Tumor cells produce vascular endothelial growth factor (VEGF) which interact with the membrane or cytoplasmic VEGF receptors (VEGFRs) to promote cell growth in an angiogenesis-independent fashion. Apatinib, a highly selective VEGFR2 inhibitor, is the only effective drug for patients with terminal gastric cancer (GC) who have no other chemotherapeutic options. However, its treatment efficacy is still controversy and the mechanism behind remains undetermined. In this study, we aimed to investigate the role of autocrine VEGF signaling in the growth of gastric cancer cells and the efficacy of Apatinib treatment.

The rapid production and release of a large number of inflammatory cytokines can cause excessive local and systemic inflammation in severe acute pancreatitis (SAP) and multiple organ dysfunction syndrome (MODS), especially pancreatitis-associated acute lung injury (P-ALI), which is the main cause of early death in patients with SAP. The NLRP3 inflammasome plays an important role in the maturation of IL-1β and the inflammatory cascade. Here, we established a model of SAP using wild-type (NLRP3+/+) and NLRP3 knockout (NLRP3-/-) mice by intraperitoneal injections of caerulein (Cae) and lipopolysaccharide (LPS). Pathological injury to the pancreas and lungs, the inflammatory response, and neutrophil infiltration were significantly mitigated in NLRP3-/- mice. Furthermore, INF-39, an NLRP3 inflammasome inhibitor, could reduce the severity of SAP and P-ALI in a dose-dependent manner. Our results suggested that SAP and P-ALI were alleviated by NLRP3 deficiency in mice, and thus, reducing NLRP3 expression may mitigate SAP-associated inflammation and P-ALI.

Incomplete radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) could initiate malignant transition. Patient-derived xenograft (PDX) mice model was established to investigate the effect of VEGF pathway in incomplete RFA of HCC with high fidelity. Cancer stem cell markers and metastatic markers were increased after incomplete RFA, with increased VEGFR1 and decreased VEGFR2 expression. In vitro experiments revealed sublethal heat treatment promoted migration ability of HepG2, HCCLM3, and SMMC7721 cells, which coincided with enhanced ability of sphere formation and up-regulation of VEGFR1, CD133, CD44, and EpCAM. Moreover, HCC cells secreted more VEGF after heat-treatment. VEGF promoted migration and enhanced stemness of HCC cells, which could not be suppressed by VEGFR2 inhibitor. PIGF, the ligand of VEGFR1, significantly increased migration and stemness of HCC cells. Blocking VEGFR1 reduced heat-induced enhancement of migration and stemness, whereas inhibition of VEGFR2 could not. In conclusion, VEGFR1 plays a critical role in sublethal heat treatment-induced enhancement of migration and stemness in HCC, suggesting that VEGFR1 may serve as a potential and promising therapeutic target for preventing recurrence after RFA.

To develop a radiomics algorithm, improving the performance of detecting recurrence, based on posttreatment CT images within one month and at suspicious time during follow-up.

Recommended regular saline flushing presents clinical ineffectiveness for hemodialysis (HD) patients at high risk of bleeding with heparin contraindication. Regional citrate anticoagulation (RCA) has previously been used with a Ca2+ containing dialysate with prefiltered citrate in one arm (RCA-one). However, anticoagulation is not always achievable and up to 40% results in serious clotting in the venous expansion chamber. In this study, we have transferred one-quarter of the TSC from the prefiltered to the post filter based on RCA-one, which we have called RCA-two. The objective of this study was to compare the efficacy and safety of RCA-two with either saline flushing or RCA-one in HD patients with a high bleeding risk.

A previous study showed that a mutation in Autographa californica multiple nucleopolyhedrovirus pkip (ac24) led to severe defects in progeny budded virion production and very late gene transcription at non-permissive temperature. To dissect the underlying mechanism, our early study showed that PKIP is associated with nucleocapsid of budded virion and involved in nucleocapsid assembly. However, how pkip affects very late gene transcription has not been determined. In the present study, double-stranded RNA was used to silence pkip expression during virus infection, resulting in the significant reduction of occlusion body production and polyhedrin expression. To find out whether PKIP regulates polyhedrin expression by affecting the transcription of other viral genes for very late gene expression, a comparative transcriptome analysis of viral genes was performed by RNA sequencing and the result showed that silencing pkip specifically down-regulated transcription of very late genes, while the transcription patterns of the viral genes associated with very late gene transcription were not affected. Since PKIP was reported to interact with and stimulate the activity of virus-encoded protein kinase PK1 and PK1 was involved in the hyperphosphorylation of viral basic protein P6.9, which was required for the maximal hyperexpression of very late genes, we sought to determine the association between PKIP and P6.9. Further experiments showed that PKIP interacted with P6.9 during virus infection, and the deletion of pkip resulted in decreased hyperphosphorylation of P6.9. Taken together, our results indicated that PKIP is involved in hyperphosphorylation of P6.9, which in return maybe required for hyperexpression of very late genes.

The role of transarterial chemoembolization (TACE) as the standard treatment for intermediate-stage hepatocellular carcinoma (HCC) is being challenged by increasing studies supporting liver resection (LR); but evidence of survival benefits of LR is lacking. We aimed to compare the overall survival (OS) of LR with that of TACE for the treatment of intermediate-stage HCC in cirrhotic patients.

To examine the protective effects of appropriate personal protective equipment for frontline healthcare professionals who provided care for patients with coronavirus disease 2019 (covid-19).

Podocyte injury is sufficient to cause glomerulosclerosis and proteinuria, eventually leading to kidney failure. Previous studies found that podocytes and neurons had similar biological characteristics. Growth-associated protein-43 (GAP-43) is a growth cone protein in neurons, and a marker of axonal and synaptic growth. However, it is not known whether GAP-43 is expressed in podocytes. Compared with normal glomerular podocytes, GAP-43 was significantly reduced in patients with glomerular diseases. GAP-43 also significantly reduced in lipopolysaccharide (LPS)-treated podocytes. We found that the decreased expression of nephrin, the cell marker of the podocyte, was significantly recovered with GAP-43 overexpression. In contrast, the migration ability in LPS-treated podocyte was reduction after GAP-43 overexpressing. Moreover, overexpression of GAP-43 attenuated podocyte apoptosis by up-regulating the ratio of Bcl-2/Bax with LPS treatment. Finally, Plaue and Rcan1 which are downstream target gene of NFATc1 decreased with overexpression of GAP-43 podocytes. We concluded that GAP-43 attenuated podocyte injury by inhibiting calcineurin/NFATc1 signaling. The findings may provide a promising treatment for podocyte injury-related diseases.

Background: Gliomas are the most common intracranial malignant neoplasms and have high recurrence and mortality rates. Recent literatures have reported that centromere protein N (CENPN) participates in tumor development. However, the clinicopathologic significance and biological functions of CENPN in glioma are still unclear. Methods: Clinicopathologic data and gene expression profiles of glioma cases downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases were utilized to determine the associations between the expression of CENPN and clinical features of glioma. Kaplan-Meier and ROC curves were plotted for prognostic analysis. Gene set enrichment analysis (GSEA) and single sample gene set enrichment analysis (ssGSEA) were applied to identify immune-related functions and pathways associated with CENPN' differential expression. In vitro experiments were conducted to investigate the impacts of CENPN on human glioma cells. Results: Elevated CENPN expression was associated with unfavorable clinical variables of glioma patients, which was validated in clinical specimens obtained from our institution by immunohistochemical staining (IHC). The GSEA and ssGSEA results revealed that CENPN expression was strongly correlated with inflammatory activities, immune-related signaling pathways and the infiltration of immune cells. Cell experiments showed that CENPN deficiency impaired cell proliferation, migration and invasion ability and increased glioma apoptosis. Conclusion: CENPN could be a promising therapeutic target for glioma.

Glioma is a lethal primary tumor of central nervous system. Ferroptosis is a newly identified form of necrotic cell death. Triggering ferroptosis has shown potential to eliminate aggressive tumors. GPX7, a member of glutathione peroxidase family (GPXs), has been described to participate in oxidative stress and tumorigenesis. However, the biological functions of GPX7 in glioma are still unknown.

Emerging SARS-CoV-2 variants of concern (VOCs) harboring multiple mutations in the spike protein raise concerns on effectiveness of current vaccines that rely on the ancestral spike protein. Here, we design a quadrivalent mosaic nanoparticle vaccine displaying spike proteins from the SARS-CoV-2 prototype and 3 different VOCs. The mosaic nanoparticle elicits equivalent or superior neutralizing antibodies against variant strains in mice and non-human primates with only small reduction in neutralization titers against the ancestral strain. Notably, it provides protection against infection with prototype and B.1.351 strains in mice. These results provide a proof of principle for the development of multivalent vaccines against pandemic and potential pre-emergent SARS-CoV-2 variants.

Preoperative evaluation of microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC) is important for surgical strategy determination. We aimed to develop and establish a preoperative predictive model for MVI status based on DNA methylation markers.

The tumor microenvironment is distinctive in primary and secondary liver cancer. B cells represent an important component of immune infiltrates. Here, we demonstrated that B cells are an important regulator in hepatocellular carcinoma (HCC) and colorectal cancer liver metastasis (CRLM) microenvironments. B cells displayed distinct developmental trajectories in HCC and CRLM. Single-cell analysis revealed that IgG+ plasma cells preferentially accumulated in HCC, whereas IgA+ plasma cells were preferentially enriched in CRLM. Mechanistically, IgG+ plasma cells in HCC were recruited by tumor-associated macrophages via the CXCR3-CXCL10 axis, whereas IgA+ plasma cells in CRLM were recruited by metastatic tumor cells via CCR10-CCL28 signaling. Functionally, IgG+ plasma cells preferentially promoted protumorigenic macrophages formation in HCC, and IgA+ plasma cells preferentially induced granulocytic myeloid-derived suppressor cells activation in CRLM. Clinically, increased infiltration of IgG+ plasma cells and macrophages in HCC was correlated to worse survival, whereas increased intratumoral IgA+ plasma cells and neutrophils in CRLM indicated poor prognosis. Taken together, this study demonstrated plasma and myeloid cell-mediated immunosuppression in HCC and CRLM, suggesting that selectively modulating primary or secondary tumor-related immunosuppressive regulatory networks might reprogram the microenvironment and provide an immunotherapeutic strategy for treating liver cancer.

To explore the characteristics, influencing factors, and effect of different treatments on the survival in patients with first primary cervical cancer (CC) and second primary CC. Data of 33,934 eligible patients with CC were extracted from the Surveillance, Epidemiology, and End Results (SEER) database in 2004-2015. We also included 176 patients with CC from the Affiliated Dongyang Hospital of Wenzhou Medical University. Univariate and multivariate Cox proportional hazard models were used to screen the potential influencing factors associated with the survival in patients with hazard ratios (HRs) and 95 % confidence intervals (CIs). Subgroup analyses of age, American Joint Committee on Cancer (AJCC) stages, tumor grades and histologic types were conducted to explore the association between different treatments and survival in different populations. The 5-year mortality was 43.08 % for patients with first primary CC and that was 58.13 % for patients with second primary CC. We found that the relationships between age, histologic type, tumor grade, tumor size, AJCC tumor-node-metastasis (TNM) stage, surgery, chemotherapy, radiotherapy and the first primary CC and second primary CC were different (all P < 0.05). Additionally, the results of subgroup analyses indicated that the choice of surgery, chemotherapy, and radiotherapy should be adjusted according to the different health conditions of the patients. In conclusion, the causal relationship between characteristics, influencing factors, and treatments and survival in patients with primary CC diagnosed as different time periods are needed further exploration.

Once excessive, neurological disorders associated with inflammatory conditions will inevitably cause secondary inflammatory damage to brain tissue. Immunosuppressive therapy can reduce the inflammatory state, but resulting infections can expose the patient to greater risk. Using specific immune tolerance organs or tissues from the body, brain antigen immune tolerance treatment can create a minimal immune response to the brain antigens that does not excessively affect the body's immunity. However, commonly used immune tolerance treatment approaches, such as those involving the nasal, gastrointestinal mucosa, thymus or liver portal vein injections, affect the clinical conversion of the therapy due to uncertain drug absorption, or inconvenient routes of administration. If hepatic portal intravenous injections of brain antigens could be replaced by normal peripheral venous infusion, the convenience of immune tolerance treatment could certainly be greatly increased. We attempted to encapsulate brain antigens with minimally immunogenic nanomaterials, to control the sizes of nanoparticles within the range of liver Kupffer cell phagocytosis and to coat the antigens with a coating material that had an affinity for liver cells. We injected these liver drug-loaded nanomaterials via peripheral intravenous injection. With the use of microparticles with liver characteristics, the brain antigens were transported into the liver out of the detection of immune armies in the blood. This approach has been demonstrated in rat models of surgical brain injury. It has been proven that the immune tolerance of brain antigens can be accomplished by peripheral intravenous infusion to achieve the effect of treating brain trauma after operations, which simplifies the clinical operation and could elicit substantial improvements in the future.

Hepatocellular carcinoma (HCC) is an aggressive disease with high recurrence rate. However, current staging systems were lack of predictive capacity for HCC recurrence. We aimed to develop prognostic nomograms based on inflammation-related markers for HCC patients underwent hepatectomy.

Systemic inflammatory response syndrome (SIRS), a major process of severe acute pancreatitis (SAP), usually occurs after various activated proinflammatory cytokines, which are produced by macrophages such as liver macrophages. Macrophages can secrete not only proinflammatory mediators but also inhibitory inflammatory cytokines such as IL-10, leading to two different functional states defined as "polarization". The main purpose of this study was to demonstrate the polarization of liver macrophages during severe acute pancreatitis and to explore whether the polarization of these activated Liver macrophages could be reversed in vitro.

α-l-Fucosidase 1 (FUCA1), a lysosomal enzyme that catalyses the hydrolytic cleavage of the terminal fucose residue, has been reported to be involved in tumorigenesis. However, the clinical significance and biological roles of FUCA1 in glioma remain largely unknown. We analyzed FUCA1 expression according to data in Oncomine, The Cancer Genome Atlas, and Chinese Glioma Genome Atlas databases and further verified FUCA1 expression with immunohistochemistry and real-time PCR analysis in glioma tissues. The results showed that FUCA1 overexpression was significantly associated with high-grade glioma as well as high mortality rates in the survival analysis. Data analyzed in cBioPortal showed that alterations in FUCA1 (1.4%) were correlated with worse survival in glioblastoma multiforme patients. Functional experiments showed that downregulation of FUCA1 suppressed glioma growth in vitro and in vivo. Conversely, overexpression of FUCA1 had the opposite effects on glioma. Mechanistically, transient inhibition of FUCA1 promoted the formation of large acidic vacuoles, as revealed by staining with acridine orange, increased the ratio of LC3-B/LC3-A, and modified the expression of Beclin-1 and Atg12, which are autophagic markers. Upregulation of FUCA1 attenuated starvation-induced autophagy in glioma. In addition, lower levels of tumor-infiltrating macrophages, including CD68+ (-30%), F4/80+ (-50%), and CD11c+ macrophages (-50%), were identified in FUCA1-downregulated glioma tissues, and CCL2/CCL5 neutralizing Abs blocked this effect. These results show that FUCA1 could serve as a potential therapeutic target for the treatment of patients with glioma by enhancing autophagy and inhibiting macrophage infiltration.

Porphyran possesses various activities, while the effects of the porphyran from Porphyra haitanensis (PPH) on obesity are rarely reported. In this study, C57BL/6J male mice were fed with HFD combined with PPH gavage (50 mg/kg/d) for 16 weeks, and body weight was measured once a week. After that, serum, adipose, and liver tissues were collected for physiological and biochemical analyses. Our research indicated that PPH treatment alleviated obesity in HFD-fed mice. PPH alleviated fat accumulation in serum, liver, and adipose tissues. In addition, PPH activated the AMPK-HSL/ACC pathway in epididymal adipose tissue to reduce lipid accumulation. Moreover, PPH turned white adipose into brown and activated the PGC 1α-UCP 1-mitochondrial pathway in scapular adipose tissue to generate more heat. Interestingly, PPH regulated colonic microbiota homeostasis in obese mice, including significant elevation of Roseburia and Eubacterium and marked reduction of Helicobacter. Moreover, Spearman's correlation analysis demonstrated that regulation of gut microbiota can decrease lipid accumulation. In summary, our study illustrated that PPH possesses the potential to be developed as an anti-obesity agent.