ABSTRACT
CNS prophylaxis is commonly used in Diffuse Large B-Cell Lymphoma (DLBCL) patients with risk features for CNS relapse. This systematic review and meta-analysis compares CNS relapse rates with and without CNS prophylaxis, for patients at intermediate to high CNS relapse risk. Studies reporting CNS relapse risk category and CNS outcomes with and without CNS prophylaxis for antiCD20-CHOP treated DLBCL patients were included. 10 studies with 3770 patients at intermediate to high CNS relapse risk were analyzed. No significant difference in the pooled Absolute Risk Difference (ARD 0.01, 95 % CI -0.01 to 0.02, P = 0.61) or Risk (RR 1.22, 95 % CI 0.81-1.83, P = 0.34) was noted in patients with and without CNS prophylaxis. There were also no differences within pre-specified subgroups of IV Methotrexate or IT chemotherapy. However, the quality of evidence supporting these observations was low. A meta-analysis of individual patient data will help evaluate the benefit of CNS prophylaxis strategies.
Subject(s)
Central Nervous System Neoplasms , Lymphoma, Large B-Cell, Diffuse , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/prevention & control , Cyclophosphamide , Doxorubicin , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Neoplasm Recurrence, Local , Prednisone/therapeutic use , Rituximab/therapeutic use , Vincristine/therapeutic useSubject(s)
Epstein-Barr Virus Infections/complications , Herpesvirus 4, Human/isolation & purification , Lymphohistiocytosis, Hemophagocytic/etiology , Acute Disease , Adult , Asian People , Bone Marrow/pathology , Epstein-Barr Virus Infections/diagnosis , Female , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosisABSTRACT
ChIP-seq performed on lymphoblastoid cell lines (LCLs), expressing epitope-tagged EBNA3A, EBNA3B or EBNA3C from EBV-recombinants, revealed important principles of EBNA3 binding to chromatin. When combined with global chromatin looping data, EBNA3-bound loci were found to have a singular character, each directly associating with either EBNA3-repressed or EBNA3-activated genes, but not with both. EBNA3A and EBNA3C showed significant association with repressed and activated genes. Significant direct association for EBNA3B loci could only be shown with EBNA3B-repressed genes. A comparison of EBNA3 binding sites with known transcription factor binding sites in LCL GM12878 revealed substantial co-localization of EBNA3s with RUNX3-a protein induced by EBV during B cell transformation. The beta-subunit of core binding factor (CBFß), that heterodimerizes with RUNX3, could co-immunoprecipitate robustly EBNA3B and EBNA3C, but only weakly EBNA3A. Depletion of either RUNX3 or CBFß with lentivirus-delivered shRNA impaired epitope-tagged EBNA3B and EBNA3C binding at multiple regulated gene loci, indicating a requirement for CBF heterodimers in EBNA3 recruitment during target-gene regulation. ShRNA-mediated depletion of CBFß in an EBNA3C-conditional LCL confirmed the role of CBF in the regulation of EBNA3C-induced and -repressed genes. These results reveal an important role for RUNX3/CBF during B cell transformation and EBV latency that was hitherto unexplored.
Subject(s)
Core Binding Factors/metabolism , Epstein-Barr Virus Nuclear Antigens/metabolism , Gene Expression Regulation , Binding Sites , Cell Line , Chromatin/chemistry , Chromatin/metabolism , Chromatin Immunoprecipitation , Core Binding Factor Alpha 3 Subunit/metabolism , Core Binding Factor Alpha 3 Subunit/physiology , Core Binding Factor beta Subunit/metabolism , Core Binding Factors/physiology , Enhancer Elements, Genetic , Genome, Human , Humans , Transcription Factors/metabolism , Transcription Initiation SiteABSTRACT
OBJECTIVE: This study surveyed all UK medical schools regarding their Bachelor of Medicine (MB), Doctor of Philosophy (PhD) (MB/PhD) training policy in order to map the current training landscape and to provide evidence for further research and policy development. SETTING: Deans of all UK medical schools registered with the Medical Schools Council were invited to participate in this survey electronically. PRIMARY: The number of medical schools that operate institutional MB/PhD programmes or permit self-directed student PhD intercalation. SECONDARY: Medical school recruitment procedures and attitudes to policy guidance. FINDINGS: 27 of 33 (81%) registered UK medical schools responded. Four (14%) offer an institutional MB/PhD programme. However, of those without institutional programmes, 17 (73%) permit study interruption and PhD intercalation: two do not (one of whom had discontinued their programme in 2013), three were unsure and one failed to answer the question. Regarding student eligibility, respondents cited high academic achievement in medical studies and a bachelor's or master's degree. Of the Medical schools without institutional MB/PhD programmes, 5 (21%) have intentions to establish a programme, 8 (34%) do not and 3 were unsure, seven did not answer. 19 medical schools (70%) considered national guidelines are needed for future MB/PhD programme development. CONCLUSIONS: We report the first national survey of MB/PhD training in the UK. Four medical schools have operational institutional MB/PhD programmes, with a further five intending to establish one. Most medical schools permit study interruption and PhD intercalation. The total number MB/PhD students yet to graduate from medical school could exceed 150, with 30 graduating per year. A majority of medical school respondents to this survey believe national guidelines are required for MB/PhD programme development and implementation. Further research should focus on the MB/PhD student experience. Discussion regarding local and national MB/PhD policies between medical schools and academic stakeholders are needed.
