Academic literature on the topic 'Somatically Enhanced Approach'

Background. Approximately 70% of newly diagnosed chronic lymphocytic leukemia (CLL) patients present in early Binet or Rai stage, may never require treatment, and may have a life expectancy similar to that of the general population. Two independent and recent studies have identified the clinical and immunogenetic variables associated with shorter time to first treatment (TTFT) in Binet A and Rai 0 CLL (Condoluci et al., Blood 2020; Cohen et al., Haematologica 2020). However, the clinical impact of gene mutations in predicting TTFT is not completely understood. Purpose. Using a training/validation approach, we aimed at identifying new molecular biomarkers that may predict early treatment requirement and may help clinicians to better plan the watch and wait strategy in asymptomatic early stage CLL patients. Methods. The training cohort included 295 CLL in Binet A stage who did not require treatment for at least 3 months after diagnosis. The two validation multicenter cohorts included 402 treatment-naïve Binet A CLL patients (Binet A validation cohort) and 395 untreated Rai 0 CLL patients (Rai 0 validation cohort), respectively. In the training cohort, tumor genomic DNA was isolated from peripheral blood mononuclear cells at the time of diagnosis and was analyzed in the coding exons plus splice sites of the most frequently mutated genes in CLL with a next-generation-sequencing (NGS) approach using a variant allele frequency (VAF) threshold of 5%. In the validation series, the XPO1 gene (exons 15 and 16) was analyzed by NGS or by Sanger sequencing. The primary endpoint was TTFT defined as the time interval between the date of CLL diagnosis and the date of first CLL treatment. Results. In the training cohort, NGS mutational analysis showed that XPO1 was mutated in 7 (2.4%) patients. In univariate analysis, trisomy 12 (HR 2.42; 95% CI 1.43-4.15; p=0.001), unmutated IGHV genes (HR 4.51; 95% CI 2.83-7.05; p<0.0001) and mutations of XPO1 (HR 8.88; 95% CI 3.77-20.95; p<0.0001) (Fig. 1A), NOTCH1 (HR 3.02; 95% CI 1.66-5.51; p<0.001) and SF3B1 (HR 2.65; 95% CI 1.15-6.10; p=0.022) were associated with a shorter TTFT. By multivariate analysis, XPO1 mutations (HR 4.24; 95% CI 1.72-10.44; p=0.002) and unmutated IGHV genes (HR 3.43; 95% CI 2.08-5.67; p<0.0001) maintained an independent association with a shorter TTFT. XPO1 mutational analysis was subsequently investigated in 2 independent multicenter cohorts of early stage CLL patients. In the Binet A validation cohort (N=402 patients), XPO1 was mutated in 15 (3.7%) patients and was associated with a shorter TTFT (HR 2.59; 95% CI 1.36-4.96; p=0.004) (Fig. 1B). Similarly, also in the Rai 0 validation cohort, (N=395 patients), XPO1was mutated in 8 (2.0%) patients and was associated with a shorter TTFT (HR 6.02; 95% CI 15.03-4.96; p<0.001) (Fig. 1C). Moreover, in the Rai 0 validation cohort, XPO1 mutations maintained an independent association with a shorter TTFT when corrected in multivariate analysis by the IGHV mutational status (HR 3.31; 95% CI 1.30-8.44; p=0.012). By combining the training and the validation cohorts (N=1092 patients), a total of 30 somatically acquired XPO1 mutations were identified (2.7% of patients). More precisely, 27 (90.0%) mutations affected XPO1 codon E571 and 3 (10.0%) codon D624. This finding suggests that a target sequencing or an allele-specific polymerase chain reaction based method may be used to identify XPO1 mutations in a simple and time-effective manner. From a clinical perspective, patients carrying either XPO1 E571 or D624 mutations showed superimposable outcome in terms of TTFT (p=0.345) (Fig. 1D). Conclusions. Mutations of the XPO1 gene, encoding for exportin 1 which mediates the nuclear export of proteins and RNAs, are an independent predictor of shorter TTFT validated in independent series of early stage treatment-naïve CLL patients. XPO1 mutations are conceivably gain-of-function and may enhance cell proliferation by exporting out of the nucleus with a greater extent proteins that physiologically downregulate cell proliferation. Based on these results, XPO1 mutational analysis might be incorporated in other prognostic scores and help clinicians to refine the management of the watch and wait strategy for early stage CLL. In addition, XPO1 inhibitors are particularly active in XPO1E571 mutated cells (Taylor et al., Cancer Discov 2019) providing initial pre-clinical rational for their usage in XPO1 mutated CLL patients. Figure Disclosures Scarfo: AstraZeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Del Giudice:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Other: grant for meeting partecipation; Janssen: Other: grant for meeting participation; Tolero: Membership on an entity's Board of Directors or advisory committees. Sportoletti:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Marasca:Shire: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees. Ghia:Acerta/AstraZeneca: Consultancy, Honoraria; ArQule: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Adaptive, Dynamo: Consultancy, Honoraria. Foà:Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gaidano:Sunesys: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Membership on an entity's Board of Directors or advisory committees. Rossi:AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

Abstract The non-coding regions of tumour cell genomes harbour a considerable fraction of total DNA sequence variation, but the functional contribution of these variants to tumorigenesis is ill-defined. Among these non-coding variants, somatic insertions are among the least well characterized due to challenges with interpreting short-read DNA sequences. Here, using a combination of Chip-seq to enrich enhancer DNA and a computational approach with multiple DNA alignment procedures, we identify enhancer-associated small insertion variants. Among the 102 tumour cell genomes we analyse, small insertions are frequently observed in enhancer DNA sequences near known oncogenes. Further study of one insertion, somatically acquired in primary leukaemia tumour genomes, reveals that it nucleates formation of an active enhancer that drives expression of the LMO2 oncogene. The approach described here to identify enhancer-associated small insertion variants provides a foundation for further study of these abnormalities across human cancers.

Abstract Background Cancer arises through accumulation of somatically acquired genetic mutations. An important question is to delineate the temporal order of somatic mutations during carcinogenesis, which contributes to better understanding of cancer biology and facilitates identification of new therapeutic targets. Although a number of statistical and computational methods have been proposed to estimate the temporal order of mutations, they do not account for the differences in the functional impacts of mutations and thus are likely to be obscured by the presence of passenger mutations that do not contribute to cancer progression. In addition, many methods infer the order of mutations at the gene level, which have limited power due to the low mutation rate in most genes. Results In this paper, we develop a Probabilistic Approach for estimating the Temporal Order of Pathway mutations by leveraging functional Annotations of mutations (PATOPA). PATOPA infers the order of mutations at the pathway level, wherein it uses a probabilistic method to characterize the likelihood of mutational events from different pathways occurring in a certain order. The functional impact of each mutation is incorporated to weigh more on a mutation that is more integral to tumor development. A maximum likelihood method is used to estimate parameters and infer the probability of one pathway being mutated prior to another. Simulation studies and analysis of whole exome sequencing data from The Cancer Genome Atlas (TCGA) demonstrate that PATOPA is able to accurately estimate the temporal order of pathway mutations and provides new biological insights on carcinogenesis of colorectal and lung cancers. Conclusions PATOPA provides a useful tool to estimate temporal order of mutations at the pathway level while leveraging functional annotations of mutations.

For adult English speakers studying Mandarin (Modern Standard Chinese), the acquisition of the Mandarin prosody presents major difficulties. One particularly problematic aspect of the Mandarin prosodic system, and the one singled out for research here is the acquisition of tones by second language (L2) learners of Mandarin. This thesis involves a literature review and a description of an experiment conducted for the purpose of assessing the effectiveness of a new teaching method for educating students in Mandarin prosody generally, but especially with regard to "tones." Most studies investigating the acquisition of Mandarin tones by L2 learners have treated tones as separate from other aspects of Mandarin prosody such as stress, loudness and duration. The teaching method examined in this thesis, however, takes an alternative approach. Here the acquisition of Mandarin prosody is approached as a complex dynamic that has tones as an integral part. The aims of the study are twofold: (1) to identify the principal problems encountered by most learners in order to discover the causes of recurrent error patterns and, (2) to find out how a multi-sensory approach, which in this study was called the Somatically Enhanced Approach (SEA), might influence the acquisition of Mandarin prosody in these areas. The experiment involved 22 adult Australian students studying Mandarin in the first three months of language training. The experimental component of the study consisted of an evaluation of two groups of students� oral conversations. The two groups of students were divided into a control group and an experimental group. The control group was trained in a nonmulti- sensory but communicative approach in 2001 and 2002. Their results are compared with those of a test group and with a group of students trained in the multi-sensory communicative approach (SEA) in 2003 and 2004. The test materials consisted of short dialogues that were likely to occur in everyday communication. Data was collected from each group, once during the first half of the first semester of study in each year. The findings of the experiment were that the order of difficulty of the four Mandarin tones was found to be similar for both the experimental and control groups of students. However, the order of difficulty differed from what has been reported by previous researchers. This suggests that the input and the type of task used to collect data might exert a significant influence on the learning of tones. In other words, the performance of subjects in the dialogues suggests that in the initial stages of learning, the major cause of errors was first language (L1) interference rather than the physical "difficulty" of articulating particular phonemes (or any features of Universal Grammar). Therefore, by using a multi-sensory approach (SEA) to the learning of Mandarin, it may be possible to considerablly lessen the influence of learners� L1 from the outset. Finally, a number of suggestions for improving the teaching of Mandarin prosody are made and future research directions outlined. Some salient suggestions for teaching of Mandarin prosody that arise from the research are: (1) To use movement and gesture in the early stages of learning to enhance students� perception and production of Mandarin. This approach provides students with useful memory tools for learning both in class and in self-accessed learning; (2) To teach Tone 3 not as a full Tone 3 but as a low level tone. This should not be done solely through a simple verbal explanation but through a combination of movement and gesture, provision of visual and auditory feedback and a large amount of exposure and perception training so that Tone 3 is recognised as a low level tone rather than a full Tone 3. By so doing confusion is reduced between the various realizations of Tone 3 during the initial learning stages; and (3) To caution students about the common error patterns caused by interference from their L1. This should be supplemented with opportunities for students to observe their own production of Mandarin and then experience how physically they can find ways of reducing the interference. A qualitative analysis of interview and question data obtained from this research also revealed that the extensive use of computer enhanced language learning and SEA work well together, not only efficiently conditioning students to the phonology of Mandarin, but dramatically changing students' strategies in learning and increasing their learning opportunities.

碩士
中國文化大學
華語文教學碩士學位學程
107
This study focuses on the training of sentence rhythms used by actors during performance courses. It will be applied to the teaching of Chinese language learners of TOCFL (B1) level. In the actor's mouth training, the sentence tempo method is one of the methods for actor training to speed up the speech of the native speaker. Therefore, this study is designed to use as teaching methods which are based on the theories of memory and emotional memory of Constantin Stanislavski （1969） and the Somatically-enhanced approach for teaching languages (Zhang, 2006) as the theoretical basis of this study. It is expected that these methods can improve learners’ tonal control, speed of Mandarin Chinese speech as spoken by Chinese second language speaker. Keywords: Chinese tones, Chinese speed, Chinese rhythm