bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of p53 Is a Marker of Progression in Plasma Cell Neoplasias and Is a Negative Prognostic Factor in Relapsed Disease.
Authors: Molnar Soledad , Zepeda Victor J Jimenez , Van Wier Scott , Braggio Esteban , Keats Jonathan , Kuehl Michael , Price-Troska Tammy , Ahmann Greg , Rempel Rachel , Henderson Kim , Rajkumar S. Vincent , Greipp Philip. R , Auclair Daniel , Carpten John , Baker Angela , Stewart Keith , Bergsagel P. Leif , Chng Wee Joo , Fonseca Rafael 
Published: April 2020

Abstract
Table 1. Samples to p53 deletions
p 53 deletion FISH aCGH FISH and aCGH MGUS 142 - - SMM 108 - - Newly diagnosed MM - 182 - Relapsed/refractory MM 62 156 19 HMCLs - 48 - Total 312 386 19
Background: Inactivation of p53 by mutation or allelic loss is a rare event in multiple myeloma (MM) at the time of disease diagnosis and believed to be more common in the late stages of the disease. Here we defined the prevalence of p53 deletions in monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), newly diagnosed MM, relapsed MM and human myeloma cell lines (HMCLs). Indirect mechanisms of p53 inactivation such as amplification of MDM2, or deletion of CDKN2A (p14ARF) were also investigated.
Patients and Methods: A total of 631 MM samples and 48 HMCLs were analyzed for p53 abnormalities (Table 1) and compared with a cohort of plasma cell leukemia (PCL) previously published by us. Interphase fluorescence in situ hybridization (FISH) and highresolution array-based comparative genomic hybridization (aCGH) were used to detect p53 deletions. MDM2 amplification and p14ARF loss were evaluated by aCGH. Overall survival (OS) was estimated through Kaplan Meier method.
Results: The prevalence of p53 deletions was 1.4%, 3.7%, 8.9%, 20% and 87.5% in MGUS, SMM, newly diagnosed MM, relapsed MM and HMCLs respectively (Figure 1). Of interest patients in first relapse showed a p53 deletion prevalence of 18% in comparison with 33% for patients in second relapse or more. We obtained p53 deletion status in 8 patients noted to have deletion at the time of relapse and in whom we had previous samples stored. In 7 of 8 cases deletions had been acquired (absent in the previous samples). The median OS for relapsed MM patients with or without p53 deletion were 4.2 months and 37.8 months respectively (p &lt;0.001). MDM 2 amplification and p14ARF loss was detected in 0.4% and 2% of new diagnosed MM, 0.6% and 5.1% of relapsed MM and 2% and 29% of HMCLs respectively.
Discussion: Emergence of p53 deletion/mutations denotes progression genetic events in MM. Importantly we show for the first time the overriding importance of p53 deletions as prognostic markers in relapsed MM. A molecular staging system that is based on the presence of p53 inactivation may be more powerful than classifying patients based on the loss of p53. Other abnormalities involving p53 pathway regulators like MDM2 gain and p14ARF loss are infrequent events in MM, even in advanced disease.
Figure 1. Prevalence of p53 deletions Figure 1. Prevalence of p53 deletions
Clinical and Economic Outcomes Following Full or Partial ACCP Recommended Prophylaxis in Cancer Patients at Risk of Venous Thromboembolism
Authors: Amin Alpesh , Lin Jay , Yang Guiping , Stemkowski Steve 
Published: April 2020

Abstract
Background: As hospitalized cancer patients are at high risk of venous thromboembolism (VTE), evidence-based guidelines recommend VTE prophylaxis in this population. However, although VTE prophylaxis is frequently provided to at-risk medical and surgical cancer patients, it often fails to meet the criteria for best practice recommendations. As few data are available on the impact of inappropriate prophylaxis on clinical outcomes, we compare the safety and efficacy of fully appropriate or partially appropriate VTE prophylaxis in cancer patients using data from a large hospital administrative database.
Methods: Discharges from the Premier Perspective database (Jan 02–Dec 06) with a principal diagnosis of cancer, age ≥40 years, length of stay ≥6 days, and receiving some form of VTE prophylaxis, were included in the analysis. Discharges were excluded if they were transferred from another acute care facility or had any contraindications to VTE prophylaxis. Discharges were divided into two groups:
full prophylaxis, receiving ACCP-recommended prophylaxis for a sufficient duration (length of stay minus 2 days; minimum 3 days); partial prophylaxis, receiving some form of prophylaxis that was not recommended by the ACCP guidelines, or receiving a guideline-recommended prophylaxis type, but for an insufficient duration.
VTE, readmission, bleeding, mortality rates, and total hospital costs were collected and compared between groups using multivariate regression modelling.
Results: Among the 83,794 eligible discharges, the full prophylaxis group (n = 13,387, 16%) had a lower in-hospital VTE rate than the partial prophylaxis (n = 70,407, 84%) group (0.8% vs. 2.9%; odds ratio [OR] 3.09, 95% confidence intervals [CI] 2.51–3.80). Similarly, in-hospital mortality rates were lower in the full prophylaxis group (2.6% vs. 4.2%; OR 1.48, 95% CI 1.29–1.69). No major bleeding events were observed in either group, potentially due to the miscoding of these events. The mean total hospital cost was higher for patients receiving partial prophylaxis ($17,128) than full prophylaxis ($15,284).
Conclusion: US cancer patients receiving partial prophylaxis have a higher risk of VTE and mortality than patients receiving full guideline-recommended prophylaxis, leading to a higher total hospital cost. It is important that individual hospitals improve the use of full prophylaxis to reduce both the clinical and economic burden posed by VTE.
Disclosures: Amin: sanofi-aventis: Consultancy, Financial and editorial support for this publication was provided by sanofi-aventis US, Inc., Honoraria. Lin:sanofi-aventis: Employment. Yang:sanofi-aventis: employee of Premier Inc which has received funding to perform this research from sanofi-aventis. Stemkowski:sanofi-aventis: employee of Premier Inc which has received funding to perform this research from sanofi-aventis.
Gamma-Globin Gene Expression in Adult Human Erythroblasts Is Associated with Concurrent Changes in the Nuclear Protein Levels of at Least Seven Transcription Factors.
Authors: Sripichai Orapan , Lee Y. Terry , Tanno Toshihiko , Noh Seung-Jae , Byrnes Colleen , Meier Emily Riehm , Miller Jeffery L 
Published: April 2020

Abstract
Alterations of globin-gene cluster expression mediated through cytokine signal transduction have been previously established. In adult erythroblasts, ex vivo combinatorial signaling from cytokines such as erythropoietin (EPO), stem cell factor (SCF), and transforming growth factor-beta (TGF-B) causes a robust reactivation of fetal hemoglobin. To determine if cytokine-activated expression of fetal hemoglobin significantly alters the transcript and protein abundance of nuclear transcription factors, profiling studies of transcription factor expression were performed. Primary CD34+ cells were cultured as donor-matched pairs using cytokine combinations that produced low vs. high levels of gamma-globin mRNA and fetal hemoglobin (Bhanu et al. Blood, 2005). To identify candidate genes, total RNA from 15 separate healthy volunteer donors was collected and combined into 5 pools. The pooled RNA was labeled and hybridized to Affymetrix HG-U133 Plus 2.0 GeneChips. Informatics strategies were aimed toward identifying differential expression of those transcription factors with binding motif on any of the 10 human globin gene promoter regions (553 transcription factors; 115 binding motif families), versus all transcription factors demonstrating robust expression with changes of at least 3-fold. Combining both strategies, 11 candidate transcription factors were identified (BCL11A, CBFB, EGR-1, ELK-1, HHEX, ID2, MAFF, MNDA, SOX-6, TCF3, and THRB). RNA-based descriptions of gene activity do not necessarily reflect changes in protein levels; therefore, Western analyses were performed. GATA-1 was utilized as a control, since no significant change in GATA-1 mRNA was detected by expression array profiling. Nuclear protein extracts were obtained from 3 additional donors’ CD34+ cells cultured under conditions of low vs. high gamma-globin mRNA synthesis (1.6E+06 ± 3.8E+05 and 1.5E+07 ± 6.3E+06 copies/ng total RNA, respectively). Western blot analysis revealed reproducible and robust differences in protein expression levels for 7 of the 11 candidate transcription factors (EGR-1, ELK-1, HHEX, ID2, MAFF, MNDA, and SOX-6). Two other candidates were expressed below the protein detection limit. GATA-1 and the remaining 2 candidates demonstrated no change in the nuclear protein levels. Among the group with confirmed changes in gene expression, ELK-1 and EGR-1 are downstream targets of the MAP kinase signal transduction cascade. MAFF, ID2, and SOX-6 are known regulators of globin gene expression. The differential expression of HHEX and MNDA warrants further investigation. These data demonstrate that cytokine signal transduction causes changes in the intranuclear levels of at least 7 transcription factors concurrently with activation of gamma-globin gene expression.
Placenta Endothelial Protein 1 Is a Novel Neural Guidance Molecule on Angiogenesis.
Authors: Wang Chieh-Huei , Lin Chia-Yi , Yang Chung-Chi , Chuang Yung- Jen 
Published: April 2020

Abstract
Angiogenic Processes are tightly regulated by guidance molecules for directed blood vessel growth during development and under diseased conditions. Here we report a novel protein, Placenta Endothelial Protein-1 (PEP1), which may participate in the neurovascular interaction and vessel guidance. Identified by SAGE database mining, PEP1 is highly expressed in human placenta vasculatures and is well-conserved among all vertebrates. In silico analysis predicted the potential roles of PEP1 may involve in the cell migration and cell-to-ECM interaction. To investigate the function of PEP1, we altered endogenous PEP1 expression in human umbilical vein endothelial cells (HUVECs) for subsequent angiogenesis assays. Our data indicated overexpression of PEP1 in HUVEC significantly decreased cell motility and tubular formation capability, whereas knockdown of PEP1 in HUVECs resulted in the opposing effects. To characterize PEP1 in vivo, we next examined the physiological roles of zPEP1 (PEP1 ortholog in zebrafish) during zebrafish embryonic development. Real-time quantitative PCR analysis first indicated zPEP1 to express after 16 hours post-fertilization (hpf), which coincides with the start of vascular development. To our surprise, whole mount in situ hybridization showed that zPEP1 was expressed prominently in the neural stem cells of developing nervous system, suggesting PEP1 may function as a neural guidance molecule. By injecting morpholino antisense oligos to knockdown zPEP1 expression in developing embryos, we observed stalled growth of intersegmental vessels, reaffirming the role of PEP1 in regulating angiogenesis. Besides, confocal immunocytochemistry analysis shown a co-localization of PEP1 and paxillin in HUVEC, implying the regulatory effect of PEP1 may enact via the paxillin-dependent signal pathway. Taken together, our study revealed the significant roles of PEP1 in neurovascular interaction and vascular patterning. Future analysis on this novel vessel patterning protein shall shed light on the complex communication network between nervous and vascular systems.
Cell-Driven Angiogenesis and Neurogenesis after Stroke Is Regulated by Platelet’s Microparticles.
Authors: Varon David , Haion Yael , Brill Alexander , Leker Ronen 
Published: April 2020

Abstract
Repair mechanisms based on the proliferation of endogenous cells have been identified in ischemic brain regions suggesting that precursors at the ventricular surface proliferate, migrate to sites of injury and differentiate into neurons. However, this response is significantly limited by short survival times and poor differentiation capacity of these cells. External factors can boost endogenous neural stem cells (eNSC)-dependent repair mechanisms in the cerebral cortex. Upon activation, platelets shed platelet derived microparticles (PMP) which contain a variety of growth factors central to angiogenesis and neurogenesis. We have previously reported a pro angiogenic effect of PMPs, both in vitro and in vivo. We thus hypothesized that the functional benefits obtained from the presence of newborn cells can be further enhanced by increasing the survival rates, migration and differentiation potential of these cells, as well as by promoting angiogenic response, applying PMPs at the site of a stroke. Spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO) and were given BrdU to label newborn cells. Animals were treated with vehicle or PMP delivered via a biodegradable polymer applied to the brain surface. Rats were tested with a neurological severity score and infarct volumes were measured at 90 days post –PMCAO. We used immunohistochemistry to determine the fate of newborn cells and to count blood vessels in the ischemic brain. The results show that PMP treatment led to a dose dependent increase in neurogenesis and angiogenesis at the infarct boundary zone. PMP also significantly improved behavioral deficits without affecting infarct volumes.
Rearranged Infant Acute Lymphoblastic Leukemia.
Authors: Stam Ronald W. , Den Boer Monique L. , Schneider Pauline , de Boer Jasper , Hagelstein Jill , Sallan Stephen E. , Brady Hugh J.M. , Armstrong Scott , Pieters Rob 
Published: April 2020

Abstract
MLL rearranged Acute Lymphoblastic Leukemia (ALL) represents an unfavorable and difficult to treat type of leukemia that often is highly resistant to glucocorticoids like prednisone and dexamethasone. As the response to prednisone largely determines the clinical outcome of pediatric ALL patients, overcoming resistance to these drugs may be an important step towards improved prognosis. Here we compared gene expression profiles between prednisone-resistant and prednisone-sensitive pediatric ALL patients to obtain gene expression signatures associated with prednisone resistance for both childhood (&gt;1 year of age) and MLL rearranged infant (&lt;1 year of age) ALL. Merging both signatures in search for overlapping genes associated with prednisone resistance in both patient groups we, found that elevated expression of MCL-1 (an anti-apoptotic member of the BCL-2 protein family) appeared to be characteristic for both prednisone-resistant ALL samples. To validate this observation, we determined MCL-1 expression using quantitative RT-PCR in a cohort of MLL rearranged infant ALL samples (n=23), and confirm that high-level MCL-1 expression significantly confers glucocorticoid resistance both in vitro and in vivo. Finally, down-regulation of MCL-1 in prednisone resistant MLL rearranged ALL cells by RNA interference (RNAi) markedly sensitized these cells to prednisone. Therefore we conclude that MCL-1 plays an important role in glucocorticoid resistance and that MCL- 1 suppressing agents co-administered during glucocorticoid treatment may be beneficial especially for MLL rearranged infant ALL patients.
Tubacin, An Inhibitor of HDAC6, Induces Apoptosis of Acute Lymphoblastic Leukemia Cells in Vitro and in Vivo through a Na+/K+ATPase-Dependent Pathway.
Authors: Rodriguez-Gonzalez Agustin , Simms-Waldrip Tiffany , Ikeda Alan K. , Lin Tara , Lomenick Brett , Aldana-Masangkay Grace , Mazitschek Ralph , Bradner James , Fu Cecilia , Sakamoto Kathleen M. 
Published: April 2020

Abstract
Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer. Despite effective chemotherapy, 25 to 30% of children will relapse. In adults, less than 30% of patients with ALL are cured. Therefore, it is critical that we identify novel therapies to treat ALL. We are studying the effects of a small molecule compound known as tubacin (tubulin acetylation inducer) that selectively inhibits histone deacetylase 6 (HDAC6) resulting in increased acetylation of alpha-tubulin by inhibiting one of the two catalytic domains of HDAC6. We found that treatment of both pre-B and T-ALL cell lines with tubacin inhibits growth at very low micromolar concentrations (Jurkat IC50=1μM, Loucy IC50=3μM, REH IC50=2μM, Nalm6 IC50=5μM). We also determined that there is a therapeutic window, since tubacin inhibits the growth of normal bone marrow progenitor cells in methylcellulose colony assays at 20μM and normal human lymphocytes cultured in IL-2 at an IC50 of 16μM. We next tested the effects of tubacin in vivo. SCID mice injected with pre-B ALL Nalm-6 cells were treated with tubacin intraperitoneally at 50 mg/kg/day. Preliminary data using bioluminescence imaging in SCID mouse models showed that tubacin inhibited leukemic progression in vivo. To understand the mechanism of tubacin in ALL cells, we examined both apoptosis and cell cycle regulation by PARP cleavage, activation of caspases, and propidium iodide staining with FACs analysis. Tubacin induced apoptosis of pre-B and T-ALL cells within 12 hours of treatment. There was no effect on cell cycle progression, Retinoblastoma protein phosphorylation, or p21 upregulation, which have been observed with other HDAC inhibitors. Unlike in myeloma cells, tubacin did not increase JunK/SAPK activation or accumulation of acetylated HSP90 in ALL cells. Tubacin treatment resulted in accumulation of acetylated alpha-tubulin after 1 hour and an increase in polyubiquitinated proteins after 7 hours. To address potential mechanisms of tubacin in ALL, we tested whether Na+/K+ ATPase could be contributing to apoptosis. Previous work has shown that treatment with L-glutamate dissociates the Na+/K+ ATPase complex from acetylated tubulin and restores ATPase enzymatic activity. We hypothesized that the accumulation of acetylated tubulin could potentially inhibit the activity of the cytosolic Na/K ATPase pump, which could be reversed by treatment with 1mM sodium glutamate. Preliminary data demonstrate that we can partially rescue the effects of tubacin on PARP cleavage with sodium glutamate. These results suggest that tubacin induces apoptosis through a novel pathway in ALL cells and provide rationale for targeting the aggresome pathway to treat ALL in the future.
Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LL) after Frontline Therapy with Hyper-CVAD Regimens.
Authors: Thomas Deborah A. , O’Brien Susan , Rytting Michael , Faderl Stefan , Cortes Jorge , Wierda William G. , Ravandi Farhad , Kantarjian Hagop M 
Published: April 2020

Abstract
AYAs aged 16–20 with de novo ALL or LL have superior outcomes when treated with intensive pediatric regimens; event-free survival (EFS) rates range from 60–70% compared to 30–40% after conventional adult chemotherapy [Stock W, Blood 2008, e-pub]. This is in part attributed to higher dose intensity (and cumulative dose) of the anthracycline, vincristine [VCR], corticosteroid and asparaginase components. Of note, the intensive hyper-CVAD regimen (cyclophosphamide, VCR, doxorubicin, dexamethasone alternating with methotrexate/cytarabine) was originally modeled after childhood therapy for Burkitt lymphoma. It has been applied as frontline adult ALL therapy without age restriction since 1992. In contrast to conventional adult or pediatric ALL regimens, asparaginase is not administered during the induction or consolidation phases. Modifications to the regimen have included the addition of rituximab for CD20 positive precursor B-cell ALL and LL owing to adverse influence of CD20 expression, particularly in the younger subgroup [Thomas D, Blood 2008, e-pub]. An adapted augmented Berlin-Frankfurt- Munster (BFM) regimen modeled after the CCG experience was developed specifically as frontline therapy for adolescents and adults up to age 30 in lieu of the hyper-CVAD regimen at our institution; accrual is ongoing. We reviewed the previous hyper-CVAD experience in the AYA subset. One hundred two pts aged 13 to 21 yrs (median 19 yrs) with de novo ALL (n=92) or LL (n=10) were treated with hyper-CVAD (15 with rituximab). Complete remission (CR) rate was 97%; 3-yr EFS and OS rates were 65% and 70%, respectively. Preliminary reports from other investigators suggest that an intensified pediatric approach may be feasible even up to age 60. The GRAALL-2003 study reported 42-mos EFS and OS rates of 55% and 58%, respectively, in 225 de novo ALL pts aged 15– 60 (median 31 yrs) [Huget F, ASCO 2008, abstr 7005]. Median follow-up was 37 mos. A similar cohort of pts treated with the hyper-CVAD regimens included 385 pts with a slightly older median age of 35 yrs. Median follow-up was 62 mos (range, 1–180 mos). EFS and OS rates for the entire cohort were 50% and 55%, respectively. For pts below the age of 35, these rates improved to 55% and 67%. Clearly age remains a prognostic factor even with intensive chemotherapy approaches. Outcomes with the hyper-CVAD regimens appear to more closely resemble those of the pediatric approaches than the conventional regimens. Continued monitoring of ongoing prospective clinical trials using pediatric regimens in adults is paramount to delineating the optimal approach.
High Dose Cytarabine and Clofarabine (HiDAC → CLOF) in Relapsed or Refractory Acute Myeloid Leukemia, a Phase 2 Trial.
Authors: Powell Bayard , D’Agostino Ralph , Levitan Denise , Ellis Leslie Renee , Lyerly Susan , Skiles Megan , Manuel Megan , Harrelson Robin , Kimbrough Claire , Hurd David Duane 
Published: April 2020

Abstract
High dose cytarabine (HiDAC) is the most effective single agent studied to date for the treatment of acute myeloid leukemia (AML); clofarabine (CLOF) is also an active single agent in AML. Preclinical data suggest synergy between cytarabine and clofarabine. Based on the results of a limited phase 1 trial (Blood2006; 108: 221b), we conducted a phase 2 study of HiDAC (2g/m2 over 3 hours) followed immediately by CLOF (40 mg/m2 infused over 2 hours), given daily for 5 days, in 39 adults with AML in first relapse (n = 27), second relapse (n = 3), or refractory to initial induction chemotherapy (n = 9). Prophylactic intravenous hydrocortisone was incorporated to decrease the occurrence of skin toxicity. Patients with persistent leukemia on day 12–14 (n = 12) received a second course of HiDAC → CLOF for 3 days. The mean age was 53.4 years (range 18.4 – 79.0). Accrual began March 2006 and was completed in July 2008. Thirtyseven of 39 patients are evaluable for response (two patients were treated recently and are not included in this analysis): 14/37 achieved a complete remission (CR), 2/37 a CR with incomplete blood count recovery (CRi) for an overall response (CR or CRi) in 16/37 (43%; 95% CI 27 – 59%). Twelve of 37 (32%) patients had resistant disease, 3/37 (8%) died of complications during marrow aplasia, 5/37 (14%) died of complications of their AML with unknown bone marrow status, and 1/37 (3%) refused further evaluation or treatment. CR or CRi was achieved in 11/25 patients in first relapse, 2/3 in second relapse, and 3/9 with refractory AML. Twelve patients received a second induction – 2/12 (17%) achieved a CR and 1/12 (8%) a CRi. Toxicity data are complete in 36 patients; the most frequent grade 3/4 non-hematologic toxicities were transient elevations of AST/ALT observed in 23/36 (64%) patients, hyperbilirubinemia in 8/36 (22%), infection in 16/36 (44%), and rash in 8/36 (22%). Patients who achieved CR or CRi received up to 3 additional courses of HiDAC → CLOF each daily for 5 days. Twenty-seven of 39 (69%) patients have died with a median survival of 119 days (95% CI 71 – 322 days). In summary, HiDAC → CLOF is a very active combination in adults with relapsed and refractory AML, a group in whom CR/CRi rates of 30–35% are achieved with many salvage regimens. Toxicities are comparable to other salvage regimens with transient elevations in transaminases identified as the most frequent toxicity.