Aims Non-obese non-alcoholic fatty liver disease (NAFLD) phenotype has sparked interest and frequently occurred in type 2 diabetes mellitus (T2DM). Information on associations between lipid parameters and NAFLD in non-obese patients with diabetes has been lacking. We aimed to investigate the relationships between lipid parameters and NAFLD according to obesity status and metabolic goal achievement in T2DM patients. Methods A total of 1,913 T2DM patients who were hospitalized between June 2018 and May 2021 were cross-sectionally assessed. We used logistic regression models to estimate the associations of lipid parameters with NAFLD risk according to obesity and metabolic goal achievement status. Results Higher triglycerides, non-HDL-cholesterol, and all lipid ratios including (total cholesterol/HDL-cholesterol, triglyceride/HDL-cholesterol, LDL-cholesterol/HDL-cholesterol, non-HDL-cholesterol/HDL-cholesterol), and lower HDL-cholesterol were associated with NAFLD risk in both non-obese and obese patients. The associations were stronger in non-obese patients than in obese patients. Further, the inverse associations of total cholesterol and LDL-cholesterol with NAFLD risk were only detected in non-obese patients. Triglycerides, HDL-cholesterol, and all lipid ratios studied were significantly associated with NAFLD risk, irrespective of whether the patients achieved their HbA1c, blood pressure, and LDL-cholesterol goal. The presence of poor lipids and lipid ratios were more strongly associated with NAFLD in patients who attained the HbA1c, blood pressure, and/or LDL-cholesterol goal than in those who did not achieve the goal attainment. Conclusions The associations of lipids and lipid ratios with NAFLD risk were stronger in T2DM patients who were non-obese and achieved the HbA1c, blood pressure, and/or LDL-cholesterol goal attainment.
Exosomes are small extracellular vesicles that are released from cells and that function in intercellular communication. Recently, interferon-inducible transmembrane protein 3 (IFITM3) has been identified as a highly effective anti-intracellular pathogen protein that can inhibit the invasion of a wide range of pathogenic microorganisms. However, whether Brucella infection induces secretion of exosomes and whether these exosomes contain IFITM3 protein remain unknown. Here, we focused on the immune function of extracellular IFITM3 protein in the process of Brucella infection. This study is the first to show that Brucella melitensis strain M5 ( Brucella M5) can stimulate macrophages to secrete large amounts of exosomes. Most importantly, we identified exosomes from Brucella M5-infected cells that were rich in molecules of IFITM3, and these exosomes could transmit the IFITM3 from one cell to another, thereby effectively inhibiting the intracellular survival of Brucella . Moreover, immunization with exosomes carrying IFITM3 decreased mouse spleen tissue damage and spleen colony forming unit (CFU), leading to the establishment of an anti- Brucella state in mice. In conclusion, our findings provide new insights into the anti- Brucella mechanism of IFITM3-containg exosomes, thus providing a theoretical foundation for systematic elaboration of the mechanisms of Brucella infection and host immunity. The results provide new ideas for the development of candidate vaccines for Brucella .
Osteosarcoma (OS) is the most common primary malignant pediatric bone tumor and is characterized by high heterogeneity. Studies have revealed a wide range of phenotypic differences among OS cell lines in terms of their in vivo tumorigenicity and in vitro colony-forming abilities. However, the underlying molecular mechanism of these discrepancies remains unclear. The potential role of mechanotransduction in tumorigenicity is of particular interest. To this end, we tested the tumorigenicity and anoikis resistance of OS cell lines both in vitro and in vivo. We utilized a sphere culture model, a soft agar assay, and soft and rigid hydrogel surface culture models to investigate the function of rigidity sensing in the tumorigenicity of OS cells. Additionally, we quantified the expression of sensor proteins, including four kinases and seven cytoskeletal proteins, in OS cell lines. The upstream core transcription factors of rigidity-sensing proteins were further investigated. We detected anoikis resistance in transformed OS cells. The mechanosensing function of transformed OS cells was also impaired, with general downregulation of rigidity-sensing components. We identified toggling between normal and transformed growth based on the expression pattern of rigidity-sensing proteins in OS cells. We further uncovered a novel TP53 mutation (R156P) in transformed OS cells, which acquired gain of function to inhibit rigidity sensing, thus sustaining transformed growth. Our findings suggest a fundamental role of rigidity-sensing components in OS tumorigenicity as mechanotransduction elements through which cells can sense their physical microenvironment. In addition, the gain of function of mutant TP53 appears to serve as an executor for such malignant programs.
Background The incidence of mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) is low. To improve our understanding of this rare tumor type and optimally guide clinical treatment, associated risk factors, clinical manifestations, and prognosis must be explored. Aim To identify risk factors that influence the prognosis of patients with gastroenteropancreatic MiNEN (GEP-MiNEN). Methods We retrospectively analyzed the clinical data of 46 patients who were diagnosed with GEP-MiNEN at the First Affiliated Hospital of Bengbu Medical College (Anhui, China) between January 2013 and December 2017. Risk factors influencing the prognosis of the patients were assessed using Kaplan-Meier curves and cox regression models. We compared the results with 55 randomly selected patients with gastroenteropancreatic GEP neuroendocrine tumors, 47 with neuroendocrine carcinomas (NEC), and 58 with poorly differentiated adenocarcinoma. Results Among the 46 patients with GEP-MiNEN, thirty-five had gastric tumors, nine had intestinal tumors (four in the small intestine and five in the colon and rectum), and two had pancreatic tumors. The median age of the patients was 66 (41-84) years, and the male-to-female ratio was 2.83. Thirty-three (71.7%) patients had clinical stage III and IV cancers. Distant metastasis occurred in 14 patients, of which 13 had metastasis to the liver. The follow-up period was 11-72 mo, and the median overall survival was 30 mo. Ki-67 index ≥ 50%, high proportion of NEC, lymph node involvement, distant metastasis, and higher clinical stage were independent risk factors affecting the prognosis of patients with GEP-MiNEN. The median overall survival was shorter for patients with NEC than for those with MiNEN (14 mo vs 30 mo, P = 0.001), but did not significantly differ from those with poorly differentiated adenocarcinoma and MiNEN (30 mo vs 18 mo, P = 0.453). Conclusion A poor prognosis is associated with rare, aggressive GEP-MiNEN. Ki-67 index, tumor composition, lymph node involvement, distant metastasis, and clinical stage are important factors for patient prognosis.
Objectives Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Microwave ablation is regarded as a safe and effective therapy for the treatment of HCC and has gained considerable attention as a rapidly expanding curative ablation option. This study aims to review the current application of microwave ablation therapy (MAT) for HCC. Methods A literature search was conducted in the PubMed (MEDLINE) database from inception up to August 2016, with no limitations imposed on language or study type, about the application of MAT for HCC. Results MAT for HCC has been reported to be effectively delivered through open laparotomy, laparoscopy and a percutaneous approach for appropriate patients, with many different tools for imaging guidance, including ultrasound, X-ray fluoroscopy, CT, MRI, PET-CT and combined US/CT-MRI. MAT provides the advantages of short treatment duration, a controllable wound and large ablation areas, and may even have the potential to enhance host resistance to malignancies. It is recommended as a first-line therapy for patients with very early and early stage HCC, and is a palliative option for advanced HCC. For tumors larger than 3 cm in diameter with an incomplete capsule, or with visible satellite lesions, or tumors in difficult anatomic locations, combination therapy with other treatments, such as TACE, PEI, iodine-125 particles, immunotherapy, etc, should be considered. Conclusions MAT has gained recognition in the treatment of early or advanced HCC. With the development of image guidance, multiple innovative instruments and different combination therapy modalities, MAT is a promising therapy for development and clinical application in the future. Acknowledgments This research was financially supported by Sichuan University (Grant No. 2016SCU11033).
RNA interference (RNAi) is widely used for functional studies and has been proposed as a potential therapeutic agent. Current RNAi systems are largely efficient, but have limitations including transient effect, the need for viral handling and potential insertional mutations. Here, we describe a simple L1 retrotransposon-based system for the delivery of small interfering RNA (siRNA) and stable silencing in human cells. This system demonstrated long-term siRNA expression and significant reduction in both exogenous and endogenous gene expression by up to 90%. Further characterization indicated that retrotransposition occurred in a controlled manner such that essentially only one RNAi-cassette was integrated into the host genome and was sufficient for strong interference. Our system provides a novel strategy for stable gene silencing that is easy and efficient, and it may have potential applications for ex vivo and in vivo molecular therapy.
Gene therapy has been investigated a lot in both basic research and clinical trials.[1] The first antisense oligodeoxyribonucleotide (ODN) drug, Vitravene (Fomivirsen), was approved by the United States Food and Drug Administration (FDA) in 2005.[2] After this approval, more and more clinical trials are conducted, not only for ODNs, but also for other nucleic acids drugs, such as plasmid vectors and small interference RNAs (siRNAs). However, delivery efficiency is a big barrier for the clinical application of gene drugs. It is necessary to overcome their large molecular weight, large size, and negative charge. Nucleasemediated degradation is also an issue, decreasing the performance of gene drugs. Currently, there are two major categories of methods for gene delivery, viral vectors and nonviral carriers. Viral vectors have higher delivery efficiency than nonviral carriers; whereas nonviral carriers are less toxic and immunogenic. Another important feature for the nonviral delivery system is that they offer delivery on genes with various sizes, which facilitates the potential application of oligonucleotides, such as antisense ODNs and siRNAs. Read More...
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