New drug approvals for 2022: Synthesis and clinical applications.

The U.S. Food and Drug Administration has approved a total of 37 new drugs in 2022, which are composed of 20 chemical entities and 17 biologics. In particular, 20 chemical entities, including 17 small molecule drugs, 1 radiotherapy, and 2 diagnostic agents, provide privileged scaffolds, breakthrough clinical benefits, and a new mechanism of action for the discovery of more potent clinical candidates. The structure-based drug development with clear targets and fragment-based drug development with privileged scaffolds have always been the important modules in the field of drug discovery, which could easily bypass the patent protection and bring about improved biological activity. Therefore, we summarized the relevant valuable information about clinical application, mechanism of action, and chemical synthesis of 17 newly approved small molecule drugs in 2022. We hope this timely and comprehensive review could bring about creative and elegant inspiration on the synthetic methodologies and mechanism of action for the discovery of new drugs with novel chemical scaffolds and extended clinical indications.

Metabolomics-transcriptomics joint analysis: unveiling the dysregulated cell death network and developing a diagnostic model for high-grade neuroblastoma.

High-grade neuroblastoma (HG-NB) exhibits a significantly diminished survival rate in comparison to low-grade neuroblastoma (LG-NB), primarily attributed to the mechanism of HG-NB is unclear and the lacking effective therapeutic targets and diagnostic model. Therefore, the current investigation aims to study the dysregulated network between HG-NB and LG-NB based on transcriptomics and metabolomics joint analysis. Meanwhile, a risk diagnostic model to distinguish HG-NB and LG-NB was also developed. Metabolomics analysis was conducted using plasma samples obtained from 48 HG-NB patients and 36 LG-NB patients. A total of 39 metabolites exhibited alterations, with 20 showing an increase and 19 displaying a decrease in HG-NB. Additionally, transcriptomics analysis was performed on NB tissue samples collected from 31 HG-NB patients and 20 LG-NB patients. Results showed that a significant alteration was observed in a total of 1,199 mRNAs in HG-NB, among which 893 were upregulated while the remaining 306 were downregulated. In particular, the joint analysis of both omics data revealed three aberrant pathways, namely the cAMP signaling pathway, PI3K-Akt signaling pathway, and TNF signaling pathway, which were found to be associated with cell death. Notably, a diagnostic model for HG-NB risk classification was developed based on the genes MGST1, SERPINE1, and ERBB3 with an area under the receiver operating characteristic curve of 0.915. In the validation set, the sensitivity and specificity were determined to be 75.0% and 80.0%, respectively.

Risk factors of early liver dysfunction after liver transplantation using grafts from donation after citizen death donors.

BACKGROUND: As an early complication after liver transplantation, early allograft dysfunction (EAD) indicates a poor prognosis. This study analyzes the risk factors related to early allograft dysfunction (EAD) after liver transplantation using grafts from donation after citizen death (DCD) to provide a reference for the prevention of EAD after DCD liver transplantation. METHODS: A total of 32 patients who underwent DCD liver transplantation in the organ transplantation center of our hospital from September 2013 to January 2021 were enrolled in this study. The patients were divided into the EAD group and non-EAD group according to whether they developed EAD after transplantation. The general data of the donors and recipients before transplantation, intraoperative conditions, and clinical data within one week after transplantation were compared between the two groups, and related complications were statistically analyzed. The follow-up time was one week postoperatively or, if they died within the first week postoperatively, until the patient died. RESULTS: The subjects included 10 females and 22 males, and the incidence of postoperative EAD was 25% (8/32). Four patients (12%) had primary malignant tumors (primary liver cancer and cholangiocarcinoma), and five donors (15%) had fatty liver. The univariate analysis revealed that the donor BMI (P = 0.005), degree of fatty liver (P = 0.025), aspartate aminotransferase (P = 0.001), alanine aminotransferase (P < 0.001), and total bilirubin (P = 0.009) were related to the occurrence of EAD after DCD liver transplantation. By analyzing the correlation between the incidence EAD and postoperative complications after liver transplantation using grafts from DCD donors, it was shown that the incidence of primary nonfunction (PNF) is related to EAD (P = 0.024). CONCLUSION: Donor BMI, the degree of fatty liver, and preoperative liver function are risk factors for EAD after DCD liver transplantation, and the occurrence of EAD after DCD liver transplantation significantly increases the probability of PNF.

An Analysis of the Risk Factors for New-Onset Diabetes Mellitus After Liver Transplantation.

OBJECTIVE: To investigate the risk factors related to new-onset diabetes mellitus (NODM) and the significance of IL-6. METHODS: A retrospective analysis was conducted on clinical data from 64 patients who received either a living donor liver transplantation or a donation after circulatory death from September 2013 to October 2020 and attended regular follow-up visits for six or more months. During follow-up, patients were randomized into groups and followed up until the completion of the study or the death of the patient. RESULTS: The incidence of NODM was 31.25% (n = 20). The median age in the NODM group was 52.15 years (p < 0.01). Age (OR = 1.089; 95% CI: 0.0211-0.1495, p = 0.003) and elevated preoperative IL-6 (OR = 1.122; 95% CI: 0.0619-0.1677, p = 0.029) were found to be independent risk factors for NODM. HBV-induced liver cirrhosis, warm ischemia time (WIT), body mass index (BMI), and high preoperative fasting blood glucose (FBG) were also found to be risk factors for NODM. The recipient had a higher risk of NODM if the donor had a high BMI and poor hepatic function. The concentrations of IL-6, procalcitonin (PCT), FBG, and tacrolimus (TAC) in the first month postoperatively were significantly higher in the NODM group than in the NO-NODM group. The survival rate of the patients was not affected by NODM. CONCLUSION: HBV-induced liver cirrhosis, WIT, BMI, and high preoperative FBG levels are risk factors for NODM, and age and preoperative IL-6 levels are independent risk factors. To a certain extent, higher BMI and poor hepatic function had reference significance for the incidence of NODM. Patients with a high concentration of FBG, IL-6, and TAC in the first month postoperatively had an increased risk of suffering from NODM.