scrutinize the frequency of anemia in chronic psychiatric patients and the clinical and sociodemographic factors that could affect this frequency.Methods: All inpatients in our clinic who satisfied the study criteria and received treatment between April 2014 and April 2015 were included in this cross-sectional study. Sociodemographic data for 378 patients included in the study and hemoglobin (Hb and hematocrit values observed during their admission to the hospital were recorded in the forms. Male patients with an Hb level of <13 g/dL and nonpregnant female patients with an Hb level of <12 g/dL were considered as anemic.Findings: Axis 1 diagnoses demonstrated that 172 patients had depressive disorder, 51 patients had bipolar disorder, 54 patients had psychotic disorder, 33 patients had conversion disorder, 19 patients had obsessive-compulsive disorder, 25 patients had generalized anxiety disorder, and 24 patients had other psychiatric conditions. It was also determined that 25.4% of the patients suffered from anemia. Thirty-five percent of females and 10% of males were considered as anemic. The frequency of anemia was the highest among psychotic disorder patients (35%, followed by generalized anxiety disorder patients (32%, and obsessive-compulsive disorder patients (26%. Anemia was diagnosed in 22% of depressive disorder patients, 25% of bipolar disorder patients, and 24% of conversion disorder patients.Results: The prevalence of anemia among chronic psychiatry patients is more frequent than the general population

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)

A novel ubiquitin ligase is deficient in Fanconi anemia.

NARCIS (Netherlands)

Meetei, AR; Winter, de J.P.; Medhurst, A.L. dr.; Wallisch, M; Waisfisz, Q.; Vrugt, van der H.J.; Oostra, A.B.; Yan, Z; Ling, C; Bishop, CE; Hoatlin, M.E.; Joenje, H.

2003-01-01

Fanconi anemia is a recessively inherited disease characterized by congenital defects, bone marrow failure and cancer susceptibility. Cells from individuals with Fanconi anemia are highly sensitive to DNA-crosslinking drugs, such as mitomycin C (MMC). Fanconi anemia proteins function in a DNA damage

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... for gastrointestinal bleeding To see if gastrointestinal bleeding is causing your iron-deficiency anemia, your doctor may order the following procedures to guide treatment . Fecal ...

Sickle Cell Anemia: MedlinePlus Health Topic

Science.gov (United States)

... Cell Disease Also called: Hemoglobin SS disease, Sickle cell anemia On this page Basics Summary Start Here Diagnosis ... red blood cells. This is a condition called anemia , and it can make you feel tired. The ...

Comparative evaluation of the efficacy of the cyclooxygenase pathway inhibitor and nitric oxide synthase inhibitor in the reduction of alveolar bone loss in ligature induced periodontitis in rats: An experimental study

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Rekha Jagadish

2014-01-01

Full Text Available Background: Alveolar bone loss is the most striking feature of periodontal disease. The aim of this study was to investigate the effect of a cyclooxygenase (COX pathway inhibitor and nitric oxide synthase (NOS inhibitor in the reduction of alveolar bone loss in an experimental periodontal disease (EPD model. Materials and Methods: The study was conducted on 60 Wistar rats divided into three groups of 20 rats each and then subjected to a ligature placement around the left maxillary second molars. Group 1 rats were treated with COX inhibitor (diclofenac sodium 10 mg/kg/d, group 2 with NOS inhibitor (aminoguanidine hydrochloride 10 mg/kg/d and group 3 served as controls, receiving only saline, intraperitoneally 1h before EPD induction and daily until the sacrifice on the 11 th day. Leukogram was performed before ligation, at 6 h and at the first, seventh and 11 th days after EPD induction. After sacrifice, all the excised maxillae were subjected to morphometric and histometric analysis to measure the alveolar bone loss. Histopathological analysis was carried out to estimate cell influx, alveolar bone and cementum integrity. Results: Induction of experimental periodontitis in the rat model produced pronounced leucocytosis, which was significantly reduced by the administration of diclofenac sodium and aminoguanidine on the 11 th day. In morphometric and histometric examinations, both the test drugs significantly (P < 0.05 inhibited the alveolar bone loss as compared with the control group. Conclusion: Both COX inhibitor and NOS inhibitor are equally effective in inhibiting the inflammatory bone resorption in an experimental periodontitis model.

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... Supplement Fact Sheet (NIH) Iron-Deficiency Anemia (National Library of Medicine, MedlinePlus) ... Privacy Policy Freedom of Information Act (FOIA) Accessibility Copyright and Usage No FEAR ...

C-terminal peptides of tissue factor pathway inhibitor are novel host defense molecules.

Science.gov (United States)

Papareddy, Praveen; Kalle, Martina; Kasetty, Gopinath; Mörgelin, Matthias; Rydengård, Victoria; Albiger, Barbara; Lundqvist, Katarina; Malmsten, Martin; Schmidtchen, Artur

2010-09-03

Tissue factor pathway inhibitor (TFPI) inhibits tissue factor-induced coagulation, but may, via its C terminus, also modulate cell surface, heparin, and lipopolysaccharide interactions as well as participate in growth inhibition. Here we show that C-terminal TFPI peptide sequences are antimicrobial against the gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, gram-positive Bacillus subtilis and Staphylococcus aureus, as well as the fungi Candida albicans and Candida parapsilosis. Fluorescence studies of peptide-treated bacteria, paired with analysis of peptide effects on liposomes, showed that the peptides exerted membrane-breaking effects similar to those seen for the "classic" human antimicrobial peptide LL-37. The killing of E. coli, but not P. aeruginosa, by the C-terminal peptide GGLIKTKRKRKKQRVKIAYEEIFVKNM (GGL27), was enhanced in human plasma and largely abolished in heat-inactivated plasma, a phenomenon linked to generation of antimicrobial C3a and activation of the classic pathway of complement activation. Furthermore, GGL27 displayed anti-endotoxic effects in vitro and in vivo in a mouse model of LPS shock. Importantly, TFPI was found to be expressed in the basal layers of normal epidermis, and was markedly up-regulated in acute skin wounds as well as wound edges of chronic leg ulcers. Furthermore, C-terminal fragments of TFPI were associated with bacteria present in human chronic leg ulcers. These findings suggest a new role for TFPI in cutaneous defense against infections.

Epidemiology of aplastic anemia in Japanese radiological technicians

International Nuclear Information System (INIS)

Kitabatake, Takashi; Watanabe, Tsuyoshi; Saito, Akira; Nakamura, Minoru.

1976-01-01

Among Japanese radiological technicians, four deaths from aplastic anemia have been recorded. Based on this fact, some epidemiological considerations are tried. During the period from 1930 to 1960, the population of radiological technicians is estimated to be 74,400 man-years, in which 0.5 aplastic anemias are expected. However actually three died from aplastic anemia. This difference is statistically significant at the 1% level. On the other hand, in the period from 1961 to 1973, the observed value is 1 against 0.7 expected. It is concluded that aplastic anemia had been frequently induced among Japanese radiological technicians in the era when there was much exposure to occupational radiation. (auth.)

Aplastic anemia and related disorders in atomic bomb survivors

International Nuclear Information System (INIS)

Ichimaru, Michito; Tomonaga, Yu; Matsunaga, Masako; Sadamori, Naoki; Ishimaru, Toranosuke.

1978-01-01

Whether the incidence of aplastic anemia significantly increases due to the later effect of atomic-bomb radiation was studied. After the data of aplastic anemia which occurred within 1950 - 1973 were evaluated and the diagnoses of the cases were certified, the incidence of aplastic anemia per 109,000 inhabitants of the cities of Hiroshima and Nagasaki was calculated and compared according to the dose of atomic-bomb radiation. There was no increase in the incidence according to an increase in radiation dose, and there was no fact that aplastic anemia increased in a certain period either. Most of the atomic-bomb survivors who were close to the epicenter and were clinically diagnosed as aplastic anemia had leukemia lesion or myeloid proliferating lesion, and it is likely to be that pathological changes resembling aplastic anemia may appear in a certain phase of myeloid proliferation or as a phenotype of myeloid proliferation. An evaluation was made on cases of aplastic anemia of other groups, but the doses of atomic-bomb radiation which they received were not so much to give effect on the bone marrow except only two cases. (Ueda, J.)

FAKTOR-FAKTOR YANG MEMPENGARUHI ANEMIA PADA REMAJA

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Dewi Permaesih

2012-09-01

Full Text Available Anemia in Indonesia is a public health problem. The prevalence still have a tendency to increase. The main antecedent factor for anemia is the lack of iron intake. The purpose of this analysis is to learn and find other factors besides iron. Sources of data were from the study of morbidity and disability of the Household Health Survey, 2001. The respondents were adolescents between 10-19 years of age. Data on social economic status, illness records, medicine consumption, physical activities and smoking habits were collected by interview during household visits. Data on anemia were identified from the results of hemoglobin determination by HemoCue. The nutrition status was found from the calculation of Body Mass Index. Data on energy consumption were taken from food expenditure for meal data from SUSENAS. Variable used for the purpose of this analysis were age, gender, smoking habit, alcohol drinking, breakfast, the use of time for physical activities, IMT, hemoglobin value and energy consumption. Data analyse were conducted in 3 stages,i.e., univariate, bivariate and multivariate analyse. Overall, the prevalence of anemia among adolescents was found to be 25.5%; 21% for adolescent boys and 30% for adolescent girls. Around 27.1% adolescents reside in the village and 22.6% in the city. Adolescents who consume > 70% energy from being suggested were around 38% respondents. Seventeen percent was classified as thinny adolescent based on IMT indicator. The result on bivariate analyse showed that respondents who were less educated have a significant relation (p < 0.05 with getting anemia (OR=3.8; 95% CI=1.9-7.2. Male adolescents have lower risk to get anemia (OR=0.6; 95% CI 0.5-7.3. Other variables that showed significant relation with anemia were smoking (OR 1.35; 95% CI 1-1.8, breakfast habit (OR 0.6 ;95% CI 0.4-0.9 and sufficient energy consumption (OR 0.7; 95% CI 0.6-0.9. Result of multiple regression logistic test indicate that variables related

Iron deficiency and anemia in heart failure.

Science.gov (United States)

Çavuşoğlu, Yüksel; Altay, Hakan; Çetiner, Mustafa; Güvenç, Tolga Sinan; Temizhan, Ahmet; Ural, Dilek; Yeşilbursa, Dilek; Yıldırım, Nesligül; Yılmaz, Mehmet Birhan

2017-03-01

Heart failure is an important community health problem. Prevalence and incidence of heart failure have continued to rise over the years. Despite recent advances in heart failure therapy, prognosis is still poor, rehospitalization rate is very high, and quality of life is worse. Co-morbidities in heart failure have negative impact on clinical course of the disease, further impair prognosis, and add difficulties to treatment of clinical picture. Therefore, successful management of co-morbidities is strongly recommended in addition to conventional therapy for heart failure. One of the most common co-morbidities in heart failure is presence of iron deficiency and anemia. Current evidence suggests that iron deficiency and anemia are more prevalent in patients with heart failure and reduced ejection fraction, as well as those with heart failure and preserved ejection fraction. Moreover, iron deficiency and anemia are referred to as independent predictors for poor prognosis in heart failure. There is strong relationship between iron deficiency or anemia and severity of clinical status of heart failure. Over the last two decades, many clinical investigations have been conducted on clinical effectiveness of treatment of iron deficiency or anemia with oral iron, intravenous iron, and erythropoietin therapies. Studies with oral iron and erythropoietin therapies did not provide any clinical benefit and, in fact, these therapies have been shown to be associated with increase in adverse clinical outcomes. However, clinical trials in patients with iron deficiency in the presence or absence of anemia have demonstrated considerable clinical benefits of intravenous iron therapy, and based on these positive outcomes, iron deficiency has become target of therapy in management of heart failure. The present report assesses current approaches to iron deficiency and anemia in heart failure in light of recent evidence.

Severe combined immunodeficiency (SCID) presenting with neonatal aplastic anemia.

Science.gov (United States)

Scott, Angela; Glover, Jason; Skoda-Smith, Suzanne; Torgerson, Troy R; Xu, Min; Burroughs, Lauri M; Woolfrey, Ann E; Fleming, Mark D; Shimamura, Akiko

2015-11-01

Aplastic anemia in the neonate is rare. We report a case of severe combined immunodeficiency (SCID) presenting with neonatal aplastic anemia. This report highlights the importance of considering SCID early in the evaluation of neonatal aplastic anemia prior to the development of infectious complications. © 2015 Wiley Periodicals, Inc.

Anemia: monosymptomatic celiac disease. A report of 3 cases

NARCIS (Netherlands)

Depla, A. C.; Bartelsman, J. F.; Mulder, C. J.; Tytgat, G. N.

1990-01-01

Patients with monosymptomatic celiac disease (CD) can escape diagnosis for a long period. Anemia is a common finding in CD, although anemia as the sole symptom is relatively unknown. We report on three patients who presented with iron deficiency anemia and no other symptom, in whom CD was considered

Fanconi anemia genes act to suppress a cross-linker-inducible p53-independent apoptosis pathway in lymphoblastoid cell lines

NARCIS (Netherlands)

Kruyt, F. A.; Dijkmans, L. M.; van den Berg, T. K.; Joenje, H.

1996-01-01

Hypersensitivity to cross-linking agents such as mitomycin C (MMC) is characteristic of cells from patients suffering from the inherited bone marrow failure syndrome. Fanconi anemia (FA). Here, we link MMC hypersensitivity of Epstein-Barr virus (EBV)-immortalized FA lymphoblasts to a high

Observação de anemia hemolítica auto-imune em artrite reumatóide Observation of autoimmune hemolytic anemia in rheumatoid arthritis

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Ricardo A. S. Souza

2003-01-01

Full Text Available Artrite reumatóide é uma doença difusa do tecido conjuntivo que se caracteriza pelo acometimento articular e sistêmico. Disfunções hematológicas como anemia ocorrem em até 65% dos pacientes, sendo a anemia das doenças crônicas a forma mais comum. A anemia hemolítica auto-imune pode estar associada à difusa do tecido conjuntivo, sendo classicamente associada ao lúpus eritematoso sistêmico e fazendo parte dos seus critérios de classificação. A presença de anemia hemolítica auto-imune em artrite reumatóide é relatada raramente na literatura e os mecanismos etiopatogênicos para o seu desenvolvimento ainda não estão esclarecidos. Descrevemos um caso de artrite reumatóide no adulto e outro de artrite reumatóide juvenil que desenvolveram anemia hemolítica auto-imune e discutimos os prováveis mecanismos etiopatogênicos envolvidos.Rheumatoid arthritis is a connective tissue disease characterized by articular and systemic involvement. Hematological abnormalities such as anemia may occur in up to 65% of the patients, with chronic disease anemia being the commonest form. Autoimmune hemolytic anemia can be associated with different connective tissue diseases, particularly systemic lupus erythematosus and it is part of its classification criteria. On the other hand, the presence of autoimmune hemolytic anemia in rheumatoid arthritis has rarely been described in the literature and the pathogenic mechanisms for its development remain unclear. We describe here a case of rheumatoid arthritis and another of juvenile rheumatoid arthritis that developed to autoimmune hemolytic anemia and present the probable etiopathogenic mechanisms.

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... Learn more about participating in a clinical trial . View all trials from ClinicalTrials.gov . Visit Children and Clinical ... Resources NHLBI resources Your Guide to Anemia [PDF, 1. ...

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.

Towards a Molecular Understanding of the Fanconi Anemia Core Complex

Science.gov (United States)

Hodson, Charlotte; Walden, Helen

2012-01-01

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. PMID:22675617

Hypersensitivities for Acetaldehyde and Other Agents among Cancer Cells Null for Clinically Relevant Fanconi Anemia Genes

OpenAIRE

Ghosh, Soma; Sur, Surojit; Yerram, Sashidhar R.; Rago, Carlo; Bhunia, Anil K.; Hossain, M. Zulfiquer; Paun, Bogdan C.; Ren, Yunzhao R.; Iacobuzio-Donahue, Christine A.; Azad, Nilofer A.; Kern, Scott E.

2014-01-01

Large-magnitude numerical distinctions (>10-fold) among drug responses of genetically contrasting cancers were crucial for guiding the development of some targeted therapies. Similar strategies brought epidemiological clues and prevention goals for genetic diseases. Such numerical guides, however, were incomplete or low magnitude for Fanconi anemia pathway (FANC) gene mutations relevant to cancer in FANC-mutation carriers (heterozygotes). We generated a four-gene FANC-null cancer panel, inclu...

Prevalence and risk factors of anemia in children

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Cristie Regine Klotz Zuffo

2016-07-01

Full Text Available Objective: To identify the prevalence and factors associated with anemia in children attending Municipal Early Childhood Education Day Care Center (Centros Municipais de Educação Infantil [CMEI] nurseries in Colombo-PR. Methods: Analytical, cross-sectional study with a representative sample of 334 children obtained by stratified cluster sampling, with random selection of 26 nurseries. Data collection was conducted through interviews with parents, assessment of iron intake by direct food weighing, and hemoglobin measurement using the finger-stick test. Bivariate association tests were performed followed by multiple logistic regression adjustment. Results: The prevalence of anemia was 34.7%. Factors associated with anemia were: maternal age younger than 28 years old (p = 0.03, male children (p = 0.02, children younger than 24 months (p = 0.01, and children who did not consume iron food sources (meat + beans + dark green leafy vegetables (p = 0.02. There was no association between anemia and iron food intake in CMEI. However, iron intake was well below the recommended levels according to the National Education Development Fund resolution, higher prevalence of anemia was observed in children whose intake of iron, heme iron, and nonheme iron was below the median. Conclusions: In terms of public health, the prevalence of anemia is characterized as a moderate problem in the studied population and demonstrates the need for coordination of interdisciplinary actions for its reduction in CMEI nurseries. Resumo: Objetivo: Identificar a prevalência e os fatores associados à anemia em crianças que frequentam berçários de Centros Municipais de Educação Infantil (CMEI de Colombo-PR. Métodos: Estudo analítico, de caráter transversal, com amostra representativa de 334 crianças obtida por amostragem estratificada por conglomerados, com seleção aleatória de 26 berçários. A coleta de dados foi realizada por meio de entrevista com os

Fanconi Anemia Proteins and Their Interacting Partners: A Molecular Puzzle

Science.gov (United States)

Kaddar, Tagrid; Carreau, Madeleine

2012-01-01

In recent years, Fanconi anemia (FA) has been the subject of intense investigations, primarily in the DNA repair research field. Many discoveries have led to the notion of a canonical pathway, termed the FA pathway, where all FA proteins function sequentially in different protein complexes to repair DNA cross-link damages. Although a detailed architecture of this DNA cross-link repair pathway is emerging, the question of how a defective DNA cross-link repair process translates into the disease phenotype is unresolved. Other areas of research including oxidative metabolism, cell cycle progression, apoptosis, and transcriptional regulation have been studied in the context of FA, and some of these areas were investigated before the fervent enthusiasm in the DNA repair field. These other molecular mechanisms may also play an important role in the pathogenesis of this disease. In addition, several FA-interacting proteins have been identified with roles in these “other” nonrepair molecular functions. Thus, the goal of this paper is to revisit old ideas and to discuss protein-protein interactions related to other FA-related molecular functions to try to give the reader a wider perspective of the FA molecular puzzle. PMID:22737580

Hematocrit, anemia, and arm preference for blood sample collection ...

African Journals Online (AJOL)

Background: Anemia in pregnancy is a common cause of maternal morbidity and mortality in developing countries. Regular review of hematocrit (HCT) and anemia patterns in pregnancy is necessary in our environment. Aim: The aim was to determine the average HCT, prevalence, and pattern of anemia, as well the arm ...

The Effects of Anemia on Pregnancy Outcome in Patients with Pyelonephritis

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Sarah K. Dotters-Katz

2013-01-01

Full Text Available Objective. Pyelonephritis is a common infectious morbidity of pregnancy. Though anemia is commonly associated with pyelonephritis, there are little data describing the effect of pyelonephritis with anemia on pregnancy outcomes. The purpose of this study was to further assess the association of anemia with infectious morbidity and pregnancy complications among women with pyelonephritis. Study Design. We conducted a retrospective cohort study of pregnant women admitted to Duke University Hospital between July 2006 and May 2012 with pyelonephritis. Demographic, laboratory, and clinical data from the subject’s pregnancy and hospitalizations were analyzed. Patients with pyelonephritis and anemia (a hematocrit < 32 were compared to those without anemia. Descriptive statistics were used to compare the two groups. Results. 114 pregnant women were admitted with pyelonephritis and 45 (39.5% had anemia on admission. There was no significant difference in age, race, preexisting medical conditions, or urine bacterial species between patients with anemia and those without. Women with anemia were more likely to deliver preterm (OR 3.3 (95% CI 1.07, 11.4, . When controlling for race and history of preterm delivery, women with anemia continued to have increased odds of preterm birth (OR 6.0, CI 1.4, 35, . Conclusion. Women with pyelonephritis and anemia are at increased risk for preterm delivery.

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... making new blood cells. Visit our Aplastic Anemia Health Topic to learn more. Read ... to review family history, lifestyle, unhealthy environments, or other factors that increase your risk of ...

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... complications, including heart failure and development delays in children. Explore this Health ... red blood cells. Iron-deficiency anemia usually develops over time because your body’s intake of iron ...

Immune hemolytic anemia

Science.gov (United States)

... intravenous immunoglobulin (IVIG) or removal of the spleen (splenectomy) may be considered. You may receive treatment to ... need special treatment. In most people, steroids or splenectomy can totally or partially control anemia.

Association of mild anemia with cognitive, functional, mood and quality of life outcomes in the elderly: the "Health and Anemia" study.

Directory of Open Access Journals (Sweden)

Ugo Lucca

Full Text Available BACKGROUND: In the elderly persons, hemoglobin concentrations slightly below the lower limit of normal are common, but scant evidence is available on their relationship with significant health indicators. The objective of the present study was to cross-sectionally investigate the association of mild grade anemia with cognitive, functional, mood, and quality of life (QoL variables in community-dwelling elderly persons. METHODS: Among the 4,068 eligible individuals aged 65-84 years, all persons with mild anemia (n = 170 and a randomly selected sample of non-anemic controls (n = 547 were included in the study. Anemia was defined according to World Health Organization (WHO criteria and mild grade anemia was defined as a hemoglobin concentration between 10.0 and 11.9 g/dL in women and between 10.0 and 12.9 g/dL in men. Cognition and functional status were assessed using measures of selective attention, episodic memory, cognitive flexibility and instrumental and basic activities of daily living. Mood and QoL were evaluated by means of the Geriatric Depression Scale-10, the Short-Form health survey (SF-12, and the Functional Assessment of Cancer Therapy-Anemia. RESULTS: In univariate analyses, mild anemic elderly persons had significantly worse results on almost all cognitive, functional, mood, and QoL measures. In multivariable logistic regressions, after adjustment for a large number of demographic and clinical confounders, mild anemia remained significantly associated with measures of selective attention and disease-specific QoL (all fully adjusted p<.046. When the lower limit of normal hemoglobin concentration according to WHO criteria was raised to define anemia (+0.2 g/dL, differences between mild anemic and non anemic elderly persons tended to increase on almost every variable. CONCLUSIONS: Cross-sectionally, mild grade anemia was independently associated with worse selective attention performance and disease-specific QoL ratings.

STUDY OF ANEMIA IN ADOLESCENT SCHOOL GIRLS OF BHOPAL

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Rakesh Kakkar

2011-06-01

Full Text Available Background: Iron-deficiency anemia is the most common form of malnutrition, early intervention during adolescence (girls can prevent high morbidity and mortality of these future mothers. Objectives: To study prevalence & factors contributing to anaemia among adolescent school girls. Material and Methods: Area or region addressed – Iron deficiency anemia in adolescent girls. Present study was conducted among 317 adolescent (10-19Yrs government schoolgirls of Bhopal city from June2005-July2006. Three study groups were selected from three different girls’ school by random sampling method. Statistical analysis was done with SPSS. Result & Conclusion: Overall prevalence was 58.4% among adolescent schoolgirls. Prevalence of anemia was dependent on the knowledge about prevention of anemia, literacy level, food habits, birth order & also frequency of Iron rich source viz. green leafy vegetable & non vegetarian diet. While there was no significant relation of anemia with duration of menstrual flow but there was significant (P<0.05 difference in number of anaemic cases with age at menarche i.e. with higher age at menarche; there was more chances of anemia. Level of anemia was higher (p<0.05 in early adolescent (10 -13 Years age group (81% as compared to middle (58.3% and late adolescent (17-19 years age group girls (48.7%.

MEK Inhibitors Reverse cAMP-Mediated Anxiety in Zebrafish

DEFF Research Database (Denmark)

Lundegaard, Pia R.; Anastasaki, Corina; Grant, Nicola J.

2015-01-01

Altered phosphodiesterase (PDE)-cyclic AMP (cAMP) activity is frequently associated with anxiety disorders, but current therapies act by reducing neuronal excitability rather than targeting PDE-cAMP-mediated signaling pathways. Here, we report the novel repositioning of anti-cancer MEK inhibitors...... as anxiolytics in a zebrafish model of anxiety-like behaviors. PDE inhibitors or activators of adenylate cyclase cause behaviors consistent with anxiety in larvae and adult zebrafish. Small-molecule screening identifies MEK inhibitors as potent suppressors of cAMP anxiety behaviors in both larvae and adult...... zebrafish, while causing no anxiolytic behavioral effects on their own. The mechanism underlying cAMP-induced anxiety is via crosstalk to activation of the RAS-MAPK signaling pathway. We propose that targeting crosstalk signaling pathways can be an effective strategy for mental health disorders, and advance...

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... improved health for people with iron-deficiency anemia. Recipient Epidemiology Donor Studies program findings help to protect blood donors . NHLBI’s Recipient Epidemiology Donor Studies (REDS) program , which began in ...

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... lead to iron-deficiency anemia include: End-stage kidney failure, where there is blood loss during dialysis. People who have chronic kidney disease also often take other medicines—such as ...

Chemical, computational and functional insights into the chemical stability of the Hedgehog pathway inhibitor GANT61.

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Calcaterra, Andrea; Iovine, Valentina; Botta, Bruno; Quaglio, Deborah; D'Acquarica, Ilaria; Ciogli, Alessia; Iazzetti, Antonia; Alfonsi, Romina; Lospinoso Severini, Ludovica; Infante, Paola; Di Marcotullio, Lucia; Mori, Mattia; Ghirga, Francesca

2018-12-01

This work aims at elucidating the mechanism and kinetics of hydrolysis of GANT61, the first and most-widely used inhibitor of the Hedgehog (Hh) signalling pathway that targets Glioma-associated oncogene homologue (Gli) proteins, and at confirming the chemical nature of its bioactive form. GANT61 is poorly stable under physiological conditions and rapidly hydrolyses into an aldehyde species (GANT61-A), which is devoid of the biological activity against Hh signalling, and a diamine derivative (GANT61-D), which has shown inhibition of Gli-mediated transcription. Here, we combined chemical synthesis, NMR spectroscopy, analytical studies, molecular modelling and functional cell assays to characterise the GANT61 hydrolysis pathway. Our results show that GANT61-D is the bioactive form of GANT61 in NIH3T3 Shh-Light II cells and SuFu -/- mouse embryonic fibroblasts, and clarify the structural requirements for GANT61-D binding to Gli1. This study paves the way to the design of GANT61 derivatives with improved potency and chemical stability.

Anemia do lactente: etiologia e prevalência Anemia in infancy: etiology and prevalence

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Maria Claret C.M. Hadler

2002-01-01

Full Text Available Objetivo: verificar a prevalência de anemia, anemia ferropriva e deficiência de ferro em lactentes, de unidade pública de saúde, no município de Goiânia, Brasil, analisar e correlacionar as variáveis bioquímicas e hematológicas. Métodos: realizou-se estudo transversal. De 120 mães entrevistadas, foram incluídos 110 lactentes de 6 a 12 meses de idade, a termo e não gemelares. Dados socioeconômicos e hematológicos foram obtidos. Colheu-se sangue venoso dos lactentes em jejum para realização do hemograma completo por contagem eletrônica, ferro sérico, ferritina sérica e proteína C-reativa, os quais foram utilizados na avaliação da etiologia ferropriva nos anêmicos. Crianças com hemoglobina Objective: To verify the prevalence of anemia, iron deficiency anemia and iron deficiency in infants, at a Public Health Unit in the city of Goiânia - Brazil; to analyze and to correlate the hematologic and biochemical variables. Methods: A cross-sectional study was carried out. One hundred and ten full-term infants of the 120 mothers interviewed were included. The infants aged between six and twelve months and there were not twins. Socioeconomic and hematologic data was obtained. Venous blood was taken from fasting infants in order to carry out a complete hemogram through electronic cell counting, serum iron, serum ferritin and C-reactive protein, which were used in the evaluation of the etiology of iron deficiency in the anemic infants. Children with hemoglobin < 11g/dL were considered anemic. Results: The prevalence of anemia was 60.9%. In the diagnosis of the iron deficiency etiology in infants without an inflammation process, when considering the alteration of hemoglobin plus two more indices among mean corpuscular volume (MCV or mean corpuscular hemoglobin (MCH or serum ferritin or serum iron, the prevalence of the iron deficiency was 87%. Nevertheless, when red cell distribution width (RDW was included in the indices, the

An Ixodes ricinus Tick Salivary Lectin Pathway Inhibitor Protects Borrelia burgdorferi sensu lato from Human Complement.

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Wagemakers, Alex; Coumou, Jeroen; Schuijt, Tim J; Oei, Anneke; Nijhof, Ard M; van 't Veer, Cornelis; van der Poll, Tom; Bins, Adriaan D; Hovius, Joppe W R

2016-04-01

We previously identified tick salivary lectin pathway inhibitor (TSLPI) in Ixodes scapularis, a vector for Borrelia burgdorferi sensu stricto (s.s.) in North America. TSLPI is a salivary protein facilitating B. burgdorferi s.s. transmission and acquisition by inhibiting the host lectin complement pathway through interference with mannose binding lectin (MBL) activity. Since Ixodes ricinus is the predominant vector for Lyme borreliosis in Europe and transmits several complement sensitive B. burgdorferi sensu lato (s.l.) strains, we aimed to identify, describe, and characterize the I. ricinus ortholog of TSLPI. We performed (q)PCRs on I. ricinus salivary gland cDNA to identify a TSLPI ortholog. Next, we generated recombinant (r)TSLPI in a Drosophila expression system and examined inhibition of the MBL complement pathway and complement-mediated killing of B. burgdorferi s.l. in vitro. We identified a TSLPI ortholog in I. ricinus salivary glands with 93% homology at the RNA and 89% at the protein level compared to I. scapularis TSLPI, which was upregulated during tick feeding. In silico analysis revealed that TSLPI appears to be part of a larger family of Ixodes salivary proteins among which I. persulcatus basic tail salivary proteins and I. scapularis TSLPI and Salp14. I. ricinus rTSLPI inhibited the MBL complement pathway and protected B. burgdorferi s.s. and Borrelia garinii from complement-mediated killing. We have identified a TSLPI ortholog, which protects B. burgdorferi s.l. from complement-mediated killing in I. ricinus, the major vector for tick-borne diseases in Europe.

Sideropenic anemia in preschool children and risk factors

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Stojanović Dušica

2006-01-01

Full Text Available INTRODUCTION: Sideropenic anemia is one of the most common nutritional disorders in the world. The children are at higher risk of iron deficiency than adults due to their rapid growth during infancy and relatively higher requirements of iron. OBJECTIVE: The objective of our study was to investigate the prevalence of sideropenic anemia in pre-school children and relevant risk factors. METHOD: Study on sideropenic anemia of preschool children was performed in Zaječar Municipality in 2003. Subjects: all children, age 6-7 years, who lived in the Zaječar Municipality (554 children. The investigation included: interview of children's parents and laboratory analysis of blood. RESULTS: The frequency of sideropenic anemia was 5.23% in tested children (hemoglobin level less than 11g/dl. Sex and place of residence had no significant impact on hemoglobin concentration in blood of children. Likewise, social status and education of parents had no significant impact on iron deficiency anemia. Higher incidence of infections was found in children with lower hemoglobin concentration in blood (p<0.05. It made no difference if children attended the kindergarten or not. Nutrition of children in kindergarten does not correct domestic nutrition, which should be one of its basic roles. CONCLUSION: Since sideropenic anemia gives rise to serious health problems, such as poor cognitive and motor development and behavioral problems, it is important to take corrective measures regarding domestic and social nutrition of children. Therefore, it is necessary to take action in preventing the sideropenic anemia and provide normal growth and development.

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

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Fecher, Leslie A; Sharfman, William H

2015-01-01

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. PMID:26604681

APLASTIC ANEMIA ET CAUSA OF SUSPECT VIRAL HEPATITIS INFECTION: A CASE REPORT

OpenAIRE

I Wayan Wawan Lismana

2014-01-01

Aplastic anemia is anemia that occurs because of a failure of hematopoiesis is relatively rarebut can be life threatening. The cause of aplastic anemia itself is still largely unknown oridiopathic. Minority of cases mainly due to a virus infection, one of which is viral hepatitishas long been known to cause symptoms of aplastic anemia. This report discusses thesuspected aplastic anemia caused by hepatitis virus infection. Course of the disease or theprognosis of aplastic anemia varies, but a ...

Assessment of anemia during CT pulmonary angiography

International Nuclear Information System (INIS)

Jung, Caroline; Groth, Michael; Bley, Thorsten A.; Henes, Frank O.; Treszl, András; Adam, Gerhard; Bannas, Peter

2012-01-01

Objectives: Anemia is associated with increased mortality in patients with acute symptomatic pulmonary embolism (PE). The purpose of this study was to evaluate the feasibility of Hounsfield unit (HU) measurements on the single unenhanced trigger slice of pulmonary CT angiography scans for diagnosis of anemia. Material and Methods: 150 consecutive patients (median age 64 ± 16 years) with suspected PE underwent pulmonary CT angiography. Two radiologists, blinded to laboratory results, performed HU measurements in the single unenhanced trigger scan independently by region-based analysis (ROI). HU values from ascending and descending aorta and the calculated mean of both were correlated with serum hemoglobin levels. Inter- and intraobserver variability was determined for HU measurements, and ROC analysis was performed for diagnosis of anemia. Calculated linear models were used to assess formulas for estimation of hemoglobin levels from HU measurements. Results: HU measurements revealed high intra- and interrater reliability (ICC > 0.981 and ICC > 0.965, respectively). Calculated mean HU values showed a strong correlation with serum hemoglobin levels (r = 0.734), which allowed generation of different formulas for calculation of hemoglobin levels from HU measurements. ROC analyses confirmed a high sensitivity (80.4 for men; 91.3 for women) and specificity (84.0 for men; 84.9 for women) for diagnosing anemia. Conclusion: Diagnosis of anemia and quantification of hemoglobin levels upon a single unenhanced trigger scan of pulmonary CT angiography is feasible. We suggest disclosing the anemic state in the radiological report, independent of the presence of PE, since anemia carries increased risks of morbidity and mortality.

Assessment of anemia during CT pulmonary angiography

Energy Technology Data Exchange (ETDEWEB)

Jung, Caroline, E-mail: cjung@uke.de [Department of Diagnostic and Interventional Radiology, University Hospital Eppendorf, Martinistrasse 52, 20246 Hamburg (Germany); Groth, Michael; Bley, Thorsten A.; Henes, Frank O. [Department of Diagnostic and Interventional Radiology, University Hospital Eppendorf, Martinistrasse 52, 20246 Hamburg (Germany); Treszl, András [Department of Medical Biometry and Epidemiology, University Hospital Eppendorf, Martinistrasse 52, 20246 Hamburg (Germany); Adam, Gerhard; Bannas, Peter [Department of Diagnostic and Interventional Radiology, University Hospital Eppendorf, Martinistrasse 52, 20246 Hamburg (Germany)

2012-12-15

Objectives: Anemia is associated with increased mortality in patients with acute symptomatic pulmonary embolism (PE). The purpose of this study was to evaluate the feasibility of Hounsfield unit (HU) measurements on the single unenhanced trigger slice of pulmonary CT angiography scans for diagnosis of anemia. Material and Methods: 150 consecutive patients (median age 64 ± 16 years) with suspected PE underwent pulmonary CT angiography. Two radiologists, blinded to laboratory results, performed HU measurements in the single unenhanced trigger scan independently by region-based analysis (ROI). HU values from ascending and descending aorta and the calculated mean of both were correlated with serum hemoglobin levels. Inter- and intraobserver variability was determined for HU measurements, and ROC analysis was performed for diagnosis of anemia. Calculated linear models were used to assess formulas for estimation of hemoglobin levels from HU measurements. Results: HU measurements revealed high intra- and interrater reliability (ICC > 0.981 and ICC > 0.965, respectively). Calculated mean HU values showed a strong correlation with serum hemoglobin levels (r = 0.734), which allowed generation of different formulas for calculation of hemoglobin levels from HU measurements. ROC analyses confirmed a high sensitivity (80.4 for men; 91.3 for women) and specificity (84.0 for men; 84.9 for women) for diagnosing anemia. Conclusion: Diagnosis of anemia and quantification of hemoglobin levels upon a single unenhanced trigger scan of pulmonary CT angiography is feasible. We suggest disclosing the anemic state in the radiological report, independent of the presence of PE, since anemia carries increased risks of morbidity and mortality.

Upregulated LINE-1 Activity in the Fanconi Anemia Cancer Susceptibility Syndrome Leads to Spontaneous Pro-inflammatory Cytokine Production.

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Brégnard, Christelle; Guerra, Jessica; Déjardin, Stéphanie; Passalacqua, Frank; Benkirane, Monsef; Laguette, Nadine

2016-06-01

Fanconi Anemia (FA) is a genetic disorder characterized by elevated cancer susceptibility and pro-inflammatory cytokine production. Using SLX4(FANCP) deficiency as a working model, we questioned the trigger for chronic inflammation in FA. We found that absence of SLX4 caused cytoplasmic DNA accumulation, including sequences deriving from active Long INterspersed Element-1 (LINE-1), triggering the cGAS-STING pathway to elicit interferon (IFN) expression. In agreement, absence of SLX4 leads to upregulated LINE-1 retrotransposition. Importantly, similar results were obtained with the FANCD2 upstream activator of SLX4. Furthermore, treatment of FA cells with the Tenofovir reverse transcriptase inhibitor (RTi), that prevents endogenous retrotransposition, decreased both accumulation of cytoplasmic DNA and pro-inflammatory signaling. Collectively, our data suggest a contribution of endogenous RT activities to the generation of immunogenic cytoplasmic nucleic acids responsible for inflammation in FA. The additional observation that RTi decreased pro-inflammatory cytokine production induced by DNA replication stress-inducing drugs further demonstrates the contribution of endogenous RTs to sustaining chronic inflammation. Altogether, our data open perspectives in the prevention of adverse effects of chronic inflammation in tumorigenesis. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Anemia and hemoglobin levels among Indigenous Xavante children, Central Brazil.

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Ferreira, Aline Alves; Santos, Ricardo Ventura; Souza, July Anne Mendonça de; Welch, James R; Coimbra, Carlos E A

2017-01-01

To evaluate the prevalence of anemia, mean hemoglobin levels, and the main nutritional, demographic, and socioeconomic factors among Xavante children in Mato Grosso State, Brazil. A survey was conducted with children under 10 years of age in two indigenous Xavante communities within the Pimentel Barbosa Indigenous Reserve. Hemoglobin concentration levels, anthropometric measurements, and socioeconomic/demographic data were collected by means of clinical measurements and structured interviews. The cut-off points recommended by the World Health Organization were used for anemia classification. Linear regression analyses with hemoglobin as the outcome and Poisson regression with robust variance and with the presence or absence of anemia as outcomes were performed (95%CI). Lower mean hemoglobin values were observed in children under 2 years of age, without a significant difference between sexes. Anemia was observed among 50.8% of children overall, with the highest prevalence among children under 2 years of age (77.8%). Age of the child was inversely associated with the occurrence of anemia (adjusted PR = 0.60; 95%CI 0.38-0.95) and mean hemoglobin values increased significantly with age. Greater height-for-age z-score values reduced the probability of having anemia by 1.8 times (adjusted PR = 0.59; 95%CI 0.34-1.00). Presence of another child with anemia within the household increased the probability of the occurrence of anemia by 52.9% (adjusted PR = 1.89; 95%CI 1.16-3.09). Elevated levels of anemia among Xavante children reveal a disparity between this Indigenous population and the national Brazilian population. Results suggest that anemia is determined by complex and variable relationships between socioeconomic, sociodemographic, and biological factors.

Multivariable Discriminant Analysis for the Differential Diagnosis of Microcytic Anemia

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Eloísa Urrechaga

2013-01-01

Full Text Available Introduction. Iron deficiency anemia and thalassemia are the most common causes of microcytic anemia. Powerful statistical computer programming enables sensitive discriminant analyses to aid in the diagnosis. We aimed at investigating the performance of the multiple discriminant analysis (MDA to the differential diagnosis of microcytic anemia. Methods. The training group was composed of 200 β-thalassemia carriers, 65 α-thalassemia carriers, 170 iron deficiency anemia (IDA, and 45 mixed cases of thalassemia and acute phase response or iron deficiency. A set of potential predictor parameters that could detect differences among groups were selected: Red Blood Cells (RBC, hemoglobin (Hb, mean cell volume (MCV, mean cell hemoglobin (MCH, and RBC distribution width (RDW. The functions obtained with MDA analysis were applied to a set of 628 consecutive patients with microcytic anemia. Results. For classifying patients into two groups (genetic anemia and acquired anemia, only one function was needed; 87.9% β-thalassemia carriers, and 83.3% α-thalassemia carriers, and 72.1% in the mixed group were correctly classified. Conclusion. Linear discriminant functions based on hemogram data can aid in differentiating between IDA and thalassemia, so samples can be efficiently selected for further analysis to confirm the presence of genetic anemia.

Fanconi anemia (FA) binding protein FAAP20 stabilizes FA complementation group A (FANCA) and participates in interstrand cross-link repair.

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Leung, Justin Wai Chung; Wang, Yucai; Fong, Ka Wing; Huen, Michael Shing Yan; Li, Lei; Chen, Junjie

2012-03-20

The Fanconi anemia (FA) pathway participates in interstrand cross-link (ICL) repair and the maintenance of genomic stability. The FA core complex consists of eight FA proteins and two Fanconi anemia-associated proteins (FAAP24 and FAAP100). The FA core complex has ubiquitin ligase activity responsible for monoubiquitination of the FANCI-FANCD2 (ID) complex, which in turn initiates a cascade of biochemical events that allow processing and removal of cross-linked DNA and thereby promotes cell survival following DNA damage. Here, we report the identification of a unique component of the FA core complex, namely, FAAP20, which contains a RAD18-like ubiquitin-binding zinc-finger domain. Our data suggest that FAAP20 promotes the functional integrity of the FA core complex via its direct interaction with the FA gene product, FANCA. Indeed, somatic knockout cells devoid of FAAP20 displayed the hallmarks of FA cells, including hypersensitivity to DNA cross-linking agents, chromosome aberrations, and reduced FANCD2 monoubiquitination. Taking these data together, our study indicates that FAAP20 is an important player involved in the FA pathway.

Retinal phlebitis associated with autoimmune hemolytic anemia.

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Chew, Fiona L M; Tajunisah, Iqbal

2009-01-01

To describe a case of retinal phlebitis associated with autoimmune hemolytic anemia. Observational case report. A 44-year-old Indian man diagnosed with autoimmune hemolytic anemia presented with a 1-week history of blurred vision in both eyes. Fundus biomicroscopy revealed bilateral peripheral retinal venous sheathing and cellophane maculopathy. Fundus fluorescent angiogram showed bilateral late leakage from the peripheral venous arcades and submacular fluid accumulation. The retinal phlebitis resolved following a blood transfusion and administration of systemic steroids. Retinopathy associated with autoimmune hemolytic anemia is not well known. This is thought to be the first documentation of retinal phlebitis occurring in this condition.

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.

BRCA1 interacts directly with the Fanconi anemia protein FANCA.

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Folias, Alexandra; Matkovic, Mara; Bruun, Donald; Reid, Sonja; Hejna, James; Grompe, Markus; D'Andrea, Alan; Moses, Robb

2002-10-01

Fanconi anemia (FA) is a rare autosomal recessive disease characterized by skeletal defects, anemia, chromosomal instability and increased risk of leukemia. At the cellular level FA is characterized by increased sensitivity to agents forming interstrand crosslinks (ICL) in DNA. Six FA genes have been cloned and interactions among individual FANC proteins have been found. The FANCD2 protein co-localizes in nuclear foci with the BRCA1 protein following DNA damage and during S-phase, requiring the FANCA, C, E and G proteins to do so. This finding may reflect a direct role for the BRCA1 protein in double strand break (DSB) repair and interaction with the FANC proteins. Therefore interactions between BRCA1 and the FANC proteins were investigated. Among the known FANC proteins, we find evidence for direct interaction only between the FANCA protein and BRCA1. The evidence rests on three different tests: yeast two-hybrid analysis, coimmunoprecipitation from in vitro synthesis, and coimmunoprecipitation from cell extracts. The amino terminal portion of FANCA and the central part (aa 740-1083) of BRCA1 contain the sites of interaction. The interaction does not depend on DNA damage, thus FANCA and BRCA1 are constitutively interacting. The demonstrated interaction directly connects BRCA1 to the FA pathway of DNA repair.

Iron-Deficiency Anemia

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Full Text Available ... an increased risk for iron-deficiency anemia because of your age, unhealthy environments, family ... 12 months, especially if they are fed only breast milk or are fed formula that is not fortified ...

[Equine Infectious Anemia (EIA)].

Science.gov (United States)

Kaiser, A; Meier, H P; Straub, R; Gerber, V

2009-04-01

Equine Infectious Anemia (EIA) is a reportable, eradicable epizootic disease caused by the equine lentivirus of the retrovirus family which affects equids only and occurs worldwide. The virus is transmitted by blood, mainly by sanguivorous insects. The main symptoms of the disease are pyrexia, apathy, loss of body condition and weight, anemia, edema and petechia. However, infected horses can also be inapparent carriers without any overt signs. The disease is diagnosed by serological tests like the Coggins test and ELISA tests. Presently, Switzerland is offi cially free from EIA. However, Switzerland is permanently at risk of introducing the virus as cases of EIA have recently been reported in different European countries.

An analysis of anemia and child mortality

NARCIS (Netherlands)

Brabin, B. J.; Premji, Z.; Verhoeff, F.

2001-01-01

The relationship of anemia as a risk factor for child mortality was analyzed by using cross-sectional, longitudinal and case-control studies, and randomized trials. Five methods of estimation were adopted: 1) the proportion of child deaths attributable to anemia; 2) the proportion of anemic children

Management of Iron-Deficiency Anemia in Inflammatory Bowel Disease

DEFF Research Database (Denmark)

Nielsen, Ole Haagen; Ainsworth, Mark; Coskun, Mehmet

2015-01-01

Anemia is the most frequent complication of inflammatory bowel disease (IBD), but anemia, mostly due to iron deficiency, has long been neglected in these patients. The aim was to briefly present the pathophysiology, followed by a balanced overview of the different forms of iron replacement...... available, and subsequently, to perform a systematic review of studies performed in the last decade on the treatment of iron-deficiency anemia in IBD. Given that intravenous therapies have been introduced in the last decade, a systematic review performed in PubMed, EMBASE, the Cochrane Library......, and the websites of WHO, FDA, and EMA covered prospective trials investigating the management of iron-deficiency anemia in IBD published since 2004. A total of 632 articles were reviewed, and 13 articles (2906 patients) with unique content were included. In general, oral supplementation in iron-deficiency anemia...

Aldehyde dehydrogenase 2 in aplastic anemia, Fanconi anemia and hematopoietic stem cells.

Science.gov (United States)

Van Wassenhove, Lauren D; Mochly-Rosen, Daria; Weinberg, Kenneth I

2016-09-01

Maintenance of the hematopoietic stem cell (HSC) compartment depends on the ability to metabolize exogenously and endogenously generated toxins, and to repair cellular damage caused by such toxins. Reactive aldehydes have been demonstrated to cause specific genotoxic injury, namely DNA interstrand cross-links. Aldehyde dehydrogenase 2 (ALDH2) is a member of a 19 isoenzyme ALDH family with different substrate specificities, subcellular localization, and patterns of expression. ALDH2 is localized in mitochondria and is essential for the metabolism of acetaldehyde, thereby placing it directly downstream of ethanol metabolism. Deficiency in ALDH2 expression and function are caused by a single nucleotide substitution and resulting amino acid change, called ALDH2*2. This genetic polymorphism affects 35-45% of East Asians (about ~560 million people), and causes the well-known Asian flushing syndrome, which results in disulfiram-like reactions after ethanol consumption. Recently, the ALDH2*2 genotype has been found to be associated with marrow failure, with both an increased risk of sporadic aplastic anemia and more rapid progression of Fanconi anemia. This review discusses the unexpected interrelationship between aldehydes, ALDH2 and hematopoietic stem cell biology, and in particular its relationship to Fanconi anemia. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Comprehensive Review of Preschool Age Anemia in the Pacific Island Jurisdictions.

Science.gov (United States)

Lin, Tiffany F; Huang, James N; Cash, Haley L

2017-12-01

Anemia can be an indicator of poor nutrition and health, and it can have significant consequences. Children are disproportionately affected by anemia. This comprehensive review summarizes the available literature on anemia prevalence in young children in the islands of the Oceania region. The anemia prevalence, the criteria used for diagnosis, the date the data was reported, and the types of samples collected were reviewed. Anemia prevalence estimates were reported for eighteen of the Pacific Island Jurisdictions. From the fifteen data sources that were evaluable, anemia prevalence ranged from 12.3% to over 70%. A major limitation in the data is a lack of representative primary data from many of the jurisdictions in the region. Prevalance estimates reported for those jurisdictions are estimated by regression analysis from the World Health Organization (WHO). Moreover, the primary data available does not use standardized reporting criteria. Nevertheless, this review serves as a new baseline for further investigations on the prevalence of anemia and a baseline for evaluating public health prevention and treatment measures to detect and improve anemia prevalence in the Pacific.

Iron-Deficiency Anemia

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Full Text Available ... A-Z Clinical Trials Publications and Resources Health Education and Awareness ... If your doctor diagnoses you with iron-deficiency anemia, your treatment will depend on the cause and severity of the condition. Your ...

Iron-Deficiency Anemia

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Full Text Available ... making new blood cells. Visit our Aplastic Anemia Health Topic to learn more. ... recommend that you take iron supplements, also called iron pills or oral iron, by mouth once or several times a ...

Iron-Deficiency Anemia

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Full Text Available ... anemia may cause the following complications: Depression Heart problems. If you do not have enough hemoglobin-carrying red blood cells, your heart has to work harder to move oxygen-rich blood through your ...

The reverse-mode NCX1 activity inhibitor KB-R7943 promotes prostate cancer cell death by activating the JNK pathway and blocking autophagic flux.

Science.gov (United States)

Long, Zhou; Chen, BaiJun; Liu, Qian; Zhao, Jiang; Yang, ZhenXing; Dong, XingYou; Xia, LiuBin; Huang, ShengQuan; Hu, XiaoYan; Song, Bo; Li, LongKun

2016-07-05

We explored the effects of KB-R7943, an inhibitor of reverse-mode NCX1 activity, in prostate cancer (PCa). NCX1 was overexpressed in PCa tissues and cell lines, and higher NCX1 levels were associated higher PCa grades. At concentrations greater than 10 μM, KB-R7943 dose-dependently decreased PC3 and LNCaP cell viability. KB-R7943 also increased cell cycle G1/S phase arrest and induced apoptosis in PC3 cells. KB-R7943 increased autophagosome accumulation in PCa cells as indicated by increases in LC3-II levels and eGFP-LC3 puncta. Combined treatment with chloroquine (CQ) and KB-R7943 decreased P62 and increased LC3-II protein levels in PC3 cells, indicating that KB-R7943 blocked autophagic flux. KB-R7943 induced autophagosome accumulation mainly by downregulating the PI3K/AKT/m-TOR pathway and upregulating the JNK pathway. In xenograft experiments, KB-R7943 inhibited tumor growth. Combined treatment with KB-R7943 and an autophagy inhibitor inhibited growth and increased apoptosis. These results indicate that KB-R7943 promotes cell death in PCa by activating the JNK signaling pathway and blocking autophagic flux.

Anemia of chronic disease is the more frequent type of anemia seen in patients with chronic idiopathic neutropenia of adults.

Science.gov (United States)

Papadaki, H A; Eliopoulos, D G; Valatas, V; Eliopoulos, G D

2001-04-01

This study describes the frequency and the type of anemia seen in patients with nonimmune chronic idiopathic neutropenia of adults (NI-CINA). We found that NI-CINA patients had low hemoglobin levels and increased serum concentrations of erythropoietin (EPO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta). The hemoglobin levels correlated positively with the number of circulating neutrophils and inversely with the levels of EPO and TNF-alpha but not of IL-1beta. Anemia, defined as the reduction of the hemoglobin below 12.0 g/dl for women and 13.3 g/dl for men, was found in 23 out of 148 patients studied, a proportion of 15.5%. Two of the anemic patients had iron deficiency anemia (8.7%), 11 had anemia of chronic disease (ACD; 47.8%) presenting with normal or slightly reduced erythrocytic indices, low serum iron, and increased serum ferritin, and the remaining ten had anemia of undefined pathogenesis (AUP; 43.5%) with normal or slightly decreased erythrocytic indices, serum iron ranging from 43 to 88 microg/dl, and ferritin values ranging from 12 to 50 ng/ml. We conclude that ACD is the more frequent type of anemia seen in patients with NI-CINA, and that pro-inflammatory cytokines, notably TNF-alpha, may be involved in the pathogenesis of both ACD and AUP, given that serum levels of the cytokine were significantly increased and that the EPO response to anemia was blunted in these patients. These findings further support our previously reported suggestion for the possible existence, in NI-CINA patients, of an unrecognized low-grade chronic inflammatory process that may be involved in the pathogenesis of the disorder.

Iron-Deficiency Anemia

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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...

HUBUNGAN KEKURANGAN VITAMIN A DENGAN ANEMIA PADA ANAK USIA SEKOLAH

Directory of Open Access Journals (Sweden)

Idrus Jus’at

2014-08-01

Full Text Available Anemia, terutama anemia defisiensi  besi, masih merupakan  masalah kesehatan masyarakat di Indonesia. Prevalensi anemia masih tinggi pada kelompok risiko tinggi yaitu ibu hamil, menyusui, balita, anak usia sekolah dan WUS. Selain kekurangan zat besi dalam  konsumsi  makanan dan penyakit infeksi, berbagai faktor mempunyai kontribusi relatif terhadap anemia. Tulisan ini bertujuan untuk mengetahui kontribusi relatif  status  retinol  terhadap  anemia  pada  anak  usia  sekolah.  Penelitian  dilakukan  di   Tasikmalaya  dan Ciamis  pada  173  anak  umur  5-9  tahun  dari  keluarga  miskin.  Hasil  penelitian  menunjukkan  prevalensi anemia  14,5  persen, prevalensi kurang vitamin A  (KVA  10,9  persen. Konsumsi energi, protein, zat besi, vitamin  C,  vitamin  B12,  folat,  dan  seng  masih  di  bawah  AKG  (2004.  Setelah  dikontrol  dengan  asupan energi,  protein,  dan  vitamin  B12  anak  yang  menderita  KVA  memiliki  odds  ratio  3,33  kali  untuk  menjadi anemia (p=0.063, 95%, CI 0,93-11.84 dibandingkan anak yang tidak KVA. Kata kunci: anemia, defisiensi vitamin A, anak usia sekolah

Treatment and management of myelofibrosis in the era of JAK inhibitors.

Science.gov (United States)

Keohane, Clodagh; Radia, Deepti H; Harrison, Claire N

2013-01-01

Myelofibrosis (MF) can present as a primary disorder or evolve from polycythemia vera (PV) or essential thrombocythemia (ET) to post-PV MF or post-ET MF, respectively. MF is characterized by bone marrow fibrosis, splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, and a collection of debilitating symptoms. Until recently, the therapeutic options for patients with MF consisted of allogeneic hematopoietic stem cell transplant (alloHSCT), the use of cytoreductive agents (ie, hydroxyurea), splenectomy and splenic irradiation for treatment of splenomegaly, and management of anemia with transfusions, erythropoiesis-stimulating agents (ESAs), androgens, and immunomodulatory agents. However, with increased understanding of the pathogenesis of MF resulting from dysregulated Janus kinase (JAK) signaling, new targeted JAK inhibitor therapies, such as ruxolitinib, are now available. The purpose of this article is to review the clinical features of MF, discuss the use and future of JAK inhibitors, reassess when and how to use conventional MF treatments in the context of JAK inhibitors, and provide a perspective on the future of MF treatment.

Iron-Deficiency Anemia

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Full Text Available ... and dark green leafy vegetables. Foods rich in vitamin C, such as oranges, strawberries, and tomatoes, may ... of other nutrients in your blood, such as vitamin B12 or folic acid. Visit our Pernicious Anemia ...

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Full Text Available ... your blood, such as vitamin B12 or folic acid. Visit our Pernicious Anemia Health Topic to learn ... recommend options such as taking your supplements with food, lowering the dose, trying a different type of ...

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Full Text Available ... as most of a newborn’s iron stores are developed during the third trimester of pregnancy. Children between ... This makes it harder to stop bleeding and can increase the risk of iron-deficiency anemia from ...

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Full Text Available ... Activities Obesity, Nutrition, and Physical Activity Population and Epidemiology Studies Women’s Health All Science A-Z Grants ... health for people with iron-deficiency anemia. Recipient Epidemiology Donor Studies program findings help to protect blood ...

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