bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coagulation and Resuscitation Patterns Following Transfusion with Polymerized Hemoglobin Based Oxygen Carrier (HBOC-201) after Severe Hemorrhage in Swine.
Authors: Arnaud Francoise , Hammett Michael , Philbin Nora , Rice Jennifer , Dong Frank , Flournoy Shannon , Pearce Bruce , McCarron Richard , Freilich Daniel 
Published: April 2020

Abstract
INTRODUCTION: Blood substitutes can alleviate problems related to blood typing and blood availability in civilian and combat trauma casualties. The aim of this study was to assess the effect of transfusions of a blood substitute, HBOC-201 (Biopure Corp, Cambridge, MA) (HBOC), as a resuscitation fluid in severe controlled hemorrhagic shock (HS).
METHODS: Yucatan pigs underwent a 55% EBV controlled hemorrhage by catheter withdrawal. Animals (n=24) were either non-resuscitated (NON) or resuscitated with HBOC or with buffered hydroxyethyl starch (HEX) at an initial rate of 10 ml/kg. Additional infusions were given at 5 ml/kg if hypotension or tachycardia persisted during the 4 hr period following HS. Thereafter, animals received simulated hospital care up to 72 hr with access to blood transfusions for Hb &lt; 7g/dl. In-vivo parameters (vital signs and in vivo bleeding time (BT)), as well as coagulation (PT, PTT, fibrinogen), thromboelastography (TEG) and in vitro bleeding time (PFA-CT) were assayed on blood samples obtained at various times after HS.
RESULTS: Although not statistically significant, HBOC allowed 100% survival compared to 75% with HEX and 25% for NON. It also restored the mean arterial pressure more rapidly compared to HEX. HBOC and HEX groups received similar resuscitation fluid volumes and showed similar hemodilution during the prehospital phase with comparable BT. PFA-CT increased abruptly for both groups remaining elevated at 24 h for HBOC. Other hemostasis parameters were better controlled in the HBOC group compared to HEX: TEG-MA was less suppressed and PT was lower with HBOC. TEG-R was unchanged but indicated delayed hypocoagulation in the HBOC group by 24 hr. At simulated hospital arrival 4 hr after HS, only 10% of animals in the HBOC group required blood transfusions compared to 100% in HEX group. By 72 hr most hematological parameters returned to normal.
CONCLUSIONS: Although HBOC-201 caused less coagulopathy than HEX during fluid resuscitation, it resulted in mild, delayed, and transient coagulopathy by 24 hr. Moreover, HBOC-201 reduced blood transfusion requirements, supporting use of this oxygen-carrying fluid for hemorrhagic shock.
The opinions contained herein are the ones of the authors and are not to be construed as official or reflecting the views of the Navy department or the naval service at large.
Figure Figure
Transfusion Related Acute Lung Injury (TRALI): A Tertiary Care Hospital Experience.
Authors: Strupp Annie , Ilstrup Sarah 
Published: April 2020

Abstract
Background: The 500 bed tertiary care hospital provides Level 1 trauma services, solid organ transplant services and an extensive cardiovascular surgery program.
Methods: Transfusion reaction records for January 2000 – June 2004 were reviewed.
Results: 39 suspected transfusion related acute lung injury reactions reported during this time at a rate of 1:1036 transfused blood products (1:4961 for RBC, 1:1031 for Apheresis Platelets, and 1:522 for FFP). There were 26 male patients, average age of 62.2 years (17–87 years) and 13 females, average age of 62.5 years (24–82 years).
All 39 patients developed acute lung injury within 6 hours of transfusion characterized by acute onset of hypoxia, without evidence of volume overload and chest xrays (performed in 34/39) showing evidence of new bilateral pulmonary infiltrates.
Patients received an average of 2.5 blood products (1–8), and 13/39 (33%) received only one product. FFP was 66% (65/98 units) of implicated product transfused, leukoreduced RBC 24% (24/98, all additive solution products), and leukoreduced platelet pheresis 9% (9/98 units). Of the patients that only received one product, 8/13 (62%) were transfused with a RBC.
Many (74%, 29/39) patients experiencing possible TRALI reactions had underlying risk factors (some patients had more than one underlying problem) including: probable sepsis (5), multiple trauma (2), cardiopulmonary bypass (6), underlying pulmonary disease (5), liver transplant (2), cardiac transplant (1), hematologic malignancy (4), TTP (3), recent surgery (5).
The reaction occurred during or immediately following transfusion in 60% (23/39) of patients, and in 77% (30/39) within 30 minutes of completion of transfusion. Of the recipients that reacted immediately 39% (9/23) of the implicated donors had HLA antibodies (Class I and Class II), and of those reacting within 30 minutes 47% (14/30) of donors had HLA antibodies. 7.7% (3/39) reactions were fatal.
Of implicated donors, 59% (58/98) are female, and 41% male (40/98). 10 donors gave a history of transfusion (1 male, 9 females). 74% (42/57 (1 female couldn’t be contacted)) had been pregnant, with the average number of pregnancies 4.0 (range 1–9), with 67% (28/42) of these donors having 3 or more pregnancies.
Donor antibody testing (Granulocyte Agglutination Assay (GA), Granulocyte Immunofluorescence Assay (GIF), and HLA Antibody Screen (HLA)) was performed only on donors that had been pregnant and/or had received a transfusion, therefore only one male donor was tested and was negative. Of the female donors 62% (36/58) were tested, 29% (17/58) did not meet testing criteria and 9% (5/58) were not available for testing. Of those tested, 31% (11/36) were negative. 69% (25/36) had HLA antibodies. 8% (2/25) with HLA antibodies also had antibodies with granulocyte specificity.
Conclusion: The etiology(ies) and prevention of TRALI reactions require additional investigation of both blood donors and recipients, although HLA antibodies appear to be involved.
Time-Sequenced G-CSF (Lenograstim) for the Treatment of Adult Acute Lymphoblastic Leukemia - Seven Year Follow-Up of the Polish Adult Leukemia Group 4–96 Study.
Authors: Giebel Sebastian , Holowiecki Jerzy , Krawczyk-Kulis Malgorzata , Kyrcz-Krzemien Slawomira , Hellmann Andrzej , Dmoszynska Anna , Paluszewska Monika , Robak Tadeusz , Konopka Lech , Seferynska Ilona , Skotnicki Aleksander , Baran Wojciech , Adamczyk-Cioch Maria , Wrzesien-Kus Agata , Jagoda Krystyna 
Published: April 2020

Abstract
The goal of the study was to evaluate long-term outcome of patients treated within 4–96 trial by the Polish Adult Leukemia Group (PALG). Sixty four patients with newly diagnosed acute lymphoblastic leukemia (ALL) (median age 26 years, range 16–58) were randomly assigned to receive chemotherapy alone (n=31) or chemotherapy and glucosylated G-CSF (lenograstim) (n=33). Both groups were well-balanced in terms of age, initial WBC, immunophenotype and bcr/abl positivity. Induction therapy consisted of epirubicin+vincristin (Epi/Vcr) on days 1, 8, 15, 22, prednisone on days 1–28, L-asparaginase 8 doses starting from day 13; consolidation treatment included twice methotrexate+etoposide (Mtx/Vep), twice high dose cytarabine and cyclophosphamide (HDAraC/Ctx), CNS irradiation and intrathecal Mtx. In T-derived ALL, additional HDAraC/Ctx was administered instead of the first Mtx/HDAraC. During induction patients received G-CSF 150 μg/m2 sc. on days 2–6, 9–13, 16–20, 23-until the neutrophil recovery &gt;1.0x109/L, starting 36 hours after Epi/Vcr, finishing 48 hours before the next dose; in consolidation - following each HDAraC/Ctx course on days 5–16. High risk patients having a donor were performed allogeneic hematopoietic cell transplantation in first complete remission, whereas those without a donor were given autologous transplant. At seven years the overall survival rate equalled 42% for G-CSF group and 24% for the controls (p=0.11). There was also a trend to higher probability of leukemia-free survival in advantage of patients receiving the cytokine (38% vs. 20%, p=0.17). The above differences might have resulted from: 1) Higher CR rate in the G-CSF group compared to the controls (94% vs. 87%), 2) Better adherence to the chemotherapy protocol (faster completion of induction-consolidation programme by 19 days, p=0.005, less dose reductions or delays), which in turn might have influenced the risk of relapse.
We conclude that time sequenced G-CSF administration may improve long-term outcome of adult ALL patients although the study including larger population is required to confirm this hypothesis.
Re-Targeting of an NK Cell Line (NK92) with Specificity for CD19 Efficiently Kills Human B-Precursor Leukemia Cells.
Authors: Romanski Annette , Uherek Christoph , Bug Gesine , Muller Tina , Rossig Claudia , Kampfmann Manuela , Krossok Nicola , Hoelzer Dieter , Seifried Erhard , Wels Winfried , Ottmann Oliver G. , Tonn Torsten 
Published: April 2020

Abstract
The continuously growing Natural killer (NK) cell line NK-92 is highly cytotoxic against malignant cells of various origin without affecting normal human cells. It is the only NK cell line that has entered clinical trials to date. Acute lymphoblastic leukemias (ALL) show variable sensitivity towards NK cells including NK-92-lysis. All T-ALL cell lines tested (MOLT-3, MOLT-4 and CEM-T) display moderate sensitivity to NK cytotoxicity with approximately 22±2 – 24±2% killing at an effector to target (E:T) ratio of 10:1, respectively. Comparable results were obtained with primary patient derived T-ALLs (n=4), displaying specific killing rates of 17±5 – 20±2%. In contrast, B lineage ALL cell lines (NALM-6, SEM, REH, JKB, BV173, SupB15, TOM-1, TMD5) and cells derived from patients (n=11) were resistant to NK-92-mediated lysis, with specific killing rates ranging from 2±1% to 13±3% at an E:T ratio of 10:1. Approaches to overcome resistance of B-precursor ALL by re-targeting may shed light on the specific reasonable mechanism conferring resistance and lead to novel therapeutic strategies. Here we have generated genetically modified NK-92 cells expressing a chimeric antigen receptor specific for the pan B cell antigen CD19 which is universally expressed by B lineage leukemia cells. This receptor fragment kindly provided by H. Zola (Child Health Research Institute North Adelaide, Australia) consists of the CD19 specific scFv(CD19) antibody fragment, a flexible hinge region, the CD3 ζ chain and a Myc-tag. Transduced cells were selected with G418, and surface expression of the chimeric scFv(CD19)-ζ construct was verified by FACS analysis using the Myc-tag-specific mAb 9E10. No difference in cytotoxic activity of NK-92 and transduced NK-92-scFv(CD19)-ζ cells towards CD19 negative targets (K562, MOLT-4) was found. In contrast, NK-92-scFv(CD19)-ζ cells specifically and efficiently lysed CD19 expressing B precursor leukemia cells (NALM-6, SEM, B173, SupB15, TOM-1, TMD5) including cells that were completely resistant to cytolytic activity of parental NK-92 cells. Killing of SupB15 and BV173 cells was 10,0±0,8% and 12,0±8,5% with parental NK92 vs. 58,2±14,8% and 52,3±4,1% lysis with NK92 cells expressing the CD19 specific scFv(CD19) antibody fragment. These results demonstrate that efficient retargeting of NK-cell cytotoxicity can be achieved, and might allow the generation of potent cell-based therapeutics. Since the widespread resistance of B precursor ALL blasts to NK cell cytotoxicity is not caused by mechanisms commonly relevant in tumors, this model may allow dissection of possible mechanisms of resistance.
The Acquired CD40L Deficiency in B-CLL Is Reversible and Due To Contact Dependant and Independent Factors.
Authors: Buggins Andrea G.S. , Richards Julie , Patten Piers E.M. , Mufti Ghulam J. , Devereux Stephen 
Published: April 2020

Abstract
Interactions between CD40L (CD154) and its receptor CD40, are of central importance in T-cell mediated B-cell activation, proliferation and isotype switching and the regulation of antigen presentation by dendritic cells. Peripheral blood T lymphocytes from patients with B cell chronic lymphocytic leukemia (B-CLL) have an acquired defect of activation induced CD40L expression that might contribute to the immunodeficiency characteristic of the disease. In view of recent reports that T-cells within bone marrow and lymph node pseudofollicles express CD40L we have re-examined the mechanism of the deficiency in PB cells. Activation of normal resting naïve and memory (CD45RA+ and −) T-cells with PMA and ionomycin increased the number expressing surface CD40L from a mean of 2 and 0% to 81.2 and 66.5% respectively. In line with previous reports, up-regulation of CD40L by CD4+45RA+ and CD4+45RA− T-cells from patients with B-CLL was reduced to a mean of 11.8% and 2.6%. This defect is reversible since removal of T-cells from the malignant clone by CD3 selection increased the number of cells able to up-regulate CD40L to 62.2% and 61.8% for naïve and memory CD4 subsets. To investigate whether this phenomenon is due to cell contact or soluble mediators, washed leukemic cells or supernatant (SN) harvested from the same cell number were incubated with normal donor T-cells for 48 hours then stimulated for 4 hours with PMA and Ionomycin. B-CLL SN reduced CD40L up-regulation by a mean of 51% (range 14–86, n=17, p&lt;0.0001) but co-culture reduced this further to a mean of 17% (range 7–33%, n=8, p&lt;0.0001). Other markers of T-cell activation were similarly affected, for example T-cell IL-2 production was reduced to 40.1% ( 6.2% SEM, p &lt; 0.0001) of the level seen in the absence of B-CLL SN. Although SN and cell contact both prevented CD40L up-regulation, only cell contact caused its down-regulation in pre-activated T-cells (reduced to 94% of normal with SN, [range 93–96%, n=3, p=0.5] and 14% of normal with co-culture [range 4.3–21.7%, n=6, p p&lt;0.0001]). The acquired CD40L deficiency observed in patients with B-CLL is thus reversible and mediated by contact with leukemic cells and soluble mediator(s). B-CLL cells are known to secrete a number of factors that might produce this effect. Studies using blocking monoclonal antibodies and immuno-adsorption excluded the most likely candidates including TGF-beta, soluble CD40 and soluble IL-2R. These findings indicate that regulation of the CD40/CD40L system in B-CLL is more complex than previously reported however the impact of this on disease pathogenesis needs to be determined.
Identification of a Subset of Aplastic Anemia Patients Highly Responsive to Danazol.
Authors: Yamazaki Hirohito , Chuhjo Tatsuya , Sugimori Chiharu , Ishiyama Ken , Nakao Shinji 
Published: April 2020

Abstract
Treatment of patients refractory to immunosuppressive therapy is a major problem in the management of aplastic anemia (AA). Some patients who are ineligible for allogeneic stem cell transplantation have been successfully treated with anabolic steroids although little is known about the common characteristics of these patients. In order to characterize high responders to danazol, we retrospectively studied 44 AA (13 male and 31 female) patients who were treated with 300 mg of danazol daily for at least 3 months. All patients had been previously treated with ATG+CsA or CsA alone without appreciable effects before danazol therapy. Peripheral blood of these patients was examined for the presence of PNH-type cells and clonality in granulocytes using sensitive flow cytometry (Blood100: 3897, 2002) and the improved HUMARA assay (Blood102: 1211, 2003). 24 of 44 (55%) patients attained PR or CR according to the response criteria proposed by Camitta. All 3 lineage cells increased in the responders. The rate of response in female patients (21/31, 68%) was significantly higher than that (3/13, 23%) in male patients (P=0.0058). There was no difference in the response rate between older (&gt;50 years) patients (75%) and younger (&lt;50 years) patients (60%) in female patients, indicating that the effect of danazol is not affected by a female sex hormone. Increased PNH-type cells were detectable in 2 (8.3%) of 24 responders and in 6 (40%) of 15 non-responders. The HUMARA assay revealed presence of clonal granulocyte population in 13 (76%) of 17 responders and 2 (33%) of 6 non-responders, respectively. For a female patient without increased PNH type cells who has not responded to immunosuppressive therapy, the rate of response to danazol was 64%. Probability of 3-year survival in responders to danazol was 100% while that in non-responders to the therapy was 90%. Univariate analysis revealed that negativity for increased PNH-type cell and being female were significantly associated with good response to danazol. These findings indicate that danazol is a useful drug in the treatment of a subset of female AA patients characterized by refractoriness to conventional immunosuppressive therapy and absence of increased PNH-type cells. Given the high frequency of clonal hematopoiesis in responders to danazol, this anabolic steroid may stimulate expansion of a small number of stem cells that survived non-immune marrow insult.
Decreased Expression of Stem Cell-Specific Genes in Aplastic Anemia; Possible Regulation of HOXB4 Gene by GATA-2.
Authors: Yokoyama Hisayuki , Harigae Hideo , Takahashi Shinichiro , Okitsu Yoko , Yamamoto Johji , Tohmiya Yasuo , Fujiwara Minami , Ishizawa Kenichi , Kameoka Junichi , Minegishi Naoko , Kaku Mitsuo , Sasaki Takeshi 
Published: April 2020

Abstract
Aplastic anemia (AA) is characterized by reduced hematopoiesis resulting in pancytopenia. It is suggested that a certain immunological attack to hematopoietic stem cells play an important role in developing AA. However, limited information is available for the intrinsic characteristics of stem cells in AA. Previous work in our laboratory showed decreased expression of GATA-2 gene in CD34 positive cells in AA, suggesting that there is an aberrant expression of stem cell-specific genes in stem cells in AA. Recently it is emerged that some genes such as HOXB4 and BMI-1, function for the proliferation and maintenance of stem cells. In this study, we examined expression levels of HOXB4 and BMI-1 in CD34 positive cells by quantitative PCR in 10 patients with AA and 13 with idiopathic thrombocytopenic purpura (ITP). Between these two factors, the expression level of HOXB4 was markedly decreased in AA compared with in ITP, whereas that of BMI-1 was not. Moreover, the expression level of GATA-2 in these populations was significantly correlated to HOXB4 gene expression (Spearman’s rank correlation, r=0.6573 p&lt;0.01) compared to that of BMI-1(r=0.4107, p&gt;0.05). As they functions as a transcription factor, these results raise the possibility that GATA-2 and HOXB4 regulate each other. To explore this possibility, first, we cloned HOXB4 5′flanking region by PCR and performed promoter analysis. Since the previous report showed that the region from −164 to −116 was important for promoter activity of HOXB4 gene, we focused on a GATA element located at −160. When this element was deleted, the reporter activity was decreased to 60% of wild-type in K562 cells. Furthermore, co-transfection of GATA-2 expression vector significantly activates the reporter gene in a dose dependent manner. EMSA revealed that GATA-2 binds specifically to this element. On the other hand, the active region both of exon 1S and 1G promoter of GATA-2 gene, which was identified by the promoter analysis, did not contain the consensus sequence recognized by HOXB4. These findings suggest that in stem cells in AA, the decreased expression of GATA-2 gene lead to the reduced HOXB4 gene expression, which may responsible for the development of the disease.
Association of Telomere Length in Dyskeratosis Congenita Lymphocytes with Increased Sensitivity to Radiation and Anti-Mitotic Agents.
Authors: Beasley Michael A. , Singhal Vibha , Klingelhutz Aloysius J. , Akabogu Ike , Goldman Frederick D. 
Published: April 2020

Abstract
Dyskeratosis congenita (DC) is a premature aging syndrome characterized by progressive bone marrow failure, abnormal skin pigmentation and nail dystrophy. We have recently described an autosomal dominant form of DC (AD DC) in a large three-generation kindred that is due to a mutation in the gene encoding human telomerase RNA (hTR). Importantly, we have noted progressive shortening of telomeres in lymphocytes from the most recent generation, correlating with earlier onset of severe cytopenias in some of these patients. While telomere shortening is a normal consequence of the aging process, DC patients display accelerated telomere shortening in many somatic cell types. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative therapy for marrow failure in DC. However, HSCT in DC is generally poorly tolerated and associated with significant morbidity, perhaps as a consequence of increased sensitivity of dividing cells to cytotoxic agents. To test this hypothesis, we characterized lymphocytes from nine AD DC patients and age matched controls that had been placed in long term culture following in vitro exposure to irradiation (137Cs) and varying doses of Taxol. Cell proliferation and viability were quantitated by direct visual counting on a hemocytometer, and flow cytometry was employed to assess apoptosis and cell surface expression of senescent markers. CD57 and CD95, markers of cellular senescence and apoptosis, were significantly upregulated on DC T lymphocytes after two weeks in culture relative to controls. In addition to DC lymphocytes having a decreased proliferative capacity, an increased sensitivity to Taxol was noted, with an average decrease of 21% in cell growth relative to similarly treated control cells. This effect was also noted in irradiated DC cells. Finally, DC lymphocytes displayed an increased apoptotic index in the presence of varying doses of Taxol. These results suggest that telomere shortening may be an important factor in determining cellular tolerance to cytotoxic therapy and support the concept of reduced intensity HSCT regimens in both aged individuals and DC patients.
Increased TCF-4 Expression Correlates with Reduced Caspase-3 Induction and Confers Resistance to Bortezomib.
Authors: Shringarpure Reshma , Bhole Deepak , Burger Renate , Catley Laurence , Podar Klaus , Tai Yu-Tzu , Hideshima Teru , Mitsiades Constantine , Munshi Nikhil C. , Chauhan Dharminder , Anderson Kenneth C. 
Published: April 2020

Abstract
Bortezomib (PS-341 / Velcade®) has achieved responses in the setting of relapsed refractory multiple myeloma, yet some patients either fail to respond or become refractory after an initial response. Moreover, despite the essential role of proteasomes in cell proliferation, not all tumor cell types respond to Bortezomib treatment. To define mechanisms for differential sensitivity to Bortezomib, we used gene expression profiling to compare global gene expression patterns in SUDHL-4 and SUDHL-6 B-cell lymphoma cell lines, which respond differentially to Bortezomib treatment. Of genes that were differentially expressed in the two cell lines, we chose to further examine differential expression of the transcription factor ‘T-cell factor 4′ (TCF-4), a downstream effector in Wnt signaling. TCF-4 expression was 15 fold higher in resistant SUDHL-4 cells compared to sensitive SUDHL-6 cells by microarray analysis, which was confirmed by real-time PCR. TCF-4 was constitutively associated with ß-catenin, its transcriptional co-activator, only in resistant SUDHL-4 cells, but not in sensitive SUDHL-6 cells. TCF-4 overexpression was associated with increased transcription of TCF-4 target genes cyclin D1 (3.48 fold) and c-myc (1.7 fold). Since all TCF-4 target genes are not defined, we also confirmed increased transcription by the TCF-4 / ß-catenin complex using TCF-4 / ß-catenin driven reporter genes. Increased TCF-4 expression in resistant SUDHL-4 cells was associated with lower induction of caspase-3 expression and activity in response to Bortezomib. Importantly, siRNA-mediated downregulation of TCF-4 sensitized cells to Bortezomib treatment, suggesting that blocking TCF-4 can restore sensitivity to Bortezomib-induced apoptosis. Our studies provide the rationale to use small molecule antagonists of TCF-4 / ß-catenin interaction to overcome Bortezomib resistance and improve patient outcome.