Discovery medicine最新文献

Objective: The aim of this study is to determine the role of serum exosomal miRNAs as potential non-invasive biomarkers for distinguishing no-or-mild fibrosis from significant fibrosis in patients with chronic hepatitis B (CHB).

Methods: Next-generation sequencing was used to identify fibrosis-related serum exosomal miRNAs in 9 CHB patients. The candidate exosomal miRNAs were further validated by qRT-PCR in 282 CHB patients. Receiver operating characteristic curves were generated to assess the diagnostic performance of exosomal miRNAs and other non-invasive models.

Results: Seventy-two miRNAs were differentially expressed in serum exosomes between patients with no-or-mild fibrosis and significant fibrosis. The expression of serum exosomal miR-92a-3p and miR-146a-5p progressively increased with the aggravation of liver fibrosis in the validation cohort. Multivariate analysis identified miR-92a-3p (P<0.001), miR-146a-5p (P<0.001), and liver stiffness measurement (LSM) (P=0.012) as independent predictors for significant fibrosis. The area under the receiver operating characteristic curve (AUROC) of exosomal miR-92a-3p (AUROC=0.88) was significantly higher than that of APRI (aspartate aminotransferase-to-platelet ratio index) (AUROC=0.72, P<0.001), FIB-4 (AUROC=0.71, P<0.001), and LSM (AUROC=0.80, P=0.022) for identifying significant fibrosis. Similarly, the AUROC of exosomal miR-146a-5p (AUROC=0.82) was also significantly better than that of APRI (AUROC=0.72, P=0.009), FIB-4 (AUROC=0.71, P=0.002), and comparable to LSM (AUROC=0.80, P=0.551) for discriminating significant fibrosis.

Conclusion: Serum exosomal miR-92a-3p and miR-146a-5p are superior to APRI, FIB-4, and LSM for diagnosing significant fibrosis in CHB patients and offer a promising non-invasive alternative to liver biopsy.

Background: Few studies reported the risk factors of fatal outcome of hospitalized patients with coronavirus disease 2019 (COVID-19). We aimed to identify the independent risk factors associated with fatal outcome of hospitalized COVID-19 patients.

Methods: The clinical data of 109 consecutive COVID-19 patients including 40 (36.7%) common cases and 69 (63.3%) severe cases were included and analyzed.

Results: Multivariate regression analysis indicated that platelets (PLT, OR, 0.988; 95% CI, 0.978-0.998; P=0.017) and C-reactive protein (CRP) (OR, 1.047; 95% CI, 1.026-1.068; P<0.001) levels were the independent risk factors of fatal outcome in COVID-19 patients. The optimal cut-off value of PLT counts for predicting fatal outcome was 161x109/L with the area under receiver operating characteristic curve (AUROC) of 0.824 (95% CI, 0.739-0.890). The optimal cut-off value of CRP for the prediction of fatal outcome was 46.2 mg/L with the AUROC of 0.954 (95% CI, 0.896-0.985). The CRP levels had higher predictive values for fatal outcome than PLT (P=0.016). The cumulative survival rate was significantly higher in patients with PLT>161x109/L compared with patients with PLT≤161x109/L (89.4% vs. 12.5%, log-rank test X2=72.17; P<0.001). Survival rate of COVID-19 patients was prominently higher in CRP≤46.2 mg/L patients compared with patients with CRP>46.2 mg/L (95.9% vs. 22.9%, log-rank test X2=77.85; P<0.001).

Conclusions: PLT counts and CRP levels could predict fatal outcome of hospitalized COVID-19 patients with relatively high accuracy.

A large number of studies on the metabolism of immune cells in anti-tumor response have been carried out in recent years. It is proved that metabolic reprogramming can determine the differentiation and functions of immune cells. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells in the tumor microenvironment (TME). They can significantly inhibit the anti-tumor response of T cells and play an important role in promoting tumor growth, metastasis, and invasion. This review summarizes the energy metabolic pathways of MDSCs in the TME, such as fatty acid oxidation (FAO), glycolysis, and amino acids (AAs) metabolism, and highlights the importance of metabolic reprogramming of MDSCs for its immunosuppressive functions.

Background: Uterine corpus endometrial carcinoma (UCEC) is the second most common malignancy of female reproductive system. Though most UCEC are diagnosed at an early age, the mortality has increased. It is important to develop new targets for prognosis evaluation and treatment.

Methods: Expression profiles of 19 m6A regulators and UCEC samples' epidemiologic information were obtained from GTEx and TCGA datasets. Nonnegative matrix factorization (NMF) was used to cluster UCEC samples into three groups and overall survival (OS) was compared among them. Multivariate cox proportional hazard model was used to select targets for the construction of m6A-related prognosis prediction signature. A nomogram consisting of m6A-related signature, stage, and histology was provided for clinical application.

Results: Eighteen m6A regulators were found to be differentially expressed between normal sample and UCEC samples. There was a significant difference in the OS probability among three clusters with different expression levels of m6A. VIRMA, YTHDF3, and IGF2BP1 were picked as UCEC prognosis prediction signatures and the prognostic value was confirmed. Risk score estimated by this signature was demonstrated to be the independent prognostic factor for UCEC.

Conclusion: Aberrant expression of m6A RNA methylation regulators was significantly associated with the development and prognosis of UCEC. A three-gene signature consisting of VIRMA, YTHDF3, and IGF2BP1 may effectively predict the prognosis of UCEC patients.

mTOR (the mammalian target of rapamycin) is a serine/threonine kinase that can regulate a variety of signaling pathways, including cell growth, proliferation, and apoptosis. mTOR can regulate the proliferation and migration of endothelial cells and smooth muscle cells during the occurrence and progression of atherosclerosis. By inhibiting or activating mTOR at different time points, atherosclerotic vulnerable plaques can be stabilized and the occurrence and progression of atherosclerosis can be impeded. The mTOR signaling pathway plays a multifaceted role in the progression of atherosclerosis. mTOR and its interactions with molecular targets in the mechanisms of atherosclerosis and cardiovascular diseases are reviewed in this article, taking into consideration their potential of opening up novel therapeutic avenues.

Remdesivir is a broad-spectrum antiviral agent. With the rapid spread of Coronavirus disease 2019 (COVID-19) globally, remdesivir is taking the spotlight for COVID-19 treatment. Despite the promising signs of anti-CoV activity in several preclinical and clinical studies, more data of remdesivir in the treatment of COVID-19 is still needed for evaluating its efficacy.

Neoadjuvant therapy is used to treat breast cancer through preventive agents. This new type of chemotherapy is prescribed according to the size of the tumor, so as to reduce the tumor mass and give more surgical options. Neoadjuvant hormone treatment is also helping to shrink breast cancer in lymph nodes or elsewhere in the breast before surgery. A significant aspect of the treatment is to predict breast tumor response to neoadjuvant chemotherapy. Here, the latest advanced breast tumor response techniques have been presented for this type of therapy. These techniques are classified into three categories: deep and machine learning, quantitative ultrasound spectroscopy, and magnetic resonance imaging. These methods were important for the prediction of a tumor's chemical response to the neoadjuvant chemotherapy. Tumor response assessment leads to effective chemical treatment, which decreases the size of the breast tumor and allows surgery to remove the tumor effectively.

Background: Acute pancreatitis (AP) is a serious and can be lethal disease, with an incidence of 13 to 45 per 100,000 individuals per year. The underlying mechanism of AP is not fully understood. Exosomes have recently been identified as intercellular messengers that can participate in the pathogenesis of various diseases. Exosomes secreted by noninflammatory acinar cells may affect the activated and injured acinar cells during AP.

Aim: To investigate the effect of exosomes derived from acinar cells on the pathogenesis of AP.

Methods: Nanoparticle tracking analysis was applied to evaluating the exosomes derived from AR42J acinar cells. The viability and apoptosis of AP in vitro model cells were evaluated. Wistar rats were used to establish the in vivo AP rat model and the levels of serum pro-inflammatory cytokines and morphological changes in the pancreatic tissues were assessed. RNA sequencing and Kyoto Encyclopedia of Genes and Genomes databases (KEGG) based RNA enrichment analyses were applied to exploring the mechanisms underlying the effect of exosomes on the pathogenesis of AP.

Results: Acinar cell exosomes reduced the level of intracellular ROS production and improved the viability of AP model acinar cells by inhibiting apoptosis during AP. The exosomes decreased the circulating levels of IL-6 and TNF-alpha, and reduced the pathological scores and wet/dry weight ratios of pancreatic tissue in AP in vivo model rats. Among the upregulated and downregulated RNAs analyzed, the MAPK and NF-kappaB signaling pathways might be involved in the mechanisms underlying the protective effects of acinar cell-derived exosomes in AP.

Conclusion: Acinar cell-derived exosomes could reduce the apoptosis and ROS production in acinar cells during AP, and may alleviate the severity of AP via the MAPK and NF-kappaB signaling pathways.

Alzheimer's disease (AD), Lewy Body Dementia (LBD), and Parkinson's disease (PD) form a continuum that may explain multiple aspects of age-related neurodegeneration. Inflammaging, the long-term result of the chronic physiological stimulation of the innate immune system, is integral to this process. The gut microbiome plays an important role in inflammaging, as it can release inflammatory products and communicate with other organs and systems. Although AD and PD are molecularly and clinically distinct disorders, their causes appear to underlie LBD. All three conditions lie on a continuum related to AD, PD, or LBD in vulnerable persons. Inflammation in AD is linked to cytokines and growth factors. Moreover, cytokines and neurotrophins profoundly affect PD and LBD. Growth factors, neurotrophins and cytokines are also involved in embryo neural development. Cytokines influence gene expression, metabolism, cell stress, and apoptosis in the preimplantation embryo. The responsible genes are silenced around birth. But if activated by inflammaging and viruses in the brain decades later, they could destroy the same neural structures they created in utero. For this reason, the pathology and progression of AD, LBD, and PD would be unique. Embryonic reactivation could explain two well documented features of AD. 1) NSAIDs reduce AD risk but fail as a treatment. 2) NSAIDs reduce AD risk because they suppress inflammaging. But they are not a treatment because they cannot silence the embryonic genes that have become active and damage the brain.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a global crisis due to strong infectivity and fast transmission speed. Some patients with Coronavirus Disease 2019 (COVID-19) progress rapidly and may develop fatal complications, which brings serious challenges in disease assessment and treatment. Recent progress in the understanding of the molecular biology of SARS-CoV-2 has led to the identification of a variety of laboratory biomarkers that could be potentially applied to clinical practice for the diagnosis, treatment, and prognosis of patients with COVID-19. In this review we summarize the updated status on the identification of COVID-19 related laboratory markers, and propose further direction on the application of these markers to clinical diagnosis and management of patients with COVID-19.