A bibliometric study on the utilization of lenvatinib in hepatocellular carcinoma (2014-2022).

Background: The REFLECT phase-III trial has demonstrated the efficacy of lenvatinib in improving the overall survival of advanced hepatocellular carcinoma (HCC) patients, comparable to sorafenib. The rapidly evolving landscape of hepatocellular carcinoma therapy presents new avenues for lenvatinib. This study aims to provide a scientometric analysis of publications and predict research hotspots in this field. Methods: Relevant publications were sourced from the Web of Science Core Collection (WoSCC) database up until November 2022. The bibliometrix tool in R was employed for scientometric analysis and visualization. Results: A total of 879 publications from 2014 to 2022 were obtained from WoSCC that met the established criteria. These studies involved 4,675 researchers from 40 countries, with an average annual growth rate of 102.5%. The highest number of publications was from Japan, followed by China, Italy, and the United States. The largest proportion of studies, 14.0% (n = 123), was contributed by FUDAN UNIV. The studies were published in 274 journals, with CANCERS (n = 53) being the top journal, followed by FRONTIERS IN ONCOLOGY (n = 51) and HEPATOLOGY RESEARCH (n = 36). The top ten journals accounted for 31.5% of the 879 studies. The most prolific authors were Kudo M (n = 51), Hiraoka A (n = 43), and Tsuji K (n = 38). A total of 1,333 keywords were analyzed, with the present research hotspots being "immune checkpoint inhibitors," "prognosis," and "pd-1." Co-occurrence clustering analysis revealed the top keywords, authors, publications, and journals. Strong collaboration was identified in the field. Conclusion: This scientometric and visual analysis provides a comprehensive summary of the published articles on lenvatinib in HCC during 2014-2022, highlighting the research hotspots, knowledge domain, and frontiers. The results can provide insights into future research directions in this field.

Identification and characterization of BmNPV Bm5 protein required for the formation of nuclear vesicle structures.

BmNPV infection induces nuclear vesicle-like structures and its Bm5 protein mediates the intranuclear lipid accumulation, which is thought to participate in the formation of nuclear vesicles. However, the relationship between viral-induced nuclear vesicles and Bm5 protein is still unclear. Here, our results indicated that BmNPV Bm5 protein participated in the baculovirus infection-induced nuclear vesicle-like structures' invagination thereby influencing the production of occlusion-derived virion (ODV) and occlusion body (OB). The process of nuclear vesicle-like structures' formation was dispensable for the transport or recruitment of ODV major envelope proteins, such as P74 and Bm14. Furthermore, baculovirus-induced nuclear F-actin might provide a direct mechanical force to mediate the scission of large vesicle-like structures from the nuclear membrane. Collectively, these findings illustrated a BmNPV Bm5 protein-induced nuclear membrane invagination pathway and revealed the function of nuclear vesicle-like structures in ODV production.

Overexpression Bombyx mori HEXIM1 Facilitates Immune Escape of Bombyx mori Nucleopolyhedrovirus by Suppressing BmRelish-Driven Immune Responses.

Bombyx mori nucleopolyhedrovirus (BmNPV), a typical arthropod-specific enveloped DNA virus, is one of the most serious pathogens in silkworm farming, but the potential mechanisms of the evasion of innate immune responses from BmNPV infection are still poorly understood. HEXIM1 is an RNA-binding protein, best known as an inhibitor of positive transcription elongation factor b (P-TEFb), which controls transcription elongation by RNA polymerase II. In this study, Bombyx mori HEXIM1 (BmHEXIM1) was cloned and characterized, and its expression was found to be remarkably upregulated after BmNPV infection. Furthermore, BmHEXIM1 was detected to increase the proliferation of BmNPV, and its full length is essential for assisting BmNPV immune escape by suppressing BmRelish-driven immune responses. This study brought new insights into the mechanisms of immune escape of BmNPV and provided theoretical guidance for the breeding of BmNPV-resistant silkworm varieties.

Efficacy and safety evaluations of anlotinib in patients with advanced non-small cell lung cancer treated with bevacizumab.

Objective: The purpose of this study is to evaluate the efficacy and safety of anlotinib in patients with advanced non-small cell lung cancer (NSCLC) who had previously received bevacizumab. Methods: The participants were histopathologically or cytologically diagnosed advanced NSCLC patients whose disease progressed after at least one type of systemic therapy and who had previously received bevacizumab treatment. The patients were on 3-week administration cycles, including 2 weeks on-treatment (12 mg anlotinib oral route, once a day) and 1 week off-treatment. The primary end point of the trial was overall survival (OS). The secondary end points were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety. Results: As of the data collection deadline (31 March 2021), 30 patients were enrolled in the study and received anlotinib treatment. All patients were included in the data set except one, who withdrew their consent after the start of treatment. The median follow-up period was 12.1 months (range, 3.6-25.0 months), and 29 patients were included in the evaluation of the treatment. Of the 29 patients, no CR cases occurred. In total, three patients (10.2%) showed a PR, 21 (72.4%) had SD, and five patients (17.2%) had PD. The objective response rate (ORR) was 10.2% (3 of 29 patients), and the disease control rate (DCR) was 82.7% (24 of 29 patients). The median progression-free survival (PFS) was 5.6 months (95% CI, 5.0-6.1 months; Figure 2). The median overall survival (OS) was 10.6 months (95% CI, 9.4-11.8 months; Figure 3). The overall tolerance of the anlotinib treatment was high among the enrolled patients. No treatment-related grade four or five toxicities were observed. Of the 29 patients, one patient's anlotinib administration was reduced to 8 mg/day due to hypertension and headache. Most adverse events (AEs) were grade one or two; the most common AEs were fatigue (51.7%), hypertension (41.3%), hand-foot syndrome (41.4%), anorexia (34.5%) and hypertriglyceridemia (34.5%). Conclusion: Anlotinib demonstrated favourable activity and manageable toxicity in NSCLC patients who were treated with bevacizumab previously.

BmNPV p35 Reduces the Accumulation of Virus-Derived siRNAs and Hinders the Function of siRNAs to Facilitate Viral Infection.

Antiviral immunity involves various mechanisms and responses, including the RNA interference (RNAi) pathway. During long-term coevolution, viruses have gained the ability to evade this defense by encoding viral suppressors of RNAi (VSRs). It was reported that p35 of baculovirus can inhibit cellular small interference RNA (siRNA) pathway; however, the molecular mechanisms underlying p35 as a VSR remain largely unclear. Here, we showed that p35 of Bombyx mori nucleopolyhedrovirus (BmNPV) reduces the accumulation of virus-derived siRNAs (vsiRNAs) mapped to a particular region in the viral genome, leading to an increased expression of the essential genes in this region, and revealed that p35 disrupts the function of siRNAs by preventing them from loading into Argonaute-2 (Ago2). This repressive effect on the cellular siRNA pathway enhances the replication of BmNPV. Thus, our findings illustrate for the first time the inhibitory mechanism of a baculovirus VSR and how this effect influences viral infection.

Actin Contributes to the Hyperexpression of Baculovirus Polyhedrin (polh) and p10 as a Component of Transcription Initiation Complex (TIC).

Hyperexpression of polh and p10, two very late genes, is one of the remarkable characteristics in the baculovirus life cycle. However, the mechanisms underlying the hyperexpression of these two genes are still incompletely understood. In this study, actin was identified as a highly potential binding partner of polh and p10 promoters by conducting DNA pull-down and LC-MS/MS analyses. Inhibiting actin dynamics delayed and decreased the transcription of polh and p10. Actin interacted with viral RNA polymerase and transcription regulators, and the nuclear import of viral polymerase was inhibited with the disruption of actin dynamics. Simultaneously, the high enrichment of actin in polh and p10 promoters discovered via a chromatin immunoprecipitation (ChIP) assay indicated that actin was a component of the viral polymerase TIC. Moreover, overexpression of actin surprisingly upregulated the expression of luciferase (Luc) under the control of polh and p10 promoters. Taken together, actin participated in the hyperexpression of polh and p10 as a component of TIC. These results facilitate the promotion of the expression efficiency of foreign genes in the baculovirus expression vector system (BEVS).

RNAi-based immunity in insects against baculoviruses and the strategies of baculoviruses involved in siRNA and miRNA pathways to weaken the defense.

Protection against viral infection in hosts concerns diverse cellular and molecular mechanisms, among which RNA interference (RNAi) response is a vital one. Small interfering RNAs (siRNAs), microRNAs (miRNAs) and PIWI interacting RNAs (piRNAs) are primary categories of small RNAs involved in RNAi response, playing significant roles in restraining viral invasion. However, during a long-term coevolution, viruses have gained the ability to evade, avoid, or suppress antiviral immunity to ensure efficient replication and transmission. Baculoviruses are enveloped, insect-pathogenic viruses with double-stranded circular DNA genomes, which encode suppressors of siRNA pathway and miRNAs targeting immune-related genes to mask the antiviral activity of their hosts. This review summarized recent findings for the RNAi-based antiviral immunity in insects as well as the strategies that baculoviruses exploit to break the shield of host siRNA pathway, and hijack cellular miRNAs or encode their own miRNAs that regulate both viral and cellular gene expression to create a favorable environment for viral infection.

CLK2 promotes occurrence and development of non-small cell lung cancer.

PURPOSE: To explore the role of CDC-like kinase 2 (CLK2) in the development and progression of lung cancer and its regulatory mechanism. METHODS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay was used to detect the expressions of micro ribonucleic acid (miR)-573 and CLK2 in non-small cell lung cancer (NSCLC) cell lines or tissues. The cell proliferative ability after overexpression of CLK2 was determined via cell counting kit-8 (CCK-8) and 5-Ethynyl-2'- deoxyuridine (EdU) assays. It was verified using dual-luciferase reporter assay and gain-loss assay that CLK2 was the target gene of miR-573, which was regulated by miR-573. According to the reverse assay, the effect of CLK2 on the proliferation of NSCLC cells was regulated by miR-573. RESULTS: In qRT-PCR, the expression of CLK2 in NSCLC tissues and cell lines significantly rose. The CLK2 expression was increased in patients with stage Ⅲ-Ⅳ NSCLC and metastasis. According to survival analysis, highly-expressed CLK2 indicated a worse prognosis. The receiver operating characteristic (ROC) curves showed that CLK2 possessed the potential as a biomarker. It was found using the bioinformatics prediction that CLK2 was a potential target of miR-573. The results of dual-luciferase reporter assay confirmed that there was a binding relation between the two, and up-regulation of miR-573 could obviously inhibit the expression of CLK2. In qRT-PCR, the miR-573 expression in lung cancer tissues obviously declined, which was significantly negatively correlated with the expression of CLK2. CCK-8 and EdU assays manifested that the proliferation of lung cancer cells could be markedly enhanced through up-regulating CLK2. Finally, the results of reverse assay showed that up-regulating miR-573 could partially reverse the promoting effect of CLK2 on cell proliferation. CONCLUSIONS: Highly-expressed CLK2 significantly enhances the proliferation of lung cancer cells, thereby promoting the occurrence and development of lung cancer, which may be regulated by miR-573.

Prognostic value of using glucosylceramide synthase and cytochrome P450 family 1 subfamily A1 expression levels for patients with triple-negative breast cancer following neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NACT) has been considered to be the preferred treatment option for early operable triple-negative breast cancer (TNBC). However, resistance to drugs remains to be the barrier to the efficacy of NACT. Glucosylceramide synthase (GCS) and cytochrome P450 family 1 subfamily A1 (CYP1A1) have been previously associated with drug resistance in breast cancer. The present study aimed to explore whether the expression levels of GCS and/or CYP1A1 are associated with the prognosis of TNBC after NACT. Immunohistochemistry was used to detect and measure GCS and CYP1A1 expression. Associations between GCS or CYP1A1 expression and the clinicopathological characteristics, pathological complete response (pCR), clinical complete response (cCR) and disease-free survival (DFS) were analyzed. GCS expression was found to be associated with tumor size (P=0.021) and TNM staging (P=0.042), whilst CYP1A1 expression was associated with lymph node metastasis (P = 0.026) and TNM staging (P=0.034). The expression levels of GCS (P=0.024) and CYP1A1 (P=0.027) were upregulated after NACT. GCS and CYP1A1 expression were positively correlated (P=0.003; r=0.327). No difference was observed between the GCS+ (P=0.188) or CYP1A1+ group (P=0.073) and the GCS- or CYP1A1- group in terms of pCR. However, compared with that in the GCS+CYP1A1+ group, the pCR was markedly increased in the GCS-CYP1A1- group (P=0.031). The cCR was lower in the GCS+ (P=0.021) and CYP1A1+ groups (P=0.016) compared with in the GCS- or CYP1A1- group. The DFS rate (57.9 vs. 65.4%; P=0.049) was lower in the GCS+CYP1A1+ group compared with that in the GCS-CYP1A1- group. However, there was no statistical significance after P-value was adjusted for multiple comparisons using Bonferroni correction. In conclusion, co-expression of GCS and CYP1A1 was associated with pCR and DFS in TNBC, which may serve a role in the prediction of the prognosis of patients with TNBC following treatment with NACT.

An integrated pan-cancer analysis of TFAP4 aberrations and the potential clinical implications for cancer immunity.

Studies have shown that transcription factor activating enhancer binding protein 4 (TFAP4) plays a vital role in multiple types of cancer; however, the TFAP4 expression profile is still unknown, as is its value within the human pan-cancer analysis. The present study comprehensively analysed TFAP4 expression patterns from 33 types of malignancies, along with the significance of TFAP4 for prognosis prediction and cancer immunity. TFAP4 displayed inconsistent levels of gene expression across the diverse cancer cell lines, and displayed abnormal expression within most malignant tumours, which closely corresponded to overall survival. More importantly, the TFAP4 level was also significantly related to the degree of tumour infiltration. TFAP4 was correlated using gene markers in tumour-infiltrating immune cells and immune scores. TFAP4 expression was correlated with tumour mutation burden and microsatellite instability in different cancer types, and enrichment analyses identified TFAP4-associated terms and pathways. The present study comprehensively analysed the expression of TFAP4 across 33 distinct types of cancers, which revealed that TFAP4 may possibly play a vital role during cancer formation and development. TFAP4 is related to differing degrees of immune infiltration within cancers, which suggests the potential of TFAP4 as an immunotherapy target in cancers. Our study demonstrated that TFAP4 plays an important role in tumorigenesis as a prognostic biomarker, which highlights the possibility of developing new targeted treatments.

Bombyx mori nucleopolyhedrovirus F-like protein Bm14 is a factor for viral-induced cytopathic effects via regulating oxidative phosphorylation and cellular ROS levels.

Bombyx mori nucleopolyhedrovirus (BmNPV) is highly pathogenic to Bombyx mori, silkworm, which causes serious cytopathic effects (CPEs) during infection. However, the role of viral protein in the virus-induced CPEs remains unclear. Here, we discovered that BmNPV infection induced severe CPEs including titer-dependent cell floating and changes in cellular surface morphology. Further explorations revealed the involvement of F-like protein (Bm14), a viral envelope protein, in inducing cytotoxicity and detachment of adherent BmN cells, and its disruption significantly impaired the virus infection-mediated CPEs. Intriguingly, transcriptomic analysis identified the tight association of Bm14 deletion with the activation of cellular oxidative phosphorylation pathway, consistent with the elevated mitochondrial membrane potential (MMP) levels and ATP concentrations as well as reduced ROS levels. Collectively, our results characterized for the first time the novel role of Bm14 in accelerating viral-induced cytopathogenicity via suppressing the cellular oxidative phosphorylation levels and upregulating the ROS levels.

Bioinformatic analysis and in vitro validation of a five-microRNA signature as a prognostic biomarker of hepatocellular carcinoma.

BACKGROUND: Existing research has identified correlations between numerous microRNAs (miRNAs) and the prognosis of hepatocellular carcinoma (HCC). However, the role of a combination of miRNAs in predicting HCC survival requires further elucidation. METHODS: miRNA expression profiles and clinical data from HCC patients were downloaded from The Cancer Genome Atlas (TCGA). Differentially expressed (DE) miRNAs in tumor versus normal samples were identified. All HCC patients were randomly assigned to a training cohort or a validation cohort at a ratio of 1 to 1. A least absolute shrinkage and selection operator (LASSO) Cox regression model was subsequently employed to establish the miRNA signature. The constructed miRNA signature was then developed and validated. RESULTS: In total, 127 DE miRNAs were detected between HCC and paracancerous tissue using HCC RNA sequencing (RNA-Seq) data extracted from TCGA database. LASSO Cox regression generated a five-miRNA signature consisting of has-mir-105-2, has-mir-9-3, has-mir-137, has-mir-548f-1, and has-mir-561 in the training cohort. This risk model was significantly related to survival (P=5.682e-6). Log-rank tests and multivariate Cox regression analyses revealed the five-miRNA signature as an independent prognostic indicator [HR =3.285, 95% confidence interval (CI): 1.737-6.213], with the area under curve (AUC) of the miRNA signature being 0.728. The effects of the miRNA signature were further confirmed in the validation cohort and in the OncomiR Cancer Database and Gene Expression Omnibus (GEO) dataset. Functional enrichment analysis revealed the potential effects of the five-miRNA signature in tumor-related biological pathways and processes. Cell Counting Kit-8, Transwell, and wound healing assays, were used to evaluate the role of has-mir-137 in HCC cell proliferation and migration in vitro. CONCLUSIONS: We established a novel five-miRNA signature which reliably predicted prognosis in HCC patients and which could be used to assist in both strategic counseling and personalized management in HCC.

Clinical Implications of Aberrant PD-1 and CTLA4 Expression for Cancer Immunity and Prognosis: A Pan-Cancer Study.

Combination therapy with inhibitors of cytotoxic T lymphocyte-associated protein (CTLA)4 and programmed death (PD)-1 has demonstrated efficacy in cancer patients. However, there is little information on CTLA4 and PD-1 expression levels and their clinical significance across diverse cancers. In this study, we addressed this question by analyzing PD-1 and CTLA4 levels in 33 different types of cancer along with their prognostic significance using The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia datasets. Liver hepatocellular carcinoma (LIHC) patients receiving cytokine-induced killer cell (CIK) immunotherapy at Sun Yat-sen University cancer center were enrolled for survival analysis. The correlation between PD-1/CTLA4 expression and cancer immunity was also analyzed. The results showed that PD-1 and CTLA4 transcript levels varied across cancer cell lines, with aberrant expression detected in certain cancer types; Kaplan-Meier analysis with the Cox proportional hazards model showed that this was closely related to overall survival in breast invasive carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, acute myeloid leukemialymphoma, uterine corpus endometrial carcinoma, and uveal melanoma in TCGA. High serum PD-1 and CTLA4 levels predicted better survival in LIHC patients receiving CIK therapy. PD-1 and CTLA4 levels were found to be significantly correlated with the degree of tumor cell infiltration using Tumor Immune Estimation Resource, Estimating Relative Subsets of RNA Transcripts, and Estimation of Stromal and immune Cells in Malignant Tumor Tissues Using Expression Data as well as with tumor-infiltrating lymphocyte marker expression; they were also related to tumor mutation burden, microsatellite instability, mismatch repair, and the expression of DNA methyltransferases in some cancer types. Gene set enrichment analysis of 33 cancer types provided further evidence for associations between PD-1/CTLA4 levels and cancer development and immunocyte infiltration. Thus, PD-1 and CTLA4 play important roles in tumorigenesis and tumor immunity and can serve as prognostic biomarkers in different cancer types.

Bombyx mori nucleopolyhedrovirus Bm46 is essential for efficient production of infectious BV and nucleocapsid morphogenesis.

Bombyx mori nucleopolyhedrovirus (BmNPV) orf46 (Bm46), the orthologues of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) ac57, is a highly conserved gene in group Ⅰ and group Ⅱ nucleopolyhedroviruses (NPVs). However, its function in viral life cycle is unclear. Our results indicated that Bm46 transcript was detected from infected cells at 12 h post infection, while Bm46 protein was detectable from 24 to 72 h post infection. Upon the deletion of Bm46, fewer infectious BVs were produced by titer assays, but neither viral DNA synthesis nor occlusion bodies (OBs) production was affected. Electron microscopy revealed that Bm46 knockout interrupted nucleocapsid assembly and occlusion-derived virus (ODV) embedding, resulting in aberrant capsid-like tubular structures accumulated in the RZ (ring zone). Interestingly, this abnormally elongated capsid structures were consistent with the immunofluorescence microscopy results showing that VP39 assembled into long filaments and cables in the RZ. Moreover, DNA copies decreased by 30 % in occlusion bodies (OBs) produced by Bm46-knockout virus. qRT-PCR and Western blot analysis showed that the expression of VP39 was affected by Bm46 disruption. Taken together, our findings clearly pointed out that Bm46 played an important role in BV production and the proper formation of nucleocapsid morphogenesis.

Dynamic chromatin accessibility profiling reveals changes in host genome organization in response to baculovirus infection.

DNA viruses can hijack and manipulate the host chromatin state to facilitate their infection. Multiple lines of evidences reveal that DNA virus infection results in the host chromatin relocation, yet there is little known about the effects of viral infection on the architecture of host chromatin. Here, a combination of epigenomic, transcriptomic and biochemical assays were conducted to investigate the temporal dynamics of chromatin accessibility in response to Bombyx mori nucleopolyhedrovirus (BmNPV) infection. The high-quality ATAC-seq data indicated that progressive chromatin remodeling took place following BmNPV infection. Viral infection resulted in a more open chromatin architecture, along with the marginalization of host genome and nucleosome disassembly. Moreover, our results revealed that chromatin accessibility in uninfected cells was regulated by euchromatic modifications, whereas the viral-induced highly accessible chromatin regions were originally associated with facultative heterochromatic modification. Overall, our findings illustrate for the first time the organization and accessibility of host chromatin in BmNPV-infected cells, which lay the foundation for future studies on epigenomic regulation mediated by DNA viruses.

Bombyx mori nucleopolyhedrovirus F-like protein Bm14 is a type I integral membrane protein that facilitates ODV attachment to the midgut epithelial cells.

Our previous study showed that the Bombyx mori nucleopolyhedrovirus (BmNPV) F-like protein Bm14 is intrinsically related to the production of occlusion bodies, occlusion-derived virus (ODV) embedding and virulence in infected larvae. However, the exact mechanism by which Bm14 affects primary infection remains unknown. In this report, we characterized the detailed distribution and topology of Bm14 in occlusion bodies (OBs) and ODVs, and then further investigated the functional role of Bm14 in primary infection. A combination of Western blot and immunoelectron microscopy showed that Bm14 is mainly present on the surface of ODVs within OBs, but rarely in the OB matrix. Further phase separation and topology analysis of Bm14 by selective permeabilization revealed that Bm14 is a type I integral membrane protein with an N-terminus hidden in the endoplasmic reticulum (ER) lumen and a C-terminus exposed to the cytosol. In vivo assays demonstrated that the disruption of bm14 impaired the interactions of ODV with midgut epithelia, resulting in delayed spread in larval tissues. As the essential trigger of primary infection, some per os infectivity factors (PIFs) were verified to interact with Bm14 via a series of coimmunoprecipitation analyses. Further partially denaturing SDS-PAGE and BN-PAGE assays clearly showed that the deletion of bm14 did not affect the formation and presence of the PIF complex. In conclusion, Bm14 functions as a type I integral membrane protein to regulate ODV attachment to the midgut epithelial cells.

Post-translational modification of baculovirus-encoded proteins.

Post-translational modifications (PTMs) are the chemical modifications of proteins after translation, and are very important to guarantee the proper biological functions of these proteins. Baculoviruses are pathogenic viruses that infect invertebrates and have large circular double-stranded DNA genomes. Many proteins encoded by baculoviruses have been reported to have PTMs, including phosphorylation, glycosylation, ubiquitination, acetylation, and etc. However, up to now no overview of this information has been produced. In this review, we have summarized the PTMs that have been reported in baculovirus. As a majority of the studies on baculovirus have focused on Autographa californica multiple nucleopolyhedrovirus (AcMNPV) and Bombyx mori nucleopolyhedrovirus(BmNPV), this review is focused primarily on these viruses.

Prognostic value of insulin-like growth factor 2 mRNA-binding protein 3 and vascular endothelial growth factor-A in patients with primary non-small-cell lung cancer.

Insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) and vascular endothelial growth factor-A (VEGF-A) may play important roles in the process of tumor progression and tumor angiogenesis. The aim of the present study was to examine the co-expression of IMP3 and VEGF-A in primary human non-small cell lung cancer (NSCLC), to investigate the association between these two expression levels and determine the clinicopathological implications, including changes to microvessel density (MVD), and to assess the prognostic value of co-expression. Using immunohistochemical staining, the expression of IMP3, VEGF-A and CD34 expression was detected in 128 primary NSCLC tissue samples. According to the expression of IMP3 and VEGF-A, the cases were divided into four groups. Next, the clinicopathological features, MVD and survival time were investigated across the different groups. The immunohistochemical analyses demonstrated that there was a significant correlation between IMP3 and VEGF-A expression in NSCLC (r=0.181; P=0.041). Co-expression of IMP3 and VEGF-A was significantly associated with larger primary tumor size (P=0.016), poorer differentiation (P=0.014), more advanced Tumor-Node-Metastasis stage (P=0.012), increased MVD (P=0.004) and positive lymph node metastasis (P=0.002). Survival analysis demonstrated that cases with IMP3 and VEGF-A double-positive staining were significantly associated with lower survival rates compared with cases with double-negative staining (P=0.039). In the early NSCLC (I-IIa) subgroup, the mean survival time of the double-positive staining group was significantly shorter compared with that of the double-negative staining group (P=0.015). Co-expression of IMP3 and VEGF-A was associated with angiogenesis and a poorer prognosis in NSCLC, and may therefore play a critical role in NSCLC progression.

Bombyx mori nucleopolyhedrovirus protein Bm11 is involved in occlusion body production and occlusion-derived virus embedding.

Bombyx mori nucleopolyhedrovirus (BmNPV) orf11 (bm11) is a highly conserved gene with unknown function. It is homologous to AcMNPV orf19. In this study, a bm11 knockout virus was constructed and its role was investigated. Expression analysis indicated that bm11 is a late gene and confocal microscopy analysis demonstrated that Bm11 localizes predominantly in the nuclear ring zone at the late phase of infection. The bm11 deletion did not affect budded virus (BV) production or viral genome replication, but markedly reduced the production of occlusion bodies (OBs) and the embedding of occlusion-derived viruses (ODVs). Bio-assays showed that Bm11 was involved in BmNPV infectivity in vivo by direct injection. In conclusion, our results demonstrated that although Bm11 is not essential for BV production or mature ODV formation, it affects OB production and ODV occlusion.

Mitofusin-2 acts as biomarker for predicting poor prognosis in hepatitis B virus related hepatocellular carcinoma.

OBJECTIVE: To investigate the expression of Mitofusin-2 (MFN2) in HCC tissues and its role in the development of HCC. METHODS: A total of 107 HCC specimens were collected for tissue microarray analysis and immunohistochemistry (IHC) analysis. The relationship between MFN2 expression and clinical features of patients with HCC was analyzed. RESULTS: Expression level of MFN2 in HCC tissues was 0.92 ± 0.78, significantly lower than that of matched paracancerous liver tissues (1.25 ± 0.75). Patients with low expression of MFN2 had significantly higher rates of cirrhosis than those with high expression of MFN2 (P = 0.049). Kaplan-Meier survival analysis showed that HCC patients with low expression of MFN2 had a worse prognosis in overall survival than HCC patients with high expression of MFN2 (P = 0.027). Patients with high expression of MFN2 had a better prognosis in disease-free survival compared with HCC patients with low expression of MFN2 (P = 0.047). Vascular invasion and MFN2 expression were shown to be prognostic variables for overall survival in patients with HCC. Multivariate analysis showed that vascular invasion (P < 0.001) and MFN2 expression (P = 0.045) were independent prognostic factors for overall survival. Vascular invasion (P < 0.001) and MFN2 expression (P = 0.042) were independent risk factors associated with disease-free survival. CONCLUSION: Our data revealed that MFN2 expression was decreased in HCC samples. High MFN2 expression was correlated with longer survival times in patients with HCC and served as an independent factor for better outcomes. Our study therefore provides a promising biomarker for the prognostic prediction of HCC and a potential therapeutic target for the disease.