Research Brief

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Cross-validated stepwise regression for identification of novel non-nucleoside reverse transcriptase inhibitor resistance associated mutations

<p>Abstract</p> <p>Background</p> <p>Linear regression models are used to quantitatively predict drug resistance, the phenotype, from the HIV-1 viral genotype. As new antiretroviral drugs become available, new resistance pathways emerge and the number of resistance associated mutations continues to increase. To accurately identify which drug options are left, the main goal of the modeling has been to maximize predictivity and not interpretability. However, we originally selected linear regression as the preferred method for its transparency as opposed to other techniques such as neural networks. Here, we apply a method to lower the complexity of these phenotype prediction models using a 3-fold cross-validated selection of mutations.</p> <p>Results</p> <p>Compared to standard stepwise regression we were able to reduce the number of mutations in the reverse transcriptase (RT) inhibitor models as well as the number of interaction terms accounting for synergistic and antagonistic effects. This reduction in complexity was most significant for the non-nucleoside reverse transcriptase inhibitor (NNRTI) models, while maintaining prediction accuracy and retaining virtually all known resistance associated mutations as first order terms in the models. Furthermore, for etravirine (ETR) a better performance was seen on two years of unseen data. By analyzing the phenotype prediction models we identified a list of forty novel NNRTI mutations, putatively associated with resistance. The resistance association of novel variants at known NNRTI resistance positions: 100, 101, 181, 190, 221 and of mutations at positions not previously linked with NNRTI resistance: 102, 139, 219, 241, 376 and 382 was confirmed by phenotyping site-directed mutants.</p> <p>Conclusions</p> <p>We successfully identified and validated novel NNRTI resistance associated mutations by developing parsimonious resistance prediction models in which repeated cross-validation within the stepwise regression was applied. Our model selection technique is computationally feasible for large data sets and provides an approach to the continued identification of resistance-causing mutations.</p

Is the combination of immunotherapy and radiotherapy in non-small cell lung cancer a feasible and effective approach?

For many years, conventional oncologic treatments such as surgery, chemotherapy, and radiotherapy (RT) have dominated the field of non-small-cell lung cancer (NSCLC). The recent introduction of immunotherapy (IT) in clinical practice, especially strategies targeting negative regulators of the immune system, so-called immune checkpoint inhibitors, has led to a paradigm shift in lung cancer as in many other solid tumors. Although antibodies against programmed death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) are currently on the forefront of the immuno-oncology field, the first efforts to eradicate cancer by exploiting the host's immune system date back to several decades ago. Even then, researchers aimed to explore the addition of RT to IT strategies in NSCLC patients, attributing its potential benefit to local control of target lesions through direct and indirect DNA damage in cancer cells. However, recent pre-clinical and clinical data have shown RT may also modify antitumor immune responses through induction of immunogenic cell death and reprogramming of the tumor microenvironment. This has led many to reexamine RT as a partner therapy to immuno-oncology treatments and investigate their potential synergy in an exponentially growing number of clinical trials. Herein, the authors review the rationale of combining IT and RT across all NSCLC disease stages and summarize both historical and current clinical evidence surrounding these combination strategies. Furthermore, an overview is provided of active clinical trials exploring the IT-RT concept in different settings of NSCLC

Investigation of the effect of temper rolling on the texture evolution and mechanical behavior of IF steels using multiscale simulation

The main objective of this study is to simulate texture and deformation during the temper-rolling process. To this end, a rate-independent crystal plasticity model, based on the self-consistent scale-transition scheme, is adopted to predict texture evolution and deformation heterogeneity during temper-rolling process. For computational efficiency, a decoupled analysis is considered between the polycrystalline plasticity model and the finite element analysis for the temper rolling. The elasto-plastic finite element analysis is first carried out to determine the history of velocity gradient during the numerical simulation of temper rolling. The thus calculated velocity gradient history is subsequently applied to the polycrystalline plasticity model. By following some appropriately selected strain paths (i.e., streamlines) along the rolling process, one can predict the texture evolution of the material at the half thickness of the sheet metal as well as other parameters related to its microstructure. The numerical results obtained by the proposed strategy are compared with experimental data in the case of IF steels.French program “Investment in the future” operated by the National Research Agency (ANR)-11-LABX-0008-01, LabEx DAMAS (LST)

Effective curricula for at-risk students in vocational education:a study of teachers’ practice

Abstract Background This study focused upon a curriculum for at-risk students in vocational education aimed at enhancing students’ motivation and engagement for learning. The study explored teachers’ view on effective curricular characteristics and teachers’ strategies to create positive learning experiences for students. Methods Qualitative research has been conducted regarding four curricula for at-risk students; data were collected and examined by means of 16 focus group interviews with teachers and analysis of relevant documents. Results Teachers pointed out the central position of the student, resulting in individual trajectories. Teachers used peer group dynamics, job orientation and sports as tool for student development. Teachers regarded themselves as coaches, as experts in sport activities and as group managers. For positive learning experiences two key curricular characteristics have been identified: (1) equality in the relationship between student and teacher, (2) a positive fit between the curriculum and the students

Cross-ethnic friendships: Are they really rare? Evidence from secondary schools around London

This study examined current cross-ethnic friendship patterns in secondary schools around London, UK, and the effects of ethnic group and ethnic diversity on cross-ethnic friendship selection and quality. Questionnaires including self-report ethnic group definitions and measures of same-/cross-ethnic friendship numbers, along with the quality of 3 best cross-ethnic friends, were distributed to 684 Year 7 (aged 11) British students (256 White European, 63 Middle Easterner, 118 Black, 247 South Asian) recruited from 9 multi-ethnic secondary schools (37 classrooms) in Greater London. In contrast to most previous research which suggested the relative rarity of cross-ethnic friendships, findings showed that cross-ethnic friendships were in fact frequent and of high quality, outnumbering same-ethnic friendships for all ethnic groups. After controlling for gender, classroom gender composition, SES, percentage of available same-ethnic peers, ethnic identity and perceived ethnic discrimination, classroom ethnic diversity still had a marginally positive effect on cross-ethnic friendship selection, but had no effect on cross-ethnic friendship quality. White British children reported higher cross-ethnic friendship selection and lower cross-ethnic friendship quality compared to other ethnic groups, but this depended on classroom ethnic diversity. Implications of the findings are discussed in the light of intergroup contact and friendship formation theories. We conclude that research on cross-ethnic friendships is crucial in providing insights into how intergroup relationships are formed during early adolescence in modern multiethnic settings like London secondary schools