bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response Rates in Patients with Acute Myeloid Leukemia (AML), Treated with Azacitidine, Using WHO and International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS).
Authors: Silverman Lewis R. , McKenzie David R. , Peterson Bercedis L. , Stone Richard M. , Powell Bayard L. , Mayo Christy , Backstrom Jay T. , Larson Richard A. ,   The Cancer Leukemia Group B (CALGB)
Published: October 2019

Abstract
The CALGB conducted a series of clinical trials with azacitidine (Vidaza®) administered subcutaneously or intravenously in patients with MDS using the FAB classification (JCO2002;20:2429). Since completion of these CALGB studies (8421, 8921, 9221), a new classification system was developed by the WHO that distinguishes MDS from AML (blasts > 20%). Although studies with azacitidine in patients with AML had previously shown activity, the 75 mg/m2/day dose in the CALGB studies was lower than previously studied. Using the WHO system, the diagnosis for CALGB study patients was redefined and patients with AML were analyzed separately. Most of the 105 patients were previously considered refractory anemia with excess blasts in transformation (RAEB-T). Also, new treatment response criteria for MDS were published by the IWG (Blood2000; 96:3671). Using IWG response criteria, azacitidine patients with WHO AML in studies 8421, 8921, or 9221 had an overall response rate (CR+PR+HI) of 48% (12/25), 32% (9/28), and 37% (10/27), respectively.
Best Response using IWG Response Criteria for WHO AML Patients in Studies 8421, 8921, and 9221
Median duration of any response (CR, PR or HI) in the 33 azacitidine-treated responders was 279 days (range: 61 to 724 days). The median duration of CR in the 8 azacitidine-treated responders was not achieved; however, the 25th percentile was 115 days (range: 92 to 274+ days). In Study 9221, the median duration of transfusion independence (defined as ≥56 days) in patients independent at baseline was significantly longer in the azacitidine group compared with supportive care for red blood cells (azacitidine [n=8]: 411 days vs. supportive care [n=9]: 133 days, p=0.02) and platelets (azacitidine [n=13]: 363 days vs. supportive care [n=18]: 125 days, p=0.004). In the azacitidine group, 22% (6/27) of patients had a hemoglobin improvement to >11 g/dL that was maintained for ≥56 days compared with 8% (2/25) in the supportive care group (p=0.2). The proportions of patients with ANC >1500/m3 and platelets >100,000/mm3 lasting for ≥56 days were similar between the treatment arms. Azacitidine patients with WHO AML had a longer median survival (19.3 months) compared with the supportive care group (12.9 months) (p=0.2). Further studies investigating azacitidine in patients with AML with dysplasia are warranted.
Fludarabine Based Regimen (FLAI) Is an Effective Treatment for Induction of Multidrug Resistant Pgp-Positive Acute Myeloid Leukemia Patients.
Authors: Russo Domenico , Damiani Daniela , Malagola Michele , De Vivo Antonio , Fiacchini Mauro , Martinelli Giovanni , Piccaluga Pier Paolo , Candoni Anna , Michelutti Angela , Fanin Renato , Castelli Maurizio , Testoni Nicoletta , Ottaviani Emanuela , Rondoni Michela , Pricolo Giancarla , Mazza Patrizio , Zuffa Eliana , Zaccaria Alfonso , Raspadori Donatella , Bocchia Monica , Lauria Francesco , Bonini Alessandro , Avanzini Paolo , Gugliotta Luigi , Pierri Ivana , Gobbi Marco , Visani Giuseppe , Baccarani Michele 
Published: October 2019

Abstract
Induction treatment of acute myeloid leukemia (AML) is conventionally based on regimens containing cytarabine (Ara-C), one anthracycline and, sometimes, a third drug, such as etoposide. Primary P-glycoprotein (Pgp) overexpression is the most important mechanism of multidrug resistance (MDR) in AML cells and it is almost always associated with less response to treatment. To deal with this problem, in 1997, we started a treatment program with a regimen including Fludarabine (FLUDA) for the induction of newly diagnosed AML patients. FLUDA showed to be toxic against the MDR cells, in vitro, and able to enhance Ara-C cytotoxicity by increasing cell concentration of Ara-C 5′ triphosphate and inhibiting DNA repair. Between 1997 and 2004, 110 newly diagnosed AML patients aged less than 60 years were induced with FLAI (Fludarabine 25 mg/sqm/day days 1–5, Ara-C 2 gr/sqm/day days 1–5, Idarubicine 10 mg/sqm/day days 1, 3, 5) in the context of three consecutive prospective multicentric trials. At diagnosis, all the patients were assessed for the Pgp expression by an indirect immunofluorescence method with the anti-p170 monoclonal antibody MRK-16. The results were expressed as the mean fluorescence index (MFI) and patients with a MFI > 6 were setted as MDR+ve. We correlated the Pgp-expression, with the response to the induction.
Interestingly, the Pgp+ve (MFI > 6) patients treated with FLAI entered CR as well as the Pgp-ve (MFI < 6). Twenty-four out of 39 Pgp+ve patients (61%) and 54 out of 71 Pgp-ve patients (76%) achieved a CR after a single induction course of FLAI (p= 0.1). This observation strongly supported the original hypothesis that fludarabine could play a favourable role against MDR+ve cells. In order to validate this finding we compared the results obtained in an hystorical group of 136 newly diagnosed AML patients younger than 60 years treated with a non-fludarabine containing regimen AI (Ara-C 200 mg/sqm/day c.i. days 1 - 7, Idarubicine 10 mg/sqm/day days 1, 3, 5). In the non-fludarabine group, 22 out of 69 Pgp+ve patients (32%) and 42 out of 67 Pgp-ve patients (63%) achieved a CR after one course of the induction therapy. This difference was stastically significant (p= 0.0006). Based on these observations, we decided to conduct a match pair study to confirm the superiority of FLAI for overcoming the primary multidrug resistance Pgp-mediated in AML.
Comparative Pharmacodynamics of TGN 255, a Novel Direct Thrombin Inhibitor and Unfractionated Heparin in Healthy Volunteers.
Authors: Combe Sophie , Allen Graham , Kennedy Antony 
Published: October 2019

Abstract
Background: TGN255 is a synthetic direct thrombin inhibitor undergoing development for the prevention of arterial and venous thrombosis in high risk patients.
Methods: An open-label, heparin-controlled, cross-over study was performed in 12 healthy male volunteers to evaluate the pharmacokinetics, pharmacodynamics and safety of TGN255 and heparin given as an infusion over a 3 hour period. Doses of TGN255 were given as a bolus of 25 mg over 60 sec followed by a 3 h infusion of 40, 80, 160 mg/h. Heparin was administered as a 5000 IU bolus followed by 15 IU/kg/h infusion for 3 h. Plasma concentrations of TGN255 were evaluated using a validated LC-MS/MS method. The dynamic activity was assessed through measurement of the Activated Clotting Time (ACT), thrombin time (TT) and activated Partial Thromboplastin Time (aPTT).
Results: The plasma concentration of TGN255 rapidly increased following the bolus injection, and the pharmacokinetic profile of TGN255 was dose proportional. The effective half-life of TGN255 was 1.7 h. This short half-life was consistent with the rapid decline in the observed TT, aPTT and ACT ratios after administration was completed. The elevations in TT ratios were considerably higher than for the aPTT ratios across TGN255 groups (6.9, 11.7, 19.7 times baseline for TT and 1.7, 2, 2.4 times baseline for aPTT). The relationship between TT ratio and TGN255 plasma concentration was very well defined with a correlation coefficient of 0.94. For heparin, the TT ratios reflected a saturated system (measurements >300 s) and the aPTT ratios showed a marked increase compared to TGN255 groups (mean of 9.3 times baseline) indicating less selective behavior than TGN255 for this clotting parameter. The ratios for ACT showed a measurable elevation above baseline: mean of 1.9, 2.2, 2.7 for TGN255 groups versus 1.7 for heparin. No significant adverse events have been observed of either a general or cardiovascular nature (including hemorrhage, ECG changes, or liver function tests).
Conclusions: This study will support the entry of TGN255 into the clinical arena of cardiovascular procedures, and support its use in patients undergoing coronary artery bypass grafting.
Comparison of Enoxaparin to the Thrombin Variant Protein C Activator, W215A/E217A, in a Primate Model of Thrombosis.
Authors: Marzec Ulla M. , Bush Leslie , Gruber Andras , Hanson Stephen R. , Di Cera Enrico 
Published: October 2019

Abstract
Antithrombotic therapy by thrombomodulin-dependent activation of endogenous protein C might be safer than currently used therapies, since endogenous activated protein C (APC) is generated and probably concentrated on the endothelial surface and not in blood that escapes the blood vessels during injury. We compared the antithrombotic and antihemostatic activities of a protein C selective recombinant double mutant human thrombin (W215A/E217A; WE) that activates endogenous protein C on the endothelial surface, in vivo, with a low molecular weight heparin, enoxaparin in awake non anticoagulated baboons. Thrombosis was initiated by interposing a two part device consisting of a 2cm, 4mm ID, polyethylene terephthalate vascular graft (DVG) followed by a 2cm silicone tubing chamber, 9mm ID, into a chronic femoral arteriovenous shunt in baboons. Upon initiation of blood flow at 100mL/min, wall shear rate of 265sec−1 in the 4mm ID segment (arterial type flow) and 29sec−1 in the expansion chamber (venous type flow), platelet thrombus growth was monitored by gamma camera imaging of autologous 111In-labeled platelets for 1 hour. Fibrin accumulation was quantified by homologous 125I-labeled fibrinogen. Bleeding time and aPTT were monitored. WE was administered as a loading IV bolus (1/3 dose) 10 minutes before thrombus initiation followed by maintenance infusion (2/3 dose) for the duration of the study at 3 dose levels: 1.8 μg/kg (dose-1), 3.75 μg/kg (dose-2) and 7.5 μg/kg (dose-3). Results were compared to controls given normal saline and to 3 doses of IV enoxaparin (1/2 dose loading + 1/2 dose maintenance): 0.3 mg/kg (dose-1), 0.6 mg/kg (dose-2) and 1.2mg/kg (dose-3) (3–5 animals in each study group). WE inhibition of platelet deposition in the chamber was dose dependent and reduced by 57%, 76% and 95% for dose 1, 2 and 3 respectively, compared to controls (p < 0.05 each). Enoxaparin likewise reduced thrombosis in the chamber by 49%, 83% and 91% (p< 0.05 each) respectively at the 3 doses tested. Fibrin accumulation paralleled the platelet deposition data in the chamber. Thrombus growth on DVG was only reduced at dose level 3 for both WE and enoxaparin by 18% and 47%, respectively as determined by platelet deposition. Fibrin accumulation was reduced by 35% by WE and 51% for enoxaparin at dose 3 on the arterial thrombosis segment. Bleeding times did not increase significantly with any of the treatments except for dose-3 of enoxaparin which prolonged the bleeding time from 3.5±1.3 minutes to 5.3 ± 1.4 minutes. Prolongation of APTT was 1.14, 1.33, and 2.04 fold for WE doses 1, 2 and 3, respectively and enoxaparin prolonged the APTT by 1.25, 1.6 and 1.9 fold at dose 1, 2 and 3, respectively. We conclude that low dose WE infusion is safe and about two orders of magnitude more antithrombotic than enoxaparin infusion in the baboon model of thrombosis.
Extra-Cellular DNA in Cord Blood (CB) Plasma: Use for Sample Identification [short Tandem Repeat (STR) Analysis] and for Infectious Disease Screening in CB Banks.
Authors: Albano Maria S. , Andrus Linda , Lee Dong H. , Stevens Cladd E. , Rubinstein Pablo 
Published: October 2019

Abstract
Introduction: A commitment of CB banks is to test CB units and maternal blood for multiple genetic and infectious disease markers. As a consequence, several aliquots of blood, mononuclear cells and plasma are taken during processing for immediate and delayed testing. Whereas control of identity between aliquots containing cells can be performed by DNA assays, identity controls for plasma aliquots rely only on bar-coded label systems. We hypothesize that there is soluble extra-cellular DNA (EC-DNA) and that it can be used for identity control of plasma aliquots. The aims of our study were;
to determine the concentration of EC-DNA in CB-plasma, to evaluate whether genetic identity testing by STR analysis is feasible and to investigate whether EC-DNA allows infectious disease screening by nucleic acid testing (NAT).
Methods: CB (n=20) was collected, processed (Rubinstein et al, PNAS 1995) and EC-DNA from 200 μl of 0.45μm-filtered plasma was extracted both with the Qiagen and the High Pure Viral Nucleic Acid method (Roche). Presence of EC-DNA was evaluated by detection of HLA-DR and ALU gene sequences and by STR analysis (AmpFlSTR-Profiler Plus-Applied Biosystems). Purified HBV was added to CB and peripheral blood (PB) plasma, EC-DNA recovered as above and HBV-DNA assessed by real time PCR.
Results: All 20 samples were positive for HLA-DR by PCR and for ALU sequence by real time PCR, confirming the presence of EC-DNA in CB-plasma in concentrations of 0.022 +/− 0.012 ng/μl at the time of CB collection, rising to 0.124 +/− 0.025 ng/μl 33 hrs later; p<0.016. Concentrations observed in CB-plasma were higher than those of adult donor plasma (PB-plasma 0.005+/−0.0065 ng/μl). STR analysis was validated on cellular DNA and, when applied for EC-DNA, showed good signal strengths and low backgrounds, allowing accurate automatic allele identification with no manual corrections (genemapper software, Applied Biosystems). An increase in STR-PCR product concentration was observed when we analyzed EC-DNA samples from CB after 33hs (7017.6 +/− 2014 RFU/μl at time of CB collection and 30290.9 +/− 3164 RFU/μl after 33 hs; RFU = relative fluorescence units). HBV was recovered from all spiked units, in correspondence with the viral concentrations added. Recovery of HBV was 96 +/− 21% with high and low viral concentrations. Three mothers with HBAg/HBcore positive had also HBV-DNA in PB-plasma. Six with anti-HBcore only and 70 with anti-HBs were negative. HBV-DNA was also negative in CB-plasma for all seventy nine respective newborns.
Conclusions: there is infant EC-DNA in CB-plasma and viral nucleic acids can be obtained using the same extraction method. There is an increase of EC-DNA in CB over time that may reflect cell death. STR assay of EC-DNA can be a useful molecular tool for the identification of plasma aliquots used for infectious disease testing in CB banks.
RNA-Binding Protein VICKZ Is Expressed in a Germinal Center Associated Pattern among Lymphoma Subtypes.
Authors: Natkunam Yasodha , Vainer Gilad , Zhao Shuchun , Amir Gail , Pikarsky Eli , Hammer Anne S. , Hamilton-Dutoit Stephen , Levy Ronald , Yisraeli Joel K. , Lossos Izidore S. 
Published: October 2019

Abstract
Recent effort in the molecular characterization of diffuse large B-cell lymphoma (DLBCL) has led to the recognition that patients with DLBCL of germinal center origin exhibit a better overall survival. Thus, identification and characterization of markers of germinal center derivation are of importance in dissecting prognostic subclasses of DLBCL. The VICKZ (Vg1 RBP/Vera, IMP1, 2, 3, CRD-BP, KOC, ZBP-1) family members are RNA-binding proteins that recognize specific RNA targets and have been implicated in diverse cellular functions including cell polarity, migration, proliferation and tumorigenesis/metastasis. We generated an antibody that recognizes all three isoforms of VICKZ protein and characterized its expression in normal lymphoid tissue and in lymphoma subtypes. In normal tonsils, VICKZ protein showed a germinal center-specific pattern of expression with staining localized to the cytoplasm. Among 868 non-Hodgkin and Hodgkin lymphomas tested by immunohistochemistry on tissue microarrays, staining for VICKZ protein was present in 76% (126/165) of follicular lymphoma, 78% (155/200) of DLBCL, 90% (9/10) of mediastinal large B-cell lymphoma, and 100% (2/2) of Burkitt lymphoma. A subset of mantle cell lymphoma (11%, 2/19), extranodal (8%, 2/25), and nodal (20%, 1/5) marginal zone lymphoma and lymphoblastic lymphoma (25%, 4/13), showed VICKZ staining. The majority of lymphocyte predominant Hodgkin (92%, 12/13) and classical Hodgkin (94%, 101/108) lymphoma were found to be positive. Among T cell lymphoma, anaplastic large cell lymphoma were positive (75%, 6/9). Additional work is in progress to correlate VICKZ protein expression with other germinal center markers such as HGAL, BCL6 and CD10 as well as with prognostic subclasses of DLBCL. The differential expression pattern of VICKZ protein in lymphoma subtypes suggests a potential utility for VICKZ in the identification of subgroups of DLBCL associated with different prognoses.
Clinical Features and Outcome of 147 Patients with Diffuse Large B-Cell Lymphoma and Hepatitis C Virus Infection.
Authors: Visco Carlo , Arcaini Luca , Merli Michele , Andreoli Annalisa , Burcheri Sara , Ambrosetti Achille , Brusamolino Ercole , Lazzarino Mario , Pizzolo Giovanni , Rodeghiero Francesco 
Published: October 2019

Abstract
Hepatitis C virus (HCV) has been implicated in the pathogenesis of a subset of low-grade non-Hodgkin lymphomas. Furthermore, diffuse large B-cell lymphoma (DLBCL) has been correlated to HCV infection in several series from our geographical area (north-east of Italy), but little is known about the characteristics of such high-grade tumors. We analyzed presentation features of 147 previously untreated HCV-positive patients with DLBCL who presented to the three participating centers between 1993 and 2004. All patients were provided with complete clinical information, were HIV negative, and had been tested at tumor onset for HCV antibodies by ELISA and RIBA.
Median age at presentation was 64 years old (range 29–88), 47% were males, ECOG performance status was >1 in 20%, Ann Arbor stage was I in 20%, II in 27%, III in 26%, IV in 27%, and B-symptoms were present in 37% of patients. The International Prognostic Index (IPI) value at diagnosis was low in 18%, int/low in 23%, int/high in 32%, and high in 27% of patients. Surprisingly, DLBCL transformed from a low-grade histology represented only 7% of the whole population, while primary mediastinal DLBCL were extremely rare (1/147, <1%). Patients frequently presented as primary extranodal DLBCL (65/147, 44%). Most involved extranodal sites were skin, liver, stomach, and spleen, with the latter being the most represented syte (33% of patients). Remarkably, spleen was the only extranodal involved organ in 20% of patients. Treatment was delivered with cure-intent, and consisted of CHOP-like regimens +/− Rituximab for the large majority of patients, except for 16 (11%) patients with cirrhosis or severe hepatic dysfunction, who received mono-chemotherapy or radiotherapy. Only three (2%) HCV-positive patients had to discontinue chemotherapy due to liver function impairment. The addition of Rituximab to chemotherapy did not seem to affect patients’ tolerance to treatment. With a median follow-up of 48 months for survivors, 5-year overall survival (OS) was 75%, while 5-year failure-free survival (FFS) was 51%. In particular, the 65 patients with primary extranodal DLBCL shared a better 5-year OS (83% vs 71%, p=0.01) and FFS (75% vs 39%, p=0.009) than their nodal counterpart. Nodal origin of the tumor resulted the strongest independent adverse factor both in terms of OS and FFS in multivariate analysis.
The peculiar clinical behavior shared by HCV-positive DLBCL may disclose relevant biological features of these tumors, and may be relevant for future studies aiming to clarify the link between HCV infection and aggressive lymphoproliferative disorders.
Complete Loss or Severely Compromised Expression of the Pro-Apoptotic Protein Bax Leads to Resistance to Curcumin-Induced Apoptosis in Burkitt’s Lymphoma Cells.
Authors: Hussain Azhar R. , Al-Rasheed Maha , Manogaran Pulicat S. , Al-Kuraya Khawla S. , Uddin Shahab 
Published: October 2019

Abstract
This report compares in detail, the role of curcumin treatment in a panel of Burkitt’s lymphoma (BL) cell lines that are either expressing full length Bax with a group of cell lines that are either completely deficient or have decreased expression of Bax. Multiple apoptotic stimuli induce conformational changes in Bax, a pro-apoptotic protein from the Bcl-2 family and its deficiency is a frequent cause of chemo-resistance in a variety of malignancies including Burkitt’s lymphoma. We extent our previous studies on Burkitt’s lymphoma to determine the role of curcumin treatment on BLs. Curcumin (diferuloymethane) is a naturally occurring yellow pigment isolated from the rhizomes of the plant curcuma longa. The medicinal value of curcumin has been well recognized with its anti-oxidant, anti-inflammatory and anti-tumor activities. Curcumin is also known to induce apoptosis in a variety of cancer cells including multiple myeloma and primary effusion lymphomas. To understand the role of Bax in curcumin-induced apoptosis, we used two groups of Burkitt’s lymphoma cell lines, one that expressed the Bax protein (AS283A, KK124 and Pa682PB) and the other group either did not or had decreased expression of Bax (BML895 CA46, and LW878). Cell viability decreased in a dose-dependent manner in AS283A, PA682PB and KK124 with curcumin treatment ranging between 0–40mM whereas only minimal changes in viability was observed in BML895, CA46 and LW878 after treatment. Curcumin induced a dose-dependent apoptosis in the Bax expressing group of cell lines while the cell lines that were either completely deficient or had decreased expression of Bax did not respond to curcumin treatment and remained refractory. In AS283A, KK124, and PA682PB, curcumin induced apoptosis through truncation of BID, loss of mitochondrial potential as determined by JC1 staining with subsequent activation of caspase3 followed by cleavage of PARP. However, in the curcumin resistant cell lines, there was no change in the mitochondrial potential after curcumin treatment and therefore apoptosis did not occur. In addition, zVAD-fmk, a universal inhibitor of caspases prevented caspase3 cleavage as well as cell death in the sensitive cell lines after curcumin treatment suggesting that curcumin-induced apoptosis is caspase dependent. Our findings suggest that Bax integrity is necessary for curcumin to induce apoptosis in Burkitt’s lymphoma cells. These results provide the molecular basis and preliminary data for new treatment strategies that may incorporate curcumin in regimens for Burkitt’s lymphoma treatment.