TWF1 induces autophagy and accelerates malignant phenotype in lung adenocarcinoma via inhibiting the cAMP signaling pathway.

Many studies have shown that the actin cytoskeleton plays an essential role in the initiation and progression of cancer. As an actin-binding protein, Twinfilin1 (TWF1) plays an important role in regulating cytoskeleton-related functions. However, little is known about the expression and function of TWF1 in human tumors. The present study aimed to investigate the functional roles and the underlying molecular mechanisms of TWF1 in human lung adenocarcinoma (LUAD). By using bioinformatics databases and tumor tissues, TWF1 expression was found to be higher in LUAD tissues than in adjacent tissues and poor survival was predicted in patients with LUAD. In vitro and in vivo assays indicated that downregulation of TWF1 expression suppressed LUAD cells invasion and migration. Further studies revealed that TWF1 interacted with p62 and was involved in the regulation of autophagy. The molecular mechanisms underlying TWF1 were investigated by RNA-seq analysis and a series of functional experiments. The results showed that downregulation of TWF1 suppressed LUAD progression through the cAMP signaling pathway. Therefore, overexpression of TWF1 in LUAD promoted migration, invasion, and autophagy through the cAMP signaling pathway.

Detection and genetic characterization of Toxoplasma gondii in market-sold mussels (Mytilus edulis) in certain provinces of China.

Mussels, randomly collected from fish markets in China, were analyzed by a semi-nested PCR to detect B1 gene of Toxoplasma gondii. Out of the 2215 samples, fifty-five (2.48%) were detected T. gondii-positive. The prevalence in Shandong province, Liaoning province and Zhejiang province were 2.51%, 2.26% and 2.69%, respectively. T. gondii oocysts were more frequently detected in digestive glands (1.04%) and haemolymph (1.49%) when compared with gills (0.23%). Of the 55 positive DNA, only two samples showed complete genotype at 11 locus and were authenticated as ToxoDB Genotype #9. To our knowledge, the present study is the first to confirm the presence of T. gondii in market-sold mussels in China. The findings point to the risk of humans acquiring T. gondii infection by consuming mussels bought in the aquatic product market.

High incidence and reversible bradycardia events following alectinib initiation.

BACKGROUND: With the widespread use of alectinib in patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), its cardiotoxicity has gradually emerged, including new-onset sinus bradycardia (SB). However, the incidence, timing, severity, and risk factors of alectinib-induced bradycardia remain unknown. METHODS: From January 2020 to June 2022, 93 patients with ALK-positive NSCLC treated with alectinib were enrolled in this retrospective analysis. These patients had heart rate (HR) recorded before and after alectinib administration. By reviewing electronic medical records and follow-up, the HR changes of patients during medication were recorded. The potential risk factors associated with alectinib-induced SB were explored. RESULTS: According to an HR cut-off of 60 beats per minute (bpm), 47 patients (50.54%) experienced at least one recorded bradycardia. The mean HR of total participants before alectinib administration was 78.32 (standard deviation [SD], 9.48) and after was 64.88 (SD, 12.21). The median maximum change in HR (range) for all patients was 11 (-55, +4) bpm. For the bradycardia subgroup, the HR of most patients (76.60%) hovered around 50-60 bpm, and 61.70% of SB occurred within 3 months after alectinib administration. Multivariate analysis indicated that baseline HR (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.79-0.93, p < 0.001) and history of hypertension (OR 13.71, 95% CI 2.49-76.38, p = 0.003) were independent risk factors for alectinib-related bradycardia. CONCLUSIONS: Alectinib-induced bradycardia had a high incidence, appeared relatively early, and was reversible by dose reduction or withdrawal.

BUBs Are New Biomarkers of Promoting Tumorigenesis and Affecting Prognosis in Breast Cancer.

Background: A tumor occurs because of abnormal cell multiplication caused by many variables like a significant disturbance in the regulation of cell growth and the instability of chromosome mitosis. Budding uninhibited by benzimidazoles 1 (BUB1), BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B), and budding uninhibited by benzimidazoles 3 (BUB3) are key regulators of mitosis, and their abnormal expression is highly correlated with breast cancer (BrCa), sarcoma, hepatic carcinoma, and other malignant tumors. However, the occurrence of BUBs (BUB1, BUB1B, and BUB3) and the development of BrCa have not been systematically explained. Methods: Find out the target gene by looking up literature on PubMed and CNKI. Using the R software, TCGA, GEO, Kaplan-Meier Plotter, TIMER, and other databases, we studied the level of transcription, genetic changes, and physiological functions of BUBs in BrCa patients and their relationship with the origin, development, prognosis, immunity, and drug resistance of BrCa patients. Findings. We found that the high expression level of BUBs in BrCa tissues proposed a poor prognosis. The multivariate Cox regression analysis suggested that BUB1B and BUB3 might be independent prognostic factors of BrCa. In addition, the Metascape functional enrichment analysis showed that BUBs may be involved in the composition of the spindle, chromosome, and other structures and play a role in mitosis, sister chromatid separation, and other processes. Pathway enrichment suggests that BUBs may affect the cell cycle and lead to abnormal proliferation. Meanwhile, we also found that BUB3 can negatively regulate B lymphocytes, and BUB1 and BUB1B inhibit immune responses by promoting the secretion level of checkpoint molecules of the immune system, leading to immune escape of tumor cells. Conclusion: We speculate that BUB1, BUB1B, and BUB3 may be therapeutic targets for BrCa patients and also provide new therapeutic strategies for BrCa treatment.

Safety and efficacy of immune checkpoint inhibitors in advanced cancer patients with autoimmune disease: A meta-analysis.

Cancer patients with autoimmune disease (AID) are usually excluded from clinical trials involving immune checkpoint inhibitors (ICIs). The available electronic databases were systematically searched from inception until July 3, 2022. We recorded the incidence of immune-related adverse events (irAEs), progression-free survival (PFS), and overall survival (OS) data of included studies. This meta-analysis included 14 studies comprising 11511 participants; however, only 8716 participants were treated with ICI. Therefore, the analysis was conducted on 8716 patients (769 patients with AID compared to 7947 patients without AID). The pooled risk ratio (RR) for any grade and grade ≥3 irAEs was 1.74 (95% confidence interval [CI]: 1.27-2.37) and 1.43 (95% CI: 1.10-1.88), respectively. The irAEs in the same system as that of the AID were referred to as AID-homogeneous irAEs; in the other cases, there were referred to as AID-heterogeneous irAEs. Subgroup analysis found that the higher risk of AID-homogeneous irAEs contributed to the higher risk of overall irAEs among patients with AID. The pooled hazard ratio (HR) for PFS and OS was 1.09 (95% CI: 0.96-1.24) and 1.07 (95% CI: 0.94-1.22), respectively. The results of PFS and OS subgroup analyses matched the overall results. Patients with AID had a significantly higher risk of developing any grade and ≥3 grade irAEs under ICI therapy, specifically AID-homogeneous irAEs; however, the frequency of AID-heterogeneous irAEs in patients with AID was similar to irAEs in patients without AID. No statistically significant differences in PFS and OS were observed between the two groups.

The ecdysteroid receptor regulates salivary gland degeneration through apoptosis in Rhipicephalus haemaphysaloides.

BACKGROUND: It is well established that ecdysteroid hormones play an important role in arthropod development and reproduction, mediated by ecdysteroid receptors. Ticks are obligate hematophagous arthropods and vectors of pathogens. The salivary gland plays an essential role in tick growth and reproduction and in the transmission of pathogens to vertebrate hosts. During tick development, the salivary gland undergoes degeneration triggered by ecdysteroid hormones and activated by apoptosis. However, it is unknown how the ecdysteroid receptor and apoptosis regulate salivary gland degeneration. Here, we report the functional ecdysteroid receptor (a heterodimer of the ecdysone receptor [EcR] and ultraspiracle [USP]) isolated from the salivary gland of the tick Rhipicephalus haemaphysaloides and explore the molecular mechanism of ecdysteroid receptor regulation of salivary gland degeneration. METHODS: The full length of RhEcR and RhUSP open reading frames (ORFs) was obtained from the transcriptome. The RhEcR and RhUSP proteins were expressed in a bacterial heterologous system, Escherichia coli. Polyclonal antibodies were produced against synthetic peptides and were able to recognize recombinant and native proteins. Quantitative real-time PCR and western blot were used to detect the distribution of RhEcR, RhUSP, and RhCaspases in the R. haemaphysaloides organs. A proteomics approach was used to analyze the expression profiles of the ecdysteroid receptors, RhCaspases, and other proteins. To analyze the function of the ecdysteroid receptor, RNA interference (RNAi) was used to silence the genes in adult female ticks. Finally, the interaction of RhEcR and RhUSP was identified by heterologous co-expression assays in HEK293T cells. RESULTS: We identified the functional ecdysone receptor (RhEcR/RhUSP) of 20-hydroxyecdysone from the salivary gland of the tick R. haemaphysaloides. The RhEcR and RhUSP genes have three and two isoforms, respectively, and belong to a nuclear receptor family but with variable N-terminal A/B domains. The RhEcR gene silencing inhibited blood-feeding, blocked engorgement, and restrained salivary gland degeneration, showing the biological role of the RhEcR gene in ticks. In the ecdysteroid signaling pathway, RhEcR silencing inhibited salivary gland degeneration by suppressing caspase-dependent apoptosis. The heterologous expression in mammalian HEK293T cells showed that RhEcR1 interacts with RhUSP1 and induces caspase-dependent apoptosis. CONCLUSIONS: These data show that RhEcR has an essential role in tick physiology and represents a putative target for the control of ticks and tick-borne diseases.