bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upfront Autologous Stem Cell Transplantation Overcome the poor Prognosis of Non-Germinal Center Subtype of diffuse Large B-Cell Lymphoma in Patients with Advanced Stage and Elevated Serum Lactate Dehydrogenase
Authors: Kim Yu Ri , Kim Soo-Jeong , Cheong June-Won , Kim Yundeok , Jang Ji Eun , Lee Jung Yeon , Yang Deok-Hwan , Lee Hyewon , Eom Hyeon-Seok , Min Yoo Hong , Kim Jin Seok 
Published: October 2019

Abstract
Introduction: The role of frontline autologous hematopoietic stem cell transplantation (ASCT) high-risk diffuse large B-cell lymphoma (DLBCL) is still controversial. We investigated the role of upfront ASCT as consolidation for high-risk DLBCL treated with rituximab containing chemotherapy according to molecular classification.
Methods: A total of 195 newly diagnosed DLBCL patients with advanced stage and elevated serum lactate dehydrogenase from three centers were retrospectively analyzed. All patients achieved more than partial response (PR) after completing conventional chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) with rituximab (R-CHOP). Molecular classification was performed according to Han's algorithm.
Results: One hundred fifty (76.9%) patients achieved complete response (CR) and 45 (23.1%) patients PR after frontline R-CHOP chemotherapy. Among these patients, sixty six (33.8%) patients were received ASCT. The 2-year overall survival (OS) was 82.9% and the 2-year progression-free survival (PFS) was 72.1%. Seven (10.6%) patients were relapsed after ASCT while 29 (22.5%) patients were relapsed in non-transplant patients. Patients who treated with ASCT showed superior OS and PFS (P=0.036, P=0.005). According to final response, ASCT showed superior OS and PFS in PR patients (P = 0.024, P = 0.009) while it did not in CR patients.
Among the 128 patients that underwent immunohistochemistry for molecular classification, 36 patients (28.1%) were classified to GCB type, 92 (72.9%) patients were non-GCB type. Twenty five (27.1%) non-GCB patients received ASCT showed significant survival benefit for OS and PFS (P=0.032, P=0.011) while GCB patients did not show the survival difference according to ASCT (Figure 1). In non-GCB DLBCL, ASCT was related with superior PFS both interim and final PR status (P = 0.006, P=0.028). There was no difference for OS and PFS between GCB and non-GCB type in ASCT patients while GCB patients showed superior OS and PFS in non-transplant patients (P = 0.048, P=0.009).
Conclusions: ASCT as consolidation improved OS and PFS in high risk DLBCL patients following R-CHOP chemotherapy. Especially, it could overcome the poor prognosis of non-GCB type DLBCL. Upfront ASCT could be considered effective treatment options for non-GCB type high risk DLBCL.
Figure 1. Overall survival and progression free survival according to autologous hematopoietic stem cell transplantation in non-GCB type DLBCL. Figure 1. Overall survival and progression free survival according to autologous hematopoietic stem cell transplantation in non-GCB type DLBCL. Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.
Suppressing Hepcidin By Tocilizumab Effectively Improve Anemia in Inflammatory Diseases: Clinical Evidence and Basic Mechanisms
Authors: Yoshizaki Kazuyuki , Song Soken-Nakazawa J , Kawabata Hiroshi 
Published: October 2019

Abstract
Introduction
Dysregulated production of hepcidin is implicated in anemia of inflammation (AI) and interleukin-6 (IL-6) is a major inducer of hepcidin production. Increased imflammatory cytokines, especially IL-6 is response for pathogenesis of multicentric Castleman's disease (MCD) and rheumatoid arthritis (RA).
Patients and Method
In this study we study role of hepcidin and IL-6 in AI patients with MCD or RA, by investigating the effect of tocilizumab, an anti-IL-6 receptor antibody, on the serum hepcidin and relationship between hepcidin and iron-related parameters. The mechanism involving inflammatory anemia in MCD and RA was further analyzed in vitro by studied the transcriptional regulation of hepcidin in hepatoma-derived cell lines in the presence of cytokines, antibodies against cytokines, inhibitors of signal pathways and other hematopoietic factors.
Results
Our data showed that treatment with tocilizumab resulted in a rapid reduction of serum hepcidin-25 in MCD and RA patients. Although treatment with anti-TNF-a antibody also resulted in decrease of serum hepcidin, compared to tocilizumab therapy it decrease by a smaller margin. Furthermore, long-term reductions of hepcidin-25 were observed in ten MCD cases for one year after the start of tocilizumab treatment, which was accompanied by progressive normalization of iron-related parameters and improved disease activity. In in vitro experiments, IL-6, but not TNF-a or IL-1,-induced upregulation of hepcidin mRNA in hepatoma cell lines was completely inhibited with tocilizumab, and partially by EPO as well as TNF-a, but enhanced by BMP4 and MCD patient’s serum.
Discussion
Our results suggest that, although multiple factors affect serum hepcidin levels, IL-6 plays an essential role in the induction of hepcidin. This accounts for the long-term ameliorative effect of IL-6 blockage with tocilizumab on anemia by inhibiting hepcidin production in MCD and RA patients.

Disclosures
No relevant conflicts of interest to declare.
The Prognostic Role of Diabetes Mellitus for Cardiac Complications in a Large Cohort of Well Treated Thalassemia Major Patients
Authors: Meloni Antonella , Gamberini Maria Rita , Rossi Giuseppe , Sorrentino Francesco , D'Ascola Domenico Giuseppe , Spasiano Anna , Filosa Aldo , Cuccia Liana , Dello Iacono Nicola , Forni Gianluca , Caruso Vincenzo , Maggio Aurelio , Pitrolo Lorella , Peluso Angelo , Midiri Massimo , Missere Massimiliano , Neri Maria Giovanna , Pepe Alessia 
Published: October 2019

Abstract
Epidemiologic as well as clinical studies confirm a close link between diabetes mellitus (DM) and heart failure (HF) in the general population. In a retrospective historical thalassemia major (TM) cohort, DM was demonstrated to lead to an higher frequency of cardiac complications also independently of cardiac iron status, but not prospective data are available. So, we determined prospectively the predictive value of DM for HF, arrhythmias and cardiac complications (HF, arrhythmias and pulmonary hypertension) in TM.
We followed prospectively 537 patients enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network.
Fifty-six patients were excluded because a cardiac complication was present at the time of the first Cardiovascular Magnetic Resonance (CMR), representing our starting point.
All the considered 481 TM patients were white (29.48±8.93 years, 263 females). Mean follow-up was 57.91±18.23 months. DM was present in the 9.8% of patients.
Cardiac events were recorded in 36 patients (7.5%). There were 18 episodes of HF, 16 arrhythmias and 2 pulmonary hyperthension.
DM was a significant predictive factor for HF (hazard ratio-HR=5.62, 95%CI=2.08-15.22; P<0.0001) as well as for arrhythmias (HR=3.70, 95%CI=1.18-11.65; P=0.025) and for cardiac complications globally considered (HR=4.26, 95%CI=2.04-8.92; P<0.0001).
DM remained a significant prognosticator for HF and cardiac complications also in a multivariate model including cardiac iron.
In conclusion, DM was found to be a strong predictor for HF, arrhythmias and cardiac complications. Our findings are relevant for the prevention of glucose disorder metabolism and they stress the need to intensify the chelation therapy in patients in whom excess pancreatic iron is found by MR, where available, or when patients develop glucose metabolism disorders.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Use of Nano-Formulated Hydroxyurea Enhances Drug Delivery to Pulmonary Artery Endothelial Cells
Authors: Mohtar Omar , Dragovic Doroteja , Tagne Jean-Bosco , Klings Elizabeth S 
Published: October 2019

Abstract
The vasculopathy of sickle cell disease (SCD), characterized by a chronic hemolytic anemia, endothelial dysfunction and recurrent vasoocclusive events, underlies most of the clinical complications. Recent work has suggested that hydroxyurea (HU) enhances endothelial nitric oxide (NO) production and reduces adhesion molecule expression which may contribute to its associated observed reduction in vasoocclusive events and improved survival in SCD. However, clinically HU is under-utilized, at least in part related to medication related toxicity, stressing a need for enhanced drug delivery. The use of nano-emulsions, a class of stable emulsions formed by a monolayer of phospholipids and/or biodegradable material such as chitosan, is a mechanism by which to enhance targeted cellular delivery of therapeutics. We hypothesized that a nano-formulation of HU would enhance drug delivery to the endothelium and may be a direct way of targeting endothelial dysfunction in SCD. Nano-formulated HU (nano-HU) was developed using a phospholipid approach and this compound was found to be biologically stable for > 6 months. Human pulmonary arterial endothelial cells (HPAECs) were co-incubated with 25µM, 125µM and 250µM HU, nano-HU, or the empty nano-emulsification preparation for 48 hours. HPAEC were isolated, and stained with propidium iodide (PI) for cell cycle analysis by FACS. HPAEC treated with 25µM nano-HU demonstrated the highest level of cell viability (55%) and similar levels of S phase inhibition as HPAEC treated with 125µM HU (where 10-20% cell viability was observed). RNA isolation of treated HPAECs was performed and qPCR for VCAM1 and SLX4, a regulator of DNA damage which promotes S phase inhibition was performed. 25µM nano-HU significantly decreased VCAM1 and increased SLX4 expression compared with 25µM HU suggesting increased efficacy at lower levels of toxicity. The impact of nano-HU on endothelial gene expression is currently being evaluated by RNA-seq. Nano-formulation of HU produces a molecule which is highly stable, and able to achieve higher intracellular concentrations with lower rates of toxicity in HPAECs .which provides the opportunity to gain greater understanding of the impact of this medication on the vascular endothelium and the potential for a more targeted and better tolerated delivery of this therapeutic to patients with sickle cell disease.

Disclosures
Klings: Pfizer: Consultancy.
Vitamin D-Dependent Induction of Cathelicidin in Human Macrophages Results in Cytotoxicity Against High Grade B-Cell Lymphoma
Authors: Bruns Heiko , Büttner Maike , Fabri Mario , Mougiakakos Dimitrios , Bittenbring Joerg Thomas , Pasemann Shirin , Neumann Frank , Maurberger Anna , Kempkes Bettina , Mackensen Andreas , Gerbitz Armin 
Published: October 2019

Abstract
Infiltration by macrophages represents a characteristic morphological hallmark in high grade lymphatic malignancies such as Burkitt’s lymphoma (BL). Although macrophages can in principle target neoplastic cells and mediate antibody-dependent cytotoxicity (ADCC), tumor associated macrophages (TAMs) regularly fail to exert direct cytotoxic functions. The underlying mechanisms responsible for this observation remain unclear. Here we demonstrate that inflammatory M1 macrophages kill proliferating high grade B-cell lymphoma cells by releasing the antimicrobial peptide cathelicidin in a vitamin D-dependent fashion. Moreover, we show that cathelicidin directly induces cell death by targeting mitochondria of BL-cells. In contrast, anti-inflammatory M2 macrophages and M2-like TAMs in BL exhibit an altered vitamin D metabolism resulting in a reduced production of cathelicidin and consequently in inability to lyse BL cells. However, treatment of M2 macrophages with the bioactive form of vitamin D, 1,25D, or a vitamin D receptor agonist effectively induces cathelicidin production and triggers tumoricidal activity against BL cells. Furthermore, rituximab-mediated cytotoxicity of M2 macrophages is cathelicidin dependent and vitamin D treatment of 25D deficient volunteers improves rituximab-mediated ADCC against BL cells. These data indicate that activation of the vitamin D signaling pathway may activate antitumor activity of TAMs and improve the efficacy of ADCC.

Disclosures
No relevant conflicts of interest to declare.
ADAMTS13 Regulates Neutrophil Recruitment in a Mouse Model of Invasive Pulmonary Aspergillosis
Authors: Radsak Markus , Prüfer Steve , Ebner Katharina , Weber Michael , Reuter Sebastian , Stein Pamela , Scharrer Inge , Stassen Michael , Schild Hansjörg , Jurk Kerstin , Bosmann Markus 
Published: October 2019

Abstract
Von Willebrand factor (VWF) is secreted as an acute phase protein during inflammation. The main mechanism regulating the size and prothrombotic activity of VWF is the specific proteolytic activity of ADAMTS-13. To determine the relevance of this regulatory pathway for the innate inflammatory response by polymorphonuclear neutrophils (PMN), we employed a mouse model of invasive pulmonary aspergillosis (IPA) where PMN functionality is crucial for fungal clearance and survival. IPA was induced by intratracheal application of Aspergillus fumigatus conidia in wild-type (129/Sv/Pas) or Adamts13 deficient (Adamts13-/-) mice. After PMN depletion using a anti-Gr-1 specific antibody, all mice infected with Aspergillus fumigatus conidia developed neutropenia and succumbed due to lethal IPA. In contrast, all undepleted wild-type mice survived the infection. Interestingly, Aspergillus fumigatus infection in Adamts13-/- mice was lethal in 20% of the animals displaying a more severe course of IPA, as indicated by an increased fungal burden in lung homogenates along with increased levels of albumin and the inflammatory mediators IL-1β, IL-6, TNF-α, KC and MCP-1 in the bronchio-alveolar lavage fluid (BALF) compared to wild-type controls. Beyond this, we observed a decreased number of PMN in BALF of infected Adamts13-/- mice compared to wild-type mice. Lung histology sections demonstrated a more pronounced perivascular leukocyte infiltration in further support of a dysregulated inflammatory response in Adamts13-/- mice. Importantly, we observed no general defect in the activation of neutrophil effector functions as demonstrated by the normal induction of the oxidative burst, phagocytosis, degranulation, L-selectin shedding and apoptosis in response to formyl-peptide receptor agonists or exposure to Aspergillus fumigatus conidia or hyphae in vitro. Therefore, we conclude that the proteolytic regulation of VWF by ADAMTS-13 in an important mechanism to control PMN recruitment in the regulation of the innate inflammatory response in invasive fungal infections.

Disclosures
Radsak: Celgene: Research Funding.
Splenic Mastocytosis
Authors: ENDE NORMAN , CHERNISS EDWARD I. 
Published: October 2019

Abstract
1. A patient with splenic mastocytosis who had hypersplenism, periodic flushing and clotting defects is presented.
2. A correlation is shown between mastocytosis and elevated histamine and heparin levels in the spleen.
3. The patient is well nine months after splenectomy.
4. Wright’s stain or polychrome methylene blue stain of splenic tissue imprints is recommended as a method of demonstrating mast cells in the spleen.
5. Mast cell counts of normal spleen showed 0 to 0.25% of nucleated cells on imprint.
6. Splenic aspiration stained with Wright’s stain is satisfactory for demonstrating mastocytosis, though not dependable for true mast cell counts.
7. Cases of primary hypersplenism should routinely be reviewed for splenic mastocytosis.
8. Splenic mastocytosis is a variant of systemic mast cell disease in which involvement is predominately confined to the spleen.
A New Diagnostic and Therapeutic Approach Fibrinolysis and Hemorrhage
Authors: HEUSON J. C. , PEERS W. , TAGNON H. J. 
Published: October 2019

Abstract
1. The case is presented of a patient who underwent a cesarean section during which cardiac arrest occurred. Cardiac massage was successful in reestablishing normal heart action.
2. A severe hemorrhagic diathesis associated with fibrinolysis appeared during the period of shock associated with cardiac arrest.
3. The plasma of the patient obtained during the period of fibrinolysis was able to digest its own fibrin as well as a substrate of casein marked with radioactive iodine.
4. A new method of measurement of fibrinolysis based on the use of tagged casein is presented: the main advantage of this method is that the substrate is not contaminated with plasminogen or plasmin. In addition the products of the reaction are measured by their radioactivity. Therefore, the blank and readings in this method depend solely upon the substrate and are not contributed to by the other reagents used.
5. The proteolytic activity of the plasma from a patient with fibrinolysis was shown to be inhibited by the trypsin inhibitor from soy bean.
6. The intravenous injection of trypsin inhibitor in this patient was followed by the disappearance of fibrinolysis in her blood.
Autoimmune Hemolytic Anemia in NZB/Bl Mice Treated with the Corticosteroid Drug Betamethasone
Authors: CASEY T. P. , HOWIE J. B. 
Published: October 2019

Abstract
A controlled therapeutic trial of the corticosteroid drug betamethasone phosphate in the autoimmune hemolytic anemia of the NZB/Bl inbred strain of mice is described. In the treated group, in contrast to the controls, anemia was improved, positive Coombs tests became weaker or negative and there was a fall in titer of circulating antibody. The similarity of this disease in the mouse and in man is discussed. It is concluded that the NZB/Bl mice will prove useful in investigating the effectiveness and mode of action of therapeutic agents in autoimmune hemolytic anemia.
A Possible Immune Reaction Producing Spontaneous Remission in Leukemia
Authors: BURKETT LUTHER L. , FIELDS MURRAY L. , DIGGS LEMUEL W. 
Published: October 2019

Abstract
A patient is described in whom four phases of illness were recognized: (1) erythroleukemia, (2) brisk bone marrow plasmocytosis with Bence Jones protein in the urine suggesting multiple myeloma, (3) normality physically and of blood and bone marrow, with the exception of slight splenomegaly, (4) myeloblastic leukemia with death from Pseudomonas septicemia.
Local and reticuloendothelial plasmocytic reactions have been observed in experimental animals and in man with malignant disease, and this occurrence has been related to tumor inhibition and improved prognosis. Paraproteinemia and paraproteinuria have been noted in malignancies other than those arising from plasma cells or lymphocytes.
It is suggested that the plasmocytosis and abnormal protein in the case reported, as well as in other similar cases previously reported, may have represented an immune reaction induced by the malignancy and responsible for its remission.
Comparative Studies of Platelet Survival by Different Methods in the Rabbit
Authors: EBBE SHIRLEY , BALDINI MARIO , DONOVAN JANET 
Published: October 2019

Abstract
Four methods for measuring the survival of homologous platelets in rabbits were studied: (1) transfusion of nonradioactive platelet concentrates to thrombocytopenic recipients, (2) transfusion of concentrates of platelets labeled in vitro with Cr51-sodium chromate, (3) transfusion of concentrates of platelets labeled in vivo with P32-orthophosphate and (4) transfusion of whole blood labeled in vivo with P32-orthophosphate. The survival time of platelets in normal rabbits was 3-4 days.
From comparison of the 3 methods using platelet concentrates, the following conclusions were drawn. (1) All the platelets in a platelet concentrate were capable of recirculating after transfusion. (2) Labeling with P32 or Cr51 did not damage platelets. (3) About one-third of the Cr51 was immediately eluted from viable platelets after they were transfused. (4) Further exchange of the label in vivo did not occur to a significant degree with either Cr51 or P32. (5) Cr51 did not elute from platelets during storage of the platelets. (6) Studies of rabbit platelets had applicability in predicting the behavior of human platelets.
Role of sialic acid in erythrocyte survival
Authors: Durocher JR , Payne RC , Conrad ME 
Published: October 2019

Abstract
The role of membrane sialic acid in erythrocyte survival is unclear, although there is evidence for a reduction in sialic acid and surface charge in older erythrocytes. We reduced the surface charge of human, rat, and rabbit erythrocytes by removing sialic acid with neuraminidase.Reduction in sialic acid correlated with decreases in electrophoretic mobility and loss of PAS staining of membrane glycoproteins on polyacrylamide gels. No changes in ATP levels or deformability were found. 51Cr erythrocyte survivals in rats and rabbits showed rapid clearance of desialylated erythrocytes with sequestration by the liver.These results suggest that reduction in erythrocyte sialic acid is a mechanism of erythrocyte destruction and may be important in erythrocyte senescence.
Intrinsic material properties of the erythrocyte membrane indicated by mechanical analysis of deformation
Authors: Evans EA , La Celle PL 
Published: October 2019

Abstract
Deformation of the erythrocyte membrane by the micropipette technique permits analysis of intrinsic material characteristics of the membrane and provides a means to differentiate purely membrane factors from such extrinsic factors as surface area-to-volume ratio. Using small micropipettes (less than 0.5 microns radius) to deform cells, it is evident that the red cell membrane behaves like a solid for periods of time up to 5–10 min of sustained deformation; for long periods of strain, permanent deformations occur, indicative of the semi-solid structural character. In the time range in which the membrane behaves like a solid, the material is linearly elastic up to strains of 400%, implying a loose network structure in the membrane plane, and evaluation of the elastic parameter mu (mu for normal discocytes equals 7 x 10(-3) dynes/cm) suggests that the elements comprising the network may have a molecular weight of approximately that of the water-soluble membrane protein spectrin. Whether the network system is cross-linked or simply a polymer solution remains unanswered. Experimental data indicate that plastic flow of the membrane under conditions of protracted strain may lead to permanent deformation of the membrane, whereas uniform dilation of the membrane, requiring over 1000 times more energy than for plastic flow, results in membrane failure and lysis. Analyses of the data from larger micropipettes of limiting mean cylindrical diameter show their utility in evaluating extrinsic factors, e.g., surface area-to-volume relationships, which are related to the capability of the whole cell to form a new configuration with implicit resistance to total surface area change, as the cell enters narrow channels of the microcirculation. Thus, micropipettes with diameters in the 2.7–3.0-microns range can provide sensitive comparisons of cellular deformability of erythrocytes.