bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Certain Glycolytic Inhibitors on Aerobic Lactic Acid Production by Human Leukocytes in Vitro
Authors: MCKINNEY GORDON R. , MARTIN SAMUEL P. 
Published: October 2019

Abstract
Oxamic acid depressed aerobic lactic acid formation by normal, human leukocytes by only 20-25 per cent. Glyceraldehyde increased lactic acid production. Sorbose-1-phosphate was without effect. Iodacetate inhibited markedly, but fluoride depressed only in high concentrations. The significance of these findings regarding the mechanism of aerobic lactic acid formation by mature leukocytes is discussed.
Array CGH Analysis for PTCL-U Revealed a Distinct Subgroup with Pathological and Clinical Relevance.
Authors: Nakagawa Masao , Nakagawa-Oshiro Aya , Karnan Sivasundaram , Tagawa Hiroyuki , Nakamura Shigeo , Takeuchi Ichiro , Ohshima Koichi , Seto Masao 
Published: October 2019

Abstract
Peripheral T-cell lymphoma, unspecified (PTCL-U) is one of the most commonly encountered group among peripheral T-cell lymphomas (PTCLs). This category consists of the cases which do not belong to any of the recognized subtypes of PTCLs in the World Health Organization classification. PTCL-U comprises histologically and clinically heterogeneous groups, which makes it difficult to assess conventional therapies accurately and to develop new therapeutic targets. The first priority is thus to identify subgroups of PTCL-U. However, the molecular basis of their clinical heterogeneity is still poorly understood. Here we analyzed 51 cases of PTCL-U by means of array CGH consisting of 2304 artificial chromosome clones that cover the whole genome at a 1.3 mega base resolution. DNA gains and losses were detected in 29 cases (total regions: average 15.6, range 1–31; gains: average 8.0 regions, range 0–24; losses: average 7.6 regions, range 0–21). Regions of frequent gain(>15%; ≥5cases) were detected on 1q24.2, 1q25.1–25.2, 3q25–26.1, 3q26.2–27.1, 3q27.3–29, 4p16.2–15.2, 4q21.1–21.21, 4q21.23–28.1, 4q28.3–31.23, 4q32.1, 4q32.3–35.1, 7p, 7q, 9q31.3–32, 9q33.2–34.2, 11q14.1, 11q14.3-tel, and 16p13.2–12.2, and regions of frequent loss on 1p31.2–13.1, 2q37.3, 6q14.3, 9p21.3, 10p14–13, 10p12.31–11.22, 10q11.21–21.1, 10q23.2–23.31, 10q24.2–26.3, 13q14.11–14.2, 13q21.1–34, 16q12.1–21, 17p13.3–11.2, and 18p11.31d–11.22b. Three consecutive BAC clones at 14q32.2 and at 9p21.3 were identified as regions of recurrent high-level amplification and homozygous loss, respectively. Our array CGH analysis could reveal a distinct subgroup consisted of 29 cases which have genomic alterations. Regarding to tumor burden, histopathology, the expression of chemokine receptors, and prognosis, this subgroup displayed significantly different features compared with 22 cases showing no genomic alteration. Our findings showed that PTCL-U with genomic alteration has pathological and clinical relevance distinct from those without, implying that distinct mechanisms underlay in molecular pathogenesis of PTCL-U.
Combined VBM Chemotherapy and Involved Field (IF) Radiotherapy in Early Stage Hodgkin’s Lymphoma (HL): A Single Centre Experience.
Authors: Cocorocchio Emilia , Peccatori Fedro A. , Gigli Federica , Bassi Simona , Nassi Luca , Calabrese Liliana , Travaini Laura , Piperno Gaia , Preda Lorenzo , Pruneri Giancarlo , Liptrott Sarah J. , Alietti Alessandra , Martinelli Giovanni 
Published: October 2019

Abstract
Early stage HL patients (pts) benefit from a short course of chemotherapy combined with IF radiotherapy. In our previous experience six courses of VBM chemotherapy (Stanford regimen) were administered with IF radiotherapy. However, despite good clinical results, the schedule was modified in terms of total chemotherapy cycles delivered, in order to reduce the risk of long term toxicities. PET and CT scan were performed at staging to identify a low risk patients (pts) group. From May 2001 to November 2006, 32 treatment naïve Hodgkin’s lymphoma pts (18 male, 14 female) were treated with four courses of VBM chemotherapy (D1, 8: Vinblastine 6 mg/sm, Bleomycin 10 mg/sm, Methotrexate 30 mg/sm, repeated every 28 days) followed by IF radiotherapy. Median age was 37 years (range 16–73). Main histology was classical HL in 26 pts, while lymphocyte predominant was observed in 6 pts. Pts were all stage I-IIA (no bulky disease), no more than three sites involved, performance status 0–1 and ESR < 50. CT scans were performed before and after chemotherapy and radiotherapy. PET scans were performed before and after chemotherapy in 26 pts, and after radiotherapy if not performed before or in case of positivity after chemotherapy. Chemotherapy was usually well tolerated: three pts experienced G3-4 neutropenia while the main non- haematological toxicities recorded were G3 transaminitis in 3 pts and G1-2 neuroconstipation/abdominal pain in 18 pts. IF radiotherapy was performed one month after the last chemotherapy cycle; median dose administered was 30Gy (range 26–30.4). At the end of chemotherapy 7 pts were PET positive. While one patient developed progressive disease, the other six pts became negative after radiotherapy and are still in complete remission (CR). 29 pts (90%) completed the whole program obtaining a CR. Two pts progressed before radiotherapy, while one patient shifted to an anthracycline containing schedule after two cycles due to stable disease. With a median follow-up of 42 months (range: 7–73), all pts are alive. 1 out of 29 CR pts progressed and is now receiving intensive chemotherapy program with autologous stem cell transplant. In our experience four cycles of VBM chemotherapy combined with IF radiotherapy is an effective program. Furthermore this regimen that doesn’t contain alkylating agents or anthracyclines avoids alopecia and decreases the risk of long term toxicity. PET scan effectively helps to identify low risk early stage HL pts that can take advantage of this therapeutic approach.
Abnormally High Levels of Circulating CD34+CD38−, CD34+CD38+, and CD10+ Hematopoietic Stem and Progenitor Cells in the Peripheral Blood of B-Cell Chronic Lymphocytic Leukemia (B-CLL) Patients Suggest the Presence of Additional Therapeutic Target Cells.
Authors: Christopherson Kent W. , Paganessi Laura A. , Rhoades Darilyn R. , Dillon Hortense M. , Gezer Sefer , Larson Melissa L. , Fung Henry C. , Gregory Stephanie A. 
Published: October 2019

Abstract
Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disorder manifested by a clonal expansion of mature long-lived functionally defective lymphocytes that are predominantly of B-cell origin (>95% of cases). CLL cells typically express the pan-B-cell antigens CD19 and CD20 as wells as CD5, an antigen of mature T-cells, which is present in 95% of B-CLL patients and is helpful for diagnosis. The disease has a median survival of 8–10 years. Asymptomatic patients (RAI stages 0–2) are often not treated. RAI stages 3 & 4 are generally treated. Current therapies for CLL included a combination of monoclonal antibodies (anti-CD20 monoclonal antibody, rituximab) with purine analogs (fludarabine or pentostatin) and alkylating agents (cyclophosphamide). Current therapies to manage B-cell CLL are not curative and therefore suggest that the current strategy of targeting therapy against B-cells may leave behind residual disease that contributes to progression or relapse. The importance of more primitive Hematopoietic Stem and Progenitor cell populations in B-CLL patients has not been considered. We hypothesized that circulating cells may be spontaneously mobilized into the periphery of CLL patients and would therefore contribute to the peripheral blood microenvironment. To test this hypothesis we examined existing CLL cell populations from un-treated “watch-and-wait” B-CLL patients as compared to normal volunteer donor peripheral blood cell populations utilizing multivariate flow cytometric analysis. We determined CD34+CD38−, CD34+CD38+, and CD10 levels in normal peripheral blood to be 81.0±14.5, 497.3±78.33, and 83.6±17.5 cells/ml respectively. We report here the presence of abnormally high levels of these stem and progenitor cell populations in B-CLL patients (see table). Although the mechanism behind the release of these cells into the periphery in B-CLL patients is unknown, it is reasonable to propose that they may be contributing to the manifestation of the disease and are therefore potential novel target cell populations for future therapies.
B-CLL Patients WBC β2m CD34+CD38− CD34+CD38+ CD10+ White Blood Cell (WBC) counts are expressed as 1x106 cells/ml. All other counts are expressed as cells/ml 7.93 2.4 2,526 14.6 23,119 11.86 U 3,145 58.2 1,449 12.5 U 307 11.72 1,773 16.9 3.7 6,450 251 3,771 17.24 3.0 28 5.79 8,024 19.37 1.8 4,086 180 8,247 19.9 U 1,790 18.6 3,099 19.92 U 529 34.1 16,039 25.81 1.8 2,937 194 4,617 31.21 2.9 20,753 304 24,340 43.13 1.5 1,577 260.49 281,976 73.98 3.2 1,099 1,767 77,525 105.53 2.2 3,266 220 24,070
2-Chlorodeoxyadenosine (2-CDA) and Dexamethasone Induce Apoptosis in Multiple Myeloma (MM) Via Different Mechanisms.
Authors: Liu Bolin , Fang Zeying , Ma Jian , Dillon Thomas E. , Byers Tim E. , Thor Ann D. , Lee Choon Kee 
Published: October 2019

Abstract
Although 2-CDA has been active on B-lymphocyte derived malignancies, its potential for myeloma growth control has not been fully investigated. In the present study on a pair of MM cell lines, dexamethasone-sensitive (MM1.S) and dexamethasone-resistant (MM1.R), we sought to determine whether 2-CDA can effectively induce apoptosis and growth inhibition in both cell lines and whether there is cross resistance between 2-CDA and dexamethasone in MM1.R cells. Cell proliferation assay (MTS) releaved that 2-CDA significantly inhibited both MM1.S and MM1.R cell growth in a dose dependent manner, with the minimum (10%) and maximum (100%) inhibition concentration of 12.5 nM/L and 500 nM/L for the MM1.S, and 25 nM/L and 500 nM/L for the MM1.R cells, respectively. The IC50 values of 2-CDA in the MM1.S and MM1.R cells were 48 nM/L and 60 nM/L, respectively. No cross resistance was observed between 2-CDA and dexamethasone in the MM1.R cells. On the molecular level, dexamethasone induced PARP and caspase-9 cleavage, and increased the level of p27kip1 only in the MM1.S cells. 2-CDA treatment in both cell lines resulted in DNA fragmentation as well as strong PARP and caspase-9 cleavage, but no significant changes in the levels of P-Akt, P-MARK, p27kip1, E2F1, and cyclin D1, indicating that 2-CDA induces growth inhibition and cell death in MM cell lines likely through mitochondria-dependent apoptotic mechanism. Cell cycle analyses by flow cytometry showed that dexamethasone (5μM/L) treatment increased sub-G1 (apoptosis) cells to 8.1% only in the MM1.S cells, while the majority (87%) of cells were arrested in the G1 phase of cell cycle in 24 hours. In contrast, 2-CDA (0.5μM/L for 24 hours) strongly induced apoptosis in both cell lines (sub-G1 population increased to 19.6% and 22.1% for the MM1.S and MM1.R cells, respectively) without changing their cell cycle profiles. These data suggest that dexamethasone and 2-CDA induce apoptosis in myeloma cells via different mechanisms, which would provide a theoretical basis for combination therapy for MM with these two agents. Furthermore, our results also show that 2-CDA alone is capable of inducing apoptosis in the MM1.R cells, suggesting that 2-CDA may have therapeutic potential for MM patients with a dexamethasone-resistant phenotype.
Defibrotide for the Treatment of Veno-Occlusive Disease Post SCT: Preliminary Results of EU Compassionate Use Program in 332 Patients Confirm Promising Activity and Manageable Toxicity.
Authors: Carreras Enric , Olavarria Eduardo , Neven Benedicte , Maertens Johan , Boelens Jaap J. , Tescione Francesco , Hoyle Margaret , Ferro Laura I. , Iacobelli Massimo , Ruutu Tapani , Niederwieser Dietger 
Published: October 2019

Abstract
Introduction: Hepatic veno-occlusive disease (VOD) is one of the most significant regimen-related toxicities of stem cell transplantation (SCT), which when complicated by multi-organ failure (MOF) has a case fatality rate >90%. Defibrotide (DF) is a polydisperse oligonucleotide, with anti-thrombotic, anti-ischemic and thrombolytic properties, especially on microvasculature. Results in earlier studies of DF therapy for VOD/MOF have consistently shown manageable toxicity with promising complete response (CR) rates and D+100 survival post SCT. We report the results of the largest compassionate use program (CUP) performed to date.
Methods: Physicians in Europe requesting DF for the treatment of pts with VOD obtained the drug on a named patient basis and were requested to collect data by a standardized CRF. Patients (pts) were reviewed to identify the nature and frequency of Suspected Adverse Drug Reactions (SADR). CR and D+100 survival post-SCT were assessed with CR defined as bilirubin <2 mg/dl and resolution of VOD-related end-organ dysfunction. From February 1999 to July 2007, 332 pts (215 men (65%), 117 women (35%), with a median age of 28 years) from 96 European centers received DF (Gentium SpA, Como, Italy). Pts were both adults (208 pts 63%, range: 18–66 yrs) and pediatric (124 pts, 37%, range: 2 months-17 years). 253 pts underwent allo-SCT (77%), and 76 auto-SCT (23%). At entry, all pts had VOD defined by either Baltimore criteria (205, 62%), modified Baltimore criteria [within 35 days of SCT] (n=42, 13%), Seattle criteria (84, 25%) or were biopsy proven (n=1). MOF was present in 113 pts (34%): 90/332 (27%) pts had renal, 53/332 (16%) had respiratory and 15/332 (5%) had CNS dysfunction. Median dose of DF was 37 mg/kg/d (range: 10–120 mg/kg/d). Median duration of DF therapy was 14d. Overall, D+100 survival was 46% (154 pts). CR was achieved in 173 pts (52%), with 142 alive in CR at D+100 (82%). NR was seen in 159 (48%), with only 12 alive at D+100 (8%). In a subset of 73 pts with severe VOD (defined by Baltimore criteria and MOF), survival at D+100 was 34% (25 pts). The overall incidence of attributable SADRs was 8% (n=28) and consisted predominantly of haemorrhages (n=27, 8%), most of which proved reversible.
Conclusions: In this largest study of pts treated with DF to date, no unexpected toxicities were reported and side effects were generally manageable. CR was obtained in 52% with D+100 survival in 46%, including 34% in those pts with severe disease. This is consistent with prior studies and suggests that DF offers a relatively safe and effective treatment for hepatic VOD post SCT.
CEACAM-1 Is Involved in Graft-Versus-Host-Disease in Murine Allogeneic Bone Marrow Transplantation Models.
Authors: Lu Sydney X. , Willis Lucy , Smith Marsinay , Suh David , King Christopher , Bautista Johanne , Chow Melanie , Cabrera-Perez Javier , Hubbard Vanessa , Rotolo Jimmy , Liu Chen , Murphy George , Alpdogan Onder , Blumberg Richard , Holmes Kathryn , Turbide Claire , Beauchemin Nicole , van den Brink Marcel R.M. 
Published: October 2019

Abstract
Carcinoembryonic antigen associated cell adhesion molecule 1 (CEACAM-1) belongs to a family of carcinoembryonic antigen-associated glycoproteins. It is expressed on leukocytes, endothelium, and epithelium. Microarray analysis showed that CEACAM-1 mRNA is increased in the small bowel during gut graft-versus-host-disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT). Using CEACAM-1−/− mice as recipients or sources of donor bone marrow or T cells caused significantly worse GVHD mortality (p<0.05) compared to wildtype (WT) controls. Histopathological analysis of GVHD target organs from CEACAM-1−/− recipients of WT T cells or WT recipients of CEACAM-1−/− T cells revealed increased GVHD of the large bowel (p<0.05) but not liver or small bowel compared to WT control. Alloreactive splenic CD8 CEACAM-1−/− T cells from recipients with GVHD had increased levels of α4β7 integrin compared to WT controls. We also found increased numbers of small bowel intraepithelial lymphocytes and mesenteric lymph node cellularity in CEACAM-1−/− recipients of WT T cells and WT recipients of CEACAM-1−/− T cells, with a corresponding decrease of cellularity in peripheral lymph nodes and the liver. Adoptive transfer of CFSEhi CEACAM-1−/− T cells into WT hosts, or of WT T cells into CEACAM 1−/− hosts revealed more profound activation of T cells in CEACAM-1 deficient settings, shown by increased early CD25 expression and CD62L down-regulation on splenic CFSEdim alloreactive T cells. We found no significant differences in serum levels of TNF or IFNγ, T cell proliferation kinetics upon adoptive transfer, percentages of alloactivated CD4 or CD8 cells, intracellular levels of T-bet or IFNγ, CD8 T cell cytolytic efficiency, percentages of splenic regulatory T cells, or levels of T cell apoptosis in WT recipients of CEACAM-1−/− T cells or CEACAM-1−/− recipients of WT T cells with GVHD as compared with controls. Finally, irradiation of non-transplanted CEACAM-1−/− mice revealed increased radiation sensitivity, shown by earlier and greater lethality and increased small bowel crypt apoptosis, suggesting a role for CEACAM-1 in conditioning-related toxicity and subsequent GVHD amplification. We conclude that CEACAM-1 deficiency on donor T cells or transplant recipients results in increased gut and systemic GVHD due to increased T cell activation and elevated expression of the gut homing integrin α4β7. This suggests that the use of CEACAM-1 agonists could be a novel theraputic strategy for ameliorating acute intestinal and systemic graft-versus-host-disease.
Mutations in the Catalytic Subunit of Class IA PI3K Are Leukemogenic In Vivo.
Authors: Horn Stefan , McCubrey James A. , Stocking Carol , Trumper Lorenz , Basecke Jorg 
Published: October 2019

Abstract
The phosphoinositide 3-kinase (PI3K)-AKT pathway is a relevant signal transduction axis which regulates survival, growth and proliferation of hematopoietic cells through a variety of downstream targets. Constitutive activation of the PI3K-AKT pathway is observed in up to 70% of acute myelogenous leukemia (AML), primarily due to activating mutations in receptor tyrosine kinases (e.g. c-KIT) or RAS and is also present in T-cell-non-Hodgkins-lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, Hodgkins Lymphoma and myelodysplastic syndrome (MDS). We analyzed the effect of activating point mutations in the catalytic subunit p110alpha of class IA PI3K (PIK3CA) in hematopoietic cells. We transfected early hematopoietic, IL-3 dependent cells (Ba/F3 cell line) with point mutations in the helical (exon 9, E542K, E545A) and kinase domain (exon 20, H1047R) of the p110alpha catalytic subunit and determined the effect of PI3K-AKT pathway activation on cellular proliferation, survival and leukemogenic expansion in vitro and in vivo. We demonstrate that the p110alpha point mutations constitutively activated the PI3K-AKT pathway and resulted in factor-independent growth of Ba/F3 cells. Proliferation and survival of the cells were inhibited in a time- and dose-dependent manner using inhibitors of either PI3K or AKT. The mammalian target of rapamycin (mTOR) was demonstrated to be important for mitogenic, but not anti-apoptotic signaling of mutant PIK3CA. In a syngenic mouse model, hematopoietic cells expressing mutant p110alpha induced a leukemia-like disease. FACS analysis demonstrated a median chimerism of 68% in the bone marrow and 35% in peripheral blood of diseased mice, which were characterized by anemia, leukemic infiltration of hematopoietic organs, and 90% mortality within 5 weeks. No substantial differences were observed between E542K, E545A and H1047R. Mice, which were transplanted with an activating c-KIT point mutation (D814V), showed a significantly reduced survival and 100% died within 9 days. In conclusion our data show, that PIK3CA point mutations, by activating the PI3K-AKT pathway, confer factor-independence to hematopoietic cells in vitro and induce leukemogenic activity in vivo. As mutant c-KIT (D814V) showed enhanced leukemogenic potential, signaling through c-KIT may involve additional downstream pathways which cooperate with activated PI3K in leukemia progression. Our model is useful for the differential investigation of the leukemogenic relevance of the PI3K-AKT pathway and pharmacological inhibitor studies.
Phase II Study of High Dose Lenalidomide as Initial Treatment for Older Acute Myeloid Leukemia Patients: Early Results Show a Significant Reduction of Bone Marrow Blasts after 14 Days of Therapy.
Authors: Fehniger Todd A. , Nelson Alissa , Trinkaus Kathryn , Abboud Camille N. , Cashen Amanda F. , DiPersio John F. , Graubert Timothy A. , Ley Timothy J. , Tomasson Michael H. , Uy Geoffrey L. , Walter Matthew J. , Westervelt Peter , Vij Ravi 
Published: October 2019

Abstract
AML patients over the age of 60 years have a poor prognosis, share disease characteristics with myelodysplastic syndrome (MDS) patients, and warrant novel therapeutic approaches. Lenalidomide has immunomodulatory and anti-neoplastic properties which can induce morphologic and cytogenetic responses in MDS patients, including those with excess blasts. We hypothesized that lenalidomide may be active against AML, and have employed a high dose strategy without dose reductions for hematologic toxicities. Here, we report preliminary results from a phase II study of high dose lenalidomide for front-line treatment of AML ≥ 60 without chromosome 5q deletion or favorable cytogenetics. Treatment included 2 cycles of high dose lenalidomide (50mg/day x 14 days, 30 days of rest, 50mg/day x 21 days), followed by maintenance therapy (10 mg/day) in non-progressing patients. Fifteen patients were enrolled in the first stage between 2/27/07 and 8/3/07. Median age was 71 years (range 60–86 years); ECOG performance status was 0 (4/15, 27%), 1 (10/15, 67%), or 2 (1/15, 7%); 11/15 (73%) patients were male; and 5/15 (33%) patients had prior MDS. Cytogenetics were normal (n=9), loss of chromosome 7 (n=2), loss of chromosome 20 (n=1), trisomy 13 (n=1), or complex (n=2). Overall, the treatment regimen was well tolerated. In the first stage of the study, 12/15 patients are evaluable for day 15 bone marrow and peripheral blood blast changes following the initial high dose lenalidomide cycle (50 mg/day x 14 days). Pre-therapy WBC counts (mean ± SEM) were 13,825 ± 4,447/uL (range 1,100–45,300/uL) and day 15 WBC counts were 4,742 ± 2,136/uL (range 300–24,400/uL). Day 15 bone marrow myeloblast percentages were significantly reduced in 9/12 patients (mean ± SEM decrease of 53 ± 10%, P=0.01, range 18–100%). In addition, the bone marrow blast index (% cellularity x fraction of blasts) decreased significantly after 14 days of high dose lenalidomide (mean ± SEM reduction of 66 ± 11%, P=0.02). Moreover, 5/8 patients with circulating blasts at diagnosis showed clearance of their peripheral blasts at day 15. These findings suggest that lenalidomide is an active agent against acute myeloid leukemia. Results on AML blast changes, response by international working group criteria, and toxicities in this patient cohort with ≥4 months of follow-up will be updated and presented.