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Ulcerative colitis is an inflammatory bowel disease with multiple pathogeneses. Here, we aimed to study the therapeutic role of ulinastatin (UTI), an anti-inflammatory bioagent, and its associated mechanisms in treating colitis. Dextran sulfate sodium was administrated to induce colitis in mice, and a subgroup of colitis mice was treated with UTI. The gut barrier defect and inflammatory manifestations of colitis were determined via histological and molecular experiments. In addition, transcriptomics, metagenomics, and metabolomics were employed to explore the possible mechanisms underlying the effects of UTI. We found that UTI significantly alleviated the inflammatory manifestations and intestinal barrier damage in the mice with colitis. Transcriptome sequencing revealed a correlation between the UTI treatment and JAK-STAT signaling pathway. UTI up-regulated the expression of SOCS1, which subsequently inhibited the phosphorylation of JAK2 and STAT3, thus limiting the action of inflammatory mediators. In addition, 16S rRNA sequencing illustrated that UTI maintained a more stable intestinal flora, protecting the gut from dysbiosis in colitis. Moreover, metabolomics analysis demonstrated that UTI indeed facilitated the production of some bile acids and short-chain fatty acids, which supported intestinal homeostasis. Our data provide evidence that UTI is effective in treating colitis and support the potential use of UTI treatment for patients with ulcerative colitis. [ABSTRACT FROM AUTHOR]

Gambogic acid (GA) is considered a potent anti-tumor agent for its multiple effects on cancer cells in vitro and in vivo. Low concentrations of GA (0.3-1.2 µmol/L) can suppress invasion of human breast carcinoma cells without affecting cell viability. To get a whole profile of the inhibition on breast cancers, higher concentrations of GA and spontaneous metastatic animal models were employed. Treatment with GA (3 and 6 µmol/L) induced apoptosis in MDA-MB-231 cells and the accumulation of reactive oxygen species (ROS). Furthermore, GA induced PARP cleavage, activation of caspase-3, caspase-8, and caspase-9, as well as an increased ratio of Bax/Bcl-2. Moreover, the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c (Cyt c) from mitochondria were observed, indicating that GA induced apoptosis through accumulation of ROS and mitochondrial apoptotic pathway. GA also inhibited cell survival via blocking Akt/mTOR signaling. In vivo, GA significantly inhibited the xenograft tumor growth and lung metastases in athymic BALB/c nude mice bearing MDA-MB-231 cells. Collectively, these data provide further support for the multiple effects of GA on human breast cancer cells, as well as for its potential application to inhibit tumor growth and prevent metastasis in human cancers. Key words: gambogic acid, human breast cancer, apoptosis, multiple effects, metastasis. L'acide gambogique (AG) est considere comme etant un agent anti-tumoral puissant a cause de ses effets multiples sur les cellules cancereuses in vitro et in vivo. De faibles concentrations d'AG (0,3-1,2 µmol/L) pourraient supprimer l'invasion de cellules de carcinome mammaire chez l'humain sans affecter la viabilite cellulaire. Afin d'avoir une meilleure vue d'ensemble de cette inhibition sur les cancers mammaires, de plus fortes concentrations d'AG et des modeles animaux de metastase spontanee ont ete utilises. Un traitement a l'AG (3 et 6 µmol/L) induisait l'apoptose des cellules MDA-MB231 et l'accumulation d'especes reactives d'oxygene (ERO). De plus, l'AG induisait le clivage de la PARP, l'activation de la caspase-3, de la caspase-8 et de la caspase-9, ainsi qu'une augmentation du rapport Bax/Bcl-2. En outre, la translocation du facteur AIF (<< Apoptotic Inducing Factor >>) et la liberation de cytochrome c (Cyt c) de la mitochondrie ont ete observees, indiquant que l'AG induit l'apoptose par l'intermediaire de l'accumulation d'ERO et de la voie mitochondriale. L'AG inhibait aussi la survie cellulaire en bloquant la voie de signalisation d'Akt/mTor. In vivo, l'AG inhibait significativement la croissance de xenogreffes tumorales et la metastase pulmonaire chez des souris nues BALB/c athymiques porteuses de cellules MDA-MB-231. Dans l'ensemble, ces donnees vont dans le sens des effets multiples de l'AG sur les cellules humaines de cancer du sein, et donnent un appui supplementaire a son utilisation potentielle pour inhiber la croissance tumorale et prevenir la metastase des cancers chez l'humain. Mots-cles : acide gambogique, cancer du sein chez l'humain, apoptose, effets multiples, metastase. [Traduit par la Redaction], Introduction Traditional Chinese medicine has received increasing attention from oncologists recently. Gambogic acid (GA, [C.sub.38][H.sub.44][O.sub.8], Fig. 1A) is a polyprenylated xanthone isolated from the gamboge resin of Garcinia hanburryi tree [...]

Integrin β3 plays a key role in the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), but the development of integrin β3 inhibitors has been stalled due to the failure of phase III clinical trials for cancer treatment. Therefore, it is imperative to find a potentially effective solution to the problem of acquired resistance to EGFR-TKI for patients with integrin-β3 positive non-small-cell lung cancer (NSCLC) by exploring novel downstream targets and action mechanisms of integrin β3. In the present study, we observed that the expression of integrin β3 and AXL was significantly upregulated in erlotinib-resistant NSCLC cell lines, which was further confirmed clinically in tumor specimens from patients with NSCLC who developed acquired resistance to erlotinib. Through ectopic expression or knockdown, we found that AXL expression was positively regulated by integrin β3. In addition, integrin β3 promoted erlotinib resistance in NSCLC cells by upregulating AXL expression. Furthermore, the YAP pathway, rather than pathways associated with ERK or AKT, was involved in the regulation of AXL by integrin β3. To investigate the clinical significance of this finding, the current well-known AXL inhibitor R428 was tested, demonstrating that R428 significantly inhibited resistance to erlotinib, colony formation, epithelial–mesenchymal transformation and cell migration induced by integrin β3. In conclusion, integrin β3 could promote resistance to EGFR-TKI in NSCLC by upregulating the expression of AXL through the YAP pathway. Patients with advanced NSCLC, who are positive for integrin β3, might benefit from a combination of AXL inhibitors and EGFR-TKI therapy. [ABSTRACT FROM AUTHOR]

A C,S bonded quasi-two-coordinate Cr(II) complex, Cr(SAr*)2 (HSAr* = HSC6H3-2,6(C6H2-2,4,6-Pri3)2), has been synthesized according to literature precedent. Magnetic measurements, high-frequency/field electron paramagnetic resonance (HF-EPR) experiments and ab initio calculation studies show that the field-induced slow magnetic relaxation behaviour is caused by relatively weak axial magnetic anisotropy. [ABSTRACT FROM AUTHOR]

Hilar cholangiocarcinoma (HC) is a devastating malignancy that carries a poor overall prognosis. As a member of the AAA+ superfamily, Pontin becomes highly expressed in several malignant tumors, which contributes to tumor progression and influences tumor prognosis. In our research, Pontin expression in tumor specimens resected from 86 HC patients was detected by immunohistochemistry. Interestingly, high expression of Pontin was significantly associated with lymph node metastasis (p=0.011) and tumor node metastasis (TNM) stage (p=0.005). The Kaplan–Meier overall survival rate and multivariate analyses were performed to evaluate the prognosis of patients with HC. Patients with high Pontin expression had significantly poorer overall survival outcomes. Multivariate analyses found that Pontin was an independent prognostic factor (p=0.001). Moreover, bioinformatics analysis confirmed the increase in Pontin mRNA expression levels in cholangiocarcinoma tissues. In addition, in vitro experiments showed that Pontin expression was inhibited at the mRNA as well as protein levels after transfection with Pontin siRNA in human cholangiocarcinoma cell lines. Moreover, significant suppression of cell invasion was observed after the downregulation of Pontin. Taken together, the present study suggested that Pontin could act as a potential prognostic predictor, which might be a new valuable molecular candidate for the prevention and treatment of HC. [ABSTRACT FROM AUTHOR]

The maintenance of ordinal cell cycle phases is a critical biological process in cancer genesis, which is a crucial target for anti-cancer drugs. As an important natural isoquinoline alkaloid from Chinese herbal medicine, Berberine (BBR) has been reported to possess anti-cancer potentiality to induce cell cycle arrest in hepatocellular carcinoma cells (HCC). However, the underlying mechanism remains to be elucidated. In our present study, G0/G1 phase cell cycle arrest was observed in berberine-treated Huh-7 and HepG2 cells. Mechanically, we observed that BBR could deactivate the Akt pathway, which consequently suppressed the S-phase kinase-associated protein 2 (Skp2) expression and enhanced the expression and translocation of Forkhead box O3a (FoxO3a) into nucleus. The translocated FoxO3a on one hand could directly promote the transcription of cyclin-dependent kinase inhibitors (CDKIs) p21Cip1 and p27Kip1, on the other hand, it could repress Skp2 expression, both of which lead to up-regulation of p21Cip1 and p27Kip1, causing G0/G1 phase cell cycle arrest in HCC. In conclusion, BBR promotes the expression of CDKIs p21Cip1 and p27Kip1 via regulating the Akt/FoxO3a/Skp2 axis and further induces HCC G0/G1 phase cell cycle arrest. This research uncovered a new mechanism of an anti-cancer effect of BBR. [ABSTRACT FROM AUTHOR]

Flavonoids and flavonoid derivatives, which have significant biological and pharmacological activities, including antitumor and anti-inflammatory activities, have been widely used in human healthcare. To design a more effective flavonoid antitumor agent, we altered the flavonoid backbone with substitutions of piperazine and methoxy groups to synthesize a novel flavonoid derivative, LZ-207. The anticancer effect of LZ-207 against HCT116 colon cancer cells and the underlying mechanism of this effect were explored in this study. Specifically, LZ-207 exhibited inhibitory effects on growth and viability in several human colon cancer cell lines and induced apoptosis in HCT116 cells both in vitro and in vivo. LZ-207 treatment also suppressed the nuclear translocation of NF-κB and the phosphorylation of IκB and IKKα/β in a dose-dependent manner in both HCT116 cells and human acute monocytic leukemia THP-1 cells. Moreover, LZ-207 also reduced the secretion of the pro-inflammatory cytokine interleukin-6 (IL-6) in LPS-induced THP-1 cells, and this effect was confirmed at the transcriptional level. Furthermore, LZ-207 significantly inhibited HCT116 cell proliferation that was elicited by LPS-induced THP-1 cells in a co-culture system. These findings elucidated some potential molecular mechanisms for preventing inflammation-driven colon cancer using the newly synthesized flavonoid LZ-207 and suggested the possibility of further developing novel therapeutic agents derived from flavonoids. [ABSTRACT FROM AUTHOR]

Cancer cell invasion, one of the crucial events in local growth and metastatic spread of tumors, possess a broad spectrum of mechanisms, especially altered expression of matrix metalloproteinases. LFG-500 is a novel synthesized flavonoid with strong anti-cancer activity, whose exact molecular mechanism remains incompletely understood. This current study was designed to examine the effects of LFG-500 on tumor metastasis using in vitro and in vivo assays. LFG-500 could inhibit adhesion, migration and invasion of MDA-MB-231 human breast carcinoma cells. Meanwhile, it reduced the activities and expression of MMP-2 and MMP-9 via suppressing the transcriptional activation of NF-κB rather than AP-1 or STAT3. Moreover, LFG-500 repressed TNF-α induced cell invasion through inhibiting NF-κB and subsequent MMP-9 activity. Further elucidation of the mechanism revealed that PI3K/AKT but not MAPK signaling pathway was involved in the inhibitory effect of LFG-500 on NF-κB activation. LFG-500 could also suppress lung metastasis of B16F10 murine melanoma cells in vivo. Taken together, these results demonstrated that LFG-500 could block cancer cell invasion via down-regulation of PI3K/AKT/NF-κB signaling pathway, which provides new evidence for the anti-cancer activity of LFG-500. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is a continual ailment condition which engrosses the entire alimentary canal. The IBD can be primarily distinguished into two forms, ulcerative colitis, and Crohn's disease. The major symptoms of IBD include pustules or abscesses, severe abdominal pain, diarrhea, fistula, and stenosis, which may directly affect the patient's quality of life. A variety of mediators can stimulate the circumstances of IBD, some examples include infections by microbes such as bacteria, perturbation of the immune system and the surrounding environment of the intestines. Severe colitis was stimulated in the experimental animals through administering 4% dextran sulfate sodium (DSS) which is mixed in water ad libitum for 6 days. Eriocitrin (30 mg/kg) was then administered to the experimental animals followed by the induction of severe colitis to evaluate the therapeutic prospective of eriocitrin against the colon inflammation stimulated by DSS. In this study, eriocitrin (30 mg/kg) demonstrated significant (P < .05) attenuation activity against the DSS‐stimulated severe colitis in experimental animals. Eriocitrin counteracted all of the clinical deleterious effects induced by DSS, such as body‐weight loss, colon shortening, histopathological injury, accretion of infiltrated inflammatory cells at the inflamed region and the secretion of inflammatory cytokines. The results clearly showed that eriocitrin effectively attenuated DSS‐induced acute colitis in experimental animals. [ABSTRACT FROM AUTHOR]

Integrin αvβ6 is associated with an extremely aggressive cancer phenotype. However, little is known about the clinicopathological significance and prognostic value of integrin αvβ6 in human hilar cholangiocarcinoma. In the present study, bioinformatics analysis demonstrated a significant increase of integrin β6 gene expression in cholangiocarcinoma tissues compared to non-tumorous tissues, which was further validated in clinical samples through RT-qPCR and western blotting analyses. Integrin αvβ6 was observed to be expressed in 48.6% of tumors, and its expression was related to a poor tumor differentiation (p = 0.002), lymph node metastasis (p< 0.001) and advanced TNM stage (p= 0.001). Furthermore, patients who were αvβ6-positive showed a significantly shorter overall survival period than those who were αvβ6-negative (p= 0.004). Multivariate analysis confirmed that integrin αvβ6 was an independent prognostic factor (p= 0.002). In addition, loss- and gain-of-function assays showed integrin αvβ6 not only played an important role in colony formation, but also protected cholangiocarcinoma cells from cisplatin-induced growth inhibition and apoptosis. ERK/MAPK signaling pathway was involved in integrin αvβ6-mediated resistance of cholangiocarcinoma cells to cisplatin. Taken together, the present findings revealed that integrin αvβ6 could serve as a potential prognostic predictor and contribute to cisplatin resistance, which might prove to be a promising target candidate for the clinical intervention of human hilar cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

Objective: E2F transcription factors are associated with tumor development, but their underlying mechanisms in gastric cancer (GC) remain unclear. This study explored whether E2Fs determine the prognosis or immune and therapy responses of GC patients., Methods: E2F regulation patterns from The Cancer Genome Atlas (TCGA) were systematically investigated and E2F patterns were correlated with the characteristics of cellular infiltration in the tumor microenvironment (TME). A principal component analysis was used to construct an E2F scoring model based on prognosis-related differential genes to quantify the E2F regulation of a single tumor. This scoring model was then tested in patient cohorts to predict effects of immunotherapy., Results: Based on the expression profiles of E2F transcription factors in GC, two different regulatory patterns of E2F were identified. TME and survival differences emerged between the two clusters. Lower survival rates in the Cluster2 group were attributed to limited immune function due to stromal activation. The E2F scoring model was then constructed based on the E2F-related prognostic genes. Evidence supported the E2F score as an independent and effective prognostic factor and predictor of immunotherapy response. A gene-set analysis correlated E2F score with the characteristics of immune cell infiltration within the TME. The immunotherapy cohort database showed that patients with a higher E2F score demonstrated better survival and immune responses., Conclusions: This study found that differences in GC prognosis might be related to the E2F patterns in the TME. The E2F scoring system developed in this study has practical value as a predictor of survival and treatment response in GC patients., Competing Interests: The authors declare there are no competing interests., (©2024 Li et al.)

Background: Colorectal cancer (CRC) is one of the most common malignant tumors and has high morbidity and mortality rates. Previous studies have shown that TSPEAR mutations are involved in the development and progression of gastric cancer and liver cancer. However, the role of TSPEAR in CRC is still unclear. Methods: In The Cancer Genome Atlas (TCGA) database, 590 CRC patients with complete survival information were analyzed. We assessed TSPEAR expression in a pan-cancer dataset from the TCGA database. Cox regression analysis was performed to evaluate factors associated with prognosis. Enrichment analysis via the R package "clusterProfiler" was used to explore the potential function of TSPEAR. The single-sample GSEA (ssGSEA) method from the R package "GSVA" and the TIMER database were used to investigate the association between the immune infiltration level and TSPEAR expression in CRC. The R package "maftools" was used to explore the association between tumour mutation burden (TMB) and TSPEAR expression in CRC. CCK-8 assays and cell invasion assays were used to detect the effect of TSPEAR and TGIF2 on the biological behavior of CRC cells. Results: Pan-cancer analysis revealed that TSPEAR was upregulated in CRC tissues compared to normal tissues and that high TSPEAR expression was associated with poorer overall survival (OS) ( p =0.0053). The expression of TSPEAR increased with increasing TNM stage, T stage, N stage, and M stage. The nomogram constructed with TSPEAR, age, and TNM stage showed better predictive value than TSPEAR, age, or TNM stage alone. Immune cell infiltration analysis revealed that high expression of TSPEAR was associated with lower immune cell infiltration. Tumor mutation burden (TMB) analysis indicated that high expression of TSPEAR was associated with lower TMB ( p =0.005), and high TMB was associated with shorter OS ( p =0.02). CCK-8 assays and cell invasion assays indicated that in vitro knockdown of TSPEAR inhibited the proliferation, migration, and invasion of CRC cells. In addition, TSPEAR expression may be regulated by the upstream transcription factor TGIF2. Conclusion: TSPEAR expression was higher in CRC tissues than in normal tissues. Its upregulation was significantly associated with a poor prognosis. Additionally, TSPEAR plays a significant role in tumor immunity and the biological behavior of CRC cells. Thus, TSPEAR may become a promising prognostic biomarker and therapeutic target for CRC patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: As the most common gastrointestinal malignancy worldwide, liver metastases occur in half colorectal cancer (CRC) patients. Early detection can help treat them early and reduce mortality in patients with colorectal cancer liver metastases (CRLM). Finding useful biomarkers for CRLM is thus essential., Methods: The TCGA and GEO databases were used to download the expression profiles and clinical data of the patients. Differential analysis screened for genes associated with CRLM, and univariate Cox regression analysis identified genes associated with prognosis. The least absolute shrinkage and selection operator (LASSO) method further preferred genes to construct a prognostic signature. Kaplan-Meier survival curves were used to show patients' overall survival (OS). Receiver operating characteristic (ROC) curves showed the accuracy of the model. Risk scores and clinical characteristics of patients were included in multivariate Cox regression analysis to identify independent risk factors, and a nomogram was constructed. The proportion of immune cells and infiltration were assessed using the 'CIBERSORT' package and the 'ESTIMATE' package., Results: We constructed a signature consisting of seven CRLM-associated genes, and signature-based risk scores have great potential in estimating the prognosis of CRC patients. Moreover, the poor response to immunotherapy in high-risk patients might contribute to the poor prognosis of individuals. Furthermore, we found that overexpression of Hepcidin antimicrobial peptide (HAMP), the only gene highly expressed in CRC and liver metastatic tissues, promoted CRC development and that it was associated with tumor mutation burden (TMB), DNA mismatch repair (MMR) genes, and microsatellite instability (MSI) in various tumors. Finally, we found that in CRC patients, low expression of HAMP also represented a better immunotherapeutic outcome, reflecting the critical role of HAMP in guiding immunotherapy., Conclusion: We identified a prognostic signature containing 7 CRLM-associated genes, and the signature was specified as an independent predictor and a nomogram containing the risk score was built accordingly. In addition, the derived gene HAMP could help guide the exploration of profitable immunotherapeutic strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Lu, Yan, Xue, He, Huang, Sun, Zhao and Li.)

Background: Given the key role of integrins in maintaining intestinal homeostasis, anti-integrin biologics in inflammatory bowel disease (IBD) are being investigated in full swing. However, the unsatisfactory efficacy and safety of current anti-integrin biologics in clinical trials limit their widespread use in clinic. Therefore, it is particularly important to find a target that is highly and specifically expressed in the intestinal epithelium of patients with IBD., Methods: The function of integrin αvβ6 in IBD and colitis-associated carcinoma (CAC) with the underlying mechanisms has been less studied. In the present study, we detected the level of integrin β6 within inflammation including colitis tissues in human and mouse. To investigate the role of integrin β6 in IBD and CAC, integrin β6 deficient mice were hence generated based on the construction of colitis and CAC model., Results: We noted that integrin β6 was significantly upregulated in inflammatory epithelium of patients with IBD. Integrin β6 deletion not only reduced infiltration of pro-inflammatory cytokines, but also attenuated disruption of tight junctions between colonic epithelial cells. Meanwhile, lack of integrin β6 affected macrophage infiltration in mice with colitis. This study further revealed that lack of integrin β6 could inhibit tumorigenesis and tumor progression in CAC model by influencing macrophage polarization, which was also involved in attenuating the degree of intestinal symptoms and inflammatory responses in mice suffering from colitis., Conclusions: The present research provides a potentially new perspective and option for the treatment of IBD and CAC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sun, Lu, Ma, Xue, Liu, Ye, Huang, Dang and Li.)

A C,S bonded quasi-two-coordinate Cr(II) complex, Cr(SAr*) 2 (HSAr* = HSC 6 H 3 -2,6(C 6 H 2 -2,4,6-Pr i 3 ) 2 ), has been synthesized according to literature precedent. Magnetic measurements, high-frequency/field electron paramagnetic resonance (HF-EPR) experiments and ab initio calculation studies show that the field-induced slow magnetic relaxation behaviour is caused by relatively weak axial magnetic anisotropy.

Our understanding of coding gene functions in lung cancer leads to the development of multiple generations of targeted drugs. Noncoding RNAs, including circular RNAs (circRNAs), have been demonstrated to play a vital role in tumorigenesis. Uncovering the functions of circRNAs in tumorigenesis and their underlying regulatory mechanisms may shed new light on the development of novel diagnostic and therapeutic strategies for human cancer. Here we report the important role of circFAT1 in lung adenocarcinoma (LUAD) progression and the potential impact of circFAT1 on LUAD treatment. We found that circFAT1 was one of the top expressed circRNAs in A549 cells by circRNA-seq and was significantly upregulated in human LUAD tissues. Multiple cellular assays with A549 and PC9 LAUD cell lines under both gain-of-function and loss-of-function conditions demonstrated that circFAT1 promoted proliferation of LUAD cells in vitro and in vivo . At molecular level, circFAT1 sequestered miR-7 to upregulate IRS2, which in turn regulated downstream ERK1/2 phosphorylation and CCND1 expression, ultimately promoting tumor progression. In addition, we showed that DDP treatment was much more effective in circFAT1 knockdown tumor cells in vitro and in a xenograft tumor model. Our results indicate that circFAT1 promote tumorigenesis in LUAD through sequestering miR-7, consequently upregulating IRS2-ERK1/2-mediated CCND1 expression, and can be a valuable therapeutic target and an important parameter for precision treatment in LUAD patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: A growing number of evidence has revealed the vital role of autophagy in pathological processes of cancer, including gastric cancer (GC). However, many previous studies only focused on exploring single pathway or limited genes of interest in GC, which only reflected partial functions of autophagy. The present study aimed to construct an autophagy-related risk signature for GC., Methods: Differentially expressed autophagy-related genes (ARGs) in GC and non-tumor samples were screened through The Cancer Genome Atlas (TCGA) database, followed by bioinformatics analysis using the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) platforms. Prognosis-related ARGs were generated by univariate and multivariate Cox regression test., Results: A total of seven prognosis-related ARGs (HSPB8, NRG2, GABARAPL1, TMEM74, DLC1, MAP1LC3C and NRG3) were determined to establish a prognostic index (PI) model, which was demonstrated to be an independent prognostic indicator for patients with GC. More importantly, it was successfully validated in an external cohort of patients from the GSE15460 dataset, indicating the useful reproducibility of this signature. In addition, the PI model was associated with immune cell infiltration estimates in GC., Conclusions: Taken together, the present study suggested that the seven ARGs-related signature could serve as an independent prognostic indicator for patients with GC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tcr-21-191). The authors have no conflicts of interest to declare., (2021 Translational Cancer Research. All rights reserved.)

In nature, cells rely on a structural framework called the "cytoskeleton" to maintain their shape and polarity. Based on this, herein a new class of cell-mimicking nanomedicine using bionic skeletons constituted by the oligomeric Au(I)-peptide complex is developed. The peptide function of degrading pathological MDM2 and MDMX is used to synthesize an oligomeric Au(I)-PMIV precursor capable of self-assembling into a clustered spherical bionic skeleton. Through coating by erythrocyte membrane, an erythrocyte-mimicking nano-cell (Nery-PMIV) is developed with depressed macrophage uptakes, increased colloidal stability, and prolonged blood circulation. Nery-PMIV potently restores p53 and p73 in vitro and in vivo by degrading MDM2/MDMX. More importantly, Nery-PMIV effectively augments antitumor immunity elicited by anti-PD1 therapy in a murine orthotopic allograft model for LUAD and a humanized patient-derived xenograft (PDX) mouse model for LUAD, while maintaining a favorable safety profile. Taken together, this work not only presents evidence showing that MDM2/MDMX degradation is a potentially viable therapeutic paradigm to synergize anti-PD1 immunotherapy toward LUAD carrying wild-type p53; it also suggests that cell-mimicking nanoparticles with applicable bionic skeletons hold tremendous promise in offering new therapies to revolutionize nanomedicine in the treatment of a myriad of human diseases., (© 2021 Wiley-VCH GmbH.)

The metastatic potential of colorectal cancer (CRC) is intensively promoted by the tumor microenvironment (TME) in a paracrine manner. As a pleiotropic inflammatory cytokine, Interleukin-6 (IL-6) is produced and involved in CRC, the same scenario where integrin α v β 6 also becomes upregulated. However, the relationship between IL-6 and integrin α v β 6 as well as their involvement in the crosstalk between CRC and TME remains largely unclear. In the present study, we demonstrated a positive correlation between the expression of IL-6 and integrin β 6 in CRC samples. The mutually promotive interaction between CRC and TME was further determined by an indirect coculture system. CRC cells could augment the secretion of IL-6 from fibroblasts, which in return induced invasion and integrin β 6 expression of CRC cells. Through the classic IL-6 receptor/STAT-3 signaling pathway, IL-6 mediated the upregulation of integrin β 6, which was involved in the invasion and epithelial-mesenchymal transition of CRC cells induced by IL-6. Taken together, our results reveal a paracrine crosstalk between IL-6 signals originating from the TME and increased the integrin β 6 level of CRC. IL-6 induces CRC invasion via upregulation of integrin β 6 through the IL-6 receptor/STAT-3 signaling pathway. Combined inhibition of IL-6 along with integrin β 6-targeted strategy may indicate new directions for antitumor strategies for CRC., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Qi Sun et al.)

Peptide-derived nanocomposites have been exhibiting fascinating biological advantages, including but not limited to excellent biocompatibility, biological degradation, high targetability and subsequent potent therapeutic efficacy. While some successes have been achieved in the nanoengineering of peptide-based architectures with defined dimensions and medical functions, enormous challenges remain about clinical nano-pharmaceutics of peptides, especially those modulating intracellular protein-protein interactions (PPIs). Methods: We developed a general method to translate intracellular-PPI-targeted peptides into a bioavailable peptide-auric s pheroidal n ano h ybrid (SNH), for which polymeric peptide-Auric precursors [Au 1+ -S-peptide] n are in-situ reduced on the surface of gold nanoseeds via a simple and mild reaction. As proofs of concept, three cytomembrane-impenetrable peptides with different physicochemical properties were successfully engineered into stable and tumor-specific SNH respectively. Results: To highlight the advantage of SNH, PMI, a hydrophobic and enzyme-intolerant peptide capable of p53 restoration, was selected to challenge the power of SNH in a colon tumor xenografts model. PMI-Au SNH in vivo suppressed tumor growth potently after three administrations: intravenous injection, intraperitoneal injection and gastric perfusion, and maintained a favorable therapeutic safety. Conclusion: This therapeutically feasible strategy of peptide nanoengineering will allow us to fabricate a series of nanomedicines to modulate carcinogenic PPIs that hide and multiply inside cells, and in all likelihood reinvigorate the development of peptide drug against wide varieties of human diseases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Cellular receptor-mediated signaling pathways play critical roles during the initial immune response to Human Cytomegalovirus (HCMV) infection. However, the involvement of type-I transmembrane glycoprotein CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) in the antiviral response to HCMV infection is still unknown. Here, we demonstrated the specific knockdown of CD147 significantly decreased HCMV-induced activation of NF-κB and Interferon-beta (IFN-β), which contribute to the cellular antiviral responses. Next, we confirmed that HCMV-encoded miR-US25-1-5p could target the 3' UTR (Untranslated Region) of CD147 mRNA, and thus facilitate HCMV lytic propagation at a low multiplicity of infection (MOI). The expression and secretion of Cyclophilin A (sCyPA), as a ligand for CD147 and a proinflammatory cytokine, were up-regulated in response to HCMV stimuli. Finally, we confirmed that CD147 mediated HCMV-triggered antiviral signaling via the sCyPA-CD147-ERK (extracellular regulated protein kinases)/NF-κB axis signaling pathway. These findings reveal an important HCMV mechanism for evading antiviral innate immunity through its encoded microRNA by targeting transmembrane glycoprotein CD147, and a potential cause of HCMV inflammatory disorders due to the secretion of proinflammatory cytokine CyPA., Competing Interests: The authors have declared no competing financial interests exist.

Interleukin-8 (IL-8), matrix metalloproteinase-9 (MMP-9) and neovascularization have been implicated to be associated with biological processes, especially cancer progression. However, few studies have investigated the role of IL-8 in human hilar cholangiocarcinoma. In this study we detected the expression of IL-8 combined with MMP-9 and microvessel density (MVD) in hilar cholangiocarcinoma to evaluate their clinicopathological significance and prognostic value. A total of 62 patients with hilar cholangiocarcinoma who underwent curative surgery were enrolled in this study. The expression of IL-8, MMP-9 and MVD were examined immunohistochemically. The correlation of IL-8 with MMP-9 expression, MVD, clinicopathological features and survival time of patients were then analyzed. Expression of IL-8 was observed in 56.5% tumors, which was related to advanced TNM stage (P = 0.026) and tumor recurrence (P = 0.018). IL-8 had a positive correlation with MMP-9 expression and MVD. Furthermore, patients with high IL-8 expression had a significantly shorter overall survival than those with low IL-8 expression (P = 0.01). Multivariate analysis confirmed IL-8 as an independent prognostic factor (P = 0.005). In conclusion, IL-8 expression significantly correlated with MMP-9 expression and MVD, and IL-8 was a valuable prognostic factor for human hilar cholangiocarcinoma.