bluuebunny/crossref_metadata_2025_split huggingface dataset:
The G20210A Prothrombin Gene Mutation and the Plasminogen Activator Inhibitor (PAI) 844GG Genotype Increase the Risk of Premature Onset of Severe Preeclampsia.
Authors: Gerhardt Andrea , Goecke Tamme W. , Beckmann Matthias W. , Scharf Rudiger E. , Zotz Rainer B. 
Published: April 2020

Abstract
Obstetrical complications such as severe preeclampsia and HELLP syndrome are associated with abnormal placental vasculature and inadequate placental maternal-fetal circulation. Hereditary risk determinants of venous thrombosis have been reported to be associated with these obstetrical complications.The magnitude of the association between thrombophilia and the obstetrical complications varies in the published studies, according to type of obstetrical complication and type of thrombophilia. No data exist so far whether these risk determinants are related to premature onset of severe preeclampsia.
We used a case-control design in 99 women with severe preeclampsia (blood pressure higher than 160/100 mm Hg; urinary protein excretion greater than 5 g per day, platelet count of less than 100.000/μl; combination of hemolysis, high serum aminotransferase concentration, and platelet count below 100.000/μl; or eclampsia) in previous pregnancies and 277 normal women to assess hereditary risk factors of venous thrombosis as risk determinants for severe preeclampsia. Moreover, a case-only design was used to assess these risk factors as risk determinants for premature severe preeclampsia. We determined the genetic risk markers factor V Leiden G1691A (FVL), the G20210A prothrombin gene mutation, the methylenetetrahydrofolate reductase polymorphism (MTHFR C677T), and the PAI A844G polymorphism. None of the women had a combined or homozygous defect of the FVL or the G20210A prothrombin gene mutation. Women with antiphospholipid syndrome were excluded. None of the women had a deficiency of antithrombin, protein C, or protein S.
Using the case-control design, there was no significant risk association of the hereditary risk factors with severe preeclampsia (FVL p=0.680, prothrombin mutation p=0.479, MTHFR 677TT genotype p=0.565, PAI 844GG genotype p=0.641). In the case-only design, the onset of severe preeclampsia was significantly earlier in women with the G20210A prothrombin gene mutation (24.5 weeks vs. 30.5 weeks, p=0.04) and in women with the PAI 844GG genotype (27.2 weeks vs. 30.7, p=0.025). No such significant difference was observed in carriers of the FVL or the MTHFR 677TT genotype. Hereditary risk factors for venous thrombosis are not risk determinants for severe preeclampsia. However, women who are carriers of the G20210A prothrombin gene mutation and the PAI 844GG genotype are at risk for premature onset of severe preeclampsia. Based on our results it appears that these risk factors do not induce the pathomechanism but modulate the course of preeclampsia.
Single Knock-In PML-RARα Expressing Murine APL Tumors Provide a Unique Model for Studying In Vivo Sensitivity and Resistance to ATRA and Arsenic Trioxide.
Authors: Greenbaum Adam M. , Holt Matthew S. , Ley Timothy K. , DiPersio John F. 
Published: April 2020

Abstract
Although approximately 70% of patients with acute promyelocytic leukemia (APL) are cured after treatment with all-trans retinoic acid (ATRA) and anthracycline based chemotherapy, those who relapse cannot be cured even with chemotherapy or arsenic trioxide salvage therapy. In order to study the molecular mechanisms of resistance to ATRA, liposomal ATRA, and arsenic trioxide, we have utilized a murine model of APL generated by “knocking in” the PML/RARα gene into the murine cathepsin G locus (Westervelt et al. Blood. 102(5):1857). Of the 76 single knock-in (SKI) mice followed for a median time of 368 days, 30 (39%) suffered from rapid-onset leukocytosis, anemia, thrombocytopenia, and hepato-splenomegaly. Spleens from these leukemic animals were removed and the tumors cells (&gt; 90% CD34+/Gr-1+ APL cells) were frozen in aliquots and banked for future passive transfer into genetically compatible recipients. The SKI mice exhibited the expected median time to death of 222 days. Attempts to expand these tumors in vitro failed, thus precluding the use of in vitro methods to generate ATRA and arsenic resistant SKI APL tumor cells. An alternate in vitro model of identifying de novo resistant SKI APL tumors to the drugs was established by incubating individual SKI APL tumors with ATRA, liposomal ATRA, and arsenic in vitro for only 3 days and using ELISA to measure upregulation of MMP-9 (gelatinase B), a surrogate marker for neutrophil differentiation. ATRA, liposomal ATRA, and arsenic induced 6.2 ± 4.4, 5.7 ± 3.5, 1.7 ± 1.0 fold increase in accumulated levels of MMP-9, respectively. These data suggest that ATRA and liposomal ATRA are more potent inducers of terminal differentiation than arsenic in these APL tumors. More importantly, the SKI APL tumors were also assessed for in vivo resistance to these agents by injecting 1 x 106 banked APL tumor cells into the peritoneal cavity of wild-type genetically compatible mice. The mice were then treated i.p. with either arsenic trioxide (0.4 mg q.d.), liposomal ATRA (0.4 mg q.d.), or diluent control. Doses were administered daily starting on day +5 until death. Tumors in the recipient mice were tracked by PCR for the transgene and FACS. The tumors proliferated in the peritoneal cavity (days 1–14) followed by migration to the bone marrow and spleen (days 14–28). By the eighth week post-injection, all mice suffered from leukocytosis and eventually died. Of the 22 banked tumors studied, only two tumors showed de novo resistance to ATRA both in vitro and in vivo. We will present data on preliminary RNA profiling and DNA sequencing of the PML-RARα transgenes in these APL tumors and attempt to correlate these results and the results of in vitro induction of MMP-9. The SKI APL tumors will provide us with unique reagents to study the biology of resistance to ATRA and arsenic trioxide.
Detection of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia by 4color Cytometry in International Multicenter Trial Minimini.
Authors: Mejstrikova Ester , Batinic Drago , Klara Dubravcic , Ng Margareth , Leung Yonna , Kappelmayer Janos , Luria Drorit , Izraeli Shai , Kalina Tomas , Vaskova Martina , Fronkova Eva , Stary Jan , Trka Jan , Hrusak Ondrej 
Published: April 2020

Abstract
FC is still not employed in MRD based treatment protocols. One problem is lack of standardization suitable for prospective trials involving multiple clinical centers and FC laboratories. Therefore, we established a MiniMini Project, an international collateral study within the ALL IC BFM 2002 treatment protocol for childhood acute lymphoblastic leukemia (ALL). The MiniMini Project provides a mainframe of minimal panel of monoclonal antibody combinations to evaluate MRD by FC. Patients (pts) are stratified according non-MRD criteria (prednisone response at day 8 in peripheral blood (PB), percentage of blasts at day 15 and day 33 in bone marrow (BM), leukocytosis, and age at diagnosis and presence of BCR/ABL or MLL/AF4 fusions). Identical immunophenotypic populations are reported in all pts regardless presenting phenotype. Each laboratory investigates at least 2 pts with B lineage ALL by the T ALL combinations and vice versa. These “cross-lineage controls” together with data on subpopulations that are negative at diagnosis were used to set the specificity cutoff values at each time point (diagnosis, day 8 BM and PB, day 15, day 33 day 52 BM). MRD levels obtained by Ig/TCR rearrangements RQ-PCR in 32 pts (24 pts BCP ALL, 8 pts T ALL) were used to define specificity thresholds. 185 pts were investigated in the participating laboratories. We used data from first Czech cohort of pts (92 pts in total, 16 pts T lineage, 74 pts B lineage, in standard risk group (SRG), n=36, IRG, n=40 and HRG, n=16) in whom clinical data as well as standard FC analysis results were available. We compared morphological percentage of blasts (used for stratification) to a level of residual disease by FC. There was high concordance in SRG of both methods, except 1 patient redirected into IRG group (M3 BM vs. only 14% of blasts by FC). In IRG, concordance was in 92.5% of pts, 3 pts should be placed in HRG group according FC. 98.9% of pts morphologically in complete remission at day 33 were confirmed by FC. Although FC data confirm a significant difference between PGR and PPR in PB specimens at day 8 (p=0.0014), there is an overlap in percentage of leukemic cells between these categories. In total, MRD level above 0.1% was observed in BM of 100, 99, 84, 32 and 3.5 % pts in days 0, 8, 15, 33 and 52, respectively and in PB of 95% pts at day 8. Our first results show feasibility of FC standardization. The choice of subpopulations and the cutoff points will be validated in an independent cohort within the same Project.
Patients with Lymphoplasmacytic Lymphoma Can Be Salvaged with Autologous Stem Cell Transplantation, Irrespectively of the Number of Previous Treatment Lines. Analysis of 146 Cases from the European Bone Marrow Transplant Registry (EBMT).
Authors: Kyriakou Charalampia A. , Goldstone Anthony H. , Sureda Anna , Yong Kwee , D’Sa Shirley , Taghipour Goli , de Elvira Carmen Ruiz , Linch David C. , Schmitz Norbert 
Published: April 2020

Abstract
Lymphoplasmacytic Lymphoma (LPL) is a relatively rare low-grade lymphoma which primarily affects elderly patients. Standard doses of alkylating agents, purine analogues and anti-CD20 monoclonal antibody effect response rates of up to 60%. However, complete response is infrequent and there is no cure. Due to indolent nature of the disease and older patients with comorbidities, evaluation of the role of high dose therapy with transplant has been infrequent in the past. Here we report a retrospective multicentre study of 146 LPL patients (94 male, 52 female), who underwent autologous stem cell transplantation (ASCT) between 1992 and 2004.
The median age was 60 years (54–67) and median time from diagnosis to transplant was 62 months (5–119). Twenty-six patients (18%) were in CR1, 35 (24%) in CR2, 30 (20%) in ≥CR3, 45 (31%) in PR, 10 (7%) primary refractory at transplant. Combination of GCSF with either Cyclophosphamide, ESHAP or AraC were mainly the stem cell mobilisation regimens used, and 18 patients with extensive prior use of purine analogues, required second attempt for harvesting. The conditioning regimens used were BEAM, Cyclophosphamide/TBI or Melphalan/TBI. The source of stem cells was PBSC in 129, BM in 11 and both in 6 patients. All patients except one had successful engraftment. With a median follow-up of 12 months (2–126), 131 (90%) patients are alive and 15 (10%) dead. Thirteen patients died from disease progression and 2 from regimen toxicity. Actuarial non- relapse mortality was 2.4% at 1 and 2 years. The actuarial OS was 90% at 1 year, 79% at 3 years and 69% at 5 years. The probability of relapse was 80% at 1 year, 53% at 3 years and 39% at 5 years. Relapse rate was not statistically significant for patients with chemosensitive disease. In conclusion this study shows that ASCT is safe, and a significant proportion of previously multitreated LPL patients can be salvaged and sustain prolonged DFS.
Elucidation of the Molecular Mechanisms by Which Inflammatory and Anti-Inflammatory Monokines Regulate Interferon (IFN)- γ Production.
Authors: Yu Jianhua , Becknell Brian , Liu Shujun , Trotta Rossana , Jaung Micheal S. , Hughes Tiffany , Marcucci Guido , Weinstein Michael B. , Caligiuri Michael A. 
Published: April 2020

Abstract
Pro-inflammatory monocyte-derived cytokines (monokines) such as interleukin (IL)-12, IL-15 and IL-18 work in concert to quickly induce IFN- γ in natural killer (NK) cells, while the anti-inflammatory monokine transforming growth factor beta 1 (TGF-β1) can suppress NK cell IFN- γ production. Here, we provide new molecular evidence as to how these monokines carry out their opposing functions. In the human NK-92 cell line we show that Smad proteins, mediators of TGF- β1 signaling, directly inhibit IFN- γ production. Using chromatin immunoprecipitation (ChIP), we found that both Smad2 and Smad4 associate with the IFN- γ promoter in the proximal region but not in other regions, such as exon 4. Luciferase reporter assays in 293T cells indicated that Smad2 alone, which does not possess a DNA binding domain, had little effect on the inhibition IFN-γ of promoter activity. In contrast, Smad3 and Smad4, both of which have DNA binding activity, dramatically suppressed IFN-γ promoter activity. Co-transfection of Smad2 and Smad4, or Smad3 and Smad4, in 293T cells resulted in synergistic repression. Interestingly, the Smad proteins also inhibited the transactivation of the IFN-γ promoter by T-BET, a recently discovered transcription factor controlling IFN- γ production in mouse T cells and NK cells. This was consistent with our data showing that TGF-β1 inhibited T-BET expression in human NK cells. Using IFN-γ promoter deletion constructs, we mapped the region responsible for Smad-mediated inhibition to the -204 proximal promoter, where Smad binding elements are enriched. In parallel, using micro-array analysis, western-blotting and semi-quantitative PCR in human primary NK cells and the NK-92 cell line, we demonstrated that the combination of the pro-inflammatory monkines IL-12 with IL-15 or IL-18 was able to antagonize multiple components of TGF- β1 signaling, including: 1) inhibition of the expression and the phosphorylation of Smad2; 2) suppression of Smad3 expression; and 3) down-regulation of the expression of the TGF- β receptor II subunit. Moreover, although these monokines had no effect on Smad4 expression, using ChIP assay we observed that Smad4 dissociated from the proximal IFN-γ promoter upon co-stimulation of NK cells with IL-12 and IL-18. In summary, our data show that TGF- β1 suppresses IFN- γ production via the direct binding of Smad proteins to the proximal IFN-γ promoter and via inhibition of T-BET, while the pro-inflammatory cytokines serve to inhibit or down modulate TGF- μ signaling components and reverse Smad binding to the proximal IFN-γ promoter. Thus, we suggest that NK cell production of IFN-γ is controlled by the integration of anti-inflammatory and pro-inflammatory monokine signals, leading to reciprocal antagonism.
A Molecular Signature of the Transcription Factor GATA1 in Acute Megakaryoblastic Leukemia of Childhood.
Authors: Bourquin Jean-Pierre , Langebrake Claudia , Subramanian Aravind , Li Xiaochun , Reinhardt Dirk , Bernard Olivier , Zwaan Christian M. , Hasle Henrik , Schrappe Martin , Golub Todd R. , Orkin Stuart H. 
Published: April 2020

Abstract
To investigate the pathogenesis of acute megakaryoblastic leukemia, AML M7 (M7), we analyzed the gene expression profiles of 113 patient samples on Affymetrix U133A GeneChips. Classification by unsupervised clustering discriminates 70 M7 samples from 12 with other AML FAB subtypes, 3 normal controls, 10 normal and remission samples of patients with Down Syndrome (DS) and 18 ALL samples from DS patients.
Further, M7 subclasses can be identified. DS samples (21 DS-M7 and 9 transient myeloproliferative disease (TMD) samples) cluster apart from non-DS M7 samples, with a few exceptions, most notably the 4 M7 samples with the translocation t(1;22). Smaller subgroups can be detected by consensus clustering in DS and non-DS M7.
The DS-non-DS distinction is not driven by differential expression of chromosome 21 genes, in particular RUNX1 expression levels are not increased in DS. Consistent with differences observed by flow cytometry, DS samples show a higher expression of ANK1, GYPA, GYPB and CD36, while non-DS M7 samples have higher VWF and CD34 expression, reflecting known morphologic differences. The hematopoietic transcription factor GATA1 is overexpressed in DS M7/TMD when compared to non-DS M7s or controls, and is among the most significant markers of the DS class. The mutation of GATA1 that is characteristic for DS is likely to affect its transcriptome specifically. By nearest neighbour analysis, about 300 genes follow the pattern of the GATA1 gene expression within a significant range by permutation testing. This GATA-1 signature is highly enriched in the DS samples and includes several known target genes of GATA1, such as GATA2, GYPA, ANK1 and ALAD. This approach should lead to the identification of genes contributing to cellular proliferation and differentiation in the context of the GATA1 mutation of DS M7.
Pilot Study to Test the Efficacy and Safety of Recombinant Factor VIIa (rFVIIa, NovoSeven™) in the Treatment of Refractory Hemorrhagic Cystitis Following High Dose Chemotherapy.
Authors: Ashrani Aneel A. , Gabriel Don A. , Gajewski James L. , Key Nigel S. 
Published: April 2020

Abstract
Background: Hemorrhagic cystitis (HC) is a known complication of high-dose cyclophosphamide, which is part of the conditioning regimen for stem cell transplantation, and is associated with significant morbidity. Treatment of HC is frequently unsatisfactory, leading to prolonged hospitalization and utilization of health care resources. High-dose recombinant factor VIIa (rFVIIa) is used as a hemostatic agent in patients with hemophilia with inhibitors. As rFVIIa enhances the generation of thrombin on activated platelets and facilitates the formation of a stable fibrin plug that is resistant to premature lysis, we conducted a pilot study to assess its efficacy and safety in the treatment of HC.
Methods: Subjects between 18–65 years with severe HC that was judged unresponsive to (a) optimization of hemostatic parameters, and (b) a trial of at least 24-hours of continuous bladder irrigation using a standardized protocol were eligible. Consented subjects were administered 80 μg/kg of rFVIIa for the first dose, and 120 μg/kg every 3 hours for up to 2 additional doses if hematuria was persistent. Response was evaluated by monitoring urine color photographically and by measuring urine hemoglobin content, using spectrophotometer. Subjects were followed for 24 hours. Complete response was defined as complete clearing of the color of urine at any time point in the 24-hour study period, and partial response was defined as slowing of hematuria, as evidenced by lightening of the color of urine.
Results: Of the 7 subjects who participated in the study, 4 had a complete response, 2 had a partial response, and 1 had no response. The response duration was temporary, and all the subjects required the administration of the three doses of rFVIIa. No major adverse effects were encountered.
Conclusion: rFVIIa appears to be effective in temporarily abating bleeding in HC. Further trials should include multiple dosing and/or addition of antifibrinolytic agents for a more durable effect.
Incidence and Risk Factors for Thromboembolism in Patients with Hematologic Malignancies Undergoing Allogeneic and Autologous Stem Cell Transplantation.
Authors: Kuderer Nicole M. , Khorana Alok A. , Friedberg Jonathan W. , Culakova Eva , Phillips Gordon L. , Francis Charles W. , Lyman Gary H. 
Published: April 2020

Abstract
Background: Thromboembolism (TE) is a common complication of hospitalized non-transplant cancer patients. To date, the extent and impact of TE in stem cell transplant patients is unknown, in part because it is considered a low risk group given the high prevalence of thrombocytopenia. The purpose of this study is to evaluate the incidence of and risk factors for TE in cancer patients undergoing stem cell transplantation.
Methods: We conducted a retrospective analysis of all discharge summaries from the 115 US academic health centers reporting to the University HealthSystem Consortium from 1995 to 2002. We identified a total of 7,087 patients with hematologic malignancies undergoing allogeneic and autologous stem cell transplantation. The incidence of and risk factors for venous and arterial TE was analyzed in univariate and multivariate logistic regression analysis with adjusted odds ratios as estimates of relative risk.
Results: TE was reported in 389 (5.5%) transplant patients with 4.8% patients developing venous and 0.7% arterial TE. The incidence of TE was greater in allogeneic (6.8%) compared to autologous (4.8%) transplant patients (p&lt;0.0001). Among those receiving allogeneic transplantations, BMT patients experienced a higher rate of TE than PBSC patients (7.5% vs 5.6%; p&lt;0.05). In multivariate logistic regression analysis, the following clinical variables were significantly associated with TE in stem call transplant patients with hematologic malignancies: gram negative sepsis (OR=1.76; 1.02–3.02; p=0.04), gram positive sepsis (OR=1.75; 1.25–2.45; p=0.001), line infections (OR=1.48; 1.11–1.97; p=0.008), central venous catheters (OR=1.74; 1.39–2.17; P&lt;0.0001), pulmonary disease (OR=1.87; 1.47–2.37; p&lt;0.0001), liver disease (OR=1.31; 1.01–1.70; p=0.04) and length of stay &gt;30 days (OR=1.66; 1.30–2.13; p&lt;0.0001). Hodgkin’s disease (OR= 0.59; 0.37–0.94; p=0.026) was associated with a lower risk of TE. In multivariate analysis, the type of transplant failed to remain an independent risk factor for TE after controlling for other transplant complications.
Conclusions: This is the first substantive report on the incidence of thromboembolism in stem cell transplant patients. We found that thromboembolic events are a frequent complication in patients with hematologic malignancies undergoing stem cell transplantation. The incidence of TE is high among most subgroups studied. Prospective studies are needed to evaluate the efficacy and safety of thromboprophylaxis in this high-risk population.
5′-AZA-2′-Deoxycytidine Induces p21/WAF Expression by Demethylation of p73 Leading to p53-Independent Apoptosis in Myeloid Leukemia.
Authors: Tamm Ingo , Wagner Mandy , Dörken Bernd , Schmelz Karin 
Published: April 2020

Abstract
The DNA methylation inhibitor 5′-Aza-2-deoxycytidine (5-Aza-CdR) has significant therapeutic value for the treatment of patients with myelodysplastic syndrome (MDS), acute and chronic myeloid leukemia (AML and CML). The demethylating effect of 5-Aza-CdR has been well characterized. In contrast, less is known about the molecular events downstream of the methylation inhibition effect. We found that 5-Aza-CdR induces apoptosis in AML cells (both, p53 mutant and wildtype) but not in epithelial or normal peripheral blood mononuclear cells (PBMC). Cell death was accompanied by activation of the mitochondrial apoptosis pathway as shown by early release of cytochrome c and AIF and loss of the mitochondrial membrane potential Δψm. Activation of caspase-3 but not -6 and -8 was detectable using western blot analysis and measurement of caspase enzymatic activity. 5-Aza-CdR treatment resulted in the induction of p21 which correlated with the arrest of AML cells in the G1 cell cycle phase. Induction of p21 expression was independent of its promoter methylation status but was mediated by 5-Aza-CdR-induced reexpression of the tumor suppressor p73, a known upstream regulator of p21. The p73 promoter was hypermethylated in AML cell lines and in primary AML cells but not in epithelial cells which were resistent towards 5-Aza-CdR. Therefore, 5-Aza-CdR-mediated specific killing of myeloid cells might be dependent on its ability to revert p73 promoter methylation and to reexpress p73 mRNA. In addition, exogenous expression of p73 rendered epithelial cells sensitive to apoptosis induced by 5-Aza-CdR or other cytostatic drugs. We therefore conclude that p73 is a relevant target for methylation-dependent efficacy of 5-Aza-CdR in AML cells.