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Abstract Background Ablation is one of the main methods for local treatment of hepatocellular carcinoma (HCC). Different from radiofrequency ablation (RFA), microwave ablation (MWA) is not limited by tissue conductivity, and can use multiple electrodes at the same time to improve ablation efficiency. In addition, MWA can form a larger ablation area, which makes it possible to completely ablate large HCC. However, MWA may be incomplete due to factors such as larger tumors or tumors in high-risk areas. The mechanism by which the cellular and tumor immune microenvironment (TIME) is involved in the in vitro effects of incomplete microwave ablation (iMWA) needs to be further elucidated. Methods H22 tumor-bearing C57BL/6 mice were treated with iMWA with several combinations of ablation power and time duration. The effects of iMWA on the genes of HCC cancer cells and the TIME were investigated by RNA sequencing, mass cytometry, immunohistochemistry, and immunofluorescence. The effect of iMWA in combination with anti-Gr-1 on HCC tumor growth was also evaluated. Results Thermal stress generated by iMWA induced coagulative necrosis and apoptosis in the region of the ablation center of HCC. RNA sequencing analysis showed that iMWA can boost chemokine CXCL5, which was further confirmed by quantitative real time polymerase chain reaction (qRT-PCR). Mass cytometry results showed that relative to Ctrl group, iMWA-treated led to decreased CD4+ T, CD8+ T, Natural killer (NK), macrophages including both M1 and M2 types but increased monocytes and bone marrow-derived suppressor cells (MDSC). Therefore, inhibiting MDSC is the main target in the later stage of iMWA. In vivo results showed that the tumor volume and weight of iMWA+ anti-Gr-1 group were significantly reduced compared with iMWA+ anti-IgG group. In addition, the merged expressions of CD11b and Gr-1 proteins were found reduced in the iMWA+ anti-Gr-1 group compared with the iMWA+ anti-IgG group by immunofluorescence staining. Immunohistochemistry suggested that CD8 was enriched in the iMWA+ anti-Gr-1 group but not in the iMWA+ anti-IgG group. Conclusion Our data suggests that iMWA and Gr-1 blocking combined therapy can further inhibit HCC growth and significantly improve the CD8+ T cells in the mouse subcutaneous tumor model, which brings good news to HCC patients.

Rhinovirus (RV) is a common pathogen that causes respiratory tract infection and can cause outbreaks in hospitals and welfare institutions. A cluster of respiratory diseases occurred in a primary school in Shenyang City, Liaoning Province, China, in 2022. In this outbreak, a total of 31 students had symptoms similar to those of upper respiratory tract infection, mainly cough and sore throat. Among them, 27 throat swabs were collected and identified for respiratory pathogens by TaqMan low-density array (TLDA), quantitative real-time polymerase chain reaction (PCR), reverse transcription-nested PCR and whole-genome sequencing. Out of the 27 specimens, 24 tested positive for RV, and 21 RV viral protein 1 sequences were obtained, of which 15 (71.43%) were identified as RV-A49, while 2 RV-A20 and 4 sequences from 2 specimens were RV-A30 coinfected with RV-C15. In addition, one whole-genome sequence (WGS) of RV-A49 was obtained, and three unique amino acid mutations were found compared to 23 WGS of RV-A49 from GenBank. In conclusion, this outbreak of upper respiratory tract infection is caused by RV, mainly RV-A49.

Abstract Metastasis remains a pivotal characteristic of cancer and is the primary contributor to cancer-associated mortality. Despite its significance, the mechanisms governing metastasis are not fully elucidated. Contemporary findings in the domain of cancer biology have shed light on the molecular aspects of this intricate process. Tumor cells undergoing invasion engage with other cellular entities and proteins en route to their destination. Insights into these engagements have enhanced our comprehension of the principles directing the movement and adaptability of metastatic cells. The tumor microenvironment plays a pivotal role in facilitating the invasion and proliferation of cancer cells by enabling tumor cells to navigate through stromal barriers. Such attributes are influenced by genetic and epigenetic changes occurring in the tumor cells and their surrounding milieu. A profound understanding of the metastatic process’s biological mechanisms is indispensable for devising efficacious therapeutic strategies. This review delves into recent developments concerning metastasis-associated genes, important signaling pathways, tumor microenvironment, metabolic processes, peripheral immunity, and mechanical forces and cancer metastasis. In addition, we combine recent advances with a particular emphasis on the prospect of developing effective interventions including the most popular cancer immunotherapies and nanotechnology to combat metastasis. We have also identified the limitations of current research on tumor metastasis, encompassing drug resistance, restricted animal models, inadequate biomarkers and early detection methods, as well as heterogeneity among others. It is anticipated that this comprehensive review will significantly contribute to the advancement of cancer metastasis research.

Abstract Despite substantial breakthroughs in the treatment of hepatocellular carcinoma (HCC) in recent years, many patients are diagnosed in the middle or late stages, denying them the option for surgical excision. Therefore, it is of great importance to find effective therapeutic targets of HCC. In this study, it is found that Gap junction protein beta‐2 (GJB2) is highly enriched in malignant cells based on single‐cell RNA sequencing and higher expression of GJB2 indicates a worse prognosis. The localization of GJB2 in HCC cancer cells is changed compared with normal liver tissue. In cancer cells, GJB2 tends to be located in the cytoplasm and nucleus, while in normal tissues, GJB2 is mainly located on the cell membrane. GJB2 is related to glycolysis, promoting NF‐κB pathway via inducing the ubiquitination degradation of IκBa, and activating HIF‐1α/GLUT‐1/PD‐L1 pathway. In addition, GJB2 knockdown reshapes tumor immune microenvironment and Salvianolic acid B inhibits the activity of GJB2. In conclusion, GJB2 promotes HCC progression by activating glycolysis through cytoplasmic translocation and generating a suppressive tumor microenvironment. Salvianolic acid B inhibits the expression of GJB2 and enhances the sensitivity of anti‐PD1 therapy, which may provide insights into the development of novel combination therapeutic strategies for HCC.

Natural plant fibers are hierarchical structures with multi-level microstructures. With advances in composite material science, these fibers have been widely used in various polymer products. Therefore, it is crucial to quantitatively understand the relationship between their microstructures and mechanical behavior. This paper utilizes the Mori-Tanaka micromechanics model, viscoelasticity theory, and Zakian’s inversion method to study the impact of plant fiber microstructure on the viscoelastic behavior of multiscale structures. At the microscopic scale, the macromolecular polymer (matrix) and cellulose (fiber) are first homogenized. The second homogenization involves the cell wall microstructure, and the third homogenization considers the porosity of the cell wall and lumen to predict the effective modulus of fiber bundles. By applying the principle of elastic-viscoelastic correspondence, the viscoelastic mechanical parameters of plant fibers are calculated. The study examines the effects of cellulose crystallinity and lumen porosity on the structural stiffness and viscoelastic properties of fibers, identifying these factors as key influences on the mechanical behavior of plant fibers. Given their significant economic potential, the feasibility of using tobacco plant fibers as bio-based materials is also explored.

Abstract Purpose Liver metastasis is one of the most important factors affecting the prognosis of patients with neuroendocrine neoplasms (NENs). Transhepatic artery embolization (TAE) is the main local treatment of NENs with liver metastasis (NENLM). This study aimed to elucidate the differences between pancreatic and rectal NENLM with a discrepancy in blood supply. Methods A total of 32 patients with NENLM of different primary sites received 102 TAE treatments at our hospital. Clinical features, such as age, sex, World Health Organization (WHO) tumour grade and progression‐free survival (PFS), were compared between patients with pancreatic and rectal NENLM with different blood supplies. The total follow‐up time is 1–5 years. Results There were 12 cases with tumours originating from the rectum or pancreas, respectively. Other tumour‐originated sites included the duodenum (two cases, 6.25%), the thymus and lung (four cases, 12.5%), and the unknown (two cases, 6.25%). The average age of patients was 51.59 years, and 17 (53.1%) were men. WHO grade 1, 2 or 3 tumours occurred in three (9.4%), 23 (71.9%) and six (18.7%) patients, respectively. Hepatic tumour burdens of low (50%) levels were found in 13 (40.6%), eight (25%) and 11 (34.4%) patients, respectively. There were more patients with hypervascular pancreatic NENLM than with hypovascular rectal NENLM (p = 0.005). Tumour shrinkage in all cases with NENLM was 50% with an objective response rate of 37.5%, disease control rate of 75% and PFS of 12 months. Disease progression (p = 0.09), tumour shrinkage (p = 0.07) and death (p = 0.19) were more prominent in the pancreatic NENLM group than in the rectal NENLM group. Progression‐free survival was not reached in the pancreatic NENLM group, which was more prominent than in the rectal NENLM group (7 months; hazard ration, 0.22; 95% confidence interval, 0.07–0.76; p = 0.016). The main adverse events were abdominal pain (71.9%) and transaminase elevation (50%), which were more common in pancreatic NENLM than in rectal NENLM. Conclusions Transhepatic artery embolization treatment is markedly effective and safe for treating NENLM, especially pancreatic NENLM.

ABSTRACTEchovirus 5 (E5) belongs to the enterovirus B (EV-B) species, which is one of the pathogens causing respiratory diseases. Only two whole genome sequences (WGSs) of E5 are available in GenBank, and few studies on E5 have been reported worldwide. In this study, human rhabdomyosarcoma (RD) cells were used to isolate E5 from respiratory samples associated with severe acute respiratory infection (SARI). The nucleotide sequence of the VP1 region and the WGSs of two E5 strains were sequenced using Sanger sequencing and high-throughput sequencing technology, respectively. Together with 31 E5 VP1 sequences and 2 WGSs downloaded from GenBank, a total of 33 complete VP1 sequences and 4 WGSs were used for genetic characterization and evolutionary analysis. Phylogenetic analysis revealed five genotypes (A–E) based on complete VP1 sequences. Evolutionary analysis showed that the time to the most recent common ancestor of E5 was approximately 1952 (95% highest posterior density [HPD] range, 1948–1953]), with a mean substitution rate of 7.74 × 10−3 subs/site/year (95% HPD range, 6.44–9.11 × 10−3). In addition, the WGS analyses showed that the nucleotide and amino acid similarities of the coding regions of the two strains obtained in this study with the prototype of the E5 strain Noyce were 80.2% and 97.2%, respectively. Recombination analysis showed that the two E5 strains may have intraspecific recombination with E6, EV-B85, and CVA9 serotypes in the nonstructural region. This study reports the isolation of E5 from SARI cases for the first time, and genetic characterization and evolutionary analysis provide valuable information on global E5 molecular epidemiology.IMPORTANCEThis study is the first report of echovirus 5 (E5) associated with severe acute respiratory infection and obtained the first E5 whole-genome sequence in China. Combined with the sequences available in the GenBank database, the first genotyping, phylogenetic characteristics, recombination, and genetic evolutionary analysis of E5 was performed in this study. Our findings providing valuable information on global E5 molecular epidemiology.

Abstract Background Circular RNAs (circRNAs) are enriched in exosomes and are extremely stable. Exosome-mediated intercellular transfer of specific biologically active circRNA molecules can drive the transformation of the tumor microenvironment and accelerate or inhibit the local spread and multifocal growth of hepatocellular carcinoma (HCC). In this study, we explored in depth about the biological roles of HCC cell-derived exosomes and exosome-transported circRNAs on HCC in vivo and in vitro. Methods Exosomes extracted from HCC cells (Huh7 and HA22T) were characterized using transmission electron microscopy, nanoparticle size tracer analysis, and western blotting. Exosomes were observed for endocytosis using fluorescent labeling. The effects of HCC cell-derived exosomes and the circ_002136 they carried on cell growth, metastasis and apoptosis were determined by CCK-8 assay, transwell assay, flow cytometry analysis and TUNEL staining, respectively. The expressions of circ_002136, miR-19a-3p and RAB1A were detected by quantitative RT-PCR (qRT-PCR). Targeted binding between miR-19a-3p and circ_002136 or RAB1A was predicted and verified by bioinformatics analysis, dual-luciferase reporter and RNA pull-down experiments. The in vivo effect of circ_002136 was determined by constructing a xenograft tumor model. Results The findings revealed that Huh7 and HA22T exosomes conferred enhanced viability as well as invasive ability to recipient HCC cells. Circ_002136 was shown for the first time to be differentially upregulated in HCC tissues and cells and transferred by HCC cell-derived exosomes. More importantly, selective silencing of circ_002136 depleted the malignant biological behaviors of HCC exosome-activated Huh7 and HA22T cells. Depletion of circ_002136 in vivo effectively retarded the growth of HCC xenograft tumors. Furthermore, a well-established circ_002136 ceRNA regulatory network was constructed, namely circ_002136 blocked miR-19a-3p expression, elevated RAB1A expression activity and stimulated HCC development. Finally, high levels of circ_002136 or RAB1A, as well as low levels of miR-19a-3p, negatively affected HCC patient survival. Conclusion The study on circ_002136 provides good data to support our insight into the mechanism of to-be-silenced circRNA as a therapeutic agent in the progression of HCC.

Abstract Background Midazolam (MDZ) is an anaesthetic that is widely used for anxiolysis and sedation. More recently, MDZ has also been described to be related to the outcome of various types of carcinomas. However, how MDZ influences the progression of hepatocellular carcinoma (HCC) and its effects on the biological function and tumour immune microenvironment of this type of tumour remain unknown. Methods The effects of MDZ on the proliferation, invasion, and migration of HCC cell lines were examined in vitro using the Cell Counting Kit 8 (CCK8), 5-ethynyl-2ʹ-deoxyuridine (EdU), Transwell, and wound healing assays. Additionally, western blotting was employed to confirm that PD-L1 was expressed. Chromatin immunoprecipitation-seq (ChIP-seq) analysis was used to pinpoint the transcriptional regulation regions of NF-κB and programmed death-ligand 1 (PD-L1). A C57BL/6 mouse model was used to produce subcutaneous HCC tumors in order to evaluate the in vivo performance of MDZ. Mass spectrometry was also used to assess changes in the tumour immunological microenvironment following MDZ injection. Results The HCC-LM3 and Hep-3B cell lines’ proliferation, invasion, and migration were controlled by MDZ, according to the results of the CCK8, EdU, Transwell, and wound healing assays. PD-L1 expression was shown by ChIP-seq analysis to be boosted by NF-κB, and by Western blotting analysis, it was shown that MDZ downregulated the expression of NF-κB. Additionally, in vivo tests revealed that intraperitoneal MDZ injections reduced HCC tumor development and enhanced the effectiveness of anti-PD-1 therapy. The CD45+ immune cell proportions were higher in the MDZ group than in the PBS group, according to the mass spectrometry results. Injection of MDZ resulted in a decrease in the proportions of CD4+ T cells, CD8+ T cells, natural killer (NK) cells, monocytes, Tregs, and M2 macrophages and a rise in the proportion of dendritic cells. Additionally, the concentrations of the cytokines IFN-g and TNF-a were noticeably raised whereas the concentrations of the CD8+ T-cell fatigue markers ICOS, TIGIT, and TIM3 were noticeably lowered. Conclusion According to this study, MDZ inhibited the progression of HCC by inhibiting the NF-κB pathway and reducing the exhaustion of CD8+ T cells. In clinical practice, MDZ combined with anti-PD-1 therapy might contribute to synergistically improving the antitumor efficacy of HCC treatment.

ABSTRACT Human respiratory syncytial virus (HRSV) is a major pathogen of lower respiratory tract infections in children (

Abstract Growing evidence demonstrates that MicroRNAs (miRNAs) play an essential role in contributing to tumor development and progression. However, the underlying role and mechanisms of miR-23b-5p in hepatocellular carcinoma (HCC) formation remain unclear. Our study showed that miR-23b-5p was downregulated in the HCC tissues and cell lines, and lower expression of miR-23b-5p was associated with more severe tumor size and poorer survival. Gain- or loss-of-function assays demonstrated that miR-23b-5p induced G0/G1 cell cycle arrest and inhibited cell proliferation both in vitro and in vivo. qRT-PCR, western blot and luciferase assays verified that Mammalian transcription factor Forkhead Box M1 (FOXM1), upregulated in HCC specimens, was negatively correlated with miR-23b-5p expression and acted as a direct downstream target of miR-23b-5p. In addition, miR-23b-5p could regulate cyclin D1 and c-MYC expression by directly targeting FOXM1. Further study revealed that restoration of FOXM1 neutralized the cell cycle arrest and cell proliferation inhibition caused by miR-23b-5p. Taken together, our findings suggest that miR-23b-5p acted as a tumor suppressor role in HCC progression by targeting FOXM1 and may serve as a potential novel biomarker for HCC diagnosis and prognosis.

Abstract Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor and an oncogene product, which plays a pivotal role in tumor progression. Therefore, targeting persistent STAT3 signaling directly is an attractive anticancer strategy. The aim of this study is to test the efficacy of a novel STAT3 small molecule inhibitor, LLL12B, in suppressing medulloblastoma cells in vitro and tumor growth in vivo. LLL12B selectively inhibited the induction of STAT3 phosphorylation by interleukin-6 but not induction of STAT1 phosphorylation by INF-γ. LLL12B also induced apoptosis in human medulloblastoma cells. In addition, LLL12B exhibited good oral bioavailability in vivo and potent suppressive activity in tumor growth of medulloblastoma cells in vivo. Besides, combining LLL12B with cisplatin showed greater inhibition of cell viability and tumorsphere formation as well as induction of apoptosis comparing to single agent treatment in medulloblastoma cells. Furthermore, LLL12B and cisplatin combination exhibited greater suppression of medulloblastoma tumor growth than monotherapy in vivo. The present study supported that LLL12B is a novel therapeutic agent for medulloblastoma and the combination of LLL12B with a chemotherapeutic agent cisplatin may be an effective approach for medulloblastoma therapy.

Immune associated cells in the microenvironment have a significant impact on the development and progression of hepatocellular carcinoma (HCC) and have received more and more attention. Different types of immune-associated cells play different roles, including promoting/inhibiting HCC and several different types that are controversial. It is well known that immune escape of HCC has become a difficult problem in tumor therapy. Therefore, in recent years, a large number of studies have focused on the immune microenvironment of HCC, explored many mechanisms worth identifying tumor immunosuppression, and developed a variety of immunotherapy methods as targets, laying the foundation for the final victory in the fight against HCC. This paper reviews recent studies on the immune microenvironment of HCC that are more reliable and important, and provides a more comprehensive view of the investigation of the immune microenvironment of HCC and the development of more immunotherapeutic approaches based on the relevant summaries of different immune cells.

We detected human metapneumovirus (HMPV) in 72 (7.1%) of 1,021 patients hospitalized with severe acute respiratory infection in Luohe, China, during 2017–2019. We detected HMPV most frequently in young children and less often in adults. HMPV genotype A2c variants 111 nt and 180 nt duplications predominated, demonstrating their continuing geographic spread.

Reestablishing an appropriate balance between T effector cells (Teff) and Tregs is essential for correcting autoimmunity. Multiple sclerosis (MS) is an immune-mediated chronic CNS disease characterized by neuroinflammation, demyelination, and neuronal degeneration, in which the Teff:Treg balance is skewed toward pathogenic Teffs Th1 and Th17 cells. STAT3 is a key regulator of Teff:Treg balance. Using the structure-based design, we have developed a potentially novel small-molecule prodrug LLL12b that specifically inhibits STAT3 and suppresses Th17 differentiation and expansion. Moreover, LLL12b regulates the fate decision between Th17 and Tregs in an inflammatory environment, shifting Th17:Treg balance toward Tregs and favoring the resolution of inflammation. Therapeutic administration of LLL12b after disease onset significantly suppresses disease progression in adoptively transferred, chronic, and relapsing-remitting experimental autoimmune encephalomyelitis. Disease relapses were also significantly suppressed by LLL12b given during the remission phase. Additionally, LLL12b shifts Th17:Treg balance of CD4+ T cells from MS patients toward Tregs and increases Teff sensitivity to Treg-mediated suppression. These data suggest that selective inhibition of STAT3 by the small molecule LLL12b recalibrates the effector and regulatory arms of CD4+ T responses, representing a potentially clinically translatable therapeutic strategy for MS.

Abstract A study was conducted to investigate the circulation of HRSV subgroup B (HRSVB) in China in recent years. HRSVB sequences from 365 samples collected in 1991, 2004 and 2008–2014 in China, together with 332 Chinese HRSVB sequences obtained from GenBank were analyzed to determine the geographic and yearly distribution of HRSVB. Phylogenetic analysis revealed these HRSVB sequences clustered into 4 genotypes with different frequencies: BA (83%), CB1 (11%), SAB (3.0%) and GB3 (0.7%). Between 2005 and 2013, there was a co-circulation of BA and non-BA genotypes in China. Genotypes BA9 and BA10 were two of the main BA genotypes detected in this study. Genotype BA9 was first detected in China in 2006 and became the predominant HRSVB genotype circulating in China from 2008 to 2014. Three different lineages were detected for both genotypes BA9 and BA10. Time to the most recent common ancestor for genotypes BA9 and BA10 was estimated for years 1997 and 1996, respectively. Results of this study not only contribute to the understanding of the circulation pattern, but also the phylogenetic pattern and evolution of HRSVB in China from 1991 to 2014.

Abstract A molecular epidemiological study of human respiratory syncytial virus (HRSV) was conducted to examine the distribution of its subgroups and genotypes, as well as to identify its transmission pattern in China. A total of 705 samples collected from 9 provinces in China between January 2008 and February 2015 were identified as HRSV-positive and were subsequently sequenced. Of these, 336 samples were HRSV subgroup A (HRSVA), 368 samples were HRSV subgroup B (HRSVB), and 1 sample contained both HRSVA and HRSVB. These 705 HRSV sequences, together with 766 HRSV sequences downloaded from GenBank, were analyzed to understand the recent circulation patterns of HRSV in China. HRSVB predominated in the 2008/2009 and 2009/2010 seasons, whereas HRSVA predominated in the 2010/2011 and 2011/2012 seasons; HRSVA and HRSVB co-circulated during 2012/2013 and 2014/2015. Phylogenetic analysis showed most of the HRSVA sequences clustered into 2 genotypes, namely, NA1 and ON1. The ON1 genotype was first detected in China in 2011, and it quickly replaced the NA1 genotype to become the most prevalent HRSVA genotype circulating in China between 2013 and 2015. Continuous epidemiological surveillance and molecular characterization of HRSV should be conducted to monitor the evolution of HRSV in China.

In this article, we presented the detailed measurements and comparisons of skeletal muscle perfusion parameters in a canine hind limb ischemia model. Data presented here is related to and supportive to the research article “Evaluation of skeletal muscle perfusion in canine hind limb ischemia model using color-coded digital subtraction angiography” [1], where interpretation of the research data presented here is available.

Due to the Expanded Program on Immunization (EPI) and supplementary immunization activities (SIAs) in China, the incidence of measles in China has decreased extensively. The incidence reached its lowest levels in contemporary history in 2012 and 2017, with incidence rates of 4.6 and 4.3 per million population, respectively. However, more than 147,000 measles cases were reported from 2013 to 2016. Furthermore, the proportions of cases in infants < 8 months and adults have been increasing since 2013, representing a considerable challenge for measles elimination in China. A total of 14,868 measles viruses were isolated from confirmed measles cases from 2011 to 2017, of which 14,631 were identified as the predominant endemic genotype, H1; 87 were identified as genotype A viruses that were vaccine associated strains; and 150 were identified as non-H1 genotype viruses. The non-H1 genotype viruses included 62 D8 viruses, 70 D9 viruses, 3 D11 viruses, 14 B3 viruses, and 1 G3 virus, which were identified as imported or import-related viruses that caused sporadic cases or small outbreaks. Most of the transmission chains detected during the period 2011-2012 were interrupted and were followed by many new transmission chains of unknown origin that spread, causing a large measles resurgence in China during 2013-2016. After 4 years of measles resurgence and continuous implementation of the routine immunization program and SIAs, the population immunity reached a sufficiently high level to interrupt most of the transmission chains; only a few strains survived, which continued to be sporadically detected in China in 2017. In the present study, the results from the combined epidemiological and molecular virological data demonstrated the great progress towards measles elimination in China by the further analysis of circulation dynamics for the endemic H1 genotype measles virus from 2011 to 2017. And this study accumulated critical baseline data on circulating wild-type measles viruses in China and provides comprehensive information to the world. These comprehensive baseline data provide evidence to support measles elimination in the future, not only in China but also in other countries worldwide. In addition, the information will be very useful to other countries for tracing their sources of measles cases and for identifying transmission links, which can help prevent potential measles outbreaks.