bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I/II Dose Escalation Trial of ONCOHIST® (Recombinant Human Histone H1.3) in Patients with Relapsed or Refractory Acute Myeloid Leukemia.
Authors: Zeppezauer Michael , Formicka-Zeppezauer Grazina , Gross Peter , Joernvall Hans , Schubert Joerg , Pfreundschuh Michael 
Published: November 2019

Abstract
Background: Histone H1.3 suppresses tumor growth of leukemic cells in vitro, ex vivo and in animal models. To evaluate toxicity and efficacy of ONCOHIST, recombinant human histone H1.3 (rhH1.3) in patients suffering from acute myelogenous leukemia, we initiated a phase-I/II dose escalation study.
Methods: This was an open-label unicentric phase I/II study. Nine patients suffering from relapsed or refractory acute myeloid leukemia (median age: 69 years, range 49 to 83 years) with a life expectancy of at least one month who were unable or unwilling to receive curative chemotherapy without major organ dysfunction were eligible for the trial. Exclusion criteria were presence of HIV, HBV, or HBC infection, heparin treatment during the 2 weeks before enrolment, and medical conditions known to potentially interfere with rhH1.3 treatment such as rheumatoid arthritis or SLE, as well as circulating anti-histone H1.3 antibodies. One treatment course consisted of 9 applications in 3 weeks. 3 patients were treated at each dose level. Starting dose level was 245 mg/m2 and in the absence of dose-limiting toxicities, the dose was increased to the next higher dose level (392 and 628 mg/m2 rhH1.3) in the third week of the treatment course. Primary endpoints of the study was the definition of the maximal tolerated dose and dose-limiting toxicities of the study drug.
Results: To date, 9 patients have been treated and all patients are evaluable for toxicity and efficacy. No side-effects were observed except for one atrial fibrillation under infusion of rhH1.3, which was considered not to be related to the study drug. All patients completed one course of therapy (9 applications), and one responding patient received a second course without side effects. No dose-limiting toxicities were observed and the maximal tolerated dose has not been reached at 628 mg/m2. With respect to efficacy, the formal criteria of response were not met in any of the 9 patients. However, two patients had a temporary increase of their platelet counts while on therapy, and in one patient platelet counts raised from 22 000/mm3 to 100 000/mm3, remaining stable for 3 months. Two patients achieved a reduction of blasts upon treatment.
Conclusion: rhH1.3 is well tolerated at the doses treated so far. While the achieved serum levels are still below the growth-inhibiting concentrations in vitro, first clinical effects have been observed. Additional patients and higher dose levels are needed to delineate the efficacy and toxicity profile of rhH1.3 for the treatment of acute myelogenous leukemias.
RGD-Substituted High Molecular Weight Hyper-Branched Polyglycerols (HPG) Are Effective Platelet Inhibitors.
Authors: Zhang Jerry G. , Krajden Oren , Kainthan Rajesh K. , Kizhakkedathu Jayachandran N. , Gyongyossy-Issa Maria I.C. 
Published: November 2019

Abstract
Peptides containing Arg-Gly-Asp (RGD) sequences are known to bind to integrins which mediate cell adhesion and therefore have been utilized in applications such as antithrombotics and tissue engineering. Although RGD and related peptides show promise, their unfavourable pharmacokinetic profiles and susceptibility to in vivo proteolysis hinder their clinical usefulness. Peptide-polymer conjugates can address one of these challenges by extending the peptide’s residence in plasma. Hyperbranched polyglycerols (HPGs) are biocompatible polyether polyols with very long plasma circulation half-lives (t1/2 ∼ 60h) and as such are ideally suited to be carriers in such conjugates. HPGs of three different molecular weights were conjugated with RGD peptides at various substitution levels. Some of the terminal hydroxyl groups of polyglycerols were converted to vinyl sulfone groups which were subsequently utilized to couple cysteine terminated RGD peptides. The following conjugates were made: 515 kDa with substitution levels of 100:1, 500:1 and 1000:1; 100 kDa with substitution levels of 100:1 and 1000:1; and 3 kDa with substitution levels of 1:1, and 10:1. RGD-coupled HPG inhibited fibrinogen binding to platelet glycoprotein IIb-IIIa as detected by flow cytometry using anti-fibrinogen. Compared to free RGD (Ic50 = 5 x 10-5 M), inhibition of fibrinogen binding increased with increasing HPG molecular weight and increasing RGD-substitution for the high MW conjugates: Ic50 for the 515 kDa conjugates were 6.3 x 10−8 M for the 100:1 substitution, 4.7 x 10-8 M for the 500:1 substitution, and 4.1 x 10−8 M for 1000:1 substitution; Ic50 for the 100 kDa conjugates were 7.0 x 10−7 M for the 100:1 substitution and 1.2 x 10−7 M for the 1000:1 substitution. Ic50 for the 3 kDa conjugates were 2 x 10−5 M for the 1:1 substitution, 2 x 10−4 M for 10:1 substitution. Similarly, platelet function, as demonstrated by MnCl2-initated aggregation was inhibited in a dose- and molecular weight-dependent manner by HPG-RGD conjugates. Platelet aggregate formation and aggregate size were confirmed by microscopy. However, unsubstituted HPG had no effect on platelet fibrinogen binding and neither conjugated nor unconjugated HPG increased platelet CD62 surface expression. Trypsin digestion (but not SBTI-treated trypsin) removed the inhibitory activity of the conjugates and thus confirmed that both fibrinogen binding and aggregation-inhibition were dependent on the RGD peptide sequence. Such multi-determinant peptide-HPG conjugates represent a new approach to the development of antithrombotic drugs.
Rivaroxaban Has Protective Effects in a Model of Disseminated Intravascular Coagulation (DIC) in Rats.
Authors: Perzborn Elisabeth , Hirth-Dietrich Claudia , Fischer Elke , Groth Martin , Hartmann Elke , Sperlich-Wulf Kerstin 
Published: November 2019

Abstract
Introduction: DIC is a complication that occurs during serious infection with Gram-negative bacteria. Endotoxin is a component of the bacterial cell wall that elicits a cytokine-mediated cascade of tissue factor-dependent hypercoagulable reactions. The resulting hypercoagulable state may be inhibited by potent anticoagulation. Rivaroxaban is an oral, direct Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. The aim of this study was to examine the effects of rivaroxaban in a rat model of endotoxin-induced DIC.
Methods: Rivaroxaban (0.1–10 mg/kg p.o.) or vehicle control (PEG400/H2O 60/40%, 5 mL/kg p.o.) were administered 30 minutes before endotoxin injection (lipopolysaccharide O55 B5 [LPS], 250 μg/kg i.v.) to conscious rats. Blood samples were withdrawn from anesthetized animals by heart puncture 4 hours after LPS injection and fibrinogen, platelet count, thrombin-antithrombin (TAT) complex levels and IL-6 were measured.
Results: The induction of DIC was indicated in the placebo + LPS group vs vehicle control by decreased fibrinogen (2.12±0.08 vs 2.69±0.10 g/L) and platelet count (571±28 vs 904±30×109/L) an increase in TAT (75±9 vs 2±1 μg/L) and IL-6 (8.6±1.23 μg/L vs 0.028±0.020 μg/L). Pretreatment with rivaroxaban (0.1–10 mg/kg p.o.) dose-dependently ameliorated the effects of LPS on fibrinogen, platelets and TAT. Rivaroxaban 10 mg/kg p.o. normalized fibrinogen (2.58±0.07 g/L) and TAT (5.6±1.2 μg/L) and increased platelet count (703±19×109/L) (Table). Rivaroxaban also slightly reduced the plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) (4.24±0.67 μg/L).
Conclusions: These results show that direct, selective inhibition of FXa by rivaroxaban effectively normalized the hypercoagulable reactions of endotoxemia with a slight modulating effect on the generation of pro-inflammatory active cytokines, such as IL-6, in the rat DIC model. Further research into the use of rivaroxaban in the management of DIC is therefore warranted.
Effects of rivaroxaban in an endotoxin-induced DIC model in rats 4 hours after LPS injection. Results show mean ± SEM. Vehicle control Placebo + LPS Rivaroxaban 1 mg/kg + LPS Rivaroxaban 10 mg/kg + LPS DIC, disseminated intravascular coagulation; IL-6, interleukin-6; LPS, lipopolysaccharide O55 B5; SEM, standard error of the mean; TAT, thrombin-antithrombin ## p<0.01 vs sham, ### p<0.001 vs sham, *p<0.05 vs LPS/placebo, ** p<0.01 vs LPS/placebo, *** p<0.001 vs LPS/placebo Fibrinogen (g/L) 2.69±0.10 n=5 2.12±0.08## n=14 2.41±0.09 n=14 2.58± 0.07** n=7 Platelets (×109/l) 904±30 n=5 571±28### n=8 655±23 n=6 703±19* n=7 TAT (μg/L) 1.8±0.8 n=5 75.2±9.4### n=14 65.3±8.0 n=14 5.6±1.2*** n=7 IL-6 (μg/ml) 0.028±0.020 n=5 8.60±1.23### n=6 5.01±0.47 n=6 4.24±0.67 n=7
A Study of Bedside Visual Art To Decrease Anxiety and Improve Pain and Mood in Cancer Patients: The Mayo Clinic Experience.
Authors: Wolanskyj Alexandra P. , Curry Elizabeth A. , Ehlers Shawna L. , Eagle Debra M. , Larson Dirk R. , Colby Colin L. , Bauer Brent A. , Scanlon Paul D. 
Published: November 2019

Abstract
Background: The treatment of cancer-related symptoms continues to represent a major challenge for health care providers. Traditional approaches often require pharmacologic interventions which have potential side effects. A wide variety of approaches using complementary and alternative medicine (including music therapy) have demonstrated some early benefit. The role of a visual art intervention on pain, anxiety and mood has not been studied to date.
Patients and Methods: Our patient population consisted of 21 Hematology inpatients at the Mayo Clinic (19 women, 2 men with a median age of 53.4 years, [range19 to 73]), with the following hematological disorders: Acute Leukemia (n = 6); Lymphoma (n = 5); Multiple Myeloma (n = 5); and a variety of other malignant conditions (n =5). Patients and their families were invited to participate actively or passively (i.e. observe) in a 1 to1 visual art intervention, conducted by a trained artist educator using different forms of art media. Baseline assessments of pain, anxiety and mood were conducted just prior to the intervention using Visual Analog scales (VAS), the Spielberger State Trait Anxiety Inventory and the Positive and Negative Affect Schedule (PANAS) respectively. The same scales were administered immediately following completion of the art intervention.
Results: Twenty of 21 patients completed the intervention, and all 20 patients actively participated. A significant improvement in positive mood scores (4.6 [95%CI: (1.7, 7.5)] or 14.6% change, p=0.003), decrease in negative mood scores (−3.4 [95%CI: (−0.7, −6.1)] or 18% change, p=0.016) and in anxiety scores (−9.2 [95%CI: (−14.2, −4.1)] or 21.6% change, p=0.001) were observed. Among the 14 patients who reported some pain (VAS>0) prior to the intervention, the mean VAS pain score improved significantly (−1.4 [95%CI: (−2.4, −0.3)] or 35.1% change, p=0.017). Universally all patients commented that they would participate in art-based interventions in the future
Conclusions Bedside visual art interventions can decrease pain and anxiety, and improve mood in hospitalized hematological patients with cancer diagnoses. These intriguing findings warrant future placebo-controlled studies, and suggest that these alternative measures should be considered as an adjunct to conventional therapies in patients with cancer-related pain, and symptoms of anxiety and decreased mood.
The MLL PHD Fingers of MLL Block MLL Fusion Protein Mediated Transformation.
Authors: Muntean Andrew G. , Hess Jay L. 
Published: November 2019

Abstract
Mixed Lineage Leukemia (MLL) is a histone H3K4 methyltransferase that is rearranged in both acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). MLL is required for the maintenance of Hox gene expression. Deregulation of Hox genes by MLL fusion proteins, which fuse MLL in frame to one of over 50 different translocation partners, is critical for transformation. In these translocations, the DNMT homology (CXXC) domain is always included, but the set of adjacent plant homeodomains (PHD), which includes four PHD fingers and a bromodomain, is invariably excluded. PHD fingers have recently been described to bind tri-methylated histone H3K4 and others report PHD domains binding transcriptional co-repressors, such as Mi-2a of the NuRD complex. However, the role of the PHD fingers in MLL is not well understood. To determine the function of the PHD fingers in MLL, we performed bone marrow transduction and colony assays with the MLL fusion protein MLL-AF9, engineered to contain the PHD domain region (MLL-PHD-AF9). These experiments showed that inclusion of the PHD fingers inhibited immortalization as shown by the absence of compact colonies in methylcellulose replating assays and inhibition of proliferation in liquid cultures. Initial experiments with PHD finger deletions to map the inhibiting activity suggest inclusion of any PHD fingers beyond the first PHD finger, results in inhibition of transformation. To monitor the transcriptional activity of the retrovirally infected bone marrow cells, total RNA was isolated from cells harvested after the second replating, when significant differences were seen in colony morphology and size. Consistent with the transformation inhibition, Hoxa9 gene expression was found to be significantly repressed with respect to expression detected in transformed MLL-AF9 cells as determined by qPCR. To confirm this effect is directly due to the MLL fusion proteins, we performed luciferase assays with an MLL responsive myc E-box luciferase construct in MLL −/− MEFs. We found a specific and robust activation of the reporter in the presence of MLL-AF9, which was severely compromised by the inclusion of the PHD fingers. Together, these results suggest the PHD fingers act as transcriptional repressors that inhibit transformation. Our results provide an explanation for the finding that translocations including the coding region for C terminal PHD fingers do not occur in human leukemias and suggest that this region is also involved in the regulation of wild type MLL. We are currently studying the mechanisms of transcriptional repression mediated by the PHD fingers by isolating interacting proteins and assessing their effect on transcription and transformation.
Prognostic Impact of Chromosomal Abnormalities in Elderly Patients with Multiple Myeloma Treated with High-Dose Melphalan (MEL140) and Autologous Stem Cell Transplantation.
Authors: Liebisch Peter , Straka Christian , Wimmer Astrid , Wendl Christiane , Hinke Axel , Ibach Stefan , Döhner Hartmut 
Published: November 2019

Abstract
Background: Although chromosomal aberrations (CA) have emerged as important outcome predictors in multiple myeloma (MM), the prognostic significance of many recurring genomic changes is still unknown. Moreover, there is only scarce data on the implication of chromosomal abnormalities in elderly patients (pts.) receiving high-dose chemotherapy (HD-CTX) followed by autologous stem cell transplantation (ASCT). Aims: To evaluate the prognostic relevance of recurring chromosomal aberrations as detected by cIg-FISH for elderly pts. with MM receiving HD-CTX and ASCT. Materials: Between 05/2001 and 08/2006, 549 pts. 60–70 yrs. of age with newly diagnosed symptomatic MM entered the DSMM II trial of the Deutsche Studiengruppe Multiples Myelom to receive two cycles of HD-CTX (melphalan 140 mg/sqm) followed by ASCT after 3–4 cycles of dexamethason-based induction chemotherapy (IC; arm A1) or no IC (arm A2). cIg-FISH and DNA probes mapping to chromosome bands 1q21.2, 9q34, 11q25, 13q14, 14q32, 17p13, and 22q11 were applied to all pts. from whom sufficient bone marrow specimen were obtained. 152 pts. with a median age of 65 yrs. for that information on all genomic loci was available were included in the present analysis. The clinical database was last updated in 04/2007.
Results: The median follow-up of time in the present series was 83 (1–264) weeks. Univariate analysis showed significantly shorter EFS in 14 out of 152 pts. (9%) with chromosome 17p13 deletion (17p−; 46 vs. 99 weeks, p<0.0001) and 18 out of 152 pts. (12%) with translocation t(4;14) (57 vs. 99 weeks, p=0.001). Clinical and laboratory variables as well as all other CA had no significant impact on EFS. Multivariate analysis revealed 17p− and t(4;14) as independent predictors of inferior EFS (p=0.0005 and p=0.01, respectively). OS was significantly shorter in pts. with 17p− (99 vs. 219 weeks, p=0.001) and in 17 out of 152 pts. (11%) with deletion of chromosome band 22q11 (127 weeks vs. not reached, p=0.002). There was a trend towards a shorter OS in pts. with t(4;14).
Conclusions: Our data suggest that HD-CTX and ASCT does not provide long-term disease control in elderly pts. with t(4;14) or 17p−. Therefore, HD-CTX and ASCT cannot be recommended for these high-risk pts. (overall ∼20% of cases). 13q− and +1q21.2 were not prognostic markers in the present study. Collection of clinical data and molecular cytogenetic analysis of further cases is ongoing.
Genome-Wide Analysis of 30 Burkitt Lymphomas Using High-Density SNP Arrays Reveals Frequent Cryptic Alterations Including Amplification of the microRNA 17-92 Locus.
Authors: Havelange Violaine , Théate Ivan , Callet-Bauchu Evelyne , Mugneret Francine , Michaux Lucienne , Barin Carole , Dastugue Nicole , Lippert Eric , Saussoy Pascale , Penther Dominique , Vikkula Miikka , Poirel Hélène A. 
Published: November 2019

Abstract
Burkitt lymphomas/leukemias (BL) are highly aggressive mature B-cell malignancies characterized by a constant MYC rearrangement. MYC deregulation is an oncogenic event known to be necessary but not sufficient in BL pathogenesis. Additional (epi)genetic alterations should cooperate, such as inactivation of the p14arf-MDM2-TP53 pathway which is frequently detected. We recently demonstrated the independent negative prognostic impact of specific chromosomal alterations, del(13q) and +7q, in childhood BL. We also showed by Multi-FISH that 13q abnormalities are more heterogeneous than expected and that13q gains are underestimated by conventional cytogenetics (CC). DNA from 30 BL (15 adults/15 children) was analyzed with 50K Xba single nucleotide polymorphisms (SNP) arrays (Affymetrix), in order to characterize additional allelic imbalances and losses of heterozygosity. 47 gains and 30 losses were found in 22 BL; 57 chromosomal imbalances were cryptic (not detected by CC). A recurring 13q amplification was detected in 6 BL. The minimal amplified region (MAR) of 4.35 Mb includes 3 candidate genes: C13orf25, GPC5 and GPC6. One C13orf25 transcripts contains a miRNA 17–92 cluster. The amplicon was unmasked with BAC probes in 2/8 other screened BL with 13q abnormalities. This amplification was associated with a terminal deletion (minimal size: 5Mb) in half cases. A recurring 11q abnormality was also assessed by FISH with a MAR of 3.2 Mb containing candidate genes such as CBL, BLR1. Acquired partial uniparental disomies (pUPD) are characterized by loss of heterozygosity without chromosomal deletion. 73 pUPD (>5 Mb) were found in 15 BL; 14 were telomeric and probably resulted from one mitotic recombination. The pathogenic role of pUPD remains unclear. Some of them may be polymorphisms also detected in healthy population. Other may reflect genomic instability but in our series, no higher incidence of pUPD was detected in BL with a complex karyotype. Thirdly, non random pUPD may render the neoplastic cell homozygous for a preexisting mutation leading to the activation of an oncogene or inactivation of a tumor suppressor gene (TSG). Four telomeric pUPD on 1p, 9p, 17p and 17q were found in at least 2 BL. We confirmed homozygous mutations of 2 TSG (TP53 and CDKN2A) located on 17p and 9p pUPD, respectively. These pUPD may be another way of p14arf-MDM2-TP53 inactivation. Moreover, these results suggest an involvement of the miR 17–92 cluster known to interact with the MYC oncogene in BL pathogenesis. The expression pattern of the different mature miR 17–92 in BL with and without 13q amplification will be presented at the meeting.
BCR/ABL and Other Oncogenic Fusion Tyrosine Kinases (FTKs) Stimulate Single Strand Annealing (SSA), the Rare and Extremely Unfaithful DNA Double-Strand Break Repair Pathway To Facilitate Genomic Instability in Hematologic Malignancies.
Authors: Cramer Kimberly , Penserga Emir T. , Reddy Akhil , Wosen Jonathan , Skorski Tomasz 
Published: November 2019

Abstract
Chromosomal translocations are responsible for the appearance of oncogenes encoding BCR/ABL-related fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGFR and NPM/ALK, which induce hematological malignancies such as chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelomonocytic leukemia (CMML), and anaplastic large cell lymphoma (ALCL). We showed that cells transformed by BCR/ABL and other FTKs generate higher levels of reactive oxygen species (ROS) than normal counterparts. Enhanced ROS production in malignant cells causes extensive oxidative DNA damage resulting in elevated numbers of DNA double strand breaks (DSBs) measured by immunofluorescence detecting histone H2AX phosphorylated on serine 139 (γ-H2AX) and localized near DSB sites. Since DSBs may be lethal for cells, they are usually repaired by homologous recombination and non-homologous end-joining. Occasionally, a third mechanism called single-strand annealing (SSA) may be involved, too. During SSA an exonuclease degrades one strand at the DNA ends until homology is revealed (for example between two Alu sequences) allowing the broken ends to anneal and the intervening sequence to be clipped off. Therefore, SSA is extremely unfaithful, resulting in a deletion of sequences between the repeats. Because ∼50% of the mammalian genome consists of repeat sequences, SSA is potentially an important pathway of mutagenesis. For example, intrachromatid SSA events can give rise to interstitial deletions leading to a loss of a tumor suppressor gene. To determine the activity of SSA, a well-defined genetic model designed to exclusively measure SSA was applied. The model consists of a reporter cassette containing two fragments of the gene encoding green fluorescent protein (GFP) with a unique I-SceI restriction site introduced into one fragment. Expression of I-SceI restrictase will cause a DSB, which if repaired by SSA will result in recovery of a functional GFP gene generating a GFP+ cell. A single copy of the SSA reporter cassette was integrated in the genomic DNA of parentals and FTK-transformed cells. Cells were transfected with an expression vector encoding I-SceI restrictase and red fluorescent protein with mitochondrial localization (RFP-Mito) to control transfection efficiency. The number of double-positive (GFP+/RFP-Mito+) cells was scored in the population of RFP-Mito+ cells. FTKs induced an approximately 3–30 fold increase of the frequency of SSA events. Therefore, elevated levels of ROS-induced DSBs combined with increased frequency of a relatively rare but extremely unfaithful SSA repair may contribute to genetic instability in hematologic malignancies induced by FTKs.