Migrating pyramidal neurons require DSCAM to bypass the border of the developing cortical plate.

During mammalian neocortex development, nascent pyramidal neurons migrate along radial glial cells and overtake earlier-born neurons to terminate at the front of the developing cortical plate (CP), leading to the outward expansion of the CP border. While much has been learned about the cellular and molecular mechanisms that underlie the migration of pyramidal neurons, how migrating neurons bypass the preceding neurons at the end of migration to reach their final positions remains poorly understood. Here, we report that Down syndrome cell adhesion molecule (DSCAM) is required for migrating neurons to bypass their post-migratory predecessors during the expansion of the upper cortical layers. DSCAM is a type I transmembrane cell adhesion molecule. It has been linked to Down syndrome through its location in the Down syndrome critical region of Chromosome 21 trisomy and to autism spectrum disorders through loss-of-function mutations. Ex vivo time-lapse imaging demonstrates that DSCAM is required for migrating neurons to bypass their post-migratory predecessors, crossing the CP border to expand the upper cortical layers. In DSCAM-deficient cortices, migrating neurons stop prematurely under the CP border, leading to thinner and denser upper cortical layers. We further show that DSCAM weakens cell adhesion mediated by N-cadherin in the upper cortical plate, allowing migrating neurons to traverse the CP border and expand the CP. These findings suggest that DSCAM is required for proper migratory termination and final positioning of nascent pyramidal neurons, which may provide insight into brain disorders that exhibit thinner upper layers of the cerebral cortex without neuronal loss.SIGNIFICANCE STATEMENTNewly born neurons in the developing mammalian neocortex migrate outward towards the cortical surface, bypassing earlier born neurons to expand the developing cortex. How migrating neurons bypass the preceding neurons and terminate at the front of the expanding cortex remains poorly understood. We demonstrate that Down syndrome cell adhesion molecule (DSCAM), linked to Down syndrome and autism spectrum disorder, is required by migrating neurons to bypass their post-migratory predecessors and terminate migration in the outwardly expanding cortical layer. Migrating neurons deficient in DSCAM stop prematurely, failing to expand the cortex. We further show that DSCAM likely mediates migratory termination by weakening cell-adhesion mediated by N-cadherin.

Localizing Positive Axillary Lymph Nodes in Breast Cancer Patients Post Neoadjuvant Therapy.

INTRODUCTION: Multiple trials demonstrated the feasibility of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy. Those trials reported > 10% false-negative rate; however, a subset analysis of the Z1071 trial demonstrated that removing the clipped positive lymph node (LN) during SLNB reduces the false-negative rate to 6.8% post neoadjuvant chemotherapy. This study examines the factors that might contribute to the ability to identify the clipped nodes post neoadjuvant therapy (NAT). MATERIALS AND METHODS: Breast cancer patients with biopsy-proven metastatic axillary LN who underwent NAT, converted to N0, had preoperative localization, and then SLNB between 2018 and 2020 at a single institution were identified. A retrospective chart review was performed. Demographic and preoperative variables were compared between localization and nonlocalization groups. RESULTS: Eighty patients who met inclusion criteria were included. A total of 39 patients were localized after NAT completion (49%). Only half of the patients with ultrasound-detectable marker clips were able to be localized. Minimal LN abnormality was seen in imaging after NAT completion in 39 patients and is significantly associated with localization; 26 (67%) were localized (Odds Ratio 4.31, P = 0.002, 95% Confidence Interval 1.69-10.98). CONCLUSIONS: Our study suggests that radiologically abnormal LNs on preoperative imaging after NAT completion are more likely to be localized. Nodes that ultimately normalize by imaging criteria remain a significant challenge to localize, and thus localization before starting NAT is suggested. A better technology is needed for LN localization after prolonged NAT for best accuracy and avoids repeated procedures.

Autoimmune HLA Alleles and Neoepitope Presentation Predict Post-Allogenic Transplant Relapse.

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can cure patients with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, many patients relapse or develop debilitating graft-versus-host disease. Transplant restores T-cell reactivity against tumor cells, implicating patient human leukocyte antigen (HLA)-dependent antigen presentation via the major histocompatibility complex as a determinant of response. We sought to identify characteristics of the HLA genotype that influence response in allo-HSCT patients. Methods: We collected HLA genotype and panel-based somatic mutation profiles for 55 patients with AML and MDS and available data treated at the University of California San Diego Moores Cancer Center between May 2012 and January 2019. We evaluated characteristics of the HLA genotype relative to relapse-free time and overall survival (OS) post-allo-HSCT using univariable and multivariable regression. Results: In multivariable regression, the presence of an autoimmune allele was significantly associated with relapse-free time (hazard ratio [HR], 0.25; p = 0.01) and OS (HR, 0.16; p < 0.005). The better potential of the donor HLA type to present peptides harboring driver mutations trended toward better relapse-free survival (HR, 0.45; p = 0.07) and significantly correlated with longer OS (HR, 0.33; p = 0.01) though only a minority of cases had an HLA mismatch. Conclusion: In this single institution retrospective study of patients receiving allo-HSCT for relapsed AML/MDS, characteristics of an individual's HLA genotype (presence of an autoimmune allele and potential of the donor HLA to better present peptides representing driver mutations) were significantly associated with better outcomes. These findings suggest that HLA type may guide the optimal application of allo-HSCT and merit evaluation in larger cohorts. ClinicalTrials.gov Identifier: NCT02478931.