e15040 Background: The molecular classification of hepatocellular carcinoma (HCC) plays a vital role in the management of precision therapy. Several molecular classification systems, mainly focusing on the tumor cells, were developed according to distinct omics features of HCC. Heterogeneous tumor microenvironment (TME) in HCC is recognized as a crucial part of inter-tumor heterogeneity. Few molecular classifications of HCC have so far taken into account both the related molecules of tumor cells and TME. Methods: Wefirstly identified the tumor purity (TP)-related and TME-related genes in the differentially expressed genes in HCC using GSE14520 data set, and separately constructed the TP-related and TME-related polygenic risk score (PRS). Secondly, according to the TP-related and TME-related PRSs, we proposed the TP-TME risk classification which was validated in two external data sets from The Cancer Genome Atlas Program and International Cancer Genome Consortium database. We also performed functional enrichment and drug repositioning analysis to reveal the potential biological heterogeneity among different subtypes. Results: The three TP-TME risk subtypes of HCC had significantly different prognosis and biological characteristics. The TP-TME low risk subtype had the best prognosis and was characterized by well-differentiated, the TP-TME high risk subtype had the worst prognosis and was characterized by aberrant activation of TGFβ and WNT pathways, and the TP-TME high risk subtype had the moderate prognosis and was characterized by exhibited activated MYC targets and proliferation-related gene sets. We also found that these three TP-TME risk subtypes may respond differently to immunotherapy (e.g., immune checkpoint inhibitors and chimeric antigen receptor-modified T cells) or other drug therapies. Conclusions: By combining separately constructed TP-related PRS and TME-related PRS, we proposed and validated a novel molecular classification system, the TP-TME risk subtyping system, to divide patients with HCC into three subtypes with distinct biological characteristics and prognosis. These findings highlight the significant clinical implications of the TP-TME risk subtyping system and provide potential personalized immunotherapy strategies for patients with HCC.
Abstract Epithelial-mesenchymal transition (EMT) has been shown to be closely associated with Oxaliplatin (OXA) resistance. Previous study found that RBM8A is highly expressed in HCC and induce EMT, suggesting that it may be involved in the regulation of OXA resistance in HCC. However, the accurate mechanism has not been concluded. In our study, ectopic expression and silencing of RBM8A were performed to explore its function. The OXA resistance potential of RBM8A and its downstream pathway was investigated using in vitro and in vivo models. The results showed that RBM8A overexpression induced EMT in OXA-resistant HCC cells, thereby affecting cell proliferation, apoptosis, migration, and invasion and promoting OXA resistance in vivo and in vitro. Moreover, whole-genome microarrays combined with bioinformatics analysis revealed that RBM8A has a wide range of transcriptional regulatory capabilities in drug-resistant HCC, including the ability to regulate several important tumor-related signaling pathways. Histone deacetylase 9 (HDAC9) is an important mediator of RBM8A activity related to OXA resistance. These data suggest that RBM8A and its related regulatory pathway represent potential markers of OXA resistance and therapeutic targets in HCC.
Abstract BACKGROUND Recent studies have found a relationship between gut microbes and the primary location of colorectal cancer (CRC). However, most of these studies had limitations in sample size or sequencing methods. In this study, we collected metagenomic data from three studies and meta-analyzed the microbiological features according to the grouping of right-side colon cancer (RCC), left-side colon cancer (LCC), and rectal cancer (RC). METHODS We first identified confounding factors (except for tumor location) by two-way ANOVA and comparing species diversity. Subsequently, the microbial compositions were compared between different tumor locations. Microbial co-occurrence networks were established based on samples with different tumor locations. A prediction model for primary tumor location was constructed using a random forest algorithm based on microbial abundance features. Finally, tumor location and confounding factors were entered in the MAASLIN2 to identify differential species. Linear discriminant analysis (LDA) also identified the differential species. RESULTS Different study sources and BMI influenced gut microbiome and significantly altered α-diversity and β-diversity, bringing the confounding effect when analyzing gut microbial features in different tumor locations. However, α-diversity and β-diversity of gut microbiome had no significant difference in tumor locations. Species belonging to the Phylum of Actinobacteria, Firmicutes, and Proteobacteria played essential linkages in the three microbial networks, while Bacteroidetes were more critical in the microbial network of RCC. There are both the same hub species and different hub species among the three networks. The random forest classification model performed well in predicting RC (class error = 0.217) but poorly classified the RCC and LCC, with an overall classification error of 0.613. In comparing colon cancer (CC) with RC, MAASLIN2 and LDA identified six species significantly enriched in RC and thirteen in CC. In comparing RCC with LCC, MAASLIN2 identified nine species significantly enriched in RCC and six significantly enriched in LCC. Some of the differential species were reported to be associated with CRC location-related Molecular and immune features. CONCLUSION This study elucidated the relationship between gut microbiome and CRC location and confirmed that RCC, LCC, and RC had different enrich patterns of microbiota.
Malignant serous effusions (MSE) are one complication in patients with advanced cancer. Endostar is a new anti-tumor drug targeting vessels which exerts potent inhibition of neovascularization. This study aimed to systematically evaluate the efficacy and safety of intraperitoneal perfusion therapy of Endostar combined with platinum chemotherapy for malignant serous effusions (MSE).Randomized controlled trials (RCTs) on intraperitoneal perfusion therapy of Endostar combined with platinum chemotherapy for malignant serous effusions were searched in the electronic data of PubMed, EMBASE, Web of Science, CNKI, VIP, CBM and WanFang. The quality of RCTs was evaluated by two independent researchers and a meta-analysis was performed using RevMan 5.3 software.The total of 25 RCTs included in the meta-analysis covered 1,253 patients, and all literature quality was evaluated as "B" grade. The meta-analysis showed that Endostar combined with platinum had an advantage over platinum alone in terms of response rate of effusions (76% vs 48%, RR=1.63, 95%CI: 1.50-1.78, P<0.00001) and improvement rate in quality of life (69% vs 44%, RR=1.57, 95%CI: 1.42-1.74, P<0.00001). As for safety, there was no significant difference between the two groups in the incidences of nausea and vomiting (35% vs 34%, RR=1.01, 95%CI: 0.87-1.18, P=0.88), leucopenia (38% vs 38%, RR=1, 95%CI: 0.87-1.15, P=0.99), and renal impairment (18% vs 20%, RR=0.86, 95%CI: 0.43-1.74, P=0.68).Endostar combined with platinum by intraperitoneal perfusion is effective for malignant serous effusions, and patient quality of life is significantly improved without the incidence of adverse reactions being obviously increased.
H5N1 avian influenza viruses demonstrate different phenotypes, such as pathogenicity after one or serial passages in mammalian hosts or cells. To establish the molecular basis of these phenotypes, we cloned isolates from the lungs of mice infected with human A/Vietnam/1194/2004 (H5N1) influenza virus. Large-plaque isolates were less pathogenic to mice than small-plaque isolates. Genome sequencing revealed that the small-plaque and large-plaque isolates differed in several amino acids. In order to assess their effects on pathogenicity in mice, two amino acid changes common to attenuated isolates, one in PB2 (I63T) and the other in PB1 (T677M), were inserted into a wild-type recombinant virus construct. The PB2 (I63T) or PB1 (T677M) mutations alone did not alter the phenotype of H5N1 virus, whereas recombinant virus with both mutations was less pathogenic than the wild-type recombinant virus. Furthermore, the PB1 (T677M) mutation showed a lower replication efficiency, although it had higher polymerase activity. The recombinant virus with the PB2 (63T) mutation replicated as well as the wild-type recombinant virus. These results suggest that the C terminus of PB1 of H5N1 influenza virus mediates virulence attenuation of H5N1 influenza virus in mice, associating with the N terminus of PB2. However, the role of the N terminus of PB2 in virulence attenuation in mice remains unclear.
415 Background: Clinical trials support the efficacy of immune checkpoint blockades (ICBs) plus chemotherapy in a subset of patients with metastatic gastric cancer (mGC). With the aim of identifying determinants of response, we developed a TMEscore assay (PCR assay with 30 genes) to assess tumor microenvironment, which was previously proved to be a robust predictive biomarker for patients treated with ICBs. Methods: Advanced GC patients treated with ICB combined with chemotherapy as first-line regimen were included in this multi-center prospective clinical trial (NCT#04850716). 65 tumor specimens obtained from 8 medical centers before treatment were applied to estimate TMEscore, PD-L1(CPS) and mismatch repair deficiency (MMR). Of 65 patients, 43 patients with treatment response and 34 patients with progression-free survival (PFS) were used to compare the predictiveness of biomarkers. Results: Theoverall response rate (ORR) and median PFS of this cohort were 39.9% and 4.67 months.Enhanced ORR was observed in TMEscore-high mGC patients (ORR = 61%), but only 16.7% in the low group. Regressive tumors (partial response, PR) had markedly higher TMEscore than stable and progressive tumors (stable disease, SD; progressive disease, PD, P = 0.001). By applying ROC curve analysis, the TMEscore was found to be an encouraging predictive biomarker that surpassed MMR and CPS statistically (AUC = 0.863, 0.525, and 0.519, respectively; Delong test, P = 0.003). Importantly, the Kaplan-Meier survival analysis demonstrated that a high TMEscore was significantly related to a more favorable PFS ( P = 0.0026, HR=0.18, 95%CI 0.06-0.55). Compared to TMEscoreA (immune score), TMEscoreB (stromal score) presented a dramatically higher hazard ratio for PFS (HR = 12.25, P = 0.0001), implicating stromal activation as a critical mechanism of intrinsic resistance to ICB plus chemotherapy. Meanwhile, PD-L1 (CPS) was not statistically associated with PFS, whether 1 or 5 were used as a cutoff to divide patients ( P = 1 and 0.22). Conclusions: This prospective clinical study indicated that the TMEscore assay is a robust biomarker for screening mGC patients who may derive survival benefit from ICB plus chemotherapy. Our data also suggest that TMEscore may be a more accurate predictive biomarker than MSI and CPS (PD-L1) for mGC patients, which warrants additional investigations in larger cohorts. Clinical trial information: NCT#04850716 .
Currently, the underlying mechanism of oxaliplatin (OXA) induced live injury is unclear. In addition, there is no standard clinical treatment for OXA‑induced acute liver injury (ALI). In this study, we established an animal model of OXA‑induced ALI, and studied the role of oxidative stress in OXA‑induced ALI and the impacts of reduced glutathione (GSH) treatment on OXA‑induced ALI. To establish an OXA‑induced ALI model, KM mice received intraperitoneal injection of OXA (8 mg/kg) for 4 days. Serum alanine aminotransferase (ALT), aspartate aminotransferase levels (AST), hepatic pathology and oxidative stress indicators in liver tissues were analyzed. To study the impact of GSH treatment on OXA‑induced ALI, mice were treated with GSH (400 mg/kg, i.p). In this ALI mouse model, ALT and AST levels were significantly increased (P<0.01). Liver pathological examination revealed varying degrees of liver cell turbidity and degeneration, even balloon‑like changes and focal necrosis, and sinusoidal hemorrhage in some cells. Compared with control group, the malondialdehyde (MDA) and GSH levels were significantly increased in OXA‑treated group (P<0.01), while the superoxide dismutase SOD and GSH‑peroxidase levels were decreased after OXA withdrawal (P<0.01). When GSH was used to treat OXA‑induced ALI mice, the pathological injury of liver tissues was alleviated, and serum ALT and AST were significantly decreased. In addition, GSH treatment could reduce the OXA‑induced increase of MDA level (P<0.05) in liver tissues, but had no impact on SOD level (P>0.05). We have successfully established an OXA‑induced ALI model. Using this model, we discover that oxidative stress plays an important role in OXA‑induced ALI. GSH‑based hepatoprotective therapy can partially inhibit oxidative stress and alleviate OXA‑induced ALI.
Abstract Background: Among male sterility factors, oligoasthenozoospermia is the most common. As people's lifestyle changes and the population ages, the incidence of oligoasthenozoospermia continues to increase. The studies have shown that about 15% of married couples in the world are affected by infertility, among which infertility caused by male factors alone accounts for about 50%. Many clinical trials have proven that Wuzi Yanzong Pill has a significant effect in the treatment of oligoasthenozoospermia. In this systematic review, we aim to evaluate the effectiveness and safety of Wuzi Yanzong Pill for oligoasthenozoospermia. Methods: We will search for PubMed, Cochrane Library, AMED, EMbase, WorldSciNet; Nature, Science online, and China Journal Full-text Database (CNKI), China Biomedical Literature CD-ROM Database (CBM), and related randomized controlled trials included in the China Resources Database. The time is limited from the construction of the library to April 2019. We will use the criteria provided by Cochrane 5.1.0 for quality assessment and risk assessment of the included studies, and use the Revman 5.3 and Stata13.0 software for meta-analysis of the effectiveness, recurrence rate, and symptom scores of oligoasthenozoospermia. Ethics and dissemination: This systematic review will evaluate the efficacy and safety of Wuzi Yanzong Pill for treating oligoasthenozoospermia. Because all of the data used in this systematic review and meta-analysis has been published, this review does not require ethical approval. Furthermore, all data will be analyzed anonymously during the review process Trial. Trial registration number: PROSPERO CRD42019119170
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