UNC13D (Unc-13 Homolog D)

Proteomic analysis is helpful for discovering new protein markers. Using a combination of FHL3, CSRP2, and FCGR3A can increase the accuracy of the pathologic diagnosis of differentiated gastric adenocarcinoma with low-grade atypia.

Our findings, in line with national and international cohorts, confirm that HSCT remains the only curative option for familial HLH, and should be performed as early as possible after achieving disease remission. Improving access to early diagnostics and HSCT could significantly enhance outcomes, particularly in genetically predisposed populations.

Finally, clinical data validated the correlation between YAP, FHL3, and KRAS expression. In conclusion, we identified a new target of Hippo-YAP signaling, FHL3, which interacts with MAZ to promote KRAS transcription and downstream oncogenic signaling pathway activation, thereby promoting HCC progression.

P1/2, N=10, Active, not recruiting, St. Jude Children's Research Hospital | Trial primary completion date: Aug 2025 --> Nov 2025

Our single-cell transcriptomic dissection of NSCLC highlights cellular heterogeneity as well as potential biomarkers associated with immune microenvironment. The findings provide a foundation for the rational development of biomarker-driven personalized treatment and therapy by extending the cell-type specificity of current designs of NSCLC therapeutics.

However, many of genetic proxies used to instrument gene expression in CD4+ T cells also act as eQTLs in other tissues, highlighting the challenges of using genetic proxies to instrument tissue-specific expression changes. We demonstrate the importance of capturing the dynamic nature of CD4+ T cells in understanding CRC risk, and prioritize genes for further investigation in cancer prevention.

In addition, to explore the implication of UNC13D c.2588G>A variant in various diseases, we reviewed 16 published studies, including data on 35 patients carrying this variant. Data showed the heterozygous variant of UNC13D c.2588G>A might act as a genetic risk factor predisposing carriers to conditions like HLH, lymphoma, etc. This study underscores the pathogenic role of the UNC13D c.2588G>A variant and expands our understanding of the genetic basis of adult-onset HLH.

Our study revealed that SCAFs were strongly correlated with cancer stemness in HCC. A novel machine learning model based on senescent CAF-related genes was constructed to accurately predict prognosis in HCC patients. Furthermore, CTHRC1 was identified as a novel prognostic and therapeutic biomarker to predict poor prognosis in HCC and promote cancer stemness and metastasis through the Notch signaling pathway, with its expression being transcriptionally regulated by SOX4.

PML also occurs as a serious adverse event for a subset of immunosuppressive therapies (e.g., natalizumab and rituximab) used to treat patients with immune disorders (e.g., multiple sclerosis and hematological malignancies). Interestingly, of the 4 genes with a PML risk variant, 2 (LY9 and STXBP2) cause or are linked to HLH. The aim of our review is two-fold: (1) raise awareness among researchers and clinicians (e.g., neurologists, oncologists, and rheumatologists) that patient genetics are a key risk factor for PML, and (2) further reinforce the rationale for screening at-risk patients for PML risk variants before prescribing a PML-linked drug.

Patients with FHL-related germline mutations exhibited a trend towards better overall survival. In conclusion, germline mutations in FHL-related genes, particularly UNC13D, may contribute to PTCL susceptibility in Chinese patients and are associated with clonal somatic mutations.

However, our sensitivity analysis revealed that the genetic proxies used to instrument gene expression in CD4+ T cells also act as eQTLs in other tissues, highlighting the challenges of using genetic proxies to instrument tissue-specific expression changes. Our study demonstrates the importance of capturing the dynamic nature of CD4+ T cells in understanding disease risk, and prioritises genes for further investigation in cancer prevention research.

Our study provides a novel perspective on the potential causal link between the low expression of FHL3 gene and the risk of CRC. More evidence is essential to further reveal the biological mechanisms underlying this association.