Factors associated with immune-related thyroid dysfunction induced by PD-1/PD-L1 inhibitors in cancer patients: an observational study.

This study aimed to identify the potential factors associated with immune thyroid dysfunction caused by programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors in cancer patients. We conducted a retrospective study of thyroid immune-related adverse events (irAEs) in cancer patients treated with PD-1/PD-L1 inhibitors at Tianjin First Central Hospital from January 2020 to March 2023. Thyroid irAEs were characterized as hypothyroidism, hyperthyroidism and thyrotoxicosis followed by hypothyroidism. A total of 175 patients were screened in the study, of whom 48 patients (27%) developed thyroid irAEs (including 24 hypothyroidism, 11 hyperthyroidism and 13 thyrotoxicosis followed by hypothyroidism) following PD-1/PD-L1 inhibitors treatment. Multivariate logistic regression analysis showed that combination therapy with PD-1/PD-L1 inhibitors and tyrosine kinase inhibitors (lenvatinib/regorafenib) and high baseline anti-TPO level were associated with the development of thyroid irAEs caused by PD-1/PD-L1 inhibitors. The nomogram models showed good discriminant ability and could bring net benefits for more patients according to the decision curve analysis. However, the model needs to be further validated in other large cohorts.

Phosphorylation of RasGRP1 by Shc3 prevents RasGRP1 degradation and contributes to Ras/c-Jun activation in hepatocellular carcinoma.

Ras guanine nucleotide-releasing protein 1 (RasGRP1), a Ras activator, is upregulated in hepatocellular carcinoma (HCC) and other kinds of cancer and is associated with the poor prognosis of patients. However, little is known about the underlying regulatory mechanisms of RasGRP1 in the context of cancer. Here, we report that RasGRP1 physically interacted with the adaptor protein Src homolog and collagen homolog 3 (Shc3). Moreover, RasGRP1 C-terminus domain (aa 607-797) bound to the central collagen-homology 1 (CH1) domain of Shc3. Subsequently, Shc3 enhanced the RasGRP1 tyrosine phosphorylation rate and stability by inhibiting its ubiquitination. Notably, the phosphorylation-mimicking mutants of RasGRP1, RasGRP1 Y704A, and Y748A, rescued the phosphorylation and ubiquitination levels of RasGRP1 in HCC cells. Further investigation showed that the RasGRP1 and Shc3 interaction induced activation of Ras and c-Jun, resulting in cell proliferation in vitro. Moreover, the regulation of Shc3/RasGRP1/Ras/c-Jun signal transduction was confirmed in vivo using the subcutaneous xenograft mouse model. Thus, we propose that continuous Shc3 overexpression may be a possible mechanism for maintaining RasGRP1 stability and that persistent activation of Ras/c-Jun signaling through the interaction of RasGRP1 and Shc3 is a key event increasing cell proliferation. Our findings suggest that the interaction of RasGRP1 and Shc3 plays an important role in HCC tumorigenesis and suggests the potential clinical usage of novel biomarkers and therapeutic targets in HCC.

Recommendation of Antimicrobial Dosing Optimization During Continuous Renal Replacement Therapy.

Continuous Renal Replacement Therapy (CRRT) is more and more widely used in patients for various indications recent years. It is still intricate for clinicians to decide a suitable empiric antimicrobial dosing for patients receiving CRRT. Inappropriate doses of antimicrobial agents may lead to treatment failure or drug resistance of pathogens. CRRT factors, patient individual conditions and drug pharmacokinetics/pharmacodynamics are the main elements effecting the antimicrobial dosing adjustment. With the development of CRRT techniques, some antimicrobial dosing recommendations in earlier studies were no longer appropriate for clinical use now. Here, we reviewed the literatures involving in new progresses of antimicrobial dosages, and complied the updated empirical dosing strategies based on CRRT modalities and effluent flow rates. The following antimicrobial agents were included for review: flucloxacillin, piperacillin/tazobactam, ceftriaxone, ceftazidime/avibactam, cefepime, ceftolozane/tazobactam, sulbactam, meropenem, imipenem, panipenem, biapenem, ertapenem, doripenem, amikacin, ciprofloxacin, levofloxacin, moxifloxacin, clindamycin, azithromycin, tigecycline, polymyxin B, colistin, vancomycin, teicoplanin, linezolid, daptomycin, sulfamethoxazole/trimethoprim, fluconazole, voriconazole, posaconzole, caspofungin, micafungin, amphotericin B, acyclovir, ganciclovir, oseltamivir, and peramivir.