CARD9 (Caspase Recruitment Domain Family Member 9)

The plasma eccDNA landscape may serve as an early and powerful non-invasive biomarker for CRC prognostication, optimizing risk stratification and guiding personalized treatment.

This study confirmed through MR analysis that CD was a potential risk factor for UVM. Additionally, CARD9 and TNFSF15 were identified as key genes closely associated with patient prognosis, providing new evidence for the pathogenic mechanisms of UVM. These findings were of significant importance for the prevention and control of UVM risk in patients with chronic inflammation, as well as for the development of personalized treatment strategies.

This persistent invasion results in excessive neutrophil recruitment and activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasomes, causing mucosal damage. In conclusion, Card9 deficiency compromises the vaginal epithelial barrier, prolongs C. albicans infection, and increases inflammation, highlighting the critical role of Card9 in maintaining immune function of vaginal mucosa.

P4, N=10, Terminated, Cedars-Sinai Medical Center | N=24 --> 10 | Trial completion date: Dec 2025 --> Jan 2025 | Recruiting --> Terminated; Recruitment challenges; changes in manufacturing

Interestingly, the combination of navitoclax, an inhibitor of BcL2 family members including BCL2L2, was synergistic in all four of the mEOC cell lines tested and substantially induced cell death through apoptosis. These data support the use of a combination of navitoclax and onvansertib as a new therapeutic strategy for mEOC.

However, Card9 deletion did not affect overall adaptive antibody production or delayed-type hypersensitivity following immunization with CFA, indicating that humoral and type 1 immune responses remained intact. These results suggest that avoiding the activation of Card9 signaling during vaccination with mycobacteria-containing vaccines may mitigate the risk of detrimental type 3 immune responses, while preserving type 1 immune responses that are effective against intracellular pathogens and cancers.

Macrophage CARD9 was elevated in heart tissues of mice under chronic ISO administration. Either whole-body CARD9 knockout or myeloid-specific CARD9 deficiency protected mice from ISO-induced inflammatory heart remodeling. ISO promoted the assembly of CBM complex and then activated NF-κB signaling in macrophages through OTUD1-mediated deubiquitinating modification. OTUD1 deletion in myeloid cells protected hearts from ISO-induced injuries in mice.

The chimeric CARD9 approach was subsequently validated by using several known disease-associated mutations in CARD10 and CARD14, and additional screening allowed us to identify several previously unknown activating natural variants in human CARD9 and CARD10. Using Genebass as a resource of exome-based disease association statistics, we found that activated alleles of CARD9 correlate with irritable bowel syndrome (IBS), constipation, osteoarthritis, fibromyalgia, insomnia, anxiety and depression, which can occur as comorbidities.

P4, N=24, Recruiting, Cedars-Sinai Medical Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024