The Type 2 Diabetes Knowledge Portal: An open access genetic resource dedicated to type 2 diabetes and related traits.

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP's comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results.

Research on Nutrition, Dental Caries Status Using Novel Methods, and Related Factors to Preschool Children in Rural Areas of Vietnam.

The study aims to examine correlations between nutrition status with different factors and dental caries of preschool children in rural areas of Vietnam. A big data based on a total of 690 children (356 boys and 334 girls), aged 2-5 years, living in Van Xuan commune, were thoroughly analyzed. Oral examinations were performed by dentists with the assistance of nursery teachers and the research team. Caries was diagnosed using criteria established by the International Caries Detection and Assessment System (ICDAS). The examined children and their parents responded to questions pertaining to dental hygiene practices. The nutrition status of preschool children was determined by the World Health Organization (WHO) standards in 2006. There are factors which have effects on the malnutrition status of children in the research. The prevalence of dental caries also contributed importantly to assess children's development. In this study, the stunting groups have a higher ratio of caries compared to the others. Children's morphology and nutritional status are associated with dental caries among the preschool children in Van Xuan commune, Vinh Tuong district, Vinh Phuc province.

Radiation therapy for triple-negative breast cancer: emerging role of microRNAs as biomarkers and radiosensitivity modifiers. A systematic review.

PURPOSE: Radiation therapy (RT) for triple-negative breast cancer (TNBC) treatment is currently delivered in the adjuvant setting and is under investigation as a booster of neoadjuvant treatments. However, TNBC radioresistance remains an obstacle, so new biomarkers are needed to select patients for any integration of RT in the TNBC therapy sequence. MicroRNAs (miRs) are important regulators of gene expression, involved in cancer response to ionizing radiation (IR) and assessable by tumor tissue or liquid biopsy. This systematic review aimed to evaluate the relationships between miRs and response to radiation in TNBC, as well as their potential predictive and prognostic values. METHODS: A thorough review of studies related to miRs and RT in TNBC was performed on PubMed, EMBASE, and Web of Science. We searched for original English articles that involved dysregulation of miRs in response to IR on TNBC-related preclinical and clinical studies. After a rigorous selection, 44 studies were chosen for further analysis. RESULTS: Thirty-five miRs were identified to be TNBC related, out of which 21 were downregulated, 13 upregulated, and 2 had a double-side expression in this cancer. Expression modulation of many of these miRs is radiosensitizing, among which miR-7, -27a, -34a, -122, and let-7 are most studied, still only in experimental models. The miRs reported as most influencing/reflecting TNBC response to IR are miR-7, -27a, -155, -205, -211, and -221, whereas miR-21, -33a, -139-5p, and -210 are associated with TNBC patient outcome after RT. CONCLUSION: miRs are emerging biomarkers and radiosensitizers in TNBC, worth further investigation. Dynamic assessment of circulating miRs could improve monitoring and TNBC RT efficacy, which are of particular interest in the neoadjuvant and the high-risk patients' settings.

An effector index to predict target genes at GWAS loci.

Drug development and biological discovery require effective strategies to map existing genetic associations to causal genes. To approach this problem, we selected 12 common diseases and quantitative traits for which highly powered genome-wide association studies (GWAS) were available. For each disease or trait, we systematically curated positive control gene sets from Mendelian forms of the disease and from targets of medicines used for disease treatment. We found that these positive control genes were highly enriched in proximity of GWAS-associated single-nucleotide variants (SNVs). We then performed quantitative assessment of the contribution of commonly used genomic features, including open chromatin maps, expression quantitative trait loci (eQTL), and chromatin conformation data. Using these features, we trained and validated an Effector Index (Ei), to map target genes for these 12 common diseases and traits. Ei demonstrated high predictive performance, both with cross-validation on the training set, and an independently derived set for type 2 diabetes. Key predictive features included coding or transcript-altering SNVs, distance to gene, and open chromatin-based metrics. This work outlines a simple, understandable approach to prioritize genes at GWAS loci for functional follow-up and drug development, and provides a systematic strategy for prioritization of GWAS target genes.

Δ133p53α enhances metabolic and cellular fitness of TCR-engineered T cells and promotes superior antitumor immunity.

BACKGROUND: Tumor microenvironment-associated T cell senescence is a key limiting factor for durable effective cancer immunotherapy. A few studies have demonstrated the critical role of the tumor suppressor TP53-derived p53 isoforms in cellular senescence process of non-immune cells. However, their role in lymphocytes, in particular tumor-antigen (TA) specific T cells remain largely unexplored. METHODS: Human T cells from peripheral blood were retrovirally engineered to coexpress a TA-specific T cell receptor and the Δ133p53α-isoform, and characterized for their cellular phenotype, metabolic profile and effector functions. RESULTS: Phenotypic analysis of Δ133p53α-modified T cells revealed a marked reduction of the T-cell inhibitory molecules (ie, CD160 and TIGIT), a lower frequency of senescent-like CD57+ and CD160+ CD8+ T cell populations, and an increased number of less differentiated CD28+ T cells. Consistently, we demonstrated changes in the cellular metabolic program toward a quiescent T cell state. On a functional level, Δ133p53α-expressing T cells acquired a long-term proliferative capacity, showed superior cytokine secretion and enhanced tumor-specific killing in vitro and in mouse tumor model. Finally, we demonstrated the capacity of Δ133p53α to restore the antitumor response of senescent T cells isolated from multiple myeloma patients. CONCLUSION: This study uncovered a broad effect of Δ133p53α isoform in regulating T lymphocyte function. Enhancing fitness and effector functions of senescent T cells by modulation of p53 isoforms could be exploited for future translational research to improve cancer immunotherapy and immunosenescence-related diseases.

Cigarette smoking induces human CCR6+Th17 lymphocytes senescence and VEGF-A secretion.

Chronic exposure to environmental pollutants is often associated with systemic inflammation. As such, cigarette smoking contributes to inflammation and lung diseases by inducing senescence of pulmonary cells such as pneumocytes, fibroblasts, and endothelial cells. Yet, how smoking worsens evolution of chronic inflammatory disorders associated with Th17 lymphocytes, such as rheumatoid arthritis, psoriasis, Crohn's disease, and multiple sclerosis, is largely unknown. Results from human studies show an increase in inflammatory CD4+ Th17 lymphocytes at blood- and pulmonary level in smokers. The aim of the study was to evaluate the sensitivity of CD4+ Th17 lymphocytes to cigarette smoke-induced senescence. Mucosa-homing CCR6+ Th17- were compared to CCR6neg -and regulatory T peripheral lymphocytes after exposure to cigarette smoke extract (CSE). Senescence sensitivity of CSE-exposed cells was assessed by determination of various senescence biomarkers (ß-galactosidase activity, p16Ink4a- and p21 expression) and cytokines production. CCR6+ Th17 cells showed a higher sensitivity to CSE-induced senescence compared to controls, which is associated to oxidative stress and higher VEGFα secretion. Pharmacological targeting of ROS- and ERK1/2 signalling pathways prevented CSE-induced senescence of CCR6+Th17 lymphocytes as well as VEGFα secretion. Altogether, these results identify mechanisms by which pro-oxidant environmental pollutants contribute to pro-angiogenic and pathogenic CCR6+Th17 cells, therefore potential targets for therapeutic purposes.

Human CCR6+ Th17 Lymphocytes Are Highly Sensitive to Radiation-Induced Senescence and Are a Potential Target for Prevention of Radiation-Induced Toxicity.

PURPOSE: This study addresses the sensitivity of different peripheral CD4+ T-lymphocyte subsets to irradiation (IR) and identifies potential targets for the prevention or treatment of radiation-induced toxicity. METHODS: This study was performed on peripheral blood mononuclear cells or sorted peripheral memory lymphocytes of CCR6+ mucosa-homing Th17/CCR6negTh and regulatory T subtypes of healthy volunteers. Cells were irradiated with a 2 Gy with or without pharmacologic inhibitors of different signaling pathways. Senescence of irradiated cells was assessed by resistance to apoptosis and determination of various senescence-associated biomarkers (senescence associated b-galactosidase activity, p16Ink4a-, p21Cdkn1a-, gH2A.X-, H2A.J expression). Cytokine production was measured in supernatants of irradiated cells by Luminex technology. RESULTS: Not all CD4+ memory T lymphocyte subsets were equally radiosensitive. High sensitivity of CCR6+Th17 lymphocytes to IR-induced senescence was shown by expression of the histone variant H2A.J, higher SA-b-Gal activity, and upregulation of p16Ink4a and p21Cdkn1a expression. Lower Annexin V staining and cleaved caspase-3, and higher expression of antiapoptotic genes Bcl-2 and Bcl-xL LF, showed that CCR6+Th17 lymphocytes were more resistant to IR-induced apoptosis than CCR6neg memory Th and regulatory T lymphocytes. After a 2 Gy IR, both CCR6+Th17 and CCR6neg cells acquired a moderate senescence-associated secretory phenotype, but only CCR6+Th17 cells secreted interleukin 8 (IL-8) and vascular endothelial growth factor-A (VEGF-A). Pharmacologic targeting of reactive oxygen species (ROS), mitogen-activated protein kinases (MAPKs), and mammalian target of rapamycin (mTOR) signaling pathways prevented the expression of senescent markers and IL-8 and VEGF-A expression by CCR6+Th17 cells after IR. CONCLUSIONS: This study suggests that IR induces senescence of CCR6+Th17 lymphocytes associated with secretion of IL-8 and VEGF-A that may be detrimental to the irradiated tissue. ROS-MAPKs signaling pathways are candidate targets to prevent this CCR6+Th17-dependent radiation-induced potential toxicity. Finally, the ratio of circulating H2A.J+ senescent CCR6+ Th17/CD4+ T lymphocytes may be a candidate marker of individual intrinsic radiosensitivity.

Stroma in normal and cancer wound healing.

It is currently believed that stroma, the connective framework of biological tissues, plays a central role in normal wound healing and in cancer. In both these contexts, stromal cellular components such as activated fibroblasts interact with complex protein networks that include growth factors, structural protein or proteinases in order to initiate and sustain an extensive remodelling process. However, although this process is usually spatially and temporally self-limited, it is unregulated in the case of cancer and leads to uncontrolled cell proliferation and invasion within tissues, metastasis and therapeutic resistance. In this review, we outline the role of stroma in normal healing, cancer and post radiotherapy, with a particular focus on the crosstalk between normal or cancer cells and fibroblasts. Understanding these mechanisms is particularly important as several stromal components have been proposed as potential therapeutic targets.

A Wake-Up Call for Routine Morbidity and Mortality Review Meeting Procedures as Part of a Quality Governance Programs in Radiation Therapy Departments: Results of the PROUST Survey.

PURPOSE: Morbidity and mortality review (MMR) meetings in radiation therapy (RT) departments aim to monitor radiation-induced toxicities and identify potential factors that may be correlated with their development and severity, particularly treatment planning errors. The aims of the Prospective Registration of Morbidity and Mortality, Individual Radiosensitivity and Radiation Technique (PROUST) survey were to make an inventory of existing MMR procedures and to describe their procedures. METHODS AND MATERIALS: The link to the web-based questionnaire of the PROUST survey was sent to 351 radiation oncologists working at 172 centers. The questionnaire included items related to organization, frequency, membership, governance, reasons for nonimplementation of MMR, and interest in its creation. RESULTS: As of July 2017, 108 responses had been received from the 172 centers, of which 107 responses were completed for analysis. All centers declared that they had initiated a quality assurance program in their department, including implementation of feedback committees dedicated to the registration, analysis, and correction of precursor events. Less than half of the centers (47%) had implemented MMR procedures. However, there was significant confusion regarding feedback committees in a majority of the centers. MMRs were organized every 6 and 12 months in 21% and 15%, respectively, of the centers. In 60% of the centers, toxicity grade ≥3 was the main reason for the MMR initiation. In routine practice, contouring and dosimetry files were reviewed by 66% and 83%, respectively, of centers practicing MMR. However, only 40% of the centers enrolled data in a registry dedicated to surveillance. Finally, 78% of centers expressed interest in initiating a consensual procedure. CONCLUSIONS: MMRs are not systematically implemented in RT departments worldwide. In France and in Europe, few departments with quality assurance programs have implemented MMRs. This survey showed that a large majority of centers are interested in implementing an MMR with a formalized procedure. Our project could help increase the interest of the RT community worldwide in this topic.

Extra-Curricular Activities Improved Reproductive Health Knowledge of Ethnic Minority High School Students in Vietnam.

Objective: To assess the effectiveness of extra-curricular activities in improving reproductive health knowledge of ethnic minority students in mountainous areas in Vietnam. Materials and methods: The study was conducted on 400 ethnic minority students at Dien Bien Dong Ethnic Minority High School in Vietnam. The selected healthy students with a similar mix of study results and grades were divided into two groups: a control group had no the extra-curricular activities on reproductive health, and an experimental group participated extra-curricular activities on reproductive health. The extra-curricular activities were designed as a series of seminars on numerous reproductive health contents. The retention of reproductive health knowledge was then evaluated by a test containing multiple-choice and single-choice questions. Results: Results showed that the percentage of students who did not correctly understand puberty signs, ovulation time during menstrual cycle, contraceptive method use and sexually transmitted diseases in the control group ranged from 34.5% - 83.5%. Despite the fact that the ethnic minority high school students' knowledge of reproductive health was poor, the percentage of students who fully understood puberty signs, ovulation time during menstrual cycle, contraceptive method use and sexually transmitted diseases significantly increased and reached at least 90% after attending extra-curricular activities on reproductive health (p < 0.05). Conclusion: The ethnic minority high school students' knowledge of reproductive health was relatively poor. Extra-curricular activities markedly increased the knowledge of many reproductive health aspects. These findings suggest that it is necessary to improve the knowledge of reproductive health for ethnic minority high school students in mountainous areas in Vietnam, and that extra-curricular activities organized as seminars are effective and suitable to provide and retain students' knowledge of reproductive health.

Ionizing radiation-induced cellular senescence promotes tissue fibrosis after radiotherapy. A review.

Ionizing radiation-exposure induces a variety of cellular reactions, such as senescence and apoptosis. Senescence is a permanent arrest state of the cell division, which can be beneficial or detrimental for normal tissue via an inflammatory response and senescence-associated secretion phenotype. Damage to healthy cells and their microenvironment is considered as an important source of early and late complications with an increased risk of morbidity in patients after radiotherapy (RT). In addition, the benefit/risk ratio may depend on the radiation technique/dose used for cancer eradication and the irradiated volume of healthy tissues. For radiation-induced fibrosis risk, the knowledge of mechanisms and potential prevention has become a crucial point to determining radiation parameters and patients' intrinsic radiosensitivity. This review summarizes our understanding of ionizing radiation-induced senescent cell in fibrogenesis. This mechanism may provide new insights for therapeutic modalities for better risk/benefit ratios after RT in the new era of personalized treatments.