bluuebunny/crossref_metadata_2025_split huggingface dataset:
GATA-1 Binding to Exon 1 Directs High Level Erythroid-Specific Expression of the Human Protoporphyrinogen Oxidase Gene.
Authors: de Vooght Karen M.K. , van Wijk Richard , van Solinge Wouter W. 
Published: October 2019

Abstract
Protoporphyrinogen oxidase (PPOX), the penultimate enzyme in the heme biosynthetic pathway, catalyzes the six-electron oxidation of protoporphyrinogen IX to protoporphyrin IX. Like other heme biosynthetic proteins, PPOX is involved in synthesizing heme for red cells (erythroid-specific expression) and as a cofactor for the respiratory cytochromes (housekeeping expression). To date, little is known about transcriptional regulation of the human PPOX gene (PPOX). We established the molecular basis for erythroid-specific expression of PPOX. Using transient in vitro transfection assays in human erythroleukemic K562 cells we studied tissue-specific expression of PPOX. We found that reporter constructs lacking exon 1 showed a 75% reduction in promoter strength in K562 cells (Figure, no 1 and 2). Hence, in vitro high-level erythroid-specific expression of PPOX is dependent on the presence of exon 1. Examination of erythroid-specific regulatory elements in exon 1 revealed two GATA-1 sites, one consensus (A/T)GATA(A/G) site (GATA-1_II AGATAA) and one non-consensus site, deviating at the first nucleotide (GATA-1_I, CGATAG). To study the relative contribution of these two GATA-1 sites to erythroid-specific transcriptional regulation, we performed in vitro transfections of wild-type and mutant (GATA → GTTA) reporter plasmids in K562 cells. We found that the highest level of transcription depended on the integrity of both sites (Figure, no 5). The consensus GATA-1_II site contributed the most to promoter strength (Figure, no 4). Subsequent electrophoretic mobility shift assay and supershift experiments using K562 nuclear extracts demonstrated that both GATA sites were able to bind GATA-1 in vitro. Our experiments showed that exon 1 was dispensable for PPOX promoter activity in human hepatoma HepG2 cells. Interestingly, in HeLa human cervical carcinoma cells the presence of exon 1 decreased promoter activity. Conclusively, exon 1 of the human PPOX gene contains two GATA-1 binding sites, which are required for high level erythroid-specific expression of PPOX and, in addition, bind GATA-1 in vitro. Our results contribute to a better understanding of the molecular mechanisms involved in differential regulation of the human PPOX promoter in erythroid and non-erythroid cells.
Figure Figure
Human Mesenchymal Stem Cells Injected Via Portal Vein Are Differentiated into Human Hepatocytes in Regenerating Rat Liver.
Authors: Won Jong-Ho , Choi Dong-Ho , Kim Jung-Hoon , Kim Sook-Ja , Cheung Hee-Jeong , Lee Nam-Su , Park Hee-Sook 
Published: October 2019

Abstract
Objectives: Human mesenchymal stem cells (MSCs) possess versatile differentiation potential ranging from mesenchyme-related multipotency to neuroectodermal and endodermal competency. Evidence has been accumulated to indicate that certain compartments of bone marrow cells are capable to differentiating into hepatocytes in vitro. In this study we attempted to examine the differentiation ability of human MSCs into hepatocytes in vitro and in vivo by injected them into rat portal vein in partially resected rat liver model.
Materials and Methods: MSCs were isolated from human bone marrow and induced differentiation with our protocol containing hepatocyte growth factor in vitro. Four - to - 5 week-old female Sprague Dawley rats were used for xenotransplantation model. Culture expanded MSCs (5 X 106 cells/rat) were injected into the portal vein and 70% hepatectomy was performed on the subsequent day. All rats were immunosuppressed with a daily intraperitoneal injection of cyclosporine A.
Results: The morphology of the MSCs was changed into hepatocyte-like cells after in vitro culture for 28days and expression of hepatocyte specific genes also confirmed with RT-PCR and immunohistochemical stain. Transplanted MSCs differentiated into hepatocytes and they surprisingly composed hepatic cords with expression of the human albumin and human hepatocyte specific genes at 21 days after infusion.
Conclusion: We have demonstrated that human MSCs can differentiate into functional hepatocyte-like cells in vitro and in vivo. Therefore, human MSCs may become an alternative source to hepatocyte regeneration or liver cell transplantation.
Clinical Efficacy and Safety of Wilate®, A New Generation, High-Purity VWF/FVIII-Concentrate with Optimized Pharmacokinetic Properties in the Treatment of Von Willebrand Disease.
Authors: Windyga Jerzy , Zarkova Antoaneta , Walter Olaf , Auerswald Guenter 
Published: October 2019

Abstract
Purpose: Wilate® represents a new generation VWF/FVIII-concentrate for the treatment of von Willebrand patients with high purity and two independent virus inactivation steps. The high purity of the product was developed to preserve the functionality of Wilate®’s VWF/FVIII complex at a physiological ratio of about 1:1.
Methods: A prospective multicenter study is conducted in 47 VWD patients to investigate the pharmacokinetics (PK) and clinical efficacy and safety of Wilate® in acute bleedings and surgical prophylaxis. For PK studies, plasma levels of VWF:RCo, FVIII:C, VWF:Ag were measured up to 72 hrs after injection of 50 IU of FVIII/kgBW. Clinical efficacy and tolerability was rated on a four-point scale. Final decisions on dosing were based on the investigators’ clinical judgment.
Summary of results: Mean half-life of VWF:RCo in type 3 patients (n=9) was 17.1 hrs. Mean recovery for VWF:RCo was 1.5 [% per IU/kg] and 2.0 [% per IU/kg] for FVIII:C. The clearance for VWF:RCo was 2.5 [ml/h/kg] for all and 3.9 [ml/h/kg] in type 3 patients. 33 patients have been treated for a total number of 658 bleeds. Of these, 31 patients (69%) were type 3 patients. The average dose/kgBW/ED was calculated to 29.3 IU FVIII:C. Furthermore efficacy and safety was studied in 16 patients undergoing 24 surgical procedures. The overall efficacy (achievement of haemostasis) of Wilate® was rated as excellent or good for 23/24 procedures (96%). One patient with a laparoscopic cholecystectomy required two additional blood transfusions. The tolerability was assessed as very good/good by investigators and patients in all surgical cases.
Conclusion: Wilate® documented favourable PK-properties in VWD patients. The interim results of these prospective clinical studies demonstrate the safety and efficacy of the double-virus-inactivated Wilate® for the treatment of acute bleeding episodes and surgical procedures in patients with VWD.
Amino Acid Regions 572–579 and 657–666 of the Spacer Domain of ADAMTS13 Provide a Common Antigenic Core Required for Binding of Antibodies in Patients with Acquired TTP.
Authors: Luken Brenda M. , Turenhout Ellen A.M. , Kaijen Paul H.P. , Fijnheer Rob , Voorberg Jan 
Published: October 2019

Abstract
Inhibitory antibodies against ADAMTS13 have been detected in the majority of patients with acquired thrombotic thrombocytopenic purpura. Epitope-mapping studies revealed that antibodies binding to the cysteine-rich/spacer domains of ADAMTS13 are present in plasma of all patients analyzed so far. We have previously shown that a major antigenic determinant located within the spacer domain. To confirm these results we constructed a recombinant fragment consisting of the disintegrin/TSR1/cysteine-rich domains of ADAMTS13 and the spacer domain of ADAMTS1. The resulting ADAMTS13/ADAMTS1 chimera did not react with IgG present in plasma of a panel of patients with acquired TTP. To identify the amino acid residues that are involved in binding of anti-ADAMTS13 antibodies, we constructed a series of 15 hybrids (designated A–O) in which 5–10 amino acids of the ADAMTS13 spacer were exchanged for the homologous sequence of ADAMTS1. Plasma from 6 patients with antibodies directed against the spacer domain was analyzed for reactivity with the ADAMTS13/ADAMTS1 chimeras. Exchange of residues 572–579 (hybrid C) and 657–666 (hybrid M) of ADAMTS13 for the corresponding sequence of ADAMTS1 completely abolished the binding of antibodies from all 6 patients. Other regions of the ADAMTS13 spacer were also involved in binding of antibodies from patient plasma. Regions 580–587 (D), 602–620 (G,H), 629–638 (J), and 667–767 (N) of the ADAMTS13 spacer domain contributed to binding of antibodies from patients 2, 4, and 5 (epitope present within regions CDGHJMN). IgG derived from patient 1 required region 602–620 (G,H) for binding to the ADAMTS13 spacer (CGHM-epitope). For antibodies of patient 3, residues 564–571 (B), 580–587 (D), and 629–638 (J) were required (BCDJM-epitope), whereas replacement of residues 602–610 (G) and 629–638 (J) greatly diminished binding of antibodies derived from patient 6 (CGJM-epitope). Despite the presumably polyclonal origin of the antibodies present in plasma of the patients, our results suggest that residues 572–579 (C) and 657–666 (M) comprise a common antigenic core region within the spacer domain that is crucial for binding of anti-ADAMTS13 antibodies in all six patients. Amino acid residues derived from other regions that spatially surround this common antigenic core further modulate binding of antibodies to the spacer domain.
Leukoreduced Packed Red Cells: Do They Have a Role in Decreasing the Incidence of Heparin Induced Thrombocytopenia?.
Authors: Atluri Prashanti , Kujawa Jennifer , Hindenburg Alexander 
Published: October 2019

Abstract
It has been demonstrated that neutrophils activate macrophages via the heparin binding protein, thus possibly contributing to the incidence of heparin induced thrombocytopenia (HIT).
It would follow that the incidence of thrombocytopenia and its sequelae may be reduced by using leukoreduced blood in patients undergoing cardiac bypass surgery. We had a unique opportunity to study this hypothesis at our institution. Due to a policy change all patients undergoing cardiac bypass surgery received LR blood intra-operatively prior to April 2005.
Subsequent to this period non-LR blood was utilized in all patients. A retrospective chart review of 197 non-LR and 316 LR patients was done. The platelet count on admission, the first five days post- op, the day of discharge, the percent drop in platelet count post-op and heparin antibody (HA) test were obtained. Thrombocytopenia was defined as an overall drop in platelet count by > 50%. The CABG and the non-CABG patients were looked at separately.
The results are as follows:
Percent of patients with > 50% drop in platelet count: all patients CABG patients non-CABG patients leukoreduced arm 64% 62.4% 73.3% non-leukoreduced arm 64.6% 61.7% 82.1% Fisher’s exact test p = 0.92 p = 0.92 p = 0.57 Percent of patients with heparin antibody positivity: all patients CABG patients non-CABG patients leukoreduced arm (n=81) 24.7% 23.3% 28.6% non-leukoreduced arm (n=39) 30.8% 35.5% 12.5% Fisher’s exact test p = 0.51 p = 0.23 p = 0.63
In both the LR and non-LR populations there is only a 0.6% difference in the number of patients with a > 50% platelet drop. The relative risk is 1.01 with the 95% confidence interval of (0.88, 1.15). This is a relatively narrow confidence interval reflective of the relatively large sample size.
Heparin antibody testing was not done on all the patients. Only those with persistent or profound thrombocytopenia had the test ordered. Overall heparin antibody positivity in both cohorts was not statistically different.
The LR arm had a slightly higher positivity rate overall. The risk ratio is 1.25 indicating that the non-LR arm is 25% more likely to have a positive antibody test compared to the LR arm. The higher positivity rate in non-CABG patients may be due to the more complex nature of the surgery relative to CABG surgery.
The non-CABG group has a higher percent of heparin antibody positivity in the LR arm.
This inconsistency may be secondary to the smaller sample size of this group. In both the CABG or non-CABG groups, there was no statistically significant difference in the percent platelet drop or heparin antibody positivity.
One can conclude that leukoreduction of red blood cell products during cardiac surgery does not significantly impact on thrombocytopenia or the development of HIT.
Two "Fast" Hemoglobin Components in Liberian Blood Samples
Authors: ROBINSON ABNER R. , ZUELZER WOLF W. , NEEL JAMES V. , LIVINGSTONE FRANK B. , MILLER MAX J. 
Published: October 2019

Abstract
Two abnormal hemoglobins, at least one of which has not previously been described, were encountered with appreciable frequency in Liberian blood samples. Some properties of these components are described.
Disseminated Neuroblastoma in an Adult Presenting the Picture of Thrombocytopenic Purpura
Authors: CHRISTENSON WILLIAM N. , ULTMANN JOHN E. , MOHOS STEVEN C. 
Published: October 2019

Abstract
A case of neuroblastoma in an adult with extensive metastatic lesions is presented. The initial symptoms and findings suggested idiopathic thrombocytopenic purpura. The blood picture and changes in the clinical picture later led to a diagnosis of acute leukemia. Autopsy disclosed the correct diagnosis, which would have been possible antemortem had the implication of pseudorosette arrangement of immature cells in the bone marrow and the possible occurrence of neuroblastoma in an adult been fully appreciated.
Histochemical Demonstration of Phosphorylase in Blood and Bone Marrow Cells
Authors: TAKEUCHI TADAO , KINOSHITA KENJI 
Published: October 2019

Abstract
Phosphorylase activity has been demonstrated histochemically in blood and bone marrow cells. The polysaccharide newly synthesized from glucose-1-phosphate by the enzyme of these cells gave a blue or violet blue iodine staining reaction. The reaction occurred in cytoplasm and the nuclei did not stain.
This was shown in the neutrophilic, eosinophilic or pseudoeosinophilic leukocytes of man, dog, rabbit and pigeon peripheral blood. It was likewise demonstrated in the bicolored leukocytes of snake, fish and frog. The reaction also appeared in the neutrophilic, pseudoeosinophilic or eosinophilic leukocytes, metamyelocytes, myelocytes and promyelocytes of human and rabbit bone marrow smears.
Immunization of Rabbits Against Human Anti-Hemophilic Factor (AHF)
Authors: RICHARDS MARVIN D. , SPAET THEODORE H. 
Published: October 2019

Abstract
Antibodies against human AHF were produced in the rabbit. These antibodies acted as anticoagulants in vitro by inactivating AHF and preventing normal thromboplastin formation. Species specificity and physical properties of the anticoagulant are described. It is postulated that similar anticoagulants occurring in humans are also antibodies produced by AHF immunization.
The Present Status of Treatment of Autoimmune Hemolytic Anemia with ACTH and Cortisone
Authors: DAMESHEK WILLIAM , KOMNINOS ZACHARIAS D. , DÉSY LOUISE 
Published: October 2019

Abstract
Forty-three patients with autoimmune hemolytic anemia (both "idiopathic" and "symptomatic") were treated with ACTH, Cortisone, or Compound F. In more recent cases not reported here, Prednisone (Meticorten) was used. Intensive and presumably adequate hormonal therapy resulted in sustained and complete clinical and hematologic responses in 65 per cent of the cases. Complete and sustained remissions were more commonly obtained in the "idiopathic" group (80 per cent remissions) than in the "symptomatic" variety. In 28 per cent of the cases, although the response was definite, it was not so striking. Complete failure was obtained in 3 cases (7%) of this series. When therapy was discontinued, following a remission, some degree of relapse developed in approximately two-thirds of the cases. In the remaining one-third, full clinical and hematologic remission continued well after discontinuance of therapy, although the persistently positive Coombs test indicated the possibility of future recurrence. Splenectomy was performed as the final therapeutic maneuver in 9 of the 43 cases and resulted in complete remissions in 6 without the further use of steroid hormones. In two cases splenectomy was followed by the development of outspoken disseminated lupus, previously undiscovered and presumably latent.
It is apparent from these studies that the steroid hormones in adequate dosage represent a remarkably effective form of therapy for at least the initial control of most cases of autoimmune hemolytic anemia. Their use for a lengthy period is often followed by a lasting remission, and the end-results of continued steroid therapy, either used alone or in some cases combined with later splenectomy, are definitely better than with splenectomy alone. Thus, control of this rather unpredictable disease has become a distinct possibility in most cases, and its management simply a matter of varying the dosage of steroid hormone.
Composite Nodular Sclerosis Hodgkin and Diffuse Large B Cell Non-Hodgkin Lymphoma Arising from the Thymus.
Authors: Sumoza Luis D. , Jorgensen Jeffrey L. , Sumoza Ilia R. 
Published: October 2019

Abstract
We report the first case of composite Nodular Sclerosis Hodgkin and Diffuse Large B-Cell Non-hodgkin’s lymphoma of the mediastinum. We present a case of an inmunocompetent patient operated on for a mediastinal tumor similar to a Thymoma, which the histological examination morphological, and immunophenotyping were performed and confirmed the existence of 2 independent, unrelated tumors. The pathology blocks submitted show a composite lymphoma, with components of both classical Hodgkin lymphoma (Hodgkin’s disease), nodular sclerosis type, grade 2 of 2 in all three blocks. One block also shows non-Hodgkin lymphoma, namely diffuse large B-cell lymphoma, with a distinct immunophenotype. The Hodgkin-Reed-Sternberg cells were positive for CD15, CD20, CD30, PAX-5 (weak/partial), and EBV (EBERs), and negative for CD45. In contrast, the large B-cells are positive for CD20, PAX-5 (strong), CD45, and CD30 (very focal), and negative for CD15 and EBERs. The large B-cell area had an increased mitotic rate. Taken together, these data indicate that these Hodgkin and the Non-Hodgkin’ lymphomas arose as a consequence of independent malignant transformation events.
Rapid Infusion of Rituximab (RIR) Is Well Tolerated and Can Safely Be Delivered in Patients with Lymphoproliferative Diseases.
Authors: Milone Jorge , Prates Virginia , Lucia Zoppegno , Ana Basquiera , Sebastian Yantorno , Marta Gelemur , Juan Garcia 
Published: October 2019

Abstract
It has been proved that Rituximab is a useful drug for the treatment of patients with lymphoma. Being a humanized antibody, it presents high specificity. Rituximab is a well tolerated medicine, although a slow infusion rate given in many hours is recommended to avoid reactions derived from the liberation of cytokines. As a consequence, patients need admissions for a treatment that can take hours. The recent demostration of its usefulness in the maintenance of the response of patients with follicular lymphomas has concluded in the revision of hospitalization time, proposing a faster infusion. We are presenting our experience with RIR, on a group of patients with lymphoproliferative diseases. We used RIR with the aim to observe the toxicity and to reduce the time of hospitalization in patients with lymphoma. We evaluated the adverse events and tested the feasibility of a 90 minutes infusion schedule for rituximab (20% of the dose administered in the first 30 minutes, remaining administered over 60 minutes). Premedication included oral paracetamol and intravenous hidrocortisone and diphenhydramine. Sixty seven RIR were used to treated 31 patients (27 non-Hodgkin Lymphoma and 4 Chronic Lymphocitic Leukemia). All of them had previously received one or more rituximab conventional infusion without grade 3 or 4 toxicity. Twenty nine patients received also CHOP or CHOP-like chemotherapy and the other two Rituximab alone as maintenance therapy. Overall RIR was well tolerated. There were 5 adverse events. Four patients developed grade one adverse events: one patient had an hypotension episode, one presented chest pain and the other two had abdominal pain. Only one patient developed a grade 3 adverse event (abdominal pain) and withdrew the RIR schedule. We conclude that rapid infusion rituximab is safe and well tolerated. The adoption of this schedule in clinical practice reduces in many hours the time of hospitalization for patients with lymphoma and may be a cost-effective strategy.
Additon of Low-Dose Interferon-alpha (LD-IFN-a) and Lenalidomide after Failure to a Combination of Thalidomide and Prednisone in Myelofibrosis with Myeloid Metaplasia (MMM).
Authors: Reale Lisa , Besa Emmanuel C. 
Published: October 2019

Abstract
Primary myelofibrosis with myeloid metaplasia (MMM) is an uncommon myeloproliferative disease with limited effective treatment options. Therapy using thalidomide and prednisone (TP) or lenalidomide (L) show variable objective response of improvement of 22% in L to 62% in TP for anemia, 50% in L to 75% in TP for thrombocytopenia, and decrease in splenomegaly in 19% with TP to 33% with L and was well-tolerated. Additional clinical benefits show resolution of leukoerythroblastosis, and a decrease in medullary fibrosis and abnormal angiogenesis. Prolonged therapy with alpha-interferon (IFN-a) can improve hematopoiesis and reverse marrow fibrosis but doses used were poorly tolerated.
Methods and Patients: Here we present five patients treated with combination T at 50 mg daily, P at 0.5 mg/kg po for 2 weeks then to 20 mg daily every other day for 3 months with no response. If this was tolerated, low-dose IFN-a (LD-IFN-a) at 1.5 million units sc. three times a week was added. The clinical and hematologic criterion of the European Myelofibrosis Network (EUMNET) were used as response criteria for our study. Three males, 2 females, age ranged from 60 to 85 years who had failed previous treatments from EPO, hydrea and transfusion support. White blood cell counts ranged from 4.3 to 29.7 B/L. Hemoglobin levels ranged from 7.3 to 11.6 g/dL. Platelets ranged from 13,000 to 283,000 B/L. Three patients developed iron overload from rbc transfusions and required iron-chelation therapy.
Results: Of the five patients, one had a CR, one had a PR and two had regression that did not meet criteria for response and one unresponsive with no splenomegaly but stable disease. We noted that the addition of LD-IFN-a decreased the elevated WBC counts and Improvement in spleen size was seen about three months after the start of treatment. One patient had a CR in his WBC count approximately a month after starting therapy. The patient with CR had normal hemoglobin but had to discontinue after a year of T due to grade 2 neuropathy and was started on 10 mg/day of L while staying on IFN-a and P. She developed anemia and required transfusions for 3 months and achieved CR with shrinkage of her spleen size from 15 to 4 cm. The patient who was unresponsive to the combination of IFN-a- TP changed from T to L was stopped after the patient developed hemolytic anemia and splenomegaly.
Conclusion: Addition of LD-IFN-a to the reported TP or L to replace T show clinical activity in patients with refractory MMM and is well tolerated with minimal toxicity. The use of lenalidomide may alleviate neuropathy but may induce hemolysis as an undesirable side effect. Further studies using low doses of these agents with varying activities to MMM in combination is needed to define their clinical use in the treatment of this disease entity in a much larger number of patients.