Search

Increasing studies have demonstrated the biological function of RNA N6-methyladenosine (m6A) modifications in tumorigenesis. However, the potential role of m6A modifications in the tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC) remains unclear.Herein, 23 m6A regulators were fetched and introduced into consensus clustering to identify distinct m6A modification patterns and develop m6A-based molecular signatures. Then, a principal component analysis algorithm was employed to construct an m6A-based scoring system to further quantify m6A modification patterns in individual tumors. Immunophenoscore (IPS) was used to estimate the immunotherapeutic response of patients.Three different m6A modification patterns with distinct prognoses and biological signatures were identified among 611 HCC samples. The TIME characteristics of these three patterns were consistent with three known immune profiles: immune-oasis, immune-excluded, and immune-inflamed phenotypes. Identifying m6A modification patterns within individual tumors based on the m6Ascore, developed under the m6A-related signature genes, contributed to elaborating biological processes, clinical outcomes, immune cell infiltration, immunotherapeutic effects, and genetic variations. The low-m6Ascore subtype, characterized by immunosuppression, suggested an immune-suppressed phenotype and a low probability of benefiting from immunotherapy. Finally, the potential function of PRDM4 in HCC was explored.This study comprehensively elucidated the indispensable role of m6A modification patterns in the complexity of TIME. The quantitative identification of m6A modification patterns in individual tumors will contribute to optimizing precision immunotherapy.

To explore the clinical efficacy and safety of Licartin combined with transcatheter hepatic arterial chemoembolization (TACE) in the treatment of middle-advanced primary liver cancer.The clinical data of 112 patients with middle-advanced primary liver cancer treated in our hospital from March 2015 to March 2017 were collected. Fifty-six patients underwent TACE combined with Licartin (Licartin+TACE group), while the remaining 56 patients were treated with TACE alone (TACE group). The short-term efficacy, peripheral hemogram, liver function, alpha fetoprotein (AFP) level, count of circulating tumor cells (CTCs) and cluster of differentiation (CD)147 phenotype before and after treatment were assessed in both groups, the incidence of adverse reactions was compared, and the postoperative survival and disease development were recorded during follow-up.At 2 weeks after treatment, the levels of ALT and AST were significantly higher in Licartin + TACE group than those in TACE group (p0.05). After treatment, the white blood cell count (WBC) and platelet count (PLT) obviously declined in both groups, and they were obviously lower in Licartin + TACE group than those in TACE group (p0.05). After treatment, the count of CTCs evidently declined in both groups compared with that before treatment (p0.05), and it was evidently lower in Licartin + TACE group than in TACE group (p0.001). All patients were followed up for 3-36 months. In Licartin + TACE group and TACE group, the mean overall survival (OS) was 13.1±3.6 months and 11.3±2.8 months, respectively, and the mean progression-free survival (PFS) was 7.9±1.4 months and 6.1±1.2 months, respectively. At the end of follow-up, the Kaplan-Meier survival curves were plotted and log-rank test found that the OS rate was remarkably superior in Licartin + TACE group to that in TACE group (p=0.047), but the PFS rate had no statistically significant difference between the two groups (p=0.372).Licartin combined with TACE has better efficacy than TACE alone in the treatment of middle-advanced primary liver cancer, with tolerable adverse reactions, which prolongs patients' survival time.

A 65-year-old female was admitted to our hospital complaining of abdominal pain for the past month. A physical examination revealed mild right upper quadrant tenderness without rebound pain and no palpable abdominal hepatomegaly or mass. Her laboratory results showed mildly impaired liver function: AST 51 U/L (normal range

Improvements in survival rates for pancreatic cancer have been slow and the morality rate continues to increase in patients. MicroRNA (miR)‑448 is reported to be significantly downregulated in several types of cancer. In this study, Rab2B is target of miR‑488 was confirmed by bioinformatics analysis and validated using a luciferase reporter assay. A total of 72 cases of pancreatic cancer in patients diagnosed at The First Affiliated Hospital, School of Medicine, Zhejiang University (Hangzhou, China) were enrolled, and cancer specimens and their adjacent normal tissues were collected for analysis. The expression levels of miR‑448 and Rab2B in these tissues and in pancreatic cancer cell lines were quantified using reverse transcription‑polymerase chain reaction analysis. miR‑448 overexpression was achieved by cell transfection. Protein expression was assessed using western blot analysis. Cell viability, cell cycle and apoptosis were analyzed using CCK‑8 assay and flow cytometry, respectively. The results revealed a negative correlation between miR‑448 and Rab2B in the pancreatic tissues and cell lines. The results of bioinformatics analysis indicated that miR‑448 directly targeted Rab2B. Aberrant miR‑448 levels in PANC‑1 cells downregulated the expression of Rab2B, and significantly decreased cell proliferation and promoted apoptosis of cancer cells. It was also found that miR‑448 mimics resulted in G0/G1 cell cycle arrest and affected the expression of cell cycle regulators, including cyclin D1, p21 and p27. In addition, the miR‑448 mimics led to inactivation of the Akt/Mammalian target of rapamycin signaling pathway. The miR‑448 mimics induced apoptosis and activated the expression of caspase‑3, caspase‑9 and poly(ADP‑ribose) polymerase. The results suggested that miR‑448 was a negative regulator of Rab2B and promoted cell cycle arrest and apoptosis in pancreatic cancer.

Due to their “tumor homing” and “immune privilege” characteristics, the use of mesenchymal stem cells (MSCs) has been proposed as a novel tool against cancer. MSCs are genetically engineered in vitro and then utilized to deliver tumoricidal agents, including prodrugs and bioactive molecules, to tumors. The genetic modification of MSCs can be achieved by various vectors, and in most cases viral vectors are used; however, viruses may be associated with carcinogenesis and immunogenicity, restricting their clinical translational potential. As such, nonviral vectors have emerged as a potential solution to address these limitations and have gradually attracted increasing attention. In this review, we briefly revisit the current knowledge about MSC-based cancer gene therapy. Then, we summarize the advantages and challenges of nonviral vectors for MSC transfection. Finally, we discuss recent advances in the development of new nonviral vectors, which have provided promising strategies to overcome obstacles in the gene modulation of MSCs.

e13508 Background: Murine double minute-2 (MDM2) has increasing clinic relevance as preclinical and early clinical evidences have showed that the MDM2 inhibitors are promising alternative treatments for patients with MDM2-amplified (-amp) and TP53-wild-type (-WT) tumors by preventing TP53 protein degradation. However, exploration into genomic landscape of MDM2/TP53 across various solid tumors in Chinese patients is still limited. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor samples were collected from 10010 Chinese patients with solid tumors and subjected to a clinical-grade next-generation sequencing (NGS)-based 450 gene panel testing carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Genomic alterations (GAs) including single base substitutions, short and long insertion/deletions (Indels), copy number variations, gene fusions, and rearrangements were analyzed. Tumor mutational burden (TMB) was measured by a NGS algorithm. Results: Amplification of MDM2 occurred in 3.3% of Chinese patients. MDM2-amp was detected most frequently in soft tissue sarcoma (STS, 11.4 %), melanoma (10.3 %) and osteosarcoma (6.3 %). Notably, MDM2-amp was revealed to be mutually exclusive with TP53-mut in most tumor types other than esophageal carcinoma (93.9 %), head and neck carcinoma (68.4%) and ovarian carcinoma (50 %). Tumors with highest frequencies of MDM2-amp/ TP53-WT were melanoma (100%), osteosarcoma (100%) and urothelial carcinoma (100 %). The most common co-altered genes accompanied with MDM2-amp were FRS2 (84%), CDK4 (38%), EGFR (26%), TP53 (17%) and GLI1 (14%). 82.8% patients who had one or more co-alterations potentially targetable with either FDA-approved or investigational agent. Moreover, TMB of MDM2-amp tumors were significantly lower than that of MDM2-WT and MDM2-mutation (-mut) tumors (median TMB: 3.1 vs. 4.6 vs. 10.8, p < 0.001 respectively). Conclusions: MDM2 amplification was found in 3.3% of 10010 Chinese cancer patients, 83.4% of whom harbored wild-type TP53 that were potentially responsive to MDM2 inhibitors. In addition, 82.8% of the patients with MDM2-amp harbored genomic co-alterations and were potentially therapy targetable. This study provided insights into identifying patients who might potentially benefit from anti-MDM2 therapies.

Background The mitochondrial GTPase mitofusin-2 (MFN2) gene encodes a mitochondrial membrane protein that can induce apoptosis of hepatocellular carcinoma (HCC) via the mitochondrial apoptotic pathway, as validated in our previous research. However, little is known of the clinical significance of MFN2 expression and its signaling pathways in HCC. Methods MFN2 mRNA expression in tumor and adjacent non-tumor tissues from 115 patients with HCC was investigated using quantitative real-time PCR. The association of the MFN2 mRNA expression level with clinical and pathological parameters was evaluated statistically, while a comparative microarray analysis was used to identify MFN2 signaling pathways in HepG2 cells. Results MFN2 was significantly (p

Significant enrichment of 93 genes in 18 pathways. (DOC 47Â kb)

DEGs after MFN2 overexpression in HepG2 cells. (DOC 197Â kb)

Patients demographic and clinicopathological characteristics. (DOC 52Â kb)

Schwannomas are neurogenic tumors that arise from the neural sheaths of peripheral nerves. These tumors can be located in any area of the human body; the most common locations are the head, neck, trunk and extremities. Pancreatic schwannomas are very rare. Over the past 40 years, only 67 cases of pancreatic schwannomas have been reported in the English literature. Here we present a case of pancreatic schwannoma in a 62-year-old male. The tumor was revealed by ultrasound and computed tomography in the neck and body of the pancreas. An accurate diagnosis was difficult to obtain preoperatively. The patient consented to the performance of a laparotomy, and the mass was found in the neck and body of the pancreas and successfully treated using a spleen-preserving distal pancreatectomy with splenic artery and vein preservation. The procedure has only been reported in one other case of pancreatic schwannoma; here we present the second reported case. Macroscopically, the tumor was well circumscribed, gray-white in color and 3.3 cm × 2.8 cm in size. Microscopically, the tumor cells were spindle-shaped and had a palisading arrangement with no atypia, which are results compatible with a benign tumor. Both hypercellular and hypocellular areas were visible. Immunohistochemically, the tumor cells were strongly positive for S-100 protein. The tumor was definitively diagnosed as a schwannoma of the pancreatic neck and body. The patient was followed for 72 mo and has been doing well without any complications.

The impact time control law is employed to carry out a salvo attack for anti-ship missiles against CIWS (close-in weapon system). An impact-time-control cooperative guidance law for multi-missiles was investigated in this paper. Firstly, the time-to-go for each missile was estimated and based on which the desired impact time was determined, and the impact time control problem was transformed into a range tracking problem. Secondly, a nonlinear model for homing guidance was proposed, which was transformed into a linear system by using feedback linearization. Lastly, a stable control law was designed by using pole placement approach. Simulation results show that all missiles can impact the target at the designated impact time very accurately.

The objectives were to study the expression of receptor-binding cancer antigen expressed on SiSo cells (RCAS1) and estrogen receptor (ER) subtypes in the normal, hyperplastic, and carcinomatous endometrium and to explore their possible role in carcinogenesis and progression of endometrial carcinoma. Immunohistochemistry and semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) were applied to detect protein and messenger RNA expression of RCAS1, ER-alpha, and ER-beta in normal, hyperplastic, and carcinomatous endometrium. Western blotting was also used to detect the RCAS1 protein expression. Immunohistochemistry showed that the high expressions of RCAS1 protein were 0% (0/20), 9.1% (2/22), 40% (8/20), and 68.0% (34/50) in normal, simple, and complex hyperplasia, atypical hyperplasia, and endometrial carcinoma, respectively. There was a significant difference between each group (P0.05). The high-level expression of RCAS1 was detected more frequently in endometrial cancer with deep myometrial invasion, vascular invasion, and positive ER-alpha (P0.05). Two staining patterns of RCAS1 were observed. All normal, simple, and complex hyperplastic endometrium showed P pattern, while all malignant endometrium were of the D pattern. In atypical endometrium, 25% (5/20) cases showed D pattern. The Western blotting and RT-PCR results correlated with the immunohistochemistry results. The expression and distribution of RCAS1 may be involved in the malignant transformation of endometrium, and RCAS1 coexpression with ER-alpha may be associated with development and metastasis of endometrial carcinoma.