Identification of a Novel Germline PPP4R3A Missense Mutation Asp409Asn on Familial Non-Medullary Thyroid Carcinoma.

Familial non-medullary thyroid carcinoma (FNMTC) accounts for 3% to 9% of all thyroid cancer cases, yet its genetic mechanisms remain unknown. Our study aimed to screen and identify novel susceptibility genes for FNMTC. Whole-exome sequencing (WES) was conducted on a confirmed FNMTC pedigree, comprising four affected individuals across two generations. Variants were filtered and analyzed using ExAC and 1000 Genomes Project, with candidate gene pathogenicity predicted using SIFT, PolyPhen, and MutationTaster. Validation was performed through Sanger sequencing in affected pedigree members and sporadic patients (TCGA database) as well as general population data (gnomAD database). Ultimately, we identified the mutant PPP4R3A (NC_000014.8:g.91942196C>T, or NM_001366432.2(NP_001353361.1):p.(Asp409Asn), based on GRCH37) as an FNMTC susceptibility gene. Subsequently, a series of functional experiments were conducted to investigate the impact of PPP4R3A and its Asp409Asn missense variant in thyroid cancer. Our findings demonstrated that wild-type PPP4R3A exerted tumor-suppressive effects via the Akt-mTOR-P70 S6K/4E-BP1 axis. However, overexpression of the PPP4R3A Asp409Asn mutant resulted in loss of tumor-suppressive function, ineffective inhibition of cell invasion, and even promotion of cell proliferation and migration by activating the Akt/mTOR signaling pathway. These results indicated that the missense variant PPP4R3A Asp409Asn is a candidate susceptibility gene for FNMTC, providing new insights into the diagnosis and intervention of FNMTC.

A Phase-Field Study of Spinodal Decomposition Impeded by Irradiation in U-Mo and U-Mo-Zr Alloys.

The phase-field method, coupled with the micro-elastic model and irradiation-induced cascade mixing model, has been employed to investigate the spinodal decomposition in U-Mo and U-Mo-Zr alloys. The microstructure evolution of U-Mo or U-Mo-Zr alloys under different initial conditions, such as the alloy composition, aging temperature and irradiation intensity, were simulated to study the effect of cascade mixing on the miscibility gap, morphology and volume fraction of the decomposed phases. The simulation results demonstrate that irradiation-induced cascade mixing impedes the process of spinodal decomposition, and that irradiation shrinks the composition range of the miscibility gap in the alloys. Irradiation-induced cascade mixing slows down the anisotropic growth rate of the spinodal decomposition, yet this phenomenon can be weakened with increasing aging temperature. Adding an appropriate amount of Zr to a U-Mo alloy can effectively prevent the contraction of the miscibility gap caused by irradiation.

Radioactive iodine therapy strategies for distinct types of differentiated thyroid cancer: a propensity score-matched analysis.

Background: The management guidelines of radioactive Iodine (RAI) therapy for distinct types of differentiated thyroid carcinoma (DTC) were the same in clinical practice. However, in distinct types DTC, differences in RAI avidity and response existed and the effect of RAI therapy could not be equated. Methods: DTC patients' data in SEER database were extracted to perform retrospective analysis. The differences between case group and control group were compared by chi-square tests. We used Kaplan-Meier statistics and Cox regression analyses to investigate cancer-specific survival (CSS). Propensity score-matched was performed to make 1:1 case-control matching. Results: 105195 patients who receiving total thyroidectomy were identified in SEER database. Compared to papillary thyroid carcinoma (PTC) (52.3%), follicular thyroid carcinoma (FTC) (63.8%) and oncocytic carcinoma of thyroid (OCA) (64.4%) had higher rates of RAI therapy. In the multivariable Cox regression model, RAI therapy was independent prognosis factor in PTC but not in OCA and FTC. In subgroup analysis, RAI therapy could improve prognosis in PTC when gross extrathyroidal extension or lymph node metastases or early survival when distant metastases (DM) were presented. However, OCA and FTC patients with DM rather than regional lesions only could benefit from RAI therapy. High-risk patients receiving RAI therapy showed a better prognosis in PTC but not in OCA and FTC. Conclusion: RAI therapy was an effective treatment for DTC and should be considered individually in PTC, OCA and FTC patients. Our results provided further guideline for treatment selection in DTC.

Effect of irradiation-induced cascade mixing on spinodal decomposition in U-Nb and U-Zr alloys: a phase field study.

The spinodal decomposition of the γ-phase in U-Nb and U-Zr alloys under irradiation was investigated using the phase-field method coupled with micro-elasticity theory and rate dependent cascade mixing model. Microstructure evolutions of spinodal decomposition in U-Nb and U-Zr alloys were simulated by considering different initial compositions and dose rates. The volume fraction and composition distribution under different cascade mixing were presented. The simulation results show that the volume fractions and equilibrium composition of the (Nb,Zr)-rich γ2-phase and the rate of spinodal decomposition are influenced by the dose rate and initial alloy composition. The cascade mixing can drive Nb or Zr atoms back into solution until a new equilibrium state between local cascade mixing and spinodal decomposition is reached. The evolution analysis indicated that irradiation-induced cascade mixing acts in opposition to thermodynamically driven spontaneous spinodal decomposition, which can not only slow down the spinodal decomposition but also reduces the composition range of the miscibility gap.