Identifying the optimal donor for natural killer cell adoptive therapy to treat paediatric B- and T-cell acute lymphoblastic leukaemia.

Objectives: Natural killer (NK) cells are an attractive source of cells for an 'off the shelf' cellular therapy because of their innate capacity to target malignant cells, and ability to be transferred between donors and patients. However, since not all NK cells are equally effective at targeting cancer, selecting the right donor for cellular therapy is critical for the success of the treatment. Recently, cellular therapies utilising NK cells from cytomegalovirus (CMV)-seropositive donors have been explored. However, whether these NK cells are the best source to treat paediatric acute lymphoblastic leukaemia (ALL) remains unclear. Methods: Using a panel of patient-derived paediatric B- and T-ALL, we assessed the ability of NK cells from 49 healthy donors to mount an effective functional response against these two major subtypes of ALL. Results: From this cohort, we have identified a pool of donors with superior activity against multiple ALL cells. While these donors were more likely to be CMV+, we identified multiple CMVneg donors within this group. Furthermore, NK cells from these donors recognised B- and T-ALL through different activating receptors. Dividing functional NK cells into 29 unique subsets, we observed that within each individual the same NK cell subsets dominated across all ALL cells. Intriguingly, this occurred despite the ALL cells in our panel expressing different combinations of NK cell ligands. Finally, we can demonstrate that cellular therapy products derived from these superior donors significantly delayed leukaemia progression in preclinical models of ALL. Conclusions: We have identified a pool of superior donors that are effective against a range of ALL cells, representing a potential pool of donors that can be used as an adoptive NK cell therapy to treat paediatric ALL

Sociodemographic variables, clinical features, and the role of preassessment cross-sex hormones in older trans people

Introduction: As referrals to gender identity clinics have increased dramatically over the last few years, no studies focusing on older trans people seeking treatment are available. Aims: The aim of this study was to investigate the sociodemographic and clinical characteristics of older trans people attending a national service and to investigate the influence of cross-sex hormones (CHT) on psychopathology. Methods: Individuals over the age of 50 years old referred to a national gender identity clinic during a 30-month period were invited to complete a battery of questionnaires to measure psychopathology and clinical characteristics. Individuals on cross-sex hormones prior to the assessment were compared with those not on treatment for different variables measuring psychopathology. Main Outcome Measures: Sociodemographic and clinical variables and measures of depression and anxiety (Hospital Anxiety and Depression Scale), self-esteem (Rosenberg Self-Esteem Scale), victimization (Experiences of Transphobia Scale), social support (Multidimensional Scale of Perceived Social Support), interpersonal functioning (Inventory of Interpersonal Problems), and nonsuicidal self-injury (Self-Injury Questionnaire). Results: The sex ratio of trans females aged 50 years and older compared to trans males was 23.7:1. Trans males were removed for the analysis due to their small number (n ¼ 3). Participants included 71 trans females over the age of 50, of whom the vast majority were white, employed or retired, and divorced and had children. Trans females on CHT who came out as trans and transitioned at an earlier age were significantly less anxious, reported higher levels of self-esteem, and presented with fewer socialization problems. When controlling for socialization problems, differences in levels of anxiety but not self-esteem remained. Conclusion: The use of cross-sex hormones prior to seeking treatment is widespread among older trans females and appears to be associated with psychological benefits. Existing barriers to access CHT for older trans people may need to be re-examined

Modeling Boundary Vector Cell Firing Given Optic Flow as a Cue

Boundary vector cells in entorhinal cortex fire when a rat is in locations at a specific distance from walls of an environment. This firing may originate from memory of the barrier location combined with path integration, or the firing may depend upon the apparent visual input image stream. The modeling work presented here investigates the role of optic flow, the apparent change of patterns of light on the retina, as input for boundary vector cell firing. Analytical spherical flow is used by a template model to segment walls from the ground, to estimate self-motion and the distance and allocentric direction of walls, and to detect drop-offs. Distance estimates of walls in an empty circular or rectangular box have a mean error of less than or equal to two centimeters. Integrating these estimates into a visually driven boundary vector cell model leads to the firing patterns characteristic for boundary vector cells. This suggests that optic flow can influence the firing of boundary vector cells

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Levels of depression in transgender people and its predictors: results of a large matched control study with transgender people accessing clinical services

Background: Depression is a serious disorder which significantly impacts wellbeing and quality of life. Studies exploring mental wellbeing in the transgender population are mostly limited by small, non-homogenous samples and lack of matched controls. This study aimed to address these limitations and explore depression rates in a large sample of transgender people, compared with matched controls from the general population, as well as factors predicting depression in those taking cross-sex hormone treatment (CHT) compared to those not. Methods: Transgender individuals (n=913) completed a measure of depression, measures which predict psychopathology (self-esteem, victimization, social support, interpersonal problems), and information regarding CHT use. Participants were matched by age and experienced gender with adults from the general population who had completed the measure of depression. Results: Individuals were categorized as having no, possible or probable depressive disorder. Transgender individuals not on CHT had a nearly four-fold increased risk of probable depressive disorder, compared to controls. Older age, lower self-esteem, poorer interpersonal function and less social support predicted depressive disorder. Use of CHT was associated with less depression. Limitations: Participants were attending a national gender identity service and therefore represent only a sub-group of transgender people. Due to the cross-sectional design, longitudinal research is required to fully confirm the finding that CHT use reduces depression. Conclusion: This study confirms that non-treated transgender individuals have an increased risk of a depressive disorder. Interventions offered alongside gender affirming treatment to develop interpersonal skills, increase self-esteem and improve social support may reduce depression and prepare individuals for a more successful transition

Roussillon, un village dans le Vaucluse, 1987

Les pages que l'on lira sur Roussillon, village du Vaucluse, en l'an de grâce 1987, sont écrites par quelqu'un qui en a entrepris pour la première fois l'étude en 1950-1951, durant une année, grâce à la coutume universitaire américaine du « congé sabbatique ». Elles sont le fait d'un homme que, par bien des côtés, on pourrait qualifier de dilettante au meilleur sens du terme, dont le nom commence à être bien connu en France, et qui a marqué discrètement mais de façon significative le développ..

Habitat et migrations à Chanzeaux (Maine-et-Loire)

Wylie Laurence, Christian William, De Ménil Georges, Yager Thomas. Habitat et migrations à Chanzeaux (Maine-et-Loire). In: Études rurales, n°29, 1968. pp. 62-102