bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Risk Pregnancies in Women with Diamond Blackfan Anaemia: A Survey of 64 Pregnancies from the French and German Registries.
Authors: Leblanc Thierry , Faivre Laurence , Meerpohl Jorg , Da Costa Lydie , Nouvel Christian , Bauters Francis , Coiffier Bertrand , Peaud Pierre-Yves , Rispal Patrick , Berrebi Alain , Berger Claire , Varet Bruno , Niemeyer Charlotte , Tchernia Gil 
Published: April 2020

Abstract
Diamond Blackfan anaemia (DBA) is a rare disorder characterised by pure red cell aplasia and inconstant congenital abnormalities. Few data are available concerning pregnancy in DBA affected women.
We report on 60 women (age&gt;18 yr) included in the French and German DBA registries. Among them, 26/60 experienced one or several pregnancies. Mean age at 1st pregnancy was 24 yr and the mean number of pregnancies by woman was 2.5. A total of 64 pregnancies occurred, 22 being normal and 42 being complicated (66%). Eight women experienced only normal pregnancies and 18 experienced at least one complicated pregnancy. Complications included abortions: 26 of which 24 were spontaneous, in utero foetal deaths:5, foetal malformations:7, intrauterine growth retardation:10, pre-term deliveries:7, gestational diabetes:2, pre-eclampsia:5 and retro-placental haematomas:3 (more than 1 complication occurred in some pregnancies). A pathological examination of the placenta was performed in 4 cases and demonstrated significant infarctions in 3.
As a result of those 64 pregnancies, only 34 children were born alive (53%) from whom 14 were DBA-affected (41%). All women survived. In most cases, treatment with transfusion or steroid was increased during pregnancy.
When complicated and normal pregnancies were compared, no obvious correlation between the outcome of the pregnancy and clinical or biological features of maternal DBA, mother treatment, genetic status (RPS19 gene mutation present or not) or the status of the child were found. This suggests that at least some complications may be related to the affected mothers, irrespective of the DBA status of their offspring. Actually, many of these complications are similar to those observed in pregnancies associated with vascular-placental disease.
Among the 34 women who did not present any pregnancy, 20 did not desire children for various reasons, 4 had a follow-up for infertility and 10 had severe polymorbidity. Infertility was likely to be treatment related (iron overload or bone marrow graft side effects).
From this study together with the literature data, we conclude that pregnancies in DBA affected women must be managed as high-risk pregnancies. Such pregnancies should therefore be carefully monitored with a satisfying control of anaemia, preferably with transfusions, and ultrasound and Doppler follow-up. Early introduction of aspirin, should be discussed especially when a woman experienced a previous complicated pregnancy. An international prospective follow-up of pregnancies in DBA is now required in order to confirm the association with placenta-vascular disease features and to improve the outcome of pregnancy in women with DBA
Somatic Mosaicism and Variable Expressivity in Diamond Blackfan Anemia (DBA): A Large Deletion Involving the 19q13 Locus in a Patient with Transient Anemia.
Authors: Garelli Emanuela , Quarello Paola , Campagnoli MariaFrancesca , Brusco Alfredo , Carando Adriana , Menegatti Elisa , Crescenzio Nicoletta , Foglia Luiselda , Dianzani Irma , Ramenghi Ugo 
Published: April 2020

Abstract
DBA (MIM 205900) is a rare, pure red blood cell aplasia of childhood due to an intrinsic defect in erythropoietic progenitors, accompanied by somatic malformations in about 40% of cases. Anemia is corrected by steroid treatment in half of patients; non-responders need chronic transfusions or stem cell transplantation. Heterozygous mutations in the RPS19 gene, mapping in the chromosomal region 19q13.2 and encoding for a ribosomal protein of the small subunit, are found in 25% of patients. Deletions spanning the 19q13 locus and involving RPS19 gene have yet been reported in literature; these patients showed more severe manifestations of the disease with skeletal malformations, profound anemia unresponsive to steroids needing regular red blood transfusions and mental retardation.
We report the first case of DBA due to mosaicism for a deletion on chromosome 19q13 involving RPS19 gene. The large deletion involving the maternal allele, spanning an interval restricted by loci D19S220 and D19S178, was identified by segregation analysis of 19q polymorphic markers. To assess the degree of mosaicism semiquantitative SNapShot analysis was performed with detection of one RPS19 copy in 60% of peripheral blood mononuclear cells. Mosaicism was also found in oral and urinary epithelium cells. Our patient had been affected since infancy by hyporegenerative anemia, that had spontaneously remitted at the age of ten; he showed neither malformations nor overt mental retardation. His parents and a brother are healthy and do not carry the deletion.
The involvement of tissues of different embryologic origin suggests that the deletion has appeared in an early stage of embryological development. Our findings explain the milder than expected phenotype and suggest that somatic mutations that lead to tissue mosaicism might contribute to variable expressivity of DBA. The presence of blood cells without deletion might also justify the observed hematologic remission. Mosaicism must be taken into account for genetic counselling in this patient.
Maintenance Dosing with Epoetin alfa Every Three Weeks (Q3W) in Anemic Patients with Cancer Receiving Chemotherapy Every Three Weeks: Final Results.
Authors: Montoya Vernon P. , Xie John , Woodman Richard C. 
Published: April 2020

Abstract
Although epoetin alfa is commonly used weekly for the treatment of chemotherapy (CT)-induced anemia, most CT is given at three week intervals. Therefore, to provide increased patient convenience we examined a dosing regimen that would allow patients to receive epoetin alfa 80,000 U Q3W during maintenance therapy. This open-label, multi-center study had two phases: Initiation Phase (IP) of 60,000 U QW to achieve target hemoglobin (Hb) of 12 g/dL (maximum duration 12 weeks), followed by a Maintenance Phase (MP) of 80,000 U Q3W to maintain Hb between 11.0 and 12.5 g/dL. Only those patients achieving Hb ≥ 12 g/dL in the IP entered the MP; once target Hb was achieved, patients proceeded to MP at the beginning of their next full CT cycle. Patients were withdrawn from the MP if Hb decreased to &lt; 11 g/dL. Doses were held for Hb &gt; 13 g/dL and reduced for rate of rise &gt; 1.3 g/dL/2 weeks. Maximum study duration (IP + MP) was 24 weeks. Patients ≥ 18 years of age with non-myeloid malignancy, baseline Hb ≤ 11 g/dL, and CT planned Q3W for ≥ 15 weeks were enrolled. Endpoints included proportion of patients achieving hematopoietic response in the IP (≥ 2 g/dL Hb increase from baseline or Hb ≥ 12 g/dL) and proportion maintaining mean Hb between 11.0 and 12.5 g/dL in the MP. Also analyzed was the proportion of patients maintaining mean Hb between 11.0 and 13.0 g/dL in the MP. A total of 115 patients were enrolled and received at least one dose of epoetin alfa; mean age was 62.2 ± 11.9 years, 66.1% were female, mean baseline Hb was 10.2 ± 0.8 g/dL, and 86.1% had solid tumors. During the IP, 84 of 115 (73.0%) patients achieved hematopoietic response (≥ 2 g/dL Hb increase from baseline or Hb ≥ 12 g/dL). Seventy-three patients (63.5%) who achieved Hb ≥ 12 g/dL entered the MP after a median of 6.0 weeks in IP and spent a mean of 9.8 weeks in MP. Fifty-four of 73 (74.0%) maintained an average Hb between 11.0 and 12.5 g/dL over the course of the MP; 64 (87.7%) maintained an average Hb between 11.0 and 13.0 g/dL over the course of the MP. Twenty-five (34.2%) patients were withdrawn from the MP because Hb decreased to &lt; 11 g/dL. Of 115 patients dosed in IP, 30 (26.1%) had doses reduced and 31 (27.0%) had doses held; of 73 patients dosed in MP, 9 (7.8%) had doses reduced and 16 (13.9%) had doses held. Fifty-one (44.3%) patients experienced serious adverse events. Eleven (9.6%) patients experienced clinically relevant thrombotic vascular events. Two and 4 patients discontinued due to adverse events in the IP and MP, respectively. Eight (7.0%) patients died during the study or within 30 days after last study dose. Although 60,000 U QW was used during the IP to achieve a HR, 40,000 U QW is the recommended initiation dose of epoetin alfa. This study suggests that epoetin alfa 80,000 U administered every three weeks to patients on a Q3W CT regimen is an effective option for maintenance therapy of CT-induced anemia.
The Minimal Epo Receptor Allele, EpoR-H, Regulates ERK1,2, (But Not JNKs or p70S6K), and Induces Pim-1, SOCS3 and Oncostatin-M (But Not BcL-XL) in Primary Erythroblasts.
Authors: Menon Madhu P. , Cuetara Bethany , Houde Estelle , Fang Jing , Bogacheva Olga , Bogachev Oleg , Karur Vinit , Ufkin Melanie , Wojchowski Don 
Published: April 2020

Abstract
In studies of core Epo receptor signals that are necessary-and-sufficient for erythroblast development, we have shown that an EpoR-PY343-Stat5 axis is required for efficient erythropoiesis during anemia. This involved analyses of knocked-in truncated Epo receptor alleles that retain only a PY343 Stat5 binding site (EpoR-H allele), or lack all cytoplasmic PY motifs (EpoR-HM allele). Presently we have analyzed core signaling capacities of these receptor forms (and the wt-EpoR) in purified developmentally-staged marrow- derived erythroblasts. Analyses of JNKs, p70s6K and ERKs revealed that JNK and p70s6K activation is mediated by non-essential C-terminal EpoR domains. ERKs, in contrast, remained coupled to EpoR-H and EpoR-HM forms. EpoR-H/PY343/Stat5 response genes that might support EpoR-H’s wild-type activity next were analyzed. Despite evidence for Stat5 binding at a Bcl-x intron-1 element, no significant Epo-induction of Bcl-x transcripts was detected for any EpoR allele. In contrast, Pim-1, oncostatin-M and SOCS-3 were induced multi-fold in wt-EpoR and EpoR-H, but not EpoR-HM erythroblasts (and for EpoR-HM, no activation of Stat-5, -1 or-3 was detectable). In addition, receptor cross-talk analyses revealed that Kit selectively modulates EpoR-PY343-Stat5- dependent SOCS-3 and oncostatin-M transcription, and enhances Pim-1 expression several-fold via apparent post-transcriptional mechanisms. Epo action therefore is proposed to depend primarily on the regulation of ERKs, Pim-1 and possibly oncostatin-M (but not JNKs, p70S6K or Bcl-x).
The PAR-1-Stimulated Platelet Subpopulation That Binds Factor Xa Also Expresses Matrixmetalloproteinase and Calpain Activities Resulting in Population-Specific GP1bα Shedding and Platelet Vesiculation.
Authors: London Fredda S. 
Published: April 2020

Abstract
We previously showed that only a subpopulation of platelets responds to stimulation by strong agonists with exposure of coagulation factor binding sites. The subpopulation of SFLLRN-amide or collagen-stimulated platelets that bound coagulation factor Xa showed 50% decreased surface glycoprotein 1bα (GP1bα) and 60% reduced forward scatter relative to unstimulated platelets. While collagen-stimulated Xa-negative platelets lost no GP1b/IX/V surface density, the PAR-1-stimulated Xa-negative population lost 25% of both GP1bα and GPIX surface density signifying decreased GP1b/IX/V complex following PAR-1 stimulation. The PAR-1-stimulated Xa-positive platelets showed a discrepancy between the surface densities of GPIX and GP1bα that suggested a procoagulant subpopulation-specific shedding of GP1bα. While Xa-positive PAR-1-stimulated platelets pretreated with 10μM GM6001, a nonspecific inhibitor of matrixmetalloproteinases, recovered 30% of the lost surface GP1bα, bringing the GP1bα /GPIX ratio to ~1, collagen-stimulated loss of GP1bα on Xa-positive platelets was little affected by GM6001 pretreatment, and GP1bα on Xa-negative platelets was unaffected by GM6001 pretreatment. While inhibition of calpains by pretreatment of platelets with 100μM calpeptin had little effect on agonist-stimulated GP1bα shedding, calpeptin pretreatment resulted in 50% decreased loss of GP1bα/GPIX from PAR-1-stimulated Xa-negative platelets, in a 35–45% loss of the Xa-positive subpopulation resulting from PAR-1 stimulation, in 25% increased forward scatter from all agonist-induced Xa-positive populations, and in a 40–50% decrease in positive events occurring outside the defined platelet region. On the contrary, GM6001 inhibition of GP1bα shedding had no effect on either the size of the Xa-positive subpopulation, on the density of binding sites or on forward scatter. Platelet vesiculation would produce smaller platelets with decreased forward scatter, and microparticles. Calpain, previously implicated in platelet vesiculation, appears to mediate specific vesiculation of Xa-positive platelets. In summary, PAR-1 agonists and collagen recruit a platelet subpopulation to undergo specific membrane changes exposing binding sites for coagulation enzymes factors IXa and Xa. This procoagulant subpopulation recruited by PAR-1 signaling is also notable for specific matrixmetalloprotease activities leading to procoagulant population-specific GP1bα shedding. Calpain activity mediates membrane vesiculation of procoagulant platelets resulting from both collagen- and PAR-1-stimulation leading to smaller procoagulant platelets and to platelet microparticles.
Akt2 Supports aIIbb3-Dependent Reorganization of the Actin Cytoskeleton in Platelets.
Authors: August Shelley , Woulfe Donna S. 
Published: April 2020

Abstract
Akt is a serine-threonine kinase with well-described roles in growth and metabolism. Previous studies from our laboratory have shown that Akt also plays important roles in platelet function in vitro and in thrombus formation in vivo. Two isoforms are present in mouse platelets, Akt1 and Akt2, with Akt2 being the dominant isoform. Our previous studies have shown that platelets from Akt2−/− mice have marked defects in aggregation, a- and dense granule secretion, and fibrinogen binding. Each of these platelet functions depends in part on the function of the major platelet integrin, aIIbb3. However, whether Akt might regulate the function of aIIbb3 is still unknown. To determine whether Akt regulates aIIbb3-dependent signaling, first the rate of thrombin-initiated clot retraction was compared in platelet-rich plasma (PRP) from wild-type versus Akt2−/− mice. Akt2−/− platelets have a delay in the aIIbb3-dependent retraction of the fibrin clot compared to their wildtype counterparts. Akt2−/− platelets also have a delay in aIIbb3-dependent spreading on immobilized fibrinogen. However, adhesion to immobilized fibrinogen was normal in these platelets, suggesting that the spreading defect is due to a defect in outside-in signaling by the integrin, rather than in fibrinogen binding. Furthermore, unstimulated platelets expressing a constitutively active form of Akt spread more rapidly on fibrinogen-coated slides and generate more filopodial extensions than wildtype platelets, suggesting that Akt activation may be sufficient to induce outside-in signaling and /or cytoskeletal remodeling. Interestingly, integrin activation was not sufficient to induce Akt phoshorylation, suggesting that integrin activity is downstream rather than upstream of Akt activation. Taken together, these results suggest that integrin aIIbb3 is not necessary for Akt activation; however, Akt promotes outside-in signaling and cytoskeletal remodeling by aIIbb3.
Mechanism of Activation and Role of Extracellular Signal Regulated Kinase in ADP-Induced Thromboxane A2 Generation in Platelets.
Authors: Garcia Analia , Shankar Haripriya , Kunapuli Satya P. 
Published: April 2020

Abstract
We have previously shown that ADP-induced thromboxane A2 generation in platelets requires co-ordinated signaling events from the Gq-coupled P2Y1 receptor and the Gi-coupled P2Y12 receptor in addition to outside-in signaling. It is also known that ADP-induced thromboxane A2 generation is completely abolished in the presence of extracellular calcium, but the mechanism of this negative regulation is not known. In this study we sought to identify the important signaling molecules in ADP-induced thromboxane A2 generation in platelets and characterize the regulation of these molecules by extracellular calcium. Erk2 activation occurred when outside-in signaling was blocked, indicating that it is a downstream event from the P2Y receptors. However, blockade of either P2Y1 or the P2Y12 receptors with corresponding antagonists completely abolished Erk phosphorylation, indicating that both P2Y receptors are required for ADP-induced Erk activation. However, blockade of Erk upstream kinase MEK had not effect on ADP-induced aggregation in aspirin-treated platelets, but dramatically inhibited aggregation as well as secretion in non-aspirinated platelets, suggesting that Erk might be important for thromboxane A2 generation. Finally, PP1 and PP2, inhibitors of Src family kinases, but not PP3, an inactive analog, abolished ADP-induced Erk phosphorylation and thromboxane A2 generation. Interestingly, ADP-induced Erk phosphorylation was completely inhibited in the presence of extracellular calcium, indicating that Erk is a key signaling molecule regulated by extracellular calcium in the negative regulation of thromboxane A2 generation. We conclude that Erk2 is activated downstream of P2Y receptors through a complex mechanism involving Src kinases and plays an important role in ADP-induced thromboxane A2 generation. We also conclude that extracellular calcium blocks ADP-induced thromboxane A2 generation through the inhibition of Erk activation.
Human Plasma Gelsolin Inhibits Cellular Responses to Platelet Activating Factor (PAF).
Authors: Magnuson-Osborn Teresia A. , Dahlgren Claes , Hartwig John H. , Stossel Thomas P. 
Published: April 2020

Abstract
Gelsolin is a highly conserved intracellular actin-binding protein with an extracellular isoform named plasma gelsolin (pGSN). Relatively high (250 mg /L) blood concentrations of pGSN decrease in response to trauma, major surgery, sepsis, burns, ionizing radiation, and hyperoxia. Depletion of pGSN to a critical (~20%) level precedes and predicts complications of primary injuries such as lung permeability changes, ARDS, assisted ventilation and death. Administration of recombinant pGSN ameliorates such complications and reduces mortality in animal models. A proposed mechanism for pGSN’s protective effects is that it inhibits inflammatory mediators generated during primary injuries, since pGSN binds bioactive mediators, including lysophospatidic acid (LPA) and endotoxin in vitro. Because of its structural similarity we hypothesized that plasma gelsolin binds also to the potent lipid mediator platelet activating factor (PAF) and report here on the inhibition of PAF-induced cellular activation. Recombinant pGSN inhibited PAF-induced P-selectin up-regulation by human platelets as measured by flow cytometry. A ten- to 40-fold molar excess (0.5–20 μM) of pGSN over PAF inhibits P-selectin expression by 40 to 80%. The concentrations of plasma gelsolin used approximate the ~2–3 μM concentrations in plasma, and the molar excess of pGSN over PAF is probably greater in biological systems, where PAF has nanomolar affinity for its receptor. pGSN also inhibited PAF-induced superoxide anion (O2-) production (measured by chemiluminescence) of human neutrophils (PMN) in a concentration-dependent manner. The inhibition was up to 80% at a concentration of 10 μM (tenfold molar excess over PAF). A phospholipid-binding peptide derived from pGSN (QRLFQVKGRR) also inhibited PAF-mediated O2- generation by PMN. The inhibition was 65% at a 1:1 molar ratio (1 μM). In conclusion pGSN interferes with PAF-induced cellular activation in vitro, suggesting a mechanism for the protective role of plasma gelsolin that has been observed in vivo.
Effect of DMT1 Mutations at Birth and in the First Years of Life.
Authors: Achille Iolascon , Maria d’Apolito , Veronica Servedio , Luigia De Falco , Antonio Piga , Clara Camaschella 
Published: April 2020

Abstract
Divalent metal transporter 1 (DMT1) is involved in dietary iron uptake on the luminal side of duodenal enterocytes and transfers iron from the endosome to the cytosol in the marrow erythroblasts. Spontaneous (mk mice and Belgrade rats) or acquired (DMT1 -/- mice) inactivation of DMT1 in rodents produces a severe microcytic anemia at birth, caused by inefficient intestinal iron absorption and defective iron utilization in erythroid cells. The first reported patient with DMT1 mutations had microcytic anemia and iron overload in adult life. We here report the hematological phenotype of a newborn with a severe mycrocytic anemia (Hb 4 g/dL, MCV 71 fL) at birth and during the first months of life. Serum iron, transferrin saturation and serum ferritin were 160 microg/L, 100% and 846 ng/ml respectively at 3 months of age. Hepatic iron overload wad documented at the age of 5 years by both non invasive SQUID and liver biopsy. Sequence analysis of genomic DNA of the family revealed that the child was compound heterozygote for two novel DMT1 mutations, inherited by the asymptomatic parents. The first change deleted 3 bp (c.310 - 3_5del CTT) in intron 4 resulting in a splicing abnormality and the skipping of exon 5. The second was C&gt;T 1246 substitution that causes arginine &gt; cysteine replacement at position 416 (p. R416C) in the protein. This missense affects an highly conserved residue in one of the putative transmembrane domains. A striking reduction of the protein in peripheral blood cells of the proband was demonstrated by western blot using an anti-DMT1 antibody. The child required blood transfusions at birth and in the first two months of life. Thereafter, treatment with subcutaneous erythropoietin mantained hemoglobin levels between 7.5–9.5 g/dL, allowing transfusion-independence. The haematological phenotype of this patient highlights the essential role of DMT1 in erythropoiesis. The early and significant hepatic iron accumulation indicates that, as in animal models, DMT1 is dispensable for liver iron uptake. Finally DMT1 inactivation in the gut is likely bypassed by other pathways of iron absorption.