bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Significance of BCL6 Translocation in Diffuse Large B-Cell Lymphoma Patients Treated with R-CHOP
Authors: Shustik Jesse , Steidl Christian , Sehn Laurie , Gascoyne Randy D 
Published: October 2019

Abstract
Translocation of the BCL6 oncogene is the most commonly-detected chromosomal abnormality in diffuse large B-cell lymphoma (DLBCL), but its prognostic significance remains uncertain. BCL6 translocation has been associated with variable outcomes in prior clinical series, and its clinical impact has not been reevaluated since the introduction of rituximab (R). The objective of this study was to determine the prognostic value of BCL6 translocation in DLBCL patients treated with both CHOP and R-CHOP immunochemotherapy.
Methods We included 163 DLBCL patients treated with CHOP (n=72) or R-CHOP (n=73) at the British Columbia Cancer Agency between the years 1999–2002. Formalin-fixed paraffin-embedded diagnostic lymph node specimens were analyzed for BCL6 translocation on tissue microarray (TMA) by fluorescence in situ hybridization (FISH), using commercially available dual-color break-apart probes (Abbott Molecular, IL, USA). Immunohistochemical analysis was performed for BCL6, CD10, and MUM1 expression, and cases were categorized as germinal centre B-cell-like (GCB) or non-GCB using a standard algorithm (Hans, Blood 2004).
Results BCL6 translocation status was evaluable in 145 cases, and was positive (BCL6+) in 26% (37/145). Median age (65 vs. 59 years, p=0.03) and overall IPI score (p=0.03) were higher in the BCL6+ than in the BCL6− subgroup. Presence of BCL6 translocation correlated with non-GCB phenotype by immunohistochemical analysis (p=0.03), and showed no significant association with BCL6 protein expression (p=0.32). Median follow-up duration was 4.8 years (range, 0.1–8.4). BCL6 translocation was associated with a trend toward decreased overall survival (OS) among patients treated with R-CHOP (5-year OS 46.7% vs. 68%, p=0.098), though not among CHOP-treated patients (5-year OS 36.4% vs.49.5%, p=0.393). Kaplan-Meier analysis limited to the BCL6+ subgroup showed no overall survival difference between patients treated with CHOP and R-CHOP (p=0.67).
Conclusions BCL6 translocations are found in approximately 25% of patients with de novo DLBCL. Presence of BCL6 translocation appears to predict unfavorable outcome in DLBCL patients treated with R-CHOP. However, the adverse prognostic impact of BCL6 translocation is confounded by an association with high IPI score and with non-GCB phenotype. Prospective analysis within large clinical trials would help to determine the independent prognostic value of this marker in the rituximab era.
High-Throughput RNA Interference Screening Identifies Synthetic Lethality Between Oncogenic KRAS Dependency and Suppression of STK33
Authors: Scholl Claudia , Frohling Stefan , Dunn Ian F. , Barbie David A. , Schinzel Anna C. , Kim So Young , Silver Serena J. , Bullinger Lars , Sandy Peter , Boehm Jesse S. , Root David E. , Jacks Tyler , Hahn William C. , Gilliland D. Gary 
Published: October 2019

Abstract
Activating RAS mutations are among the most common pathogenetic events in a broad spectrum of hematologic malignancies and epithelial tumors. However, oncogenic RAS has thus far not proven to be a tractable target for therapeutic intervention. An alternative to direct targeting of known oncogenes is to perform “synthetic lethality” screens to identify genes that are selectively required for cell viability in the context of specific cancer-causing mutations. Using this approach, we have discovered a synthetic lethal interaction between mutant KRAS, the most frequently mutated oncogene in human cancer, and inactivation of the gene encoding the STK33 serine/threonine protein kinase. To identify genes that are essential for cell viability in the context of mutant KRAS, we performed high-throughput loss-of-function RNA interference (RNAi) screens in eight human cancer cell lines (mutant KRAS, n=4; wildtype KRAS, n=4), representing seven different tumor types (acute myeloid leukemia, multiple myeloma, colon cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma), as well as normal human fibroblasts and mammary epithelial cells. We screened each cell line with a subset of the short hairpin RNA (shRNA) library developed by the RNAi Consortium (http://www.broad.mit.edu/genome_bio/trc/rnai.html) that consists of 5,024 individual shRNA constructs targeting 1,011 human genes, including the majority of known and putative protein kinase and phosphatase genes and a selection of known cancer-related genes. In these cell lines, suppression of STK33 preferentially inhibited the viability and proliferation of cells that were dependent on mutant KRAS. The differential requirement for STK33 based on oncogenic KRAS dependency was confirmed in 16 additional cell lines using in vitro transformation assays and human tumor xenograft models. Biochemical analyses support the hypothesis that STK33 promotes cell growth and survival in a kinase activity-dependent manner by regulating the activity of S6K1 as well as BAD-induced apoptosis selectively in mutant KRAS-dependent cells. Notably, molecular genetic characterization of cancer cell lines and analysis of patient-derived genomic data sets indicate that STK33 is not frequently mutated or overexpressed in human tumors. These observations identify STK33 as a potential target for the treatment of mutant KRAS-driven cancers that may have a broad therapeutic index in normal versus malignant cells, and illustrate the potential of RNAi for discovering critical functional dependencies created by oncogenic mutations that cannot be identified using other genomic technologies.
Recruitment of the SWI/SNF Chromatin Remodeling Complex by NFATc1 in the Transcriptional Regulation of the C-MYC Oncogene in Aggressive B-Cell Lymphomas
Authors: Pham Lan V. , Tamayo Archito , Zhou Hai-Jun , Lin-Lee Yen-Chiu , Fu Lingchen , Ford Richard J. 
Published: October 2019

Abstract
The NFAT (nuclear factor of activated T-cells) family of transcription factors functions as integrators of multiple signaling pathways by binding to chromatin in combination with other transcription factors and coactivators to regulate genes central for cell growth and survival in hematopoietic cells. Recent experimental evidence has implicated the calcineurin/NFAT signaling pathway for involvement in the pathogenesis of various malignancies, including large B-cell lymphoma (LBCL), a non-Hodgkin’s lymphoma subgroup that is generally responsive to conventional cancer therapies (R-CHOP), but relapse is common that subsequently leads to therapeutic resistance. Although we have shown previously that NFAT family member NFATc1 is constitutively activated and has the ability to maintain cell growth and survival in LBCL cell lines and primary cells, the molecular mechanism(s) underlying how NFATc1 regulates cell growth and survival in LBCL is still unclear. In this study, we demonstrate that the well-known oncogene c-myc is transcriptionally regulated by the transcription factor NFATc1 in LBCL, through a chromatin remodeling mechanism that involves the recruitment of the SWI/SNF chromatin-remodeling complex. In aggressive B-cell lymphoma cell lines, c-myc oncogene protein expression was shown to correlate with NFATc1 protein expression. We further showed that NFATc1 binds to a specific DNA binding element within the proximal c-myc promoter and up-regulates c-myc transcription. The SWI/SNF proteins Brg-1 and Brm, chromatin-remodeling proteins that utilize ATP hydrolysis for energy to modify chromatin structure in order to regulate gene expression, also were shown to bind to the NFAT binding site on the c-myc promoter. Confocal microscopic analysis showed that NFATc1 colocalizes with Brg-1, and co-immunoprecipitation assays showed that Brg-1 interacts with NFATc1. Both proteins interact with the c-myc promoter within the NFAT binding site, as demonstrated by chromatin-immunoprecipitation (ChIP) analysis. Induction of a constitutively active mutant of NFATc1 (caNFATc1) in an NFATc1 negative lymphoma cell line induces c-myc protein expression. Constitutively active NFATc1 also enhances Brg-1 binding to the c-myc promoter when analyzed by ChIP-qPCR assays, suggesting that NFATc1 recruits Brg-1 to the NFAT binding site in the c-myc promoter. Down-regulation of NFATc1 by chemical inhibitors (FK-506) or by validated shRNA of NFATc1, inhibited c-myc protein expression and in-vitro lymphoma cell growth. Our data indicates a novel control mechanism for the transcriptional regulation of c-myc in the pathophysiology of aggressive lymphoma B cells and suggests that targeting NFATc1 could have therapeutic value.
The HMGA1a-STAT3 axis: an “Achilles Heel” for Hematopoietic Malignancies Overexpressing HMGA1a?
Authors: Resar Linda , Hillion Joelle , Dhara Surajit , Sumter Takita Felder , Mukherjee Mita , Di Cello Francescopaolo , Belton Amy , Turkson James , Jaganathan Souyma , Cheng Linzhao , Ye Zhaohui , Lin Yingwei , Aplan Peter D. , Jove Richard , Kowalski Jeanne , Wertzler Kelsey , Reeves Ray , Elbahlouh Ossama , Bhattacharya Raka 
Published: October 2019

Abstract
Although the high mobility group A1 (HMGA1) oncogene is widely overexpressed in high-risk hematopoietic malignancies and other aggressive cancers, the molecular mechanisms underlying transformation by HMGA1 are only beginning to emerge. The HMGA1 gene encodes the HMGA1a and HMGA1b protein isoforms, which function in regulating gene expression. We showed that HMGA1 induces leukemic transformation in cultured human lymphoid cells. Inhibiting HMGA1 expression blocks the transformed phenotype in cultured human leukemia and lymphoma cells. We also engineered HMGA1a transgenic mice and all mice develop aggressive lymphoid malignancy which closely models human T-cell acute lymphoblastic leukemia. Because HMGA1 participates in transcriptional regulation, we hypothesize that it drives leukemic transformation by dysregulating specific molecular pathways. To discover genes targeted by HMGA1 in leukemic transformation, we performed gene expression profile analysis. The signaltransducer andactivator oftranscription 3 (STAT3) gene was identified as a critical downstream target of HMGA1. STAT3 mRNA and protein are up-regulated in leukemic cells overexpressing HMGA1a and activated STAT3 recapitulates the transforming activity of HMGA1a. HMGA1a binds directly to a conserved region of the STAT3 promoter in vivo and activates transcription of the STAT3 promoter in human leukemia cells. Blocking STAT3 function with a small molecule, platinum compound inhibitor (CPA-7) induces apoptosis in leukemic cells from HMGA1 transgenic mice, but not in control cells. In primary, human leukemia samples, there is a positive correlation between HMGA1a and STAT3 mRNA. Moreover, blocking STAT3 function with a dominant-negative construct in human leukemia or lymphoma cells leads to decreased cellular motility and colony formation. We also showed that treatment with a small molecule, oligonucleotide inhibitor decreases the leukemic burden in the HMGA1a transgenic mice. Our results demonstrate that the HMGA1a-STAT3 axis is a potential “Achilles heel” that could be exploited therapeutically in selected hematopoietic malignancies.
Independent Risk Factors of Catheter-Related Thrombosis (CRT) in Adult Cancer Patients: An Individual Patient-Level Data (IPD) Meta-Analysis of Randomized Clinical Trials and Prospective Cohort Studies
Authors: Saber Wael , Moua Teng , Williams Eliot C. , Verso Melina , Agnelli Giancarlo , Couban Stephen , Young Annie , De Cicco Marcello , Biffi Roberto , van Rooden Cornelis J. , Huisman Menno V. , Fagnani Daniele , Cimminiello Claudio , Moia Marco , Povoski Stephen P. , Malak Sharp , Lee Agnes Y. 
Published: October 2019

Abstract
Purpose: Symptomatic catheter-related thrombosis (CRT) complicates roughly 5% of central venous catheter insertions in cancer patients. Recent studies have failed to show a reduction in CRT with routine use of pharmacologic thromboprophylaxis in all patients. We conducted a meta-analysis of individual patient-level data to identify independent, baseline risk factors of CRT that may help to select high-risk patients for prophylaxis.
Methods: PubMed, EMBASE, CINAHL, CENTRAL, DARE, Grey literature databases were searched in all languages from 1995–2008. Only prospective studies and randomized controlled trials (RCTs) were included. The primary end-point was objectively confirmed symptomatic and asymptomatic CRT. Multivariate logistic regression analysis of 17 prespecified baseline characteristics was conducted. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated.
Results: A total sample of 5636 subjects from 5 RCTs and 7 prospective studies was included in the analysis. Among these subjects, 425 CRT events were observed (8%). In multivariate logistic regression, the use of implanted ports as compared with peripherally implanted central venous catheters (PICC), decreased CRT risk (OR = 0.43; 95% CI, 0.23–0.80). Alternatively, past history of deep vein thrombosis (DVT) (OR = 2.03; 95% CI, 1.05–3.92), subclavian venipuncture insertion technique (OR = 2.16; 95% CI, 1.07–4.34), and improper catheter tip location (OR = 1.92; 95% CI, 1.22–3.02), increased CRT risk.
Conclusions: CRT risk is increased with using PICC catheters, previous history of DVT, subclavian venipuncture insertion technique and improper positioning of the catheter tip. These factors may be useful for risk stratifying patients to select those for thromboprophylaxis. Prospective studies are needed to validate these findings.
Platelets Protect Tumors from Hemorrhage Induced by Stroma-Infiltrating Leukocytes
Authors: Ho-Tin-Noe Benoit H , Carbo Carla , Demers Melanie , Cifuni Stephen M , Goerge Tobias , Wagner Denisa D. 
Published: October 2019

Abstract
In a recent study, we showed that platelets are crucial regulators of tumor vascular homeostasis in that they continuously prevent tumor hemorrhage through secretion of their granules. However, it remains unclear what platelets target to prevent tumor bleeding. Tumors are associated with inflammation, a cause of hemorrhage in thrombocytopenia. We hypothesized that platelets protect tumors from vascular damages induced by infiltrating inflammatory cells. Here, we report that thrombocytopenia-induced tumor hemorrhage preferentially occurs at the periphery of tumors, where massive accumulation of monocytes/macrophages and neutrophils was revealed by tumor histology. To further investigate the role of tumor-infiltrating leukocytes in the induction of tumor hemorrhage in thrombocytopenic mice, we used genetically-engineered mice with a deficiency in either beta2 or beta3 integrins, or in integrin activation. We show that these mice have decreased leukocyte infiltration in the tumor stroma and are protected from thrombocytopenia-induced tumor hemorrhage. Using a model of TNFa-induced skin inflammation, we demonstrate that releasates from collagen- and thrombin-stimulated platelets inhibit neutrophil-induced vascular damage. Our results show that platelets protect tumors from vascular leakage induced by infiltrating leukocytes and that releasate from activated platelets has potent in vivo healing properties needed after leukocyte transmigration.
Non-Redundant Roles for an Epo/EpoR/STAT5 Regulated Intracellular Serpin, Serpina-3G, during Epo- and Anemia- Induced Erythropoiesis
Authors: Dev Arvind , Fang Jing , McCrann Don , Emerson Christine , Pradeep Anamika , Browne Sarah , Ashton-Rickardt Philip , Wojchowski Don M. 
Published: October 2019

Abstract
Interest in advancing a more sophisticated knowledge of EPOR action mechanisms remains intense based on the emergence of novel ESAs; cytoprotective effects of EPO and ESAs in ischemically injured tissues; and adverse effects of EPO on cancer progression. By employing primary bone marrow erythroblasts and global transcriptome analyses, we recently have discovered several previously undescribed EPO/EPOR response factors that regulate erythroid progenitor cell development. These include Cyclin-G2, the pseudokinase Tribbles-3 (TRB3), and a strongly EPO-induced intracellular serpin, Serpina-3G (S3G). Here we report on EPOR- mediated routes to S3G expression, and on phenotypes resulting from S3G’s reinforced, or disrupted expression. As determined using early-stage erythroid progenitors with minimal knocked-in EPOR alleles, S3G expression proved to depend upon an EPOR-PY343/STAT5 axis. At the protein level, S3G was cytoplasmically retained (as was S3G-flag in stably transduced G1E2 cells, and in transgenic Gata1-IE3.9int-S3G mice). Ectopic expression of S3G further revealed advantaged expansion capacities. To critically assess S3G’s function, S3G knock-out mice were prepared. Consistent with a hypothesis that S3G might affect erythropoiesis selectively during anemia, BFUe, CFUe and red cell levels in S3G-null mice at steady-state were not significantly perturbed. However, S3G’s deletion markedly impaired erythropoiesis during hemolytic anemia, and inhibited EPO- induced erythropoiesis per se. In particular, hematocrits during anemia in S3G-null mice fell to 23.0 +/− 2.2% as compared to 38.7 +/− 1.8% for S3G+/+ controls. In response to EPO, an increase in hematocrit of only 1.75 +/− 0.2% was exhibited for S3G-null mice as compared to 4.9 +/− 0.5% for S3G+/+ controls. Investigations therefore establish S3G as an important non-redundant mediator of EPO- and anemia- induced erythropoiesis. They also raise interesting new questions concerning the nature of S3G’s action pathways, and S3G’s candidate pro-erythroblast intrinsic target protease.
Sequencing Acute Myeloid Leukemia Genomes with “Next Generation” Technologies.
Authors: Mardis Elaine , Ley Timothy J. , Wilson Richard K. 
Published: October 2019

Abstract
For most patients with a sporadic presentation of acute myeloid leukemia (AML), neither the initiating nor the progression mutations responsible for disease are known. Recent attempts to identify key mutations with directed sequencing approaches, or with array-based genomic studies, have had limited success, suggesting that unbiased whole genome sequencing approaches may be required to identify most of the mutations responsible for AML pathogenesis. Until recently, whole genome sequencing has been impractical due to the high cost of conventional capillary-based sequencing and the large numbers of enriched primary tumor cells required to yield the necessary genomic DNA for library preparation. “Next Generation” sequencing approaches have changed this landscape dramatically. Using the Solexa/Illumina platform, we have now sequenced the genomic DNA of highly enriched tumor cells and normal skin cells obtained from a carefully selected patient with a typical presentation of FAB M1 AML. We obtained 98.2 billion bases of sequences from the cytogenetically normal tumor cell genome (32.7 fold haploid coverage), and 41.8 billion bases of sequence from the normal skin genome (13.9 fold coverage). Using these data, we detected diploid sequence coverage of 91% of 46,320 heterozygous SNPs, defined in the tumor genome (by array-based genotyping), and 83% diploid coverage of the skin genome. Of 2,647,695 well-supported single nucleotide variants in the tumor genome, 2,588,486 (97.7%) were also detected in the patient’s skin genome, defining them as inherited. From the remaining variants, 8 have been fully validated as somatic mutations by conventional capillary sequencing using PCR-generated amplicons. We also detected somatic mutations in the FLT3 (ITD) and NPM1 genes (a classic NPMc mutation). Based on deep read-count data of the novel variants on a 454 sequencer, we hypothesize that all of the mutations are in virtually all of the tumor cells, and all were retained at relapse 11 months later, suggesting that a single dominant clone contained all of the mutations. None of the novel mutations has previously been detected in AML cases (and none were found in any of 187 additional AML cases studied here). A number of additional potential somatic mutations in regions lying near genes (but not altering coding sequences) are currently being validated and tested for recurrence in other AML samples. Whole genome sequencing of a second M1 AML genome is now underway. These results demonstrate the power of unbiased whole genome sequencing approaches to discover cancer-associated mutations in novel candidate genes.
Immuno-Chemotherapy with Rituximab, Methotrexate, Lomustine, and Procarbazine for the Treatment of Primary CNS Lymphoma in Patients >65 Years.
Authors: Fritsch Kristina , Kasenda Benjamin , Markert Anna , Finke Jürgen , Illerhaus Gerald 
Published: October 2019

Abstract
Abstract 3712
Poster Board III-648

Introduction
Primary central nervous system lymphoma (PCNSL) is an aggressive extranodal non-Hodgkin lymphoma (NHL) confined to the CNS and/or eyes at presentation. PCNSL have a poor prognosis dispite good initial response to steroids and whole brain irradiation (WBRT). Addition of high-dose methotrexate (MTX) to therapy has improved the prognosis of patients with PCNSL, resulting in median survival rates of up to 60 months (mo). However, most patients eventually relapse. Surviving patients, particularly elderly treated with combined radio-chemotherapy are at substantial risk of developing leukoencephalopathy. We developed a protocol with high-dose MTX combined with the lipophilic alkylating agents procarbacine and lomustine and the anti-CD20 monoclonal antibody rituximab (R-MPL protocol), especially adapted for elderly patients with PCNSL. Here we report the results of 28 patients treated with combined immuno-chemotherapy with R-MPL protocol within a monocentric study.

Methods
Patients ≥65 yrs with PCNSL were treated with up to 3 cycles of R-MPL protocol: rituximab (375mg/m2 d-6, 1, 15, 29), MTX (3g/m2 d2, 16, 30), procarbazine (60 mg/m2 p.o., d1-10) and lomustine (110 mg/m2 p.o., d1). Cycles were repeated d42. Inclusion criterias were age ≥65 yrs and biopsy proven PCNSL. There was no lower limit of Karnofsky Performance Score.

Results
28 patients (median age 75 yrs., range 65-83 yrs.) received R-MPL protocol. 2 patients died, one due to pulmonary embolism 2 weeks after initiation of treatment, the other had a perforation of the sigmoid and both were not evaluable for response. Objective response was seen in 25 of 26 patients (96,2%) with 19 CR and 6 PR. In 5 patients, MTX was not tolerated after 1 (n=4) and 2 (n=1) applications due to cholestatic hepatitis (n=1) and renal impairment (n=4). 2 patients with refractory disease could successfully be salvaged with AraC/thiotepa (n=1) and HDT and ASCT (n=1), respectively. 5 patients experienced relapse and could not be salvaged. After a median follow-up of 26 mo (range 2-35) 10 patients (35,7 %) are alive and disease-free. By intend-to-treat-analysis the 12-mo and 24-mo is 69% and 52% respectively. Severe leukoencephalopathy has not been observed. Most recent follow-up data will be presented in detail.

Conclusion
The immuno-chemotherapy protocol presented here is safe and shows high efficacy in treating elderly patients with PCNSL. A prospective phase-II trial will be initiated.

Disclosures:
No relevant conflicts of interest to declare.