Multiple myeloma (MM) is an incurable plasma cell malignancy with poor survival. Autophagy, a stress-responsive catabolic process mediated by lysosomal activity, plays a crucial role in the pathophysiology of MM. Growing evidence has indicated that dysregulated microRNAs (miRNAs) are associated with the aberrant autophagy in various human cancers. However, to date, few miRNAs have been reported to directly modulate autophagy in the pathobiology of MM. In this study, we investigated the role of MIR145-3p (microRNA 145-3p) in MM, with focus on cellular processes autophagy and cell death. Our results provided evidence that downregulation of MIR145-3p expression was associated with disease progression in human MM. MIR145-3p triggered autophagic flux through direct targeting of HDAC4 (histone deacetylase 4) in MM cells, leading to enhanced apoptosis. Silencing HDAC4 recapitulated the effects of MIR145-3p, whereas enforced expression of HDAC4 abrogated the effects of MIR145-3p. Furthermore, we showed that suppression of HDAC4 by MIR145-3p resulted in upregulation of the pro-apoptotic protein BCL2L11 and caused MTORC1 inactivation, which in turn led to enhanced autophagy and cell death. Importantly, we demonstrated that MIR145-3p mimic could potentiate the anti-MM activity of bortezomib in both in vitro and in vivo experiments. Overall, our findings indicate that MIR145-3p exerted a tumor suppression function in MM by inducing autophagic cell death and suggest that MIR145-3p-based targeted therapy would represent a novel strategy for MM treatment.

Background: N⁶-Methyladenosine (m⁶A) modification has been implicated in many biological processes. It is important for the regulation of messenger RNA (mRNA) stability, splicing, and translation. However, its role in cancer has not been studied in detail. Here we investigated the biological role and underlying mechanism of m⁶A modification in hepatoblastoma (HB). Methods: We used Reverse transcription quantitative real-time PCR (RT-qPCR) and Western blotting to determine the expression of m⁶A related factors. And we clarified the effects of these factors on HB cells using cell proliferation assay, colony formation, apoptotic assay. Then we investigated of methyltransferase-like 13 (METTL3) and its correlation with clinicopathological features and used xenograft experiment to check METTL3 effect in vivo. m⁶A-Seq was used to profiled m⁶A transcriptome-wide in hepatoblastoma tumor tissue and normal tissue. Finally, methylated RNA immunoprecipitation (MeRIP) assay, RNA remaining assay to perform the regulator mechanism of MEETL3 on the target CTNNB1 in HB. Results: In this research, we discovered that m⁶A modifications are increased in hepatoblastoma, and METTL3 is the main factor involved with aberrant m⁶A modification. We also profiled m⁶A across the whole transcriptome in hepatoblastoma tumor tissues and normal tissues. Our findings suggest that m⁶A is highly expressed in hepatoblastoma tumors. Also, m⁶A is enriched not only around the stop codon, but also around the coding sequence (CDS) region. Gene ontology analysis indicates that m⁶A mRNA methylation contributes significantly to regulate the Wnt/β-catenin pathway. Reduced m⁶A methylation can lead to a decrease in expression and stability of the CTNNB1. Conclusion: Overall our findings suggest enhanced m⁶A mRNA methylation as an oncogenic mechanism in hepatoblastoma, METTL3 is significantly up-regulated in HB and promotes HB development. And identify CTNNB1 as a regulator of METTL3 guided m⁶A modification in HB.

Circular RNAs (circRNAs), a novel class of endogenous RNAs, have been recently shown to participate in cellular development and several pathophysiological processes. The identification of dysregulated circRNAs and their function in cancer have attracted considerable attention. Nevertheless, the expression profile and role of circRNAs in human hepatoblastoma (HB) remain to be studied. In this report, we analyzed the expression prolife of circRNAs in HB tissues and identified circHMGCS1 (3-hydroxy-3-methylglutaryl-CoA synthase 1; hsa_circ_0072391) as a remarkably upregulated circRNA.

Cyclic imaging of multiple proteins in a single cell is realized through CAD-HCR.

Utilizing Global Burden of Disease Study (GBD 2021) data, this study aims to illustrate trends and spatiotemporal patterns of multidrug-resistant tuberculosis (MDR-TB) burden from 1990 to 2021, and explore their potential mechanisms. This research extracted core indicators including incidence, mortality, prevalence, and disability-adjusted life years (DALYs), with their age-standardized rate (ASR). Joinpoint regression, age-period-cohort analysis, inequality analysis, and frontier analysis were applied to describe the temporal and spatial trends of the disease burden. Decomposition analysis and risk factor analysis were performed to explore factors associated with MDR-TB burden fluctuation. Bayesian Age-Period-Cohort (BAPC) model was used to project the disease burden till 2050. Global MDR-TB cases and ASRs of all indicators rose from 1990 to 2021, with heavier burden in older populations and lower socioeconomic regions. Cross-country inequality widened over time. Frontier analysis identified countries including India and Russia with considerable potential for improvement in disease control. Decomposition analysis uncovered epidemiological changes as the main driver of the growing burden globally. Risk factors of MDR-TB in different regions and age groups were heterogeneous. The numbers and ASRs of all indicators are predicted to increase by 2050. This study revealed that the global disease burden of MDR-TB increased from 1990 to 2021 and is predicted to grow till 2050. Disparities among different social-demographic regions were remarkable and extended over time. Epidemiological changes contributed most to the escalated disease burden. Targeted public health strategies should be adopted for patients in specific regions and age groups.