bluuebunny/crossref_metadata_2025_split huggingface dataset:
p19INK4d Modulates Human Terminal Erythroid Differentiation By Post-Transcriptionally Regulating GATA1 Expression
Authors: Han Xu , Zhang Jieying , Peng Yuanliang , Chen Huiyong , Chen Xiao , Zhang Yibin , Hu Xiao , Mohandas Narla , An Xiuli , Liu Jing 
Published: October 2019

Abstract
Erythropoiesis is a process during which hematopoietic stem cell (HSCs) are first committed to erythroid progenitors, which subsequently undergo terminal erythroid differentiation to produce mature red blood cells. During terminal erythroid differentiation, proerythroblasts undergo 4-5 mitoses to sequentially generate basophilic erythroblasts, polychromatic erythroblasts and orthochromatic erythroblasts that expel their nuclei to produce enucleated reticulocytes. Terminal erythropoiesis is a tightly regulated process. The most well studied regulatory mechanisms include EPO/EPOR mediated signal transduction and transcription factors among which GATA1 plays critical role. Terminal erythroid differentiation is also tightly coordinated with cell cycle exit, which is regulated by cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors (CDKI), yet their roles in erythropoiesis remain largely undefined. Our RNA-seq of human terminal erythroid differentiation shows that of seven CDKI members, only three of them, p18INK4c, p19INK4d and p27KIP1, are abundantly expressed in erythroid cells and their expressions are significantly upregulated in late stage erythroblasts, which were further confirmed by western blotting analysis. In contrast to demonstrated roles of p18INK4c and p27KIP1 in terminal erythroid differentiation, the function of p19INK4d this process has not been studied. To explore the role of p19INK4d during human erythropoiesis, we employed a shRNA-mediated knockdown approach in CD34+ cells and found that p19INK4d knockdown delayed erythroid differentiation, inhibited cell growth, led to increased apoptosis and generation of abnormally nucleated late stage erythroblasts. Unexpectedly, p19INK4d knockdown did not affect cell cycle. Rather it led to decreased GATA1 protein levels. Importantly, the differentiation and nucleus defects were rescued by ectopic expression of GATA1. As GATA1 protein is protected by nuclear HSP70, to explore the mechanism for the decreased GATA1 protein levels, we examined the effects of p19INK4d knockdown on HSP70 and found p19INK4d knockdown led to decreased nuclear localization of HSP70 due to reduced ERK activation. Further biochemical analysis revealed that p19INK4d directly binds to Ras kinase inhibitor PEBP1 and that p19INK4d knockdown increased the expression of PEBP1 which in turn led to reduced ERK activation. These results demonstrate that p19INK4d maintains GATA1 protein levels through PEBP1-pERK-HSP70-GATA1 pathway. Our findings identify previously unknown and unexpected roles for p19INK4d in human terminal erythroid differentiation via a novel pathway.

Disclosures
No relevant conflicts of interest to declare.
Single-Agent Ibrutinib in Recurrent/Refractory Central Nervous System Lymphoma
Authors: Grommes Christian , Pastore Alessandro , Gavrilovic Igor , Kaley Thomas , Nolan Craig , Omuro Antonio M. , Wolfe Julia , Pentsova Elena , Hatzoglou Vaois , Mellinghoff Ingo , DeAngelis Lisa 
Published: October 2019

Abstract
BACKGROUND: Primary Central Nervous System Lymphoma (PCNSL) is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Response rates (ORR) range between 30-60% with a PFS of 2-5 months. Ibrutinib has shown promising clinical response in Mantel cell lymphoma, CLL, and Waldenström. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL.
METHODS: Eligible patients had r/r PCNSL or Secondary CNS Lymphoma (SCNSL), age≥18, ECOG≤2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL disease, systemic disease needed to be absent.
RESULTS: Twenty patients were enrolled (3 at 560 mg; 17 at 840 mg). Median age was 69 (range 21-85); 12 were women. Median ECOG was 1 (0: 2, 1: 12, 2: 6). 65% had PCNSL and 35% SCNSL; 70% had recurrent disease. Eleven had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 6 both. Five grade 4 adverse events were observed in 4 patients (lymphopenia (2), sepsis (1), neutropenia (2)). Ten patients developed grade 3 toxicities, including lymphopenia in 3 patients, thrombocytopenia in 2, hyperglycemia in 2, lung infection in 2, neutropenia in 1, urinary tract infection in 1, colitis in 1, and fungal encephalitis in 1. The most common toxicities were hyperglycemia, anemia, and thrombocytopenia. After a median follow-up of 193 days, 19/20 patients were evaluated for response: 8 CR, 7 PR, 1 SD and 3 PD; 75% (15/20) ORR. The median PFS is 7.29 months (95% CI: 3.80-15.43 months (longest: 15.3 months)). The mean Ibrutinib concentration in the CSF 2h post administration at day 1 and 29 is 1.75 ng/mL (3.97 nM) and 2.51 ng/mL (5.6 nM) which is above the IC50 (1nM) required in vitro to reduce growth of lymphoma cells.An additional treatment arm has been added to the trial which will evaluate adverse events of the combination of ibrutinib and high-dose methotrexate chemotherapy. Enrollment into the combination arm is ongoing and updates will be presented at the meeting.
CONCLUSION: Patients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Drug concentrations in CSF are higher at steady state (day 29) and meaningful CSF concentrations are reached. Clinical response was seen in 75% of CNS lymphoma patients. A combination arm will assess the adverse events of ibrutinib in combination with high-dose methotrexate chemotherapy.

Disclosures
No relevant conflicts of interest to declare.
Gender Differences in the Development of CMR Abnormalities and Cardiac Complications: A Multicentric Prospective Study in a Large Cohort of Thalassemia Major Patients
Authors: Pepe Alessia , Maffei Silvia , Pistoia Laura , Ciancio Angela , Palazzi Giovanni , Argento Crocetta , De Franceschi Lucia , Mangione Maurizio , Vallone Antonino , Missere Massimiliano , Positano Vincenzo , Meloni Antonella 
Published: October 2019

Abstract
Introduction. We aimed to prospectively assess if the male gender was associated with an higher risk of progressive cardiac iron accumulation, development of biventricular dysfunction and myocardial fibrosis assessed by CMR, and development of cardiac complications including heart failure (HF), arrhythmias and pulmonary hypertension (PH).
Methods. We considered 1711 TM patients (899 females, 31.09±9.08 years), consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network. Myocardial iron overload was assessed by the multislice multiecho T2* technique. Biventricular function was quantified by cine images. Late gadolinium enhancement (LGE) images were acquired to detect myocardial fibrosis.
Results. Although having a similar risk of accumulating iron, males showed a significant higher risk of developing cardiac dysfunction, heart failure, arrhythmias and cardiac complications globally considered (Table 1). Figure 1 shows the Kaplan-Meier curves for the outcomes for which the male sex was a significant prognosticator. Until 20-30 years of follow-up the two lines (male and female sex) were almost overlapping while after they clearly diverged. So, patients were divided in two groups based on the follow-up duration. A significant gender-specific difference in the frequency of ventricular dysfunction and cardiac complications appeared for patients followed for at least 20 years. So, two subgroups of patients were identified: patients followed for less than 20 years and patients followed for more than 20 years. In the first subgroup males and females had a comparable risk of developing cardiac iron overload, ventricular dysfunction and cardiac complications. Conversely, if a follow-up longer than 20 years was considered, males exhibited a significant higher risk of having ventricular dysfunction, heart failure, arrhythmias, and cardiac complications.
Conclusion. Females seem to tolerate iron toxicity better, possibly as an effect of reduced sensitivity to chronic oxidative stress. According to the International Guidelines, TM patients should perform a complete cardiac evaluation every year. Our study suggested that in females older than 20 years the follow-up may be performed every 24 months, thus reducing health care costs.
Table 1 Table 1. Figure 1 Figure 1.

Disclosures
Pepe: Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc.. De Franceschi:F. Hoffmann-La Roche Ltd, Basel, Switzerland: Research Funding.
Organization and Regulation of the Human Genome
Authors: Ren Bing 
Published: October 2019

Abstract
The 3-dimensional (3D) chromatin organization plays a critical role in gene regulation. Great strides have been made recently to characterize and identify cis regulatory elements from epigenome profiles in different cell types and tissues, but efforts have just begun to functionally characterize these long-range control elements. Mapping interactions between enhancers and promoters, and understanding how the 3D landscape of the genome constrains such interactions is fundamental to our understanding of genome function. I will present recent findings related to 3D genome organization in mammalian cells, with a particular focus on how chromatin organization contributes to transcriptional regulation. I will describe higher-order organizational features that are observed at the level of both the whole chromosome and individual loci. I will highlight changes in genome organization that occur during the course of differentiation, and discuss the functional relationship between chromatin architecture and gene regulation. Taken together, mounting evidence now shows that the genome organization plays an essential role in orchestrating the lineage-specific gene expression programs through modulating long- range interactions between enhancers and target genes.

Disclosures
Ren: Arima Genomics, Inc.: Equity Ownership, Patents & Royalties; Eli Lilly: Employment.
New Concepts in Genome Regulation
Authors: Dean Ann , Lee Jongjoo , Dale Ryan , Krivega Ivan 
Published: October 2019

Abstract
Manipulating gene regulation to favor gamma-globin transcription over beta-globin transcription has been a goal of research in erythropoiesis for decades because of its relevance to amelioration of the pathophysiology of sickle cell disease and beta-thalassemia. A fundamental unanswered question in biology is how the unique pattern of gene expression, the transcriptome, of the many different individual mammalian cell types arises from the same genome blueprint and changes during development and differentiation. There is a growing appreciation that genome organization and the folding of chromosomes is a key determinant of gene transcription. Within this framework, enhancers function to increase the transcription of target genes over long linear distances. To accomplish this, enhancers engage in close physical contact with target promoters through chromosome folding, or looping. These long range interactions are orchestrated by cell type specific proteins and protein complexes that bind to enhancers and promoters and stabilize their interaction with each other. We have been studying LDB1, a member of an erythroid protein complex containing GATA1, TAL1 and LMO2. The LDB1complex activates erythroid genes through occupancy of virtually all erythroid enhancers. LDB1engages in homo- and heterotypic interactions with proteins occupying the promoters of erythroid genes to bring them into proximity with their enhancers. We find that enhancer long range looping activity can be redirected. Both targeting of the beta-globin locus control region to the gamma-globin gene in adult erythroid cells by the tethering of LDB1 or epigenetic unmasking of a silenced gamma-globin gene lead to increased locus control region (LCR)/gamma-globin contact frequency and reduced LCR/beta-globin contact. The outcome of these manipulations is robust, pan-cellular gamma-globin transcription activation with a concomitant reduction in beta-globin transcription. These examples suggest that chromosome looping can be considered a therapeutic target for gene activation or gene silencing to ameliorate genetic diseases such as sickle cell disease and beta-thalassemia.

Disclosures
No relevant conflicts of interest to declare.
Effect of Indole Compounds on Vitamin B12 Utilization
Authors: DREXLER JERRY 
Published: October 2019

Abstract
Indole and indoleacetic acid are shown to inhibit the growth of a vitamin B12 dependent microorganism, a mutant strain of Escherichia coli. It is suggested that the mechanism of that inhibition may be a competitive inhibition of some enzymatic system necessary for the utilization of vitamin B12.
Studies on Lymphocytic Function
Authors: BRAUNSTEINER H. , PAERTAN J. , THUMB N. 
Published: October 2019

Abstract
Cellular reactions in inflammed areas were observed on coverslips. After an initial granulomonocytic phase a massive infiltration by lymphocytes took place. These lymphocytes rapidly hypertrophy and become "mononuclear," "epitheloid" and even giant cells. By injecting 15 to 30 millions of these cells from tularin- (tuberculin) positive donors to negative recipients, allergy of the delayed type is specifically transferred as with lymphocytes. The function of the lymphocyte is discussed on the basis of these findings.
Clinical Evaluation of 6-Chloropurine in Leukemia of Adults
Authors: ELLISON ROSE RUTH , KARNOFSKY DAVID A. , BURCHENAL JOSEPH H. 
Published: October 2019

Abstract
1. 6-Chloropurine, an analogue of 6-mercaptopurine, has been shown to produce complete remissions in three and partial remissions in eight of 30 adults with acute leukemia. No beneficial effects were obtained in four additional patients known to be resistant to 6-mercaptopurine.
2. Three of four patients with chronic granulocytic leukemia responded to 6-chloropurine.
3. Slight objective improvement was noted in patients with lymphomas but only at the point of hematologic toxicity.
4. A high incidence of jaundice was noted, but it is difficult to relate this definitely to the therapy.
5. While 6-chloropurine appears to be slightly superior to 6-mercaptopurine in acute leukemia in adults, the pattern of response would indicate that these agents have a similar mechanism and range of therapeutic activity.
Familial Neonatal Neutropenia with Maternal Leukocyte Antibodies
Authors: BRAUN E. H. , BUCKWOLD A. E. , EMSON H. E. , RUSSELL A. V. 
Published: October 2019

Abstract
The history of a family with three cases of neonatal neutropenia is reported. During the mother’s last pregnancy leukocyte antibody titers were found to be rising, culminating in a titer of 1:512 at delivery, when leukolysins and passive transfer of antibody to the fetus in the cord blood were also demonstrated. This pregnancy resulted in an infant with a severe degree of neutropenia during its neonatal period. The original sensitization was attributed to prior transfusion with the husband’s whole fresh blood. The whole process can be compared with the sensitization produced by the Rh factors.
HEMOPOIESIS IN RIBOFLAVIN-DEFICIENT RATS
Authors: ENDICOTT K. M. , KORNBERG ARTHUR , OTT MAURINE 
Published: October 2019

Abstract
Leukopenia, granulocytopenia, and, occasionally, anemia develop in rats fed a purified diet deficient in riboflavin. Folic acid (L. casei factor) corrects the leukopenia and granulocytopenia. Riboflavin will prevent all the dyscrasias but will correct only the anemia.
The bone marrow in granulocytopenic rats is hypoplastic and is almost completely depleted of cells of the granulocytic series. Cells of the erythroid series are decreased in number. The myelogram of rats made folic acid deficient by the inclusion of sulfasuxidine in a purified diet resembles this picture and in both cases the response of the marrow and the blood to folic acid therapy is similar.
The bone marrow in riboflavin-deficient rats having both granulocytopenia and anemia is depleted of granulocytic cells but shows an erythroid hyperplasia. This myelogram differs from that seen in sulfasuxidine-induced folic acid deficiency anemia and granulocytopenia in which there is erythroid hypoplasia. The two anemias differ further in that the folic acid deficiency anemia responds to folic acid therapy whereas the riboflavin deficiency anemia responds to riboflavin therapy but not to folic acid therapy.
FURTHER OBSERVATIONS ON THE SPECIFICITY OF THE FOLIC ACID MOLECULE
Authors: SPIES TOM D. , LOPEZ GUILLERMO GARCIA , STONE ROBERT E. , MILANES FERNANDO , BRANDENBURG ROBERT O. , ARAMBURU TOMAS 
Published: October 2019

Abstract
Methyl folic acid,2 N-(4-(4-quinazoline) amino) benzoyl)-glutamic acid, the Mg salt of formyl pteroyl glutamic acid, the Mg salt of formyl pteroic acid, pteroyl aspartic acid, oxyfolic acid and oxypteroic acid have been studied as to their effect on blood regeneration in selected cases of Addisonian pernicious anemia, nutritional macrocytic anemia and tropical sprue. In the amounts administered, only the Mg salt of formyl pteroyl glutamic acid was effective in producing reticulocytosis and an increase in red blood cells, hemoglobin, white blood cells and platelets, and it was not as effective per unit of weight as was folic acid per se. Presumably this compound is slowly changed into folic acid in the body. It is of special interest that the Mg salt of formyl pteroic acid (Streptococcus lactis factor) was negative in producing hemopoiesis. These observations show the very great specificity of the folic acid molecule.
THE ACTIVATION OF PROTHROMBIN, WITH SPECIAL REFERENCE TO "THROMBOPLASTIC ENZYME" (TRYPTASE)
Authors: FERGUSON JOHN H. , TRAVIS BURTON L. , GERHEIM EARL B. 
Published: October 2019

Abstract
A number of high-potency purified prothrombin preparations,61 in 0.2-0.5 per cent solution in borate buffer (pH = 7.7), maintain for days or weeks a stable thrombin-forming ability, whether (a) with buffer alone, (b) with brain thromboplastin suspension, (c) with CaCl2. Nevertheless, they all contain a trace of thrombin and continue to activate "spontaneously" at a very slow rate. Optimal addition of Ca-salt somewhat accelerates this and usually leads to maximal (complete) thrombin formation in 2-11 days at room temperature. Except in a few cases, where ionized Ca++ is demonstrable, thromboplastin, alone, is without effect, but added with calcium, it completes the activation in a matter of minutes or hours depending principally upon the concentration used.
Experimental analysis of the activation process stresses the participation of (1) Ca-ions, (2) thromboplastic P-lipid factor (cephalin), (3) plasma and tissue tryptase (proteolytic enzyme). Each of these factors is studied in detail with reference to mode of action, optimal concentration, side-effects, and relation to inhibitors.
Inhibition of prothrombin activation may be considered under the following heads: (1) "decalcifying" agents (e.g., oxalates, citrates, etc.), which (a) depress Ca-ionization and thus prevent thrombin formation, and (b), under special circumstances, reverse the process of activation; (2) "antithromboplastic" (? anticephalin) agents, (e.g., heparin, and probably soybean trypsin-inhibitor, to some extent); (3) "antitryptase" agents (e.g., crystalline trypsin-inhibitors from pancreas and soybean), which inhibit the thromboplastic enzyme (accessory factor). Excess Ca++ slows rate of thrombin formation.
The evidence suggests that thrombin formation proceeds via an "intermediary" calcium-prothrombin-cephalin (thromboplastic phosphatide) complex or compound. The amounts of (a) thromboplastic P-lipid (cephalin or "thromboplastin") and (b) Ca++ determine both the rate of activation and the final thrombin yield. However, the ultimate ("ripe") thrombin owes none of its activity to the presence of any calcium or phospholipid.
The three types of activator (Ca, thromboplastin, and thromboplastic enzyme) occur as "trace impurities" in prothrombin preparations, but Seegers’ most purified materials are tryptase-free. Tryptase (and trypsin) are "thromboplastic" only in the presence of adequate calcium and phospholipid factors, which may, however, be "mobilized" from protein combination, including prothrombin. In this way the two basic activators are, in a sense, "catalyzed" in their prothrombin-activating reactions.
The significance of proteolytic actions (fibrinolysis, fibrinogenolysis, prothrombinolysis, and sometimes thrombinolysis) by natural tryptase of plasma and tissue origin is investigated and discussed in relation to the broader aspects of the blood-coagulation problem.
ADULT GAUCHER’S DISEASE, WITH SPECIAL REFERENCE TO THE VARIATIONS IN ITS CLINICAL COURSE AND THE VALUE OF STERNAL PUNCTURE AS AN AID TO ITS DIAGNOSIS
Authors: GROEN J. , GARRER A. H. 
Published: October 2019

Abstract
The authors present nine cases of Gaucher’s disease in which the diagnosis, suspected on clinical grounds, was definitely established by the detection of the Gaucher cells in the smear of the sternal marrow. The authors review the varieties of the clinical picture in this disease. They discuss the importance of sternal puncture with special reference to the possibility of establishing the diagnosis in subclinical cases.
THE FREQUENCY OF MEGAKARYOCYTES IN AUTOPSY SECTIONS
Authors: BRILL ROBERT , HALPERN M. M. 
Published: October 2019

Abstract
1. Megakaryocytes can be demonstrated with great frequency in the viscera.
2. Megakaryocytes were present in the lungs in all of 50 autopsies studied.
3. They were next most frequently found in the spleen.
4. The simultaneous occurrence in the various organs, in the absence of extra-medullary hematopoiesis, is roughly related to the concentration in the lungs.
5. Under normal conditions megakaryocytes in small numbers circulate in the blood stream.
EXOGENOUS HEMOCHROMATOSIS RESULTING FROM BLOOD TRANSFUSIONS
Authors: SCHWARTZ STEVEN O. , BLUMENTHAL SUNOLL A. 
Published: October 2019

Abstract
1. Five patients who died as a result of a variety of diseases, all characterized by severe anemia for which numerous transfusions had been given, and all of whom developed features of hemochromatosis are presented.
2. Eight similar cases found in the literature are summarized.
3. It is postulated that the hemochromatosis developing in these patients is the end result of the deposition and subsequently irritating action of the excess amounts of iron in the parenchymatous tissues.
4. The underlying anemia and the not infrequent transfusion reactions are thought to act as predisposing factors for the development of exogenous hemochromatosis.
5. The name Exogenous Hemochromatosis is proposed for this syndrome.
6. The clinical similarities and dissimilarities and the differences in pathogenesis between exogenous and endogenous hemochromatosis are discussed.
THE PLACE OF THE SPLEEN IN THE ENDOCRINE SYSTEM
Authors: DOWNS ARDREY W. 
Published: October 2019

Abstract
While the evidence for an endocrine function of the spleen is meagre and the exact nature of this action is not clear it does seem to be fairly well established that the spleen must be considered as an important part of the mechanism whereby a normal corpuscle, and possibly platelet, content of the circulating blood is maintained.
This regulation seems to be due to the production by the spleen of one or more hormones.
These hormones appear to affect the processes of the bone marrow and also may act upon the corpuscles in the circulating blood.
The conception of hyperactivity of the spleen in the human being seems to be firmly established but little is known of the clinical appearance of its hypoactivity.