19 research outputs found
Burkitt lymphoma classification and MYC-associated non-Burkitt lymphoma investigation based on gene expression
No full textBurkitt lymphoma and diffuse large B-cell lymphoma are two closely related types of lymphoma that are managed differently in clinical practice and the accurate diagnosis is a key point in treatment decisions. However based on current criteria combined with morphological, immunophenotypic and genetic characteristics, a significant number of cases exhibit overlapping features where diagnosis and treatment decisions are difficult to make. Especially, the prognosis have been reported significantly unfavourable in a subset of cases that are initially diagnosed as diffuse large B-cell lymphoma but bear MYC gene translocation, which is a defining feature of Burkitt lymphoma however can also be found in other lymphomas. Despite the adverse effect of MYC in aggressive lymphomas other than Burkitt lymphoma, the underlying mechanism and effective treatment is still unclear.
Recent technological advances have made it possible to simultaneously investigate an enormous number of bio-molecules, and the scientific fields associated with measuring molecular data in such a high-throughput way are usually called “omics”. For example, genomics assesses thousands of DNA sequences and transcriptomics assays large numbers of transcripts in a single experiment. These techniques together with the rapidly emerging analytical methods in bioinformatics have introduced cancer research into a new era. The growing amount of omics data have significantly influenced the understanding of lymphomas and hold great promise in classifying subtypes, predicting treatment responses that will eventually lead to personalized therapy.
Here in this study, we investigate the discrimination of Burkitt lymphoma and diffuse large B-cell lymphoma based on DNA microarray gene expression data, which has contributed most in molecular classification of lymphoma subtypes in the last decade. On the basis of two previous research level gene expression profiling classifiers, we developed a robust classifier that works effectively on different platforms and formalin fixed paraffin-embedded samples commonly used in routine clinic. The validation of the classifier on the samples from clinical patients achieves a high agreement with diagnosis made in a central haematopathology laboratory, and leads to a potential outcome indication in the patients presenting intermediate features. In addition, we explore the role of MYC in the above lymphomas. Our investigation emphasizes the inferior impact of high level MYC mRNA expression on patients’ outcome, and the functional analysis of MYC high expression associated genes show significantly enriched molecular mechanisms of proliferation and metabolic process. Moreover, the gene PRMT5 is found to be highly correlated with MYC expression which opens a possible therapeutic target for the treatment
Comparative analysis of gene expression platforms for cell‐of‐origin classification of diffuse large B‐cell lymphoma shows high concordance
No full textCell‐of‐origin subclassification of diffuse large B cell lymphoma (DLBCL) into activated B cell‐like (ABC), germinal centre B cell‐like (GCB) and unclassified (UNC) or type III by gene expression profiling is recommended in the latest update of the World Health Organization’s classification of lymphoid neoplasms. There is, however, no accepted gold standard method or dataset for this classification. Here, we compare classification results using gene expression data for 68 formalin‐fixed paraffin‐embedded DLBCL samples measured on four different gene expression platforms (Illumina wG‐DASLTM arrays, Affymetrix PrimeView arrays, Illumina TrueSeq RNA sequencing and the HTG EdgeSeq DLBCL Cell of Origin Assay EU using an established platform agnostic classification algorithm (DAC) and the classifier native to the HTG platform, which is CE marked for in vitro diagnostic use (CE‐IVD). Classification methods and platforms show a high level of concordance, with agreement in at least 80% of cases and rising to much higher levels for classifications of high confidence. Our results demonstrate that cell‐of‐origin classification by gene expression profiling on different platforms is robust, and that the use of the confidence value alongside the classification result is important in clinical applications
Differential Efficacy From the Addition of Bortezomib to R-CHOP in Diffuse Large B-Cell Lymphoma According to the Molecular Subgroup in the REMoDL-B Study With a 5-Year Follow-Up.
No full textClinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The REMoDL-B phase III adaptive trial compared rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) versus R-CHOP + bortezomib (RB-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL), stratified by molecular subtype. Primary analysis at a median follow-up of 30 months found no effect of bortezomib on progression-free survival (PFS) or overall survival (OS). Retrospective analysis using a gene expression-based classifier identified a molecular high-grade (MHG) group with worse outcomes. We present an updated analysis for patients successfully classified by the gene expression profile (GEP). Eligible patients were age older than 18 years with untreated DLBCL, fit enough for full-dose chemotherapy, and with adequate biopsies for GEP. Of 1,077 patients registered, 801 were identified with Activated B-Cell (ABC), Germinal Center B-cell, or MHG lymphoma. At a median follow-up of 64 months, there was no overall benefit of bortezomib on PFS or OS (5-year PFS hazard ratio [HR], 0.81; P = .085; OS HR, 0.86; P = .32). However, improved PFS and OS were seen in ABC lymphomas after RB-CHOP: 5-year OS 67% with R-CHOP versus 80% with RB-CHOP (HR, 0.58; 95% CI, 0.35 to 0.95; P = .032). Five-year PFS was higher in MHG lymphomas: 29% versus 55% (HR, 0.46; 95% CI, 0.26 to 0.84). Patients with ABC and MHG DLBCL may benefit from the addition of bortezomib to R-CHOP in initial therapy
The Perception of Chinese SMEs in the Apparel Industry about Incorporating CSC9000T into their Business Agenda
No full textCorporate Social Responsibility (CSR) has been discussed widely from developed countries to developing countries. Social responsibility is an old idea but a new term in China. Although there are numerous international CSR accountability standards around the world, in 2005, the China National Textile & Apparel Council (CNTAC) issued a new guideline, the China Social Compliance 9000 for the Textile & Apparel Industry (CSC9000T). CSC9000T implementation was scaled-up from ten pilot large size enterprises to a thousand Small and Medium size Enterprises (SMEs) in 2007.
This paper focuses on the perception of Chinese apparel SMEs about incorporating CSC9000T into their strategic planning. My research explores how the CSR agenda has been implemented using CSC9000T as a guideline and what benefits and challenges SMEs have faced when implementing CSC9000T. I begin with a literature review of five areas: the understanding of CSR and its relevant theories and practices; CSR and strategic management; the development of the Textile and Apparel Industry in China; and the relevant Chinese CSR policies and regulations. Based on Castak et al’s CSR framework and Vogel’s promoting CSR with government intervention and regulation, this paper discusses the implementation of CSC9000T in SMEs in China. The author discusses SMEs’ difficulties and benefits of taking CSR initiatives and implementing CSC9000T. Some practical recommendations in terms of improving SMEs’ CSR performance are also proposed to CNTAC, the Chinese government and related enterprises
Gene expression profiling in an open-label randomised phase 3 trial (REMoDL-B) of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma
No full textBackground: Biologically distinct sub-types of diffuse large B-cell lymphoma (DLBCL) can be identified using gene expression analysis to determine their cell of origin (COO), corresponding to germinal centre (GCB) or activated B‐cells (ABC). This study investigated whether adding bortezomib(B) to standard therapy could improve outcomes in these subtypes.Methods: The REMoDL-B trial is an open-label adaptive two-stage randomised controlled trial at 107 centres in the United Kingdom and Switzerland. Eligible patients (pts) had previously untreated, histologically confirmed DLBCL with sufficient diagnostic material for gene expression profiling and pathology review; age 18 years or older; Eastern Cooperative Oncology Group performance status of ≤2; bulky stage I or stage II-IV requiring full course chemotherapy; measurable disease, and cardiac, lung, renal and liver function sufficient to tolerate chemotherapy. Pts initially received 1 cycle of standard R‐CHOP. During this time, gene expression profiling by whole genome cDNA-mediated annealing, selection, extension and ligation assay was performed on routine diagnostic biopsy material. Patients were then centrally assigned (1:1) via a web-based system, with block randomisation stratified by international prognostic index and COO subtype to continue R‐CHOP +/‐ bortezomib (1.3 mg/m2 IV or 1.6 mg/m2 SC) days 1+8 for cycles 2‐6. The primary endpoint was 30 month progression‐free survival (PFS) for the GCB + ABC population. The primary analysis was intention-to-treat. The safety population consisted of all participants who received at least one dose of study drug. The study was registered at ClinicalTrials.gov: NCT01324596. We report the PFS and safety outcomes for patients in the follow-up phase after the required number of events occurred. Recruitment and treatment has completed for all participants, with long-term follow-up continuingFindings: Between June 2011 and June 2015, 1128 eligible pts were registered and a total of 918 randomised. There was no evidence for a difference in PFS in the combined GCB + ABC population between R‐CHOP (N=361)and RB‐CHOP (N=358) (30 month PFS: 70.6% vs 75.2% respectively) adjusted HR = 0.82, 95% CI 0.63 - 1.08; P=0.16. The most common Grade ≥3 adverse event experienced was haematological toxicity, with 178 (39.8%) and 187 (42.1%) of pts receiving R-CHOP and RB-CHOP experienced, respectively. However, RB‐CHOP was not associated with increased haematological toxicity and 87% of pts completed 6 cycles; Grade ≥3 neuropathy occurred in 3.8% RB‐CHOP vs 1.8% R‐CHOP pts. Serious adverse events occurred in 190 (42.5%) and 223 (50.2%) of pts, including 5 and 4 treatment-related deaths in pts receiving R-CHOP and RB-CHOP, respectively.Interpretation: This is the first large-scale study in DLBCL to use real-time molecular characterisation for prospective stratification and randomisation, and subsequent analysis of biologically distinct subgroups. The addition of bortezomib did not improve outcomes in the ABC subgroup as expected, but proteosome inhibition could be investigated as a possible means to improve the treatment of cytogenetic 'double-hit' DLBCL.Funding: Janssen-Cilag, Bloodwise and Cancer Research UK. <br/
Machining GLARE fibre metal laminates: a comparative study on drilling effect between conventional and ultrasonic-assisted drilling
No full textGLARE laminates are multi-layered metal-composite materials created from bonding sheets of metallic alloys with carbon or glass fibre layers. The application of hybrid-conventional machining processes such as ultrasonic-assisted drilling (UAD) is becoming of great interest to the aerospace industry due to its capability in reducing the cutting forces and tool wear which are directly responsible for drilling-induced delamination. There is rich literature on the conventional drilling (CD) of GLARE, but no work reported using UAD process. This study will fill this gap and investigate the UAD of GLARE laminates using an indigenously developed UAD system. The influence of spindle speed and feed rate on thrust force and surface roughness metrics (Ra and Rz) were investigated under CD and UAD regimes. The quality of the borehole and damage mechanisms in the laminate constituents was examined using scanning electron microscopy (SEM). The contribution of the drilling parameters on the measured outputs was further evaluated using the analysis of variance (ANOVA) statistical analysis. It was found that UAD resulted in a significant reduction in thrust force by up to 65% while surface roughness metrics Ra and Rz were unaffected by the type of drilling process used. SEM analysis showed irregular and fuzzier surfaces in glass fibre layers in holes machined using UAD due to the longitudinal vibration of the tool.Aerospace Manufacturing Technologie
Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit.
No full textUsing a Burkitt lymphoma-like gene expression signature, we recently defined a high-risk molecular high-grade (MHG) group mainly within germinal centre B-cell like diffuse large B-cell lymphomas (GCB-DLBCL), which was enriched for MYC/BCL2 double-hit (MYC/BCL2-DH). The genetic basis underlying MHG-DLBCL and their aggressive clinical behaviour remain unknown. We investigated 697 cases of DLBCL, particularly those with MYC/BCL2-DH (n = 62) by targeted sequencing and gene expression profiling. We showed that DLBCL with MYC/BCL2-DH, and those with BCL2 translocation, harbour the characteristic mutation signatures that are associated with follicular lymphoma and its high-grade transformation. We identified frequent MYC hotspot mutations that affect the phosphorylation site (T58) and its adjacent amino acids, which are important for MYC protein degradation. These MYC mutations were seen in a subset of cases with MYC translocation, but predominantly in those of MHG. The mutations were more frequent in double-hit lymphomas with IG as the MYC translocation partner, and were associated with higher MYC protein expression and poor patient survival. DLBCL with MYC/BCL2-DH and those with BCL2 translocation alone are most likely derived from follicular lymphoma or its precursor lesion, and acquisition of MYC pathogenic mutations may augment MYC function, resulting in aggressive clinical behaviour
Molecular high-grade B-Cell lymphoma: defining a poor-risk group that requires different approaches to therapy
No full textPurposeBiologic heterogeneity is a feature of diffuse large B-cell lymphoma (DLBCL), and the existence of a subgroup with poor prognosis and phenotypic proximity to Burkitt lymphoma is well known. Conventional cytogenetics identifies some patients with rearrangements of MYC and BCL2 and/or BCL6 (double-hit lymphomas) who are increasingly treated with more intensive chemotherapy, but a more biologically coherent and clinically useful definition of this group is required.Patients and MethodsWe defined a molecular high-grade (MHG) group by applying a gene expression–based classifier to 928 patients with DLBCL from a clinical trial that investigated the addition of bortezomib to standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. The prognostic significance of MHG was compared with existing biomarkers. We performed targeted sequencing of 70 genes in 400 patients and explored molecular pathology using gene expression signature databases. Findings were validated in an independent data set.ResultsThe MHG group comprised 83 patients (9%), with 75 in the cell-of-origin germinal center B-cell-like group. MYC rearranged and double-hit groups were strongly over-represented in MHG but comprised only one half of the total. Gene expression analysis revealed a proliferative phenotype with a relationship to centroblasts. Progression-free survival rate at 36 months after R-CHOP in the MHG group was 37% (95% CI, 24% to 55%) compared with 72% (95% CI, 68% to 77%) for others, and an analysis of treatment effects suggested a possible positive effect of bortezomib. Double-hit lymphomas lacking the MHG signature showed no evidence of worse outcome than other germinal center B-cell-like cases.ConclusionMHG defines a biologically coherent high-grade B-cell lymphoma group with distinct molecular features and clinical outcomes that effectively doubles the size of the poor-prognosis, double-hit group. Patients with MHG may benefit from intensified chemotherapy or novel targeted therapies
Multiscale modelling and experimental analysis of ultrasonic-assisted drilling of GLARE fibre metal laminates
No full textThis study aims to evaluate the effectiveness of Ultrasonic-assisted drilling (UAD) of Glass laminate aluminium reinforced epoxy (GLARE) at high cutting speeds (Spindle speeds: 3000–7500 rpm; feed rates 300–750 mm/min) by analysing the thrust force and hole quality metrics (surface roughness, hole size, and burr formations. The research also presents numerical modelling of FMLs under conventional and UAD regimes to predict thrust force using ABAQUS/SIMULIA. The thrust force and exit burrs were reduced by up to 40.83 % and 80 %, respectively. The surface roughness metrics (Ra and Rz) were slightly higher using UAD but remained within the desirable limits of surface roughness for machined aeronautical structures. The discrepancy between the simulation and experimental results was adequate and did not exceed 15 %. The current study shows that it is feasible to drill holes in GLARE using higher cutting parameters and maintain excellent hole quality, which means increased productivity and reduced costs.Group Sink
Classifying and predicting different types of voluntary turnover based on social media language
No full textM.Phil.Despite an abundance of voluntary employee turnover models in the academic literature, the predictive abilities of all extant frameworks remain unsatisfactory. Inadequate sample sizes and differentiation between turnover subtypes in previous studies using conventional data sources and research designs are major causes of this problem. This study utilized Twitter data and big data analytics to build a prediction model for two subtypes of voluntary turnover. Two types of quitters, namely plan (N = 10982) and dissatisfaction (N = 14860) were first targeted and labeled based on the matches between their published tweets and work count dictionaries pertaining each type of quit. Three types of language features (semantic dictionaries, N-Grams, Topics) were then extracted from each quitter’s historical tweets. The most powerful 10000 features were selected using chi-square test, which were in turn used to train a logistic model that can assign individuals to different turnover types based on their historical tweets. Using Q-Sort methodology, N-Grams most predictive of each type of turnover were then grouped and used to imply antecedents associated with specific turnover decision types. Results suggested that while semantic features (positive emotion, negative emotion, anger, sadness), N-Grams, and topics explained unique variance in prediction, the variance explained by topics overlapped with those explained by N-Grams. This study set the foundation for a more refined theory of turnover criterion and process with potentially high validity and inform the practices of delivering selective organizational intervention programs and automated recommendation of job positions to potential job seekers on social media.雖然用於解釋員工自願離職的模型在文獻中大量存在，但是所有現存模型的預測能力都不盡人意。在過去的研究中普遍存在的樣本不足與不分化不同的離職類型的問題是低預測能力的主要誘因。本研究利用推特數據和大數據分析技術建立了一個對兩種不同自願離職類型的預測模型。在通過離職關鍵詞收集推文後， 兩種不同的離職者（計劃型與工作不滿意型）被與其類型對應的字典識別與標記。 然後， 作者從每位離職者在宣布離職前的歷史推文中提取出三種語言特徵（語義字典，N元語法，主題），並從其中挑選出最能區分兩類離職的特徵。這些特徵被用於訓練一個能通過某人所發歷史推文判斷其屬於哪種辭職類型的邏輯回歸模型。最後，最能區分兩類離職的特徵會被用於推斷兩種類型離職的前因。结果显示語義字, N元語法, 和主題能分别解释模型的方差，但N元語法與主題所解释的方差有所重合。本研究為建立更精細區分不同離職類型與其對應的前因路徑的理論打下了基礎，並為選擇性干預員工離職和為潛在離職者自動推薦工作崗位的實踐應用提供理論支撐。Chen, Chulin.Thesis M.Phil. Chinese University of Hong Kong 2019.Includes bibliographical references (leaves 32-35).Abstracts also in Chinese.Title from PDF title page (viewed on 09, February, 2021)
