bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid Wnt/β-Catenin Pathway Activation by Tobacco Smoke Modulates Cyclooxygenase-2 Expression in Cardiac Microvascular Endothelial Cells.
Authors: Barbieri Silvia S. , Ip Dawn , Howe Louise R. , Weksler Babette B. 
Published: April 2020

Abstract
While cigarette smoking is a major risk factor for atherosclerosis and for acute cardiovascular events, the toxic components of tobacco smoke (TS) and mechanisms producing cardiovascular dysfunction are unknown. Exposure to TS increases inflammation, thrombosis, and oxidation of LDL cholesterol and we have previously found that TS exposure activates several inflammatory genes in vascular cells. To address the mechanisms of TS-induced proatherosclerotic effects, we derived an immortalized line of mouse cardiac microvascular endothelial (MMCEC) cells by transfection of primary cells with lentiviral vectors encoding genes for telomerase and SV40 T antigen. These MMCEC grow indefinitely while retaining a normal endothelial phenotype, show contact inhibition, display EC markers such as PECAM, VE-cadherin, and von Willebrand factor, and develop an inflammatory phenotype when stimulated with cytokines. In response to interleukin-1β (IL-1 β), MMCEC induce cyclooxygenase-2 (COX-2) and produce prostaglandins; these effects are enhanced by a saline extract of TS in a dose- and time-dependent manner. Increased COX-2 expression accompanies atherosclerosis, while its prostaglandin products favor cell proliferation and decrease apoptosis. Moreover, β-catenin, a key component of cell-cell interactions, and a coactivator of the TCF/LEF (T-cell transcription factor/lymphoid enhancer binding factor) family of transcription factors, is also increased in atherosclerotic plaques. We therefore studied how TS exposure affected the Wnt/β-catenin pathway. IL-1 β and TS each stimulated β-catenin translocation from the plasma membrane to the nucleus of MMCEC within 1–2 hr, but addition of TS to cells exposed to IL-1 β stimulated translocation within minutes shown by confocal microscopy and western blotting. The enhanced β-catenin translocation induced by IL-1 β/TS was linked with rapid phosphorylation of Akt and glycogen synthase kinase 3β, which in turn decreased phosphorylation of β-catenin, preventing its proteosomal degradation. Conversely, when GSK3β, which stabilizes β-catenin, was blocked, COX-2 was induced. If β-catenin expression in MMCEC was directly inhibited by transfection of cells with short interfering RNA (siRNA) induction of COX-2 expression and prostaglandin production by IL-1 β/TS was markedly diminished. In addition, LY294002, an inhibitor of phosphatidylinositol-3-kinase, and AG1478, an EGFR inhibitor, also blocked IL-1 β/TS induced Akt phosphorylation, β-catenin translocation and COX-2 expression, as did selective inhibitors of p38 MAPK and MEK-1. Our data, using a novel endothelial cell model, demonstrate that the PI3K/GSK-3β regulated β-catenin pathway is important for COX-2-related proinflammatory and proatherosclerotic effects of tobacco smoke on vascular cells and indicate the interrelated signaling pathways involved. TS-related effects may similarly modulate other proatherosclerotic genes.
Relationships of Serum Ferritin, Transferrin Saturation, and HFE Mutations and Self-Reported Diabetes Mellitus in the Hemochromatosis and Iron Overload Screening (HEIRS) Study.
Authors: Acton Ronald T. , Barton James C. , Passmore Leah , Adams Paul C. , Speechley Mark R. , Dawkins Fitzroy W. , Sholinsky Phyliss , Reboussin David M. , McLaren Gordon D. , Harris Emily L. , Bent Thomas C. , Vogt Thomas , Castro Oswaldo 
Published: April 2020

Abstract
Mean serum ferritin concentration (SF) has been positively associated with diabetes mellitus in some racial/ethnic groups. We evaluated the associations of self-reported diabetes mellitus with SF, serum transferrin saturation (TfSat), and HFE C282Y and H63D mutations in six racial/ethnic groups recruited at five Field Centers in the multi-center, primary care-based HEIRS Study. Analyses were conducted on the 97,470 participants for whom pertinent data were available. Participants who reported that they had been previously diagnosed with diabetes mellitus and/or hemochromatosis or iron overload were compared to participants who did not report a previous diagnosis. The overall prevalence of diabetes mellitus was 13.8%; the highest prevalence was observed in Native Hawaiian/Pacific Islanders (20.1%). 2.0% of all participants with diabetes mellitus and 2.2% of whites with diabetes mellitus reported that they also had hemochromatosis or iron overload. Mean SF was elevated in women with diabetes mellitus in all racial/ethnic groups and in American Indian/Alaska Native men with diabetes mellitus. Mean SF was significantly lower in Asian men with diabetes mellitus. Mean TfSat was lower (or not increased) in participants with diabetes mellitus than in those without diabetes mellitus. There was no significant association of diabetes mellitus with HFE genotype. Mean SF was greater (p &lt;0.0001) in women with diabetes mellitus than in those without diabetes mellitus for HFE genotypes except C282Y/C282Y and C282Y/H63D. There was a significant positive association of log SF and diabetes mellitus in a logistic regression analysis after adjusting for age, gender, racial/ethnic group, HFE genotype, and Field Center. We conclude that SF is significantly associated with diabetes mellitus, even at levels of SF below those typically associated with hemochromatosis or iron overload.
Ferrochelatase Mutation Screening by Denaturing High Performance Liquid Chomatography in Idiopathic Acquired Sideroblastic Anemia (Refractory Anemia with Ringed Sideroblasts) and Erythrocytic Protoporphyria.
Authors: Hecksel Kathleen A. , Dewald Gordon W. , Steensma David P. 
Published: April 2020

Abstract
BACKGROUND: The molecular etiology of idiopathic acquired sideroblastic anemia (IASA), now considered a form of myelodysplastic syndrome, is currently unknown. Romslo et al (Blood 1982) reported a patient with IASA who had moderately elevated free erythrocytic protoporphyrin (FEP); this observation is now frequently made in IASA, helping distinguish IASA (high FEP) from inherited sideroblastosis (low FEP). In addition, rare patients with erythropoietic protoporphyria (EPP)—defined by cutaneous photosensitivity, dramatically elevated FEP levels, and germline point mutations in the ferrochelatase (FECH) gene at 18q21.3—have ringed sideroblasts in their marrow. We hypothesized that patients with IASA might have acquired somatic FECH mutations.
METHODS AND RESULTS: We designed a denaturing high performance liquid chromatography (DHPLC) assay to explore this possibility and to avoid problems related to mutation screening in the setting of mixed clonality. To validate the DHPLC assay, the coding region of the FECH gene from 2 molecularly undiagnosed EPP patients without liver disease was analyzed. In one patient, both a heterozygous 69delG mutation (GenBank Accession NM_000140) and heterozygosity for the FECH expression-modulating IVS3-48C/T polymorphism were detected. In the other patient, no FECH coding mutations or polymorphisms were detected, either by DHPLC or conventional dye sequencing. FEP measurements were then obtained on 2 IASA patients and were elevated (65 and 115 mcg/dL; normal 1–10 mcg/dL) with normal urine and fecal porphyrins. Genomic DNA obtained from these 2 patients as well as archival DNA from 30 other patients with IASA was amplified and tested for FECH mutations. No coding region mutations were detected. Synonymous polymorphisms in exon 7 (rs536765) and 9 (rs536560) were found in 6/32 (19%; normal heterozygosity 0.398) and 14/32 (44%; normal heterozygosity 0.402) samples, respectively. The IVS3-48C/T polymorphism (rs2272783) was found in 3/32 (9%) (prevalence in the general population is 11%, Gouya Nat Genet 2002). In addition, 3 intronic polymorphisms not in the refSNP database were detected: IVS8+34 C/T (2/32), IVS8-61delG (5/32), and IVS9-59delA (2/32).
CONCLUSION: IASA is not associated with coding mutations in FECH. Elevation of FEP in ASA must instead be due to the lack of mitochondrial iron in the proper form for incorporation into the porphyrin ring; attention should instead focus on factors responsible for maintaining the appropriate redox state and compartmentalization of iron. DHPLC can detect FECH mutations and polymorphisms, but because of the high frequency of the latter and the consequent need to sequence multiple exons, it is not a practical screening tool for studying undiagnosed EPP patients.
Gene Expression Profiling Reveals the Profound Up-Regulation of Hypoxia-Responsive Genes in Primary Human Astrocytes.
Authors: Mense Sarah M. , Zhou Mei , Sengupta Amitabha , Lan Changgui , Bentsman Galina , Volsky David J. , Zhang Li 
Published: April 2020

Abstract
Oxygen is vital for the development and survival of mammals. Lack of oxygen and oxygen sensing mechanisms have been implicated in the pathology of many CNS disorders, including stroke, head trauma, neural developmental problems associated with preterm birth, neoplasia and neurodegenerative diseases. In response to hypoxia, the brain initiates numerous adaptive responses at the organ level as well as at the molecular and cellular level, including the alteration of gene expression. Astrocytes play critical roles in the proper functioning of the brain. They are important for maintaining ion and pH homeostasis, for the synthesis and removal of neurotransmitters, such as GABA and glutamate, and for providing glucose supply to the brain. Recent evidence indicates that astrocytes regulate synaptic activity, synaptogenesis, and neurogenesis. Thus, the manner in which astrocytes respond to hypoxia is likely important in determining the outcome of brain hypoxia. Astrocytes are generally more resistant to energy failure than neurons. Astrocytes account for at least 15% of oxidative metabolism in the brain, and their respiratory rates are maintained at 85% of the basal level until oxygen is virtually exhausted. In this report, to better understand the molecular mechanisms governing astrocytic response to hypoxia, we used microarray gene expression profiling and data analysis algorithms to identify and analyze hypoxia-responsive genes in primary human astrocytes. We also compared the gene expression patterns in astrocytes with those of human HeLa cells and pulmonary artery endothelial cells (ECs). Remarkably, in astrocytes, 5 times as many genes were up-regulated as down-regulated, whereas in HeLa and pulmonary ECs, as many or more genes were down-regulated as up-regulated. More genes encoding hypoxia-inducible functions, such as glycolytic enzymes and angiogenic growth factors, were strongly induced in astrocytes compared to HeLa cells. The extent of induction was also greater than in HeLa cells. Further, gene ontology and computational algorithms revealed that many target genes of the EGF and insulin signaling pathways and the transcriptional regulators Myc, Jun and p53 were selectively altered by hypoxia in astrocytes and in HeLa cells to a lesser degree.
Figure Figure Figure Figure
In the case of astrocytes, the overwhelming induction of target genes of the EGF and insulin pathways, which are pro-survival, and other genes encoding growth factors and functions involved in carbohydrate metabolism may underlie their relative strong resistance to ischemic/hypoxic insults. These results provide a global view of the signaling and regulatory network mediating oxygen regulation in astrocytes, in comparison with that in HeLa cells.
Immature Reticulocyte Fraction after Iron Therapy for Iron Deficiency Anemia.
Authors: Yuh Young Jin , Kim Sung Rok , Han Tae Hee 
Published: April 2020

Abstract
Background: Automated counting of reticulocyte introduced new reticulocyte parameters such as immature reticulocyte fraction(IRF). IRF is thought to be more sensitive than absolute or corrected reticulocyte count for detecting recovery of bone marrow function. The aim of this study is to assess the role of IRF for predicting the response of therapy after treatment of iron deficiency anemia.
Methods: Patients with previously untreated iron deficiency anemia (blood hemoglobin &lt; 10.0g/dL and serum ferritin &lt; 10ng/mL) were enrolled into this study. On the 8th day of iron therapy, Complete blood count(CBC) with reticulocyte count and IRF was assessed by RAM-1 reticulocyte autoanalyzer(Sysmex. Tokyo, Japan). IRF was defined as sum of the reticulocyte fraction of high-fluorescence intensity regions plus the fraction of middle fluorescence intensity regions. After 1 month of iron therapy, CBC was reassessed to evaluate the response of iron therapy. The correlation of the 8th day IRF and the change of hemoglobin level after 4 weeks of therapy was evaluated. The 8th day corrected reticulcyte count was also evaluated.
Results: From Jan. 2001 to May 2003, 27 patients with iron deficiency anemia (3 men and 24 women) entered into this study. We evaluated 21 patients, excluding 6 patients who were lost to follow-up or refused blood sampling after 1 month of iron therapy. The range of pretreatment hemoglobin level was 3.3–9.7g/dL (median 7.5/dL). The 8th day IRF was 0.06–0.39(median 0.15). Ten patients had the low IRF (IRF ≤ 0.15). Four of them (40%) had their hemoglobin level increased by more than 3g/dL. On the other side, 11 patients had high IRF (IRF &gt; 0.15) and 10 of them (91%) had their hemoglobin level increased by more than 3 g/dL. This difference was significant (P=0.024). However, the 8th day IRF was not correlated with the change of hemoglobin as strongly as the 8th day corrected reticulocyte count (Pearson coefficient 0.420 vs 0.693).
Conclusion: For the patients with iron deficiency anemia, the 8th day of treatment IRF correlates with the response of iron treatment, but the 8th day of treatment corrected reticulocyte count has a stronger correlation.
The Prevalence of Anemia among Healthy Women in Japan.
Authors: Kusumi Eiji , Kami Masahiro , Shoji Midori , Endou Shigeyuki , Kishi Yukiko , Shibata Taro , Murashige Naoko , Hamaki Tamae , Matsumura Tomoko , Yuji Koichiro , Yoneyama Akiko 
Published: April 2020

Abstract
Introduction
Anemia is common among young women. National Health and Nutrition Examination Survey (NHENES) revealed that the insufficient iron intake is one of the leading causes of anemia in the US. In Europe and the US, iron fortification of flour increased oral iron intake and decreased anemia prevalence from 30% to 10%. The National Nutrition Survey in Japan by the Ministry of Health, Labour and Welfare in 2002 revealed the estimated anemia prevalence of 19 %. Currently, no nationwide preventive policy aims at iron deficiency anemia. However, the prevalence of 19% was estimated based on 3,156 persons in the Survey.
Objective
The endpoint of this study was to estimate anemia prevalence among healthy Japanese woman based on a larger sample size.
Method
We collected data from consecutive check-up examination records of apparently healthy women in different age groups in Toranomon Hopital (between January 2002 and March 2005, n = 8,264) and Yuai Memorial Hospital (between February 1998 and February 2005, n = 5,153). We defined hemoglobin lower than 12 g/dL as anemia, hemoglobin lower than 10 g/dL as severe anemia, and mean corpuscular volume lower than 80 fl as microcytic anemia.
Results
The median age was 47 years (range, 11–87 years). Of the 13,147 persons, anemia was identified in 2,331 (17.3 %), and severe and microcytic anemia in 438 (3.3 %) and 700 (5.2 %), respectively. The prevalence of anemia and median hemoglobin values by age groups are shown in Figure. The median hemoglobin values tended to be lower in women of the age groups with high anemia prevalence.
Conclusion
The prevalence of anemia among women of child-bearing age and of working age is high in Japan. As the Japanese population is rapidly decreasing and aging, some action needs to be considered to improve quality of life during pregnancy and working efficiency.
Figure Figure.
Treatment of Severe Aplastic Anemia with Combined Immunosuppression: Antithymocyte Globulin (ATG), Cyclosporine A (CSA), and Mycophenolate Mofetil (MMF).
Authors: Scheinberg Phillip , Nunez Olga , Wu Colin O. , Young Neal S. 
Published: April 2020

Abstract
Severe aplastic anemia can be successfully treated with immunosuppressive therapies (IST) or hematopoietic stem cell transplantation (HSCT). Response rates with horse anti-thymocyte globulin (ATG) plus cyclosporine (CsA) are about 60–70%, and robust responders have excellent long term survival (Rosenfeld, Follmann et al. 2003). Relapse require reinstitution of IST and does not negatively affect survival. We introduced a third immunosuppressive agent to standard horse ATG/CsA, mycophenolate mofetil, in an attempt to improve response rate, survival and to decrease the relapse rate and clonal evolutions to myelodysplasia or leukemia. MMF blocks the proliferation of active lymphocytes by the inhibition of the enzyme inosine monophosphate dehydrogenase, an important step in purine and therefore DNA synthesis. MMF immunosuppression is due to direct inhibition of T cell proliferation and therefore, would be anticipated to favor the induction of tolerance by selective depletion of active lymphocytes. MMF has been employed as a “kidney-sparing” adjunct to CSA in renal and other solid organ transplantations, post-HSCT, and in certain autoimmune diseases with a favorable toxicity profile. A total of 104 consecutive patients with SAA were treated with horse ATG/CsA/MMF from May 1999 to June 2003 at the Warren Grant Magnuson Clinical Center at the National Institutes of Health in Bethesda, MD. Response was defined by blood counts no longer satisfying criteria for severe AA. The overall response rate at 6 months was 62%, with 24 (37% of responders) patients relapsing at a median of 389 days from ATG. Fifteen relapses occurred after CsA was discontinued at 6 months but before 18 months, while patients were still on MMF. Nine patients showed evidence of clonal evolution following ATG, five responders and 4 nonresponders. The median survival among responders was not reached and among nonresponders was 1,759 days. There was no difference in overall survival among patients who relapsed and those who did not relapse. Over half of the relapses occurred during MMF administration (15 of 24), suggesting that this drug is not active in preventing relapses among responders. Evolution to clonal disorders did not change with the intensification of immunosuppression with MMF. Despite a strong theoretical rationale for its use, MMF did not result in improvement in response or relapse rates, and it cannot be routinely recommended as a CsA-sparing agent in responders with poor tolerability to CsA.
Hematopoietic Response to Extended Dosing of Epoetin alfa 60,000 U Every 2 Weeks in Anemic Cancer Patients Not Receiving Therapy: Final Results.
Authors: Shasha Daniel , Henry David H. 
Published: April 2020

Abstract
Epoetin alfa administered weekly raises hemoglobin (Hb) in anemic cancer patients not receiving therapy. For optimal management of this group of patients more information is needed about extended dosing intervals. The objective of this open-label, single arm, multicenter study was to evaluate the hematopoietic response (HR) when anemic cancer patients not receiving chemotherapy (CT) or radiotherapy (RT) were treated with 60,000 U of epoetin alfa every two weeks (Q2W). Patients with non-myeloid malignancy, no CT within 8 weeks or RT within 4 weeks prior to study entry, and baseline Hb ≤ 11 g/dL were enrolled. Epoetin alfa was administered at 60,000 U SC Q2W for 12 weeks. If Hb increased &lt; 1 g/dL after 4 weeks, epoetin alfa was increased to 80,000 U SC Q2W. Epoetin alfa was held for Hb &gt; 13 g/dL. Patients were to receive iron supplementation daily at physician’s discretion. The primary efficacy endpoint was the proportion of patients achieving HR (defined as a ≥ 2 g/dL increase in Hb from baseline and/or Hb ≥ 12 g/dL during the treatment period, independent of transfusion within 28 days). Fifty-seven patients were enrolled and 56 met the criteria for efficacy analyses (received ≥ 1 dose of epoetin alfa and had ≥ 1 post-baseline Hb or transfusion evaluation). Mean age was 71.7 ± 9.3 years, 35.7% of patients were male, and mean baseline Hb was 10.2 ± 0.7 g/dL. HR was achieved in 43/56 (76.8%) patients. Mean change in Hb from baseline was 1.5 ± 0.8 g/dL (n=51) after 4 weeks, and 1.8 ± 1.0 g/dL (n=49) after 8 weeks on study. Nine (15.8%) patients had a dose increase and 22 (38.6%) had a dose held. Three (5.4%) patients received RBC transfusion and 37 (64.9%) received iron supplementation. The most common adverse events were peripheral edema, dizziness, nausea, and asthenia. Two (3.5%) patients experienced a clinically relevant thrombovascular event (TVE). No deaths were reported. This study suggests that cancer patients with anemia not receiving CT or RT can be treated effectively and safely with 60,000 U epoetin alfa every two weeks.
Vascular Growth Factors in Patients with Sickle Cell Disease.
Authors: Duits Ashley J. , Schnog John B. 
Published: April 2020

Abstract
Angiogenesis plays a central role in neovascular processes. In sickle cell patients neovascularization is considered a common feature that is associated with complications such as retinopathy and cerebrovascular disease. Several studies have reported increased vascular growth factor levels such as vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) in small groups of patients. Recently the angiopoietin/Tie2 system has been shown to be of major importance in vessel maturation. In order to thoroughly characterize vascular growth factor profiles in sickle cell patients we analyzed serum levels of VEGF, PlGF, Angiopoietin-1, Angiopoietin-2, Tie-2 and erythropoietin (EPO) during the asymptomatic phase as well as during painful crises in HbSS patients (n=42) and compared these to levels in HbAA controls (n=30). Also, levels were compared between patients with and without a history of acute vaso-occlusive complications the year prior to sample collection. Serum Angiopoietin-2, Tie-2 and EPO levels were significantly higher in sickle cell patients as compared to controls (p&lt;0.01, p=0.03 and p&lt;0.01 respectively), whereas PlGF and VEGF serum levels were similar between patients and controls (p= 0.21 and p=0.5). Only Angiopoietin-2 and EPO serum levels were significantly increased in sickle cell patients during acute vaso-occlusive crises as compared to levels in asymptomatic patients (p&lt;0.01 and p=0.03 respectively). No differences were detected in measured parameters between patients with a history of acute vaso-occlusive complications as compared to patients without acute vaso-occlusive complications in the preceding year. Our results show a specific pattern of angiopoietins in sickle cell patients. Considering the importance of endothelial cell activation in sickle cell disease and the regulation of endothelial cell survival and blood vessel maturation by the angiopoietin/Tie-2 system, further analysis of angiogenesis in sickle cell disease is warranted.