bluuebunny/crossref_metadata_2025_split huggingface dataset:
Histone Deacetylase 3 (HDAC3), a Component of N-CoR-TBL1/R1 Chromatin Remodeling Co-Repressor Complex, Is Recruited to the Target Gene Promoters by PML-RARα To Repress the Transcription In Vivo.
Authors: Tomita Akihiro , Atsumi Akihide , Kiyoi Hitoshi , Naoe Tomoki 
Published: April 2020

Abstract
PML-RARα is a chimeric transcription factor deeply associated with acute promyelocytic leukemia (APL). PML-RARα plays an important role in the aberrant transcription repression on the target genes of wild type retinoic acid receptors (RARα). Pharmacological concentration of all-trans retinoic acid (ATRA) induces transcription de-repression on several target genes, and results in terminal differentiation of APL cells. However, the detailed mechanisms of transcription repression by PML-RARα in vivo are still unclear. Here we demonstrated that histone deacetylase 3 (HDAC3), one component of the N-CoR (nuclear receptor co-repressor)-TBL1/R1 (transducin beta-like protein 1/relating protein) transcription repressor protein complex, is a key regulator of the transcription repression by PML-RARα in vivo. Using immunoprecipitation (IP) assay, we first demonstrated that PML-RARα physically interacted with N-CoR/HDAC3 in vivo in the absence of ligand. The interaction was dissociated by adding ATRA in the dose dependent manner. Next we showed, using chromatin immunoprecipitation (ChIP) assay, that N-CoR/HDAC3 co-repressor complex was recruited to the endogenous target gene promoters (RARβ and CYP26) through PML-RARα. The neighboring histone H4 was de-acetylated and the gene expression was significantly repressed. When HDAC3 protein is knocked down by RNA interference in PML-RARα-presenting cells, the endogenous target gene expression was significantly activated. Almost the same results were also obtained when performing the luciferase reporter assay using RARβ and CYP26 promoter reporter vectors. Previously, we have shown that N-CoR-TBLR1 is recruited to the target gene promoter through PML-RARα in the absence of ligand, resulting in the transcription repression. Consistent with these data, it is strongly suggested that N-CoR/HDAC3/TBLR1 co-repressor complex is closely related to the aberrant transcription regulation by PML-RARα in APL cells. Furthermore, we also confirmed that PLZF-RARα, which is expressed in ATRA resistant APL cells, interacted with N-CoR/HDAC3/TBLR1 in ligand independent manner. These insights provide not only the basic mechanism of transcription repression by leukemia-related chimeric transcription factors, but also the new molecular targets for the transcription therapy for leukemia.
Vascular Endothelial Growth Factor (VEGF) Is a Critical Autocrine Survival Factor in Acute Promyelocytic Leukemia (APL).
Authors: Kini Ameet R. , Roychowdhury Shantanu , Dziuma Alla , Tallman Martin S. , Nagabhushan Moolky 
Published: April 2020

Abstract
We have previously demonstrated (Kini AR et. al. Blood.2001;97:3919–24) that VEGF is expressed in APL and is regulated by all-trans retinoic acid (ATRA). In this study, we examined the role of VEGF as a autocrine survival factor in APL, by using siRNA to VEGF in cultured NB4 APL cells.
The siRNA molecules were transfected into the APL cells by electroporation and resulted in almost complete (&gt;95%) knock-down of VEGF expression. The VEGF knock-down resulted in significant apoptosis (&gt;50%) within 96 hours. To verify the specificity of the VEGF siRNA, we used a siRNA molecule with a single nucleotide mismatch mutation, as well as a scrambled siRNA molecule. These control siRNA molecules did not result in VEGF knock-down, nor did they cause apoptosis, confirming the specificity of the VEGF siRNA and its effect.
In contrast to the striking induction of apoptosis by VEGF knock-down, external blocking of VEGF and VEGF receptors by addition of neutralizing antibodies did not cause apoptosis. In addition, the concentration of VEGF within the cells was over 100-fold higher than the external VEGF concentration. These results suggest that VEGF mediates its actions through an internal autocrine mechanism. Intriguingly, immunfluorescence studies showed that VEGF is strongly expressed in the nucleus, suggesting a novel nuclear role for VEGF.
To study the possible role of the VEGF receptors in internal loops we knocked-down the VEGF receptors using siRNA molecules. VEGF receptor knock-down did not affect survival of the APL cells. To summarize, we demonstrate that VEGF is a survival factor for APL cells, and acts independent of the VEGF receptors through an internal autocrine mechanism. These results indicate that targeting internal VEGF may be an effective therapeutic strategy for APL.
G-CSF and GM-CSF Have Opposite Effects on the Growth and Survival of Cells Containing Abnormal RUNX1.
Authors: Mortazavi Fariborz , Sharma Arun , Baraoidan Marie , Ibanez Vinzon , Yang SiJun , ShriHari Kadkol , Saunthararajah Yogen 
Published: April 2020

Abstract
Primary leukemia cells can respond very differently to cytokines such as G-CSF and GM-CSF, demonstrating marked increases in colony-forming ability to one but not the other (Park et al, Blood1989; 74: 56–65). To examine if such differences might correlate with underlying molecular abnormalities, we examined the growth and survival response of hematopoietic cells containing abnormal RUNX1 variants (a frequent occurrence in leukemia and myelodysplastic syndrome) to treatment with G-CSF and GM-CSF. In the RUNX1-ETO containing cell-line Kasumi-1, GM-CSF decreased colony forming ability whereas G-CSF preserved or increased it. The 32Dcl3 murine myelomonocytic cell-line terminally differentiates in response to G-CSF or mGM-CSF. We transduced 32Dcl3 with RUNX1-ETO or Empty Vector: G-CSF promoted the growth and survival of 32D RUNX1-ETO but caused 32D Empty Vector to terminally differentiate and die. In contrast, 32D RUNX1-ETO cultured in mGM-CSF demonstrated accelerated terminal differentiation and death compared to 32D Empty Vector. Many of the RUNX1 variants seen in leukemia and myelodysplastic syndrome, including RUNX1-ETO, lack the RUNX1 C-terminal transcription regulating domain (TRD). In human CD34+ hematopoietic cells transduced with RUNX1 with TRD deleted (CD34 RUNX1noTRD), colony forming ability was retained even after &gt;40 days of culture in IMDM 10% FBS, SCF 10ng/ml, IL-3 30ng/ml, G-CSF 100ng/ml (CD34 Empty Vector lost colony forming ability after 14 days). However, culture in media supplemented with 100ng/ml GM-CSF instead of G-CSF significantly impaired colony forming ability of CD34 RUNX1noTRD compared to CD34 Empty Vector. In conclusion, RUNX1 variants seen in acute myeloid leukemia and myelodysplastic syndrome promote growth and survival in G-CSF but accelerate differentiation and death in response to GM-CSF. The molecular basis for this effect appears to relate to the presence or absence of the RUNX1 C-terminal transcription regulating domain. These findings may have clinical relevance.
Voriconazole and Liposomal Amphotericin B (Ambisome) Effectively Prevent Mold Infections in Patients (pts) with Acute Myelogenous Leukemia (AML) Following Remission Induction Chemotherapy (RIC).
Authors: Mattiuzzi Gloria N. , Estey Elihu H. , Hernandez Mike , Cabanillas Maria E. , Giles Francis , Cortes Jorge E. , O’Brien Susan , Verstovsek Srdan , Kantarjian Hagop M. 
Published: April 2020

Abstract
Invasive fungal infections (IFI) are a frequent cause of morbidity and death in pts with AML and high-risk myelodysplastic syndrome (HR-MDS). Because early diagnosis of IFI is difficult, antifungal prophylaxis (AFP) including mold-active agents has become an important strategy to reduce morbidity and mortality in this patient population and is routinely used at MDACC for AML and HR-MDS pts undergoing RIC. We retrospectively compared the efficacy and safety of 6 AFP regimens (Sept 97- July 04) among 659 evaluable pts with newly diagnosed AML and HR-MDS who received RIC and had been enrolled in our prospective AFP trials. See regimens listed in Table below. There were no significant differences among the 6 regimens with regard to key baseline characteristics (age, gender, diagnosis, cytogenetics, type of RIC, Zubrod PS, WBC count, non-fungal infection and protected environment) and median days of AFP. 37 pts (5.6%) developed IFI (yeast 3 %; mold 2.6%). No mold infections were observed among pts randomized to AMBI or VORI. With the exception of VORI, which was significantly more effective than IV ITRA (p =0.03), all comparisons of efficacy among the AFP regimens were not significant. Drug discontinuation was the highest with IV VORI (21%) and ABLC (18%). VORI was more toxic than IV ITRA, Caspo, and F+I (p=0.023, 0.001 and 0.031 respectively). VORI toxicity was reversible and consisted of visual and/or auditory hallucinations and elevation in serum bilirubin. There was a trend toward developing VORI toxicity if baseline bilirubin levels were elevated (OR=4.9; p=0.10).
We conclude that the rate of IFI in AML and HR-MDS pts undergoing RIC given mold-active AFP is 5.6 %. VORI and AMBI effectively prevented mold infections. VORI was more effective that IV ITRA but was associated with a high rate of reversible drug-related adverse events.
ABLC (n=131) AMBI (n=69) F+I (n=67) IV ITRA (n=225) CASPO (n=106) VORI (n=61) ABLC: Amphotericin B Lipid Complex: 2.5 mg/kg IV three times/week; AMBI: Liposomal Amphotericin B: 3 mg/kg IV three times/week; F+I: Fluconazole: 400 mg (tab)/d + Itraconazole: 200 mg (caps)/d; IV ITRA: IV itraconazole: 200 mg BID X 2 d, then 200 mg IV/d; CASPO: Caspofungin: 50 mg IV/d; VORI: Voriconazole: 400 mg IV BID x 2 d, then 300 mg IV BID. Median age, years (range) 65(21–87) 63(36–83) 57(19–84) 62(17–89) 65(22–82) 59(23–79) Zubrod ≤ 2 (%) 127(97) 69(100) 65(97) 214(95) 101(95) 61(100) Median days AFP (range) 17(3–32) 14(3–28) 16(3–44) 20(3–41) 21(3–38) 21(3–34) Breakthrough IFI (%) 7(5) 3(4) 3(5) 17(8) 7(7) 0     Yeast (%) 2(2) 3(4) 1(1) 11(5) 3(3) 0     Mold (%) 5(4) 0 2(3) 6(3) 4(4) 0 Drug-related AFP DC (%) 24(18) 10(14) 5(7) 23(10) 4(4) 13(21)
Fondaparinux Combined with Intermittent Pneumatic Compression (IPC) Versus IPC Alone in the Prevention of Venous Thromboembolism after Major Abdominal Surgery: The Randomized APOLLO Study.
Authors: Turpie Alexander G.G. , Bauer Kenneth A. , Caprini Joseph A. , Comp Philip P. , Gent Michael , Muntz James E. 
Published: April 2020

Abstract
Background: The selective factor Xa inhibitor fondaparinux has been shown to be at least as effective and as safe as the low-molecular-weight heparin dalteparin for venous thromboembolism (VTE) prevention after major abdominal surgery (Agnelli GA, et al. Br J Surg, 2005, In press). The benefit of fondaparinux in addition to intermittent pneumatic compression (IPC) in VTE prevention after abdominal surgery has not been evaluated.
Objective: We performed a randomized, double-blind, placebo-controlled, superiority trial to compare the efficacy and safety of fondaparinux in conjunction with IPC versus IPC alone in patients undergoing major abdominal surgery.
Methods: Patients aged at least 40 years undergoing abdominal surgery of at least 45 minutes were included. Patients at highest risk of VTE, requiring pharmacologic prophylaxis in addition to IPC were excluded at the investigator’s discretion. Patients were randomized to receive either fondaparinux 2.5 mg or placebo once daily subcutaneously for 5 to 9 days, starting 6 to 8 hours postoperatively. All patients received IPC. The primary efficacy outcome was the composite of deep-vein thrombosis detected by mandatory bilateral venography, or documented symptomatic deep-vein thrombosis or pulmonary embolism up to day 10. The main safety outcome was major bleeding during the treatment period. A blinded independent committee adjudicated all these outcomes. Follow-up lasted 32 days.
Results: Of the 1309 patients randomized between November 2001 and October 2004 (fondaparinux+IPC, n=650; placebo+IPC, n=659), 842 (64.3%) were evaluable for efficacy. The treatment groups were comparable with regard to VTE risk factors, demographic and surgical characteristics; 82% had at least one VTE risk factor (over and above being at least 40 years old and undergoing abdominal surgery). Fondaparinux significantly reduced the VTE rate from 5.3% (22/418) with placebo to 1.7% (7/424), an odds ratio reduction of 69.8% (95% CI: 27.9 to 87.3; p=0.004). Similarly, fondaparinux significantly reduced the proximal deep-vein thrombosis rate from 1.7% (7/417) to 0.2% (1/423; p=0.037). Major bleeding occurred in 1.6% (10/635) and 0.2% (1/650) of fondaparinux- and placebo-treated patients, respectively (p=0.006). None of the bleeding events were fatal or involved a critical organ.
Conclusions: Fondaparinux combined with IPC was significantly more effective than IPC alone for VTE prevention after major abdominal surgery. Although the bleeding risk was increased with fondaparinux compared with placebo, this risk was low and consistent with that observed in previous fondaparinux studies in surgical patients.
Farnesyl Transferase Inhibitor (Tipifarnib, Zarnestra; Z) in Combination with Standard Chemotherapy with Idarubicin (Ida) and Cytarabine (ara-C) for Patients (pts) with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS).
Authors: Cortes Jorge , Garcia-Manero Guillermo , O’Brien Susan , Verstovsek Srdan , Estrov Zeev , Giles Francis , Ravandi Farhad , Wright John , Kantarjian Hagop 
Published: April 2020

Abstract
Tipifarnib is a non-peptidomimetic farnesyl transferase inhibitor (FTI) with clinical activity in hematologic malignancies, including AML, MDS and CML. Pre-clinical data suggests that tipifarnib may be synergistic with some chemotherapeutic agents. We designed a phase I/II study where pts age 15 to 60 years with previously untreated AML or high-risk MDS (blasts &gt;10%) received induction with Ida 12 mg/m2/d on days 1–3, ara-C 1.5 g/m2 IV over 24 hours daily on days 1–4 (days 1–3 only if age ≥ 60 years) and Z with first cohort (7 pts) receiving 200mg orally twice daily (BID), and all others 300 mg BID x 21 days every 28 days. Pts achieving CR received consolidation (5 courses) was with Ida 8 mg/m2/d, days 1–2, ara-C 0.75 g/m2/d, days 1–3, and Z 300 mg BID x14 days every 4–6 weeks. Maintenance was with Z 300 mg BID x 21 d every 4–6 wk for 6 months. We have treated 23 pts, median age 51 yrs (19–59 yrs). Eighteen pts are evaluable for response and 13 (72%) have achieved CR and 1 CRp. Response in evaluable pts by cytogenetics was: 5/8 (83%) for diploid, 4/5 with −5/−7, 1/2 with t(8;21), and 3/5 with other abnormalities. Response by Flt3 was 11/14 (79%) for unmutated Flt3, 1/3 for mutated Flt3. Response by age (excluding t(8;21)) was 6/7 (86%) if ≤50yrs, 7/9 (78%) if &gt;50yrs. With median follow-up of 13 weeks, 1 pt has relapsed after 14 weeks and 1 died (in CR) after 18 wks. The most common grade 3 adverse events include diarrhea in 7 (30%) and hyperbilirrubinemia in 6 (26%), both transient. Thirteen pts (59%) have required treatment interruptions/dose reductions during induction. We conclude that Z combined with Ida and ara-C induces a high rate of CR in AML, with increased incidence of diarrhea and hyperbilirrrubinemia. Comparison with chemotherapy alone is warranted..
Loss of Heterozygosity on Chromosome 6q14-q24 Confers Poor Outcome on Children and Adolescents with T-Cell Lymphoblastic Lymphoma.
Authors: Burkhardt Birgit , Bruch Jochen , Mueller Franziska , Salzburg Janina , Harbott Jochen , Reiter Alfred 
Published: April 2020

Abstract
Deletions of chromosome 6q have been reported in a variety of hematological malignancies. Regarding their biological and prognostic impact, however, the data available are not conclusive. Therefore the current study focused on 60 pediatric and adolescent patients all diagnosed with T-cell lymphoblastic lymphoma (T-LBL), a clearly defined histological sub-entity of NHL, and all treated uniformly according to the protocol NHL-BFM 95. Deletions of chromosome 6 were analyzed by loss of heterozygosity (LOH) analysis of 25 microsatellite markers located on chromosome 6q14-q24 and the prognostic impact of LOH on 6q was evaluated after combing the results with clinical data of the patients.
Selection criteria for this study were 1) treatment according to multicentre protocol NHL-BFM 95, 2) T-cell immunophenotype of LBL, 3) germ line control and tumor DNA available and 4) three or more informative markers for the analysis of LOH. High-molecular weight germ line DNA was extracted from blood and bone marrow smears or frozen cells. Tumor DNA was isolated from tumor touch imprints or cytospin preparations of malignant effusions or frozen tumor cells. Paired normal and tumor DNA samples from each patient were amplified by PCR, after which fragment length analysis was performed on an ABI PRISM 3100 Genetic Analyzer.
From 04/95 until 03/03 a total of 186 patients were diagnosed with T-LBL and treated according to the protocol NHL-BFM 95. The probability of event free survival (pEFS) for these 186 patients was 79±3% (median follow-up of 4.5 (0.5–9.1) years). 60 of the 186 T-LBL patients were evaluable for LOH analysis, including 19 out of the total 25 of T-LBL patients who suffered from tumor failure. Fragment length analysis comparing germ line DNA and tumor DNA was performed for all 25 microsatellite markers per patient resulting in a total of 832 successfully analyzed markers for the whole group of 60 patients. The status of these 832 results was LOH in 10%, retention of heterozygosity in 55%, homozygosity in germ line control and tumor DNA in 25% and microsatellite instability in 9% of results respectively. In 19 out of the 60 evaluable patients (32%) LOH of at least one microsatellite marker was detected. LOH was observed in 13 out of the 19 evaluable patients with tumor failure compared to 6 out of the 41 patients without tumor failure. The probability of disease free survival (pDFS) (5y) for the 19 patients with LOH was 24±11% compared to 85±6% for the 41 patients without LOH (p &lt;0.0001). A critical region of deletion could be assigned to microsatellite markers D6S1284 and D6S1716. pDFS (5y) was 0% for patients with LOH involving these markers (n=7) compared to 82±7% for patients without LOH at these markers (n=31) (p &lt;0.0001). We conclude that LOH on chromosome 6q14-q24, especially of markers D6S1284 and D6S1716, confers poor outcome on children and adolescents with T-LBL.
VENUS - A Study To Validate Centrally Adjudicated Venous Ultrasound Against Venography after Major Orthopaedic Surgery.
Authors: Schellong Sebastian M. , Beyer Jan , Halbritter Kai , Schmidt Benjamin , Turpie Alexander G.G. , Eriksson Bengt I. , Misselwitz Frank , Kälebo Peter 
Published: April 2020

Abstract
Mandatory, bilateral, centrally adjudicated venography is currently required to assess the incidence of deep vein thrombosis (DVT) in confirmatory trials of new antithrombotic agents. Non-invasive and less cumbersome methods would be welcomed by both patients and investigators. Centrally adjudicated complete compression ultrasound (CCUS) of all leg veins could become an alternative to venography. Despite the fact that no formal validation of venography has ever been performed, CCUS will have to be externally validated against this ’gold standard’ to gain general acceptance and regulatory approval. A substudy of two recent phase IIb trials of a novel, oral anticoagulant for the prevention of venous thromboembolism in patients undergoing elective hip or knee arthroplasty was undertaken to validate CCUS against venography. The studies had similar designs and methodology, and were designed to allow the pooling of data. Mandatory bilateral venography was performed 7±2 days after surgery; CCUS was performed later the same day, with the sonographers blinded to the venography result. All sonographers were required to have completed a training course, and to have obtained personal certification for the standardized examination and documentation procedure. Venograms and CCUS videos were adjudicated centrally by two independent readers at separate locations; discrepancies were resolved by consensus reading. From the 1347 patients participating in the two trials, 870 matching pairs of evaluable venograms and CCUS videos were obtained. Observed prevalences of any DVT, including muscle vein thrombosis, were 19.1% with venography, and 13.0% with CCUS. Sensitivity and specificity values [with 95% confidence intervals (95% CI)] for detecting DVT with CCUS are shown in the table. Although false positives did not severely impair specificity, the small number of true positives detected by CCUS resulted in remarkably low sensitivity, in particular for proximal DVT. Based on these external validation figures, centrally adjudicated CCUS is not a viable technique to replace venography for the screening of DVT early after major orthopaedic surgery in confirmatory trials of novel antithrombotic agents.
DVT Sensitivity [% (95% CI)] Specificity [% (95% CI)] Any 27.4 (21.2, 33.6) 95.8 (94.8, 96.8) Proximal 13.0 (−0.7, 26.8) 99.2 (98.9, 99.7) Distal 25.9 (19.7, 32.1) 96.2 (95.3, 97.2)
Analysis of KIR Framework Loci in Patients with NK-Type Lymphoproliferative Disease of Granular Lymphocytes (LDGL).
Authors: Zambello Renato , Scquizzato Elisa , Teramo Antonella , Facco Monica , Pavan Laura , Miorin Marta , Trentin Livio , Agostini Carlo , Semenzato Gianpietro 
Published: April 2020

Abstract
To investigate whether a bias toward the presence of genes coding for activating KIRs were present in patients with NK-type lymphoproliferative disease of granular lymphocytes (NK-LDGL), by multiplex PCR analysis in this study we evaluated the KIR genotype in 35 patients with NK-LDGL and in 50 normal subjects. According to the published data in the Caucasian population, all individuals were positively scored for the framework loci (KIR2DL4+, KIR3DL2+ and KIR3DL3+). All genotypes were characterized by a gene encoding a group 1 HLA-C-specific inhibitory KIR, which was either KIR2DL1, KIR2DL2 or KIR2DL3 and at least contained one activating KIR gene. The KIR genotype analysis revealed that patients genotypes were largely represented by type B haplotype (34/35) that is characterized by the presence of multiple activating KIRs. The same KIR genotype was often shared between NK-LDGL patients. These genotypic profiles were not present in the group of controls and are infrequent (1,2%) or not still found in the Caucasian population. In contrast with literature data reporting that the frequency of haplotype A in homozigous state represents the most common condition in the Caucasian population (accounting for 1/3 of normal individuals), we surprisingly found that also almost all the controls studied (49/50) were equipped with the type B haplotype.
When the genotypic frequency was considered, the most frequently gene content found was 9 in controls and 11 or 14 in patients, indicating that patients genotypes contained a higher number of genes than controls. This picture was almost entirely due to the high variability of the activating genes number. As far as the activating genes are concerned, although the number of control individuals analyzed was still low, the frequency of KIR2DS1, KIR2DS2, KIR2DS4, KIR1D and KIR3DS1 was found to be higher in patients than in controls. This indicates that genotypic profiles of NK-LDGL patients are characterized by an increased presence of activating KIRs.
Consistent with these findings, the analysis of the KIR genes repertoire in NK-LDGL patients clearly indicates that the susceptibility to this disease is influenced by the KIR genotype and in particular by the presence of a considerable number of activating KIR genes. Moreover, we observed that healthy individuals scored as controls (all coming from the north-east of Italy) showed genotypes with a higher number of activating genes as compared to other Caucasian populations. This observation suggests that a genetic predisposition to development of NK-type LDGL might occur among the population of north-east of Italy and in turn this could explain the high frequency of NK-type LDGL in this Italian region.