Two loss-of-function ANKRD11 variants in Chinese patients with short stature and a possible molecular pathway.

KBG syndrome is a rare genetic disease characterized mainly by skeletal abnormalities, distinctive facial features, and intellectual disability. Heterozygous mutations in ANKRD11 gene, or deletion of 16q24.3 that includes ANKRD11 gene are the cause of KBG syndrome. We describe two patients presenting with short stature and partial facial features, whereas no intellectual disability or hearing loss was observed in them. Two ANKRD11 variants, c.4039_4041del (p. Lys1347del) and c.6427C > G (p. Leu2143Val), were identified in this study. Both of them were classified as variants of uncertain significance (VOUS) by ACMG/AMP guidelines and were inherited from their mothers. ANKRD11 could enhance the transactivation of p21 gene, which was identified to participate in chondrogenic differentiation. In this study, we demonstrated that the knockdown of ANKRD11 could reduce the p21-promoter luciferase activities while re-introduction of wild type ANKRD11, but not ANKRD11 variants (p. Lys1347del or p. Leu2143Val), could restore the p21 levels. Thus, our study report two loss-of-function ANKRD11 variants which might provide new insight on pathogenic mechanism that correlates ANKRD11 variants with the short stature phenotype of KBG syndrome.

Nanoclay Reinforced Integrated Scaffold for Dual-Lineage Regeneration of Cartilage and Subchondral Bone.

Tissue engineering is theoretically considered a promising approach for repairing osteochondral defects. Nevertheless, the insufficient osseous support and integration of the cartilage layer and the subchondral bone frequently lead to the failure of osteochondral repair. Drawing from this, it was proposed that incorporating glycine-modified attapulgite (GATP) into poly(1,8-octanediol-co-citrate) (POC) scaffolds via the one-step chemical cross-linking is proposed to enhance cartilage and subchondral bone defect repair simultaneously. The effects of the GATP incorporation ratio on the physicochemical properties, chondrocyte and MC3T3-E1 behavior, and osteochondral defect repair of the POC scaffold were also evaluated. In vitro studies indicated that the POC/10% GATP scaffold improved cell proliferation and adhesion, maintained cell phenotype, and upregulated chondrogenesis and osteogenesis gene expression. Animal studies suggested that the POC/10% GATP scaffold has significant repair effects on both cartilage and subchondral bone defects. Therefore, the GATP-incorporated scaffold system with dual-lineage bioactivity showed potential application in osteochondral regeneration.

Polydopamine-modified ZIF-8 nanoparticles as a drug carrier for combined chemo-photothermal osteosarcoma therapy.

Single chemotherapy often causes severe adverse effects and chemoresistance which limits therapeutic efficacy. Recently, combination of chemotherapy with photothermal therapy (PTT) have received broad attention for synergistic treatment of osteosarcoma, ultimately resulting in the enhancement of therapeutic efficacy of anticancer drugs. In this study, we have developed a novel drug delivery system based on polydopamine (pDA)-modified ZIF-8 nanoparticles loaded with methotrexate (MTX) (pDA/MTX@ZIF-8 NPs). Herein, pDA modification avoided the explosive release of the drug, and improved the biocompatibility and near-infrared (NIR) light absorbance performance of nanoparticles. The as-prepared pDA/MTX@ZIF-8 NPs could be used as drug targeting delivery system and simultaneously displayed excellent photothermal effects under NIR irradiation. Biology assays in vitro indicated that the pDA/MTX@ZIF-8 NPs were able to efficiently induce MG63 cell apoptosis through reducing mitochondrial membrane potentials (MMPs), and the introduction of photothermal agents enhanced the antitumor effect and decreased the dose of chemotherapeutic drugs. Moreover, the optimized pDA/MTX@ZIF-8 NPs (40 µg/mL) exhibited better photothermal conversion performance and facilitated tumor cells death. These results triumphantly exhibit that the pDA/MTX@ZIF-8 NPs have a synergistic effect of chemo-photothermal therapy (combination index CI = 0.346) and excellent biocompatibility, which has unexceptionable prospects for the therapy of osteosarcoma.

A Novel Loss-of-Function MKRN3 Variant in a Chinese Patient With Familial Precocious Puberty: A Case Report and Functional Study.

Background: Central precocious puberty (CPP) is one of the most common and complex problems in clinical pediatric endocrinology practice. Mutation of the MKRN3 gene can cause familial CPP. Methods and Results: Here we reported a Chinese patient bearing a novel MKRN3 mutation (c.G277A/p.Gly93Ser) and showing the CPP phenotype. Functional studies found that this mutation of MKRN3 attenuated its autoubiquitination, degradation, and inhibition on the transcriptional activity of GNRH1, KISS1, and TAC3 promoters. Conclusion: MKRN3 (Gly93Ser) is a loss-of-function mutation, which attenuates the inhibition on GnRH1-related signaling, suggesting that this mutant can lead to central precocious puberty.