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Background: The optimal maintenance therapy for rat sarcoma (RAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) metastatic colorectal cancers (mCRCs) remains unclear. It is critical to evaluate the reliability of cetuximab-capecitabine (the observation group) relative to capecitabine alone (control group). Patients and Methods: In this retrospective analysis, patients with RAS and BRAF mCRC admitted to Huizhou Municipal Central Hospital, between January 2016 and October 2020 were enrolled and treated with cetuximab plus 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as an initial therapy. Patients whose disease was controlled after at least six cycles of treatment were administered a maintenance therapy until disease progression. We also analyzed the prognosis of patients according to clinicopathological features. Altogether, 39 RAS and BRAF mCRC patients were recruited from January 2016 to October 2020, with 18 cases in the treatment group and 21 cases in the control group. The difference in baseline clinicopathological features between the two treatments is not obvious. Results: The median progression-free survival after maintenance treatment in observation group (9.5 months [95% confidence interval (CI) = 6.4–12.6]), was significantly better than the control group (7.3 months [95% CI = 5.8–8.8]). During maintenance treatment, there were no deaths caused by treatment-related adverse events, and the overall incidence of rash acne was different between the observation and control groups (p < 0.05). Most adverse events were mild and easily controlled. Primary tumor site, baseline carcinoembryonic antigen levels, and microsatellite instability status were independent prognostic factors. Conclusion: Maintenance therapy using cetuximab plus capecitabine improved survival in patients with mCRC and was well tolerated by patients. [ABSTRACT FROM AUTHOR]

Objective. To investigate the diagnostic gene biomarkers for hepatocellular carcinoma (HCC) and identify the immune cell infiltration characteristics in this pathology. Methods. Five gene expression datasets were obtained through Gene Expression Omnibus (GEO) portal. After batch effect removal, differentially expressed genes (DEGs) were conducted between 209 HCC and 146 control tissues and functional correlation analyses were performed. Two machine learning algorithms were used to develop diagnostic signatures. The discriminatory ability of the gene signature was measured by AUC. The expression levels and diagnostic value of the identified biomarkers in HCC were further validated in three independent external cohorts. CIBERSORT algorithm was adopted to explore the immune infiltration of HCC. A correlation analysis was carried out between these diagnostic signatures and immune cells. Results. A total of 375 DEGs were identified. GPC3, ACSM3, SPINK1, COL15A1, TP53I3, RRAGD, and CLDN10 were identified as the early diagnostic signatures of HCC and were all validated in external cohorts. The corresponding results of AUC presented excellent discriminatory ability of these feature genes. The immune cell infiltration analysis showed that multiple immune cells associated with these biomarkers may be involved in the development of HCC. Conclusion. This study indicates that GPC3, ACSM3, SPINK1, COL15A1, TP53I3, RRAGD, and CLDN10 are potential biomarkers associated with immune infiltration in HCC. Combining these genes can be used for early detection of HCC and evaluating immune cell infiltration. Further studies are needed to explore their roles underlying the occurrence of HCC. [ABSTRACT FROM AUTHOR]

The abnormal expression of protein tyrosine phosphatase nonreceptor type 6 (PTPN6) has been proved to be associated with the progression of colorectal cancer. However, its role in chemosensitivity and related molecular mechanism have not been clarified. It has been reported that PTPN6 was down‐regulated in colorectal cancer cells compared with the normal colorectal cells. To evaluate the effects of PTPN6 on the proliferation and survival of colorectal cancer cells, PTPN6 was overexpressed in colorectal cancer cells in the present study. We found that cell proliferation and viability were both decreased after overexpression of PTPN6. The IC50 of 5‐Fu against colorectal cells was also declined in PTPN6 transfected cells. And further, we verified that PTPN6 could down‐regulate the expression of P‐gp and MRP‐1. Moreover, SP1 was the target protein of PTPN6 predicated by ChIPBase software and confirmed through Co‐immunoprecipitation assay and it was negatively regulated by PTPN6. To further verify the effect of SP1 on chemoresistance, SP1 was overexpressed. SP1 overexpression enhanced the drug‐resistance to 5‐Fu and abrogated the effects of PTPN6 upregulation on 5‐Fu resistance. All the above changes were associated with the down‐regulation of proteins related to MAPK signalling pathway, such as phosphorylation of extracellular regulated protein kinases (ERK) and p38. In summary, PTPN6 promoted chemosensitivity of colorectal cancer cells by targeting SP1 and inhibiting the activation of MAPK signalling pathway. Significance of the study: It has been demonstrated that the abnormal expression of PTPN6 was related to the progression of colorectal cancer. However, the chemosensitivity of PTPN6 and its molecular mechanisms were still unclear. Here, we identified that PTPN6 was down‐regulated in colorectal cancer cells. Moreover, PTPN6 overexpression not only reduced cell proliferation and viability, but decreased the resistance of colorectal cells to 5‐Fu. In our research, we found that the SP1 was the target protein of PTPN6 and it was negatively regulated by PTPN6. In addition, SP1 could increase the resistance of colorectal cells to 5‐Fu. Molecular mechanism studies have shown that PTPN6 promoted the chemosensitivity of colorectal cancer cells by inhibiting the activation of MAPK signalling pathway. [ABSTRACT FROM AUTHOR]

Hantaan virus (HTNV) infection of the human body causes a severe acute infectious disease known as hemorrhagic fever renal syndrome (HFRS). The aim of this study was to correlate patient cytokine profiles to HFRS severity. In this study, we discuss the clinical significance of evaluating HFRS treatment outcomes using cytokine information. The levels of 18 cytokines were quantitatively determined in three groups: 34 HTNV IgM+ cases, 63 HTNV IgM− negative cases, and 78 healthy volunteers. The level of 14 serum cytokines were higher in the patient group than that in the healthy control group. In the 34 HTNV IgM+ patient sera, a set of 27 cytokines was further assessed. The cytokines of TNF-β, IL-1ra, and IL-6 were detected at higher level in the IgM+ group than that in the IgM− group. The deterioration of HFRS was accompanied with multiple cytokines increased, such as IL-1ra, IL-12p70, IL-10, IP-10, IL-17, IL-2, and IL-6. Our data indicate that serum cytokine levels are associated with the progression of HFRS. [ABSTRACT FROM AUTHOR]

Anti-endothelial cell antibodies (AECAs) are usually directed against the surface antigens on the vascular endothelial cells. Clinical studies suggest a pathogenic role for nonhuman leukocyte antigen in antibody-mediated rejection; however, the antigens on the donor vascular endothelium that serve as the first-line targets for an immune response during allograft rejection have not been fully identified. Here, we used immunoprecipitation and mass spectrometry to identify antigens from the sera of kidney transplant recipients who were experiencing antibody-mediated rejection. Keratin 1 (KRT1) was identified as a novel antigenic target expressed on endothelial cells. To validate our finding, we produced recombinant proteins representing the three most common alleles of KRT1. The serum used for immunoprecipitation showed a strong reaction to KRT1 recombinants in western blot and ELISA. In the kidney transplant cohort, more AECA-positive recipients than AECA-negative recipients had KRT1 antibodies (32.2% versus 11.9%, p = 0.002). Sera from 255 renal recipients were tested by ELISA. Of the 77 recipients with deteriorating graft function (serum creatinine > 120 μmol/L), 23 had anti-KRT1 antibodies. KRT1-IgG positivity was, therefore, associated with a higher risk of kidney transplant rejection (29.9% (23/77) versus 16.9% (30/178), p = 0.0187). A better understanding of this antigenic target will improve long-term allograft survival. [ABSTRACT FROM AUTHOR]

Aim Non-HLA antigens have been found to involve in organ transplant rejection. Studies have shown that most of non-HLA antigens are targets of anti-endothelial cell antibodies (AECAs) and paly role on the antibody-mediated rejection (AMR), but these antigens on the surface of endothelial cells (EC) are not yet fully identified. Methods In this study, we isolated the anti-EC specific antibodies (IgG) for the serum AECAs of renal allograft recipients with antibody adsorption and elution by human endothelial cells. The response antigen(s) were captured via immunoprecipitation using AECA obtained. Results Mass spectrometry analysis showed that the endothelia antigen Keratin-1 (KRT1) was frequently found as the target transplant antigen. Three most common KRT1 alleles were cloned, expressed and purified, using KRT1 antigens as antigens we developed an ELISA to detect anti-KRT1 antibodies in the patients with renal transplantation. The results showed that the positive rate of serum KRT1 antibodies was 20.8% (53/255) in the renal transplant recipients. Further analysis of the specificity of the anti-KRT1 antibodies and recipient’s KRT1 genotype showed that 89.3% of the patients produced anti-KRT1 antibodies that reacted with their own KRT1 antigen, suggesting that the anti-KRT1 antibodies likely belong to autoantibodies. The recipients of renal transplantation were divided into two groups according to the serum creatinine (Cr) levels. Anti-KRT1 antibodies (IgG) were detected in 29.9% (23/77) recipients with Cr > 120 μmol/L, while, it was 16.9%(30/178) in kidney transplant recipients with Cr⩽120 μmol/L. The difference is statistically significant (x 2 = 5.531, P < 0.05). Conclusions Anti-KRT1 antibodies are associated with the deterioration of renal graft function after transplantation. Detection of anti-KRT1 IgG might be beneficial for the recipients after renal transplantation. [ABSTRACT FROM AUTHOR]

Objective: Reperfusion after cerebral ischemia causes brain injury. Total saponins of Panax notoginseng (PNS) have potential roles in protecting against cerebral ischemia-reperfusion injury. However, whether PNS regulates astrocytes on oxygen-glucose deprivation/reperfusion (OGD/R) injury in rat brain microvascular endothelial cells (BMECs) and its mechanism still need further clarification., Methods: Rat C6 glial cells were treated with PNS at different doses. Cell models were established by exposing C6 glial cells and BMECs to OGD/R. Cell viability was assessed, and levels of nitrite concentration, inflammatory factors (iNOS, IL-1β, IL-6, IL-8, TNF-α), and oxidative stress-related factors (MDA, SOD, GSH-Px, T-AOC) were subsequently measured through CCK8, Grice analysis, Western blot, and ELISA, respectively. The co-cultured C6 and endothelial cells were treated with PNS for 24 hours before model establishment. Then transendothelial electrical resistance (TEER), lactate dehydrogenase (LDH) activity, brain-derived neurotrophic factor (BDNF) content, and mRNA and protein levels and positive rates of tight junction proteins [Claudin-5, Occludin, ZO-1] were measured by a cell resistance meter, corresponding kits, ELISA, RT-qPCR, Western blot, and immunohistochemistry, respectively., Results: PNS had no cytotoxicity. PNS reduced iNOS, IL-1β, IL-6, IL-8, and TNF-α levels in astrocytes, promoted T-AOC level and SOD and GSH-Px activities, and inhibited MDA levels, thus inhibiting oxidative stress in astrocytes. In addition, PNS alleviated OGD/R injury, reduced Na-Flu permeability, and enhanced TEER, LDH activity, BDNF content, and levels of tight junction proteins Claudin-5, Occludin, ZO-1 in the culture system of astrocytes and rat BMECs after OGD/R., Conclusion: PNS repressed astrocyte inflammation and attenuated OGD/R injury in rat BMECs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)