ORM 1 as a biomarker of increased vascular invasion and decreased sorafenib sensitivity in hepatocellular carcinoma.

This study aimed to clarify the role of Orosomucoid 1 (ORM1) in the development and therapy resistance in hepatocellular carcinoma (HCC). The mRNA expression level of ORM1 was analyzed via integrative analysis of Gene Express Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. The protein expression level of ORM1 in our cohort was determined using immunohistochemistry. Correlation analysis was used to investigate the relationship between ORM1 expression and clinical parameters. The Cell Counting Kit-8 assay was used to clarify the role of ORM1 in HCC malignant behaviors, including cell growth and sorafenib sensitivity, in vitro. The results indicated that ORM1 was significantly downregulated in the hepatic cancer cells compared to that in the non-cancerous cells. However, it was upregulated in microvascular invasion samples, especially in the cancer embolus compared to that in the surrounding tumor cells. Though Kaplan-Meier analysis did not show an association of ORM1 expression with the overall survival rates of HCC patients, univariate analysis indicated that ORM1 expression was highly correlated with tumor grade and stage. An in vitro assay also revealed that downregulation of ORM1 led to the suppression of tumor growth and enhancement of sorafenib sensitivity without epithelial-to-mesenchymal transition (EMT) alteration, which was consistent with our bioinformatic analysis. Hence, ORM1 played a key role in HCC tumorigenesis and may serve as a potential target for the development of therapeutics against HCC in the future.

Safety and efficacy of S1 monotherapy or combined with nab-paclitaxel in advanced elderly pancreatic cancer patients: A meta-analysis.

OBJECTIVE: To evaluate the therapeutic efficacy and safety of S1 monotherapy or combination with nab-paclitaxel for the treatment of elderly patients with metastatic or locally advanced pancreatic adenocarcinoma. METHOD: PubMed, Embase, Cochrane Central Library, China Biology Medicine, and China National Knowledge Infrastructure databases were searched without time limits according to the inclusion criteria. RevMan (Version 5.3) software was used for data extraction and meta-analysis. Objective response rate (ORR) and disease control rate (DCR) were used to evaluate therapeutic effects while side effects including leukopenia, thrombocytopenia, neurotoxicity, vomit, and alopecia were extracted for evaluation. There was no need for ethical review in this study because no ethical experiments were conducted and all data used were public data. All relevant data are within the paper and its Supporting Information files. RESULTS: Four retrospective studies comprising 308 elderly patients with metastatic or locally advanced pancreatic adenocarcinoma were included in the analysis. One hundred fifty-one patients underwent S1 monotherapy and 157 received S1 combined nab-paclitaxel. Meta-analysis indicated that compared with S1 monotherapy, S1 combined with nab-paclitaxel had higher ORR (OR 2.25, 95% CI: 1.42-3.55; P = .0005) and DCR (OR 2.94, 95% CI: 1.55-5.58; P = .0009). The adverse reaction of leukopenia was higher in the combined therapy group (OR 1.85, 95% CI: 1.09-3.13, P = .02), but no significant difference was found in thrombocytopenia, neurotoxicity, vomiting, and alopecia between the 2 groups (P > .05). CONCLUSION: Nab-paclitaxel plus S1 was more efficient in terms of ORR and DCR than S1 monotherapy in elderly pancreatic ductal adenocarcinoma patients while the side effect was controllable with a higher probability of leukopenia. Thus, combined nab-paclitaxel and S1 could be safely used in elderly patients.

Establishment and Investigation of a Multiple Gene Expression Signature to Predict Long-Term Survival in Pancreatic Cancer.

Pancreatic cancer remains a lethal type of cancer with poor prognosis. Molecular classification enables in-depth, precise prognostic assessment. This study is aimed at identifying a robust and simple mRNA signature to predict the overall survival (OS) of pancreatic cancer (PC) patients. Differentially expressed genes (DEGs) between 45 paired pancreatic tumor samples and adjacent healthy tissues were selected. For risk determination, a LASSO Cox regression model with DEGs was used to generate the OS-associated risk score formula for the training cohort containing 177 PC patients. Another five independent datasets were used as the testing cohort to determine the predictive efficiency for further validation. In total, 441 DEGs were selected after considering the enrichment of classical pathways, such as EMT, cell cycle, cell adhesion, and PI3K-AKT. A five-gene signature for risk discrimination was established with high efficacy using LASSO Cox regression in the training group. External validation showed that patients identified by the gene expression signature to be in the high-risk group had poorer prognosis compared with the low-risk patients. Further investigation identified the differential epigenetic modification patterns of the five genes, which indicated their roles in tumor progression and their effect on therapy. In conclusion, we constructed a robust five-gene expression signature that could predict the OS of PC patients, offering a new insight for risk discrimination in daily clinical practice.

MiR-193b modulates osteoarthritis progression through targeting ST3GAL4 via sialylation of CD44 and NF-кB pathway.

Osteoarthritis (OA) is a worldwide epidemic and debilitating disease. It is urgent to explore the potential molecular mechanisms of OA which has crucial roles in the treatment strategy. As a post-translational modification, sialylation mediates the progression of OA. In current study, differential expression of sialyltransferases (STs) in normal and OA cartilage tissues is detected. The ST3GAL4 expression is significantly increased and positively associated with modified Mankin's score in OA tissue. Alteration of ST3GAL4 respectively mediates the degradation of extracellular mechanisms (ECM), apoptosis and proliferation in chondrocytes. Additionally, miR-193b is identified as a direct regulatory target of ST3GAL4. Functional analysis shows that modulation of ST3GAL4 could be reversed by miR-193b. Over-expression ST3GAL4 modifies CD44 sialylation. Finally, sialylated CD44 reduces the binding capacity to lubricin and mediates the activity of the NF-кB pathway. Collectively, these researches indicate that miR-193b/ST3GAL4 axis impacts OA progression by regulating CD44 sialylation via NF-кB pathway. Our researches propose a precise molecular mechanism and provide a prospective therapeutic target in OA.

LEF1 mediates osteoarthritis progression through circRNF121/miR-665/MYD88 axis via NF-кB signaling pathway.

Osteoarthritis (OA) is a joint disease that causes great pain to patients and imposes a tremendous burden on the world's medical resources. Regulatory noncoding RNAs, including circular RNAs (circRNAs) and microRNAs (miRNAs), play an important role in OA progression. Here, we identified differential expression of transcription factor LEF1 that increased circRNA circRNF121 levels in normal and OA cartilage tissues. The expression of LEF1 and circRNF121 was positively associated with Mankin's scores. Alteration of circRNF121 mediated the degradation of extracellular mechanisms (ECM), apoptosis, and proliferation of chondrocytes. MiR-665 was identified as a direct regulatory target of circRNF121 and MYD88. Functional analysis showed that circRNF121 and MYD88 modulated ECM degradation, apoptosis, and proliferation of chondrocytes, which could be reversed by miR-665. MYD88 regulated the activity of the NF-кB signaling pathway by circRNF121 via sponging miR-665. Collectively, these data indicated that LEF1 impacted OA progression by modulating the circRNF121/miR-665/MYD88 axis via NF-кB pathway. Our research proposed a new molecular mechanism for the development of OA, and provided a prospective therapeutic target for OA.

Correction: LEF1 mediates osteoarthritis progression through circRNF121/miR-665/MYD88 axis via NF-кB signaling pathway.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Oligomeric proanthocyanidins inhibit apoptosis of chondrocytes induced by interleukin-1ß.

Oligomeric proanthocyanidin (OPC) is a water-soluble plant polyphenolic compound known for its cytoprotective effects in various tissue types. However, its effect on chondrocytes has not been well characterized. The present study aimed to investigate the effect of OPC on interleukin­1ß (IL­1ß)­induced apoptosis in chondrocytes, and to determine the mechanisms underlying the protective effects of OPC. Knee articular chondrocytes obtained from 6­week­old SPF Kunming mice were cultured and serially passaged. First­generation chondrocytes were selected for subsequent experiments following toluidine blue staining. Subsequent to IL­1ß and OPC administration, an MTT assay was performed to examine the viability rate of chondrocytes, and the optimal drug concentration was determined. The fluorescence dye 2',7'-dichlorofluorescein diacetate was used to determine the intracellular content of reactive oxygen species (ROS). Mitochondrial membrane potential (MMP) was measured using a 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide (JC­1) assay. The apoptosis rate of chondrocytes was assessed using an Annexin V­FITC/PI assay and ultrastructural changes were observed under an electron microscope. The results demonstrated that OPC increased the survival rate of chondrocytes against IL­1ß­induced apoptosis. The most significant protective effect of OPC was observed at the concentration of 0.050 mg/ml. OPC reversed the increased ROS content and MMP levels, and inhibited IL­1ß­induced apoptosis in chondrocytes. In addition, OPC was revealed to protect the ultrastructural integrity of chondrocytes. Taken together, the results of the present study suggest that OPC protects chondrocytes against IL­1ß­induced damage by decreasing ROS content and MMP levels.

The Chondrogenic Potential of Progenitor Cells Derived from Peripheral Blood: A Systematic Review.

An increasing number of studies have detected mesenchymal stromal cells (MSCs) and mesenchymal progenitor cells (MPCs) in the peripheral blood (PB). This study aimed to systematically review the possibility of using the PB as a source for chondrogenic progenitors. PubMed, the Web of Science, and Embase were searched for relevant articles. The findings of the studies were reviewed to evaluate the biological characteristics of PB-derived MSCs, chondrogenic MPCs, and their applications in cartilage repair. Thirty-six articles were included in the final analysis, 29 of which indicated that PB is a potential source for chondrogenic progenitor cells. Thirty-two studies reporting in vitro data, including 79.2% (19/24) of studies on PB MSCs and 75% (6/8) of studies on chondrogenic PB MPCs, confirmed the existence of PB MSCs and PB MPCs, respectively; all in vivo investigations showed that using PB as a cell source enhanced cartilage repair. PB MSCs were found in most of the animal studies (12/13), whereas 7 of 11 human studies described the presence of PB MSCs. This systematic review strongly indicates the existence of MSCs in the PB of animals, whereas the presence of MSCs in human PB is less clear. Although the presence of both MSCs and chondrogenic MPCs in the PB, as well as a few favorable outcomes associated with the use of PB-derived progenitors for cartilage repair in vivo, suggests that the PB is a potential alternative source of chondrogenic progenitor cells for cartilage repair, the efficacy of these cells has not been compared to those from other sources, such as bone marrow or adipose tissue in controlled studies.