Search

Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10–8): rs781716 (P = 4.71 × 10–9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10–8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10–9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10–8, OR = 0.45; P = 3.31 × 10–8, OR = 0.45; P = 1.09 × 10–8, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10–8, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10–6). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821–55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.

Prussian blue nanoparticle‐based photothermal therapy (PBNP‐PTT) is an effective tumor treatment capable of eliciting an antitumor immune response. Motivated by the ability of PBNP‐PTT to potentiate endogenous immune responses, we recently demonstrated that PBNP‐PTT could be used ex vivo to generate tumor‐specific T cells against glioblastoma (GBM) cell lines as an adoptive T cell therapy (ATCT). In this study, we further developed this promising T cell development platform. First, we assessed the phenotype and function of T cells generated using PBNP‐PTT. We observed that PBNP‐PTT facilitated CD8+ T cell expansion from healthy donor PBMCs that secreted IFNγ and TNFα and upregulated CD107a in response to engagement with target U87 cells, suggesting specific antitumor T cell activation and degranulation. Further, CD8+ effector and effector memory T cell populations significantly expanded after co‐culture with U87 cells, consistent with tumor‐specific effector responses. In orthotopically implanted U87 GBM tumors in vivo, PBNP‐PTT‐derived T cells effectively reduced U87 tumor growth and generated long‐term survival in >80% of tumor‐bearing mice by Day 100, compared to 0% of mice treated with PBS, non‐specific T cells, or T cells expanded from lysed U87 cells, demonstrating an enhanced antitumor efficacy of this ATCT platform. Finally, we tested the generalizability of our approach by generating T cells targeting medulloblastoma (D556), breast cancer (MDA‐MB‐231), neuroblastoma (SH‐SY5Y), and acute monocytic leukemia (THP‐1) cell lines. The resulting T cells secreted IFNγ and exerted increased tumor‐specific cytolytic function relative to controls, demonstrating the versatility of PBNP‐PTT in generating tumor‐specific T cells for ATCT. [ABSTRACT FROM AUTHOR]

Activating mutations in genes encoding phosphatidylinositol 3-kinase (PI3K)-AKT pathway components cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH, OMIM 603387). Here we report that individuals with MPPH lacking upstream PI3K-AKT pathway mutations carry de novo mutations in CCND2 (encoding cyclin D2) that are clustered around a residue that can be phosphorylated by glycogen synthase kinase 3β (GSK-3β). Mutant CCND2 was resistant to proteasomal degradation in vitro compared to wild-type CCND2. The PI3K-AKT pathway modulates GSK-3β activity, and cells from individuals with PIK3CA, PIK3R2 or AKT3 mutations showed similar CCND2 accumulation. CCND2 was expressed at higher levels in brains of mouse embryos expressing activated AKT3. In utero electroporation of mutant CCND2 into embryonic mouse brains produced more proliferating transfected progenitors and a smaller fraction of progenitors exiting the cell cycle compared to cells electroporated with wild-type CCND2. These observations suggest that cyclin D2 stabilization, caused by CCND2 mutation or PI3K-AKT activation, is a unifying mechanism in PI3K-AKT-related megalencephaly syndromes.

This essay presents a brief introduction to the special issue of the Journal of Rural Social Sciences focused on heirs’ property. Real property transferred over generations without a proper will or other transfer device, heirs’ property and heirs’ property owners are vulnerable to a range of challenges, from limited productive land use to the actual loss of land. A situation that is national in scope, heirs’ property rates are particularly high in the southern region of the United States and among African Americans. Articles in this special issue address operationalizing and measuring heirs’ property at the county-level, describing the characteristics of people seeking assistance with heirs’ property, and the situation and implications faced in a state with limited protections of families with heirs’ property. [ABSTRACT FROM AUTHOR]

Objective: To determine early magnetic resonance imaging (MRI) features of new multiple sclerosis (MS) lesions that will develop into paramagnetic rim lesions (PRLs), which have been associated with progressive tissue injury in MS. Methods: New contrast‐enhancing lesions observed on routine clinical MRI were imaged at 7 T within 4 weeks of observation, and 3 and 6 months later. The 6‐month MRI was used to classify PRL status (PRL or non‐PRL). The relationship between early lesion characteristics and subsequent PRL status was assessed using generalized linear mixed effects models. Random forest classification was performed to classify early predictors of subsequent PRL status. Results: From 93 contrast‐enhancing lesions in 23 MS patients, 37 lesions developed into a PRL. In lesions that developed into PRLs compared with those that did not, the average lesion T1 on the initial 7 T MRI was 1994 ms compared with 1,670 ms (p‐value <0.001), and the average volume was 168.7 mL compared with 44 mL (p‐value <0.001) in lesions that did not. These volume differences were also found on 3 T scans (p‐value <0.001), and for intensity‐normalized T1‐w (p‐value = 0.011) and fluid‐attenuated inversion recovery (p‐value = 0.005). The area under the receiver operating characteristic curve for the random forest classification with leave‐one‐out cross‐validation was found to be 0.86 using initial 7 T features. Interpretation: New MS lesions that evolve into PRLs can be identified early in lesion evolution. These findings suggest that biological mechanisms underlying PRL development begin early, which has important implications for clinical trials targeting PRLs development and subsequent therapeutics. ANN NEUROL 2023;94:736–744 [ABSTRACT FROM AUTHOR]