Up-regulated PLA2G10 in cancer impairs T cell infiltration to dampen immunity.

T cells are often absent from human cancer tissues during both spontaneously induced immunity and therapeutic immunotherapy, even in the presence of a functional T cell-recruiting chemokine system, suggesting the existence of T cell exclusion mechanisms that impair infiltration. Using a genome-wide in vitro screening platform, we identified a role for phospholipase A2 group 10 (PLA2G10) protein in T cell exclusion. PLA2G10 up-regulation is widespread in human cancers and is associated with poor T cell infiltration in tumor tissues. PLA2G10 overexpression in immunogenic mouse tumors excluded T cells from infiltration, resulting in resistance to anti-PD-1 immunotherapy. PLA2G10 can hydrolyze phospholipids into small lipid metabolites, thus inhibiting chemokine-mediated T cell mobility. Ablation of PLA2G10's enzymatic activity enhanced T cell infiltration and sensitized PLA2G10-overexpressing tumors to immunotherapies. Our study implicates a role for PLA2G10 in T cell exclusion from tumors and suggests a potential target for cancer immunotherapy.

Screws or Sutures? A Pediatric Cadaveric Study of Tibial Spine Fracture Repairs.

BACKGROUND: Tibial spine fractures are common in the pediatric population because of the biomechanical properties of children's subchondral epiphyseal bone. Most studies in porcine or adult human bone suggest that suture fixation performs better than screw fixation, but these tissues may be poor surrogates for pediatric bone. No previous study has evaluated fixation methods in human pediatric knees. PURPOSE: To quantify the biomechanical properties of 2-screw and 2-suture repair of tibial spine fracture in human pediatric knees. STUDY DESIGN: Controlled laboratory study. METHODS: Cadaveric specimens were randomly assigned to either 2-screw or 2-suture fixation. A standardized Meyers-Mckeever type 3 tibial spine fracture was induced. Screw-fixation fractures were reduced with two 4.0-mm cannulated screws and washers. Suture-fixation fractures were reduced by passing 2 No. 2 FiberWire sutures through the fracture fragment and the base of the anterior cruciate ligament. Sutures were secured through bony tunnels over a 1-cm tibial cortical bridge. Each specimen was mounted at 30° of flexion. A cyclic loading protocol was applied to each specimen, followed by a load-to-failure test. Outcome measures were ultimate failure load, stiffness, and fixation elongation. RESULTS: Twelve matched pediatric cadaveric knees were tested. Repair groups had identical mean (8.3 years) and median (8.5 years) ages and an identical number of samples of each laterality. Ultimate failure load did not significantly differ between screw (mean ± SD, 143.52 ± 41.9 7 N) and suture (135.35 ± 47.94 N) fixations (P = .760). Screws demonstrated increased stiffness and decreased elongation, although neither result was statistically significant at the .05 level (21.79 vs 13.83 N/mm and 5.02 vs 8.46 mm; P = .076 and P = .069, respectively). CONCLUSION: Screw fixation and suture fixation of tibial spine fractures in human pediatric tissue were biomechanically comparable. CLINICAL RELEVANCE: Suture fixations are not biomechanically superior to screw fixations in pediatric bone. Pediatric bone fails at lower loads, and in different modes, compared with adult cadaveric bone and porcine bone. Further investigation into optimal repair is warranted, including techniques that may reduce suture pullout and "cheese-wiring" through softer pediatric bone. This study provides new biomechanical data regarding the properties of different fixation types in pediatric tibial spine fractures to inform clinical management of these injuries.

BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome.

Mosaic-variegated aneuploidy (MVA) syndrome is a rare childhood disorder characterized by biallelic BUBR1, CEP57, or TRIP13 aberrations; increased chromosome missegregation; and a broad spectrum of clinical features, including various cancers, congenital defects, and progeroid pathologies. To investigate the mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the BUBR1L1012P mutation in mice (BubR1L1002P) and combined it with 2 other MVA variants, BUBR1X753 and BUBR1H, generating a truncated protein and low amounts of wild-type protein, respectively. Whereas BubR1X753/L1002P and BubR1H/X753 mice died prematurely, BubR1H/L1002P mice were viable and exhibited many MVA features, including cancer predisposition and various progeroid phenotypes, such as short lifespan, dwarfism, lipodystrophy, sarcopenia, and low cardiac stress tolerance. Strikingly, although these mice had a reduction in total BUBR1 and spectrum of MVA phenotypes similar to that of BubR1H/H mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype complexity. Additionally, mice carrying monoallelic BubR1 mutations were prone to select MVA-related pathologies later in life, with predisposition to sarcopenia correlating with mTORC1 hyperactivity. Together, these data demonstrate that BUBR1 allelic effects beyond protein level and aneuploidy contribute to disease heterogeneity in both MVA patients and heterozygous carriers of MVA mutations.

Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation.

Cyclin A2 activates the cyclin-dependent kinases Cdk1 and Cdk2 and is expressed at elevated levels from S phase until early mitosis. We found that mutant mice that cannot elevate cyclin A2 are chromosomally unstable and tumor-prone. Underlying the chromosomal instability is a failure to up-regulate the meiotic recombination 11 (Mre11) nuclease in S phase, which leads to impaired resolution of stalled replication forks, insufficient repair of double-stranded DNA breaks, and improper segregation of sister chromosomes. Unexpectedly, cyclin A2 controlled Mre11 abundance through a C-terminal RNA binding domain that selectively and directly binds Mre11 transcripts to mediate polysome loading and translation. These data reveal cyclin A2 as a mechanistically diverse regulator of DNA replication combining multifaceted kinase-dependent functions with a kinase-independent, RNA binding-dependent role that ensures adequate repair of common replication errors.