S100A16 is a potential target for reshaping the tumor microenvironment in the hypoxic context of liver cancer.

BACKGROUND: The research on the S100 family has garnered significant attention; however, there remains a dearth of understanding regarding the precise role of S100A16 in the tumor microenvironment of liver cancer. METHOD: Comprehensive analysis was conducted on the expression of S100A16 in tumor tissues and its correlation with hypoxia genes. Furthermore, an investigation was carried out to examine the association between S100A16 and infiltration of immune cells in tumors as well as immunotherapy. Relevant findings were derived from the analysis of single cell sequencing data, focusing on the involvement of S100A16 in both cellular differentiation and intercellular communication. Finally, we validated the expression of S100A16 in liver cancer by Wuhan cohort and multiplexed immunofluorescence to investigate the correlation between S100A16 and hypoxia. RESULT: Tumor tissues displayed a notable increase in the expression of S100A16. A significant correlation was observed between S100A16 and genes associated with hypoxic genes. Examination of immune cell infiltration revealed an inverse association between T cell infiltration and the level of S100A16 expression. The high expression group of S100A16 exhibited a decrease in the expression of genes related to immune cell function. Single-cell sequencing data analysis revealed that non-immune cells predominantly expressed S100A16, and its expression levels increased along with the trajectory of cell differentiation. Additionally, there were significant variations observed in hypoxia genes as cells underwent differentiation. Cellular communication identified non-immune cells interacting with immune cells through multiple signaling pathways. The Wuhan cohort verified that S100A16 expression was increased in liver cancer. The expression of S100A16 and HIF was simultaneously elevated in endothelial cells. CONCLUSION: The strong association between S100A16 and immune cell infiltration is observed in the context of hypoxia, indicating its regulatory role in shaping the hypoxic tumor microenvironment in liver cancer.

LncRNA SNHG1 Accelerates Cell Proliferation, Migration, and Invasion of Hepatoblastoma Through Mediating miR-6838-5p/PIM3/RhoA Axis.

Hepatoblastoma (HB) is a common primary liver malignant tumor in children. Long non-coding RNAs (lncRNAs) are closely engaged in HB progression. The role and regulatory molecule mechanism of lncRNA small nucleolar RNA host gene 1 (SNHG1) in HB remain unclear. Through qRT-PCR or western blot, we found that SNHG1 and proviral integration site for moloney murine leukemia virus 3 (PIM3) were elevated but miR-6838-5p was decreased in HB cells. Cell biology experiments revealed that SNHG1 depletion or miR-6838-5p upregulation suppressed cell proliferation, migration, and invasion of HB cells. Mechanistically, luciferase activity assay validated that miR-6838-5p could interact with SNHG1 or PIM3. SNHG1 up-regulated PIM3 expression via sponging miR-6838-5p. Moreover, miR-6838-5p inhibitor abolished SNHG1 depletion-mediated suppression of malignant behaviors in HB cells. PIM3 overexpression neutralized miR-6838-5p mimics-mediated repression of malignant phenotypes in HB cells. Furthermore, miR-6838-5p overexpression suppressed RhoA activation, which was restored by PIM3 upregulation. What's more, the results at the cellular level were further verified by nude mice tumor formation experiment. In conclusion, SNHG1 regulated miR-6838-5p/PIM3/RhoA axis to promote malignant phenotypes of HB, which might provide novel therapeutic target for HB treatment.

Prognostic value of body composition on survival outcomes in melanoma patients receiving immunotherapy.

Objective: The influence of body composition on the effectiveness of immune checkpoint inhibitors (ICIs) in patients with melanoma is still uncertain in clinical practice. Therefore, the objective of this study was to examine the potential association between body composition and clinical outcomes in patients with melanoma undergoing ICIs treatment. Methods: A systematic literature search was performed across several databases, including PubMed, Embase, Cochrane Library and Google Scholar, to gather relevant studies. The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS), assessed by hazard ratios (HR). Secondary outcomes, such as adverse events (AE), were evaluated using odds ratios (OR). Results: This meta-analysis comprised ten articles involving a total of 1,283 patients. Systemic analysis of all collected evidence revealed that body composition, including low skeletal muscle index (SMI) (OS: HR = 1.66, 95% CI = 1.13-2.43, p = 0.010; PFS: HR = 1.28, 95% CI = 1.06-1.55, p = 0.009), high subcutaneous adipose tissue density (SMD) (OS: HR = 1.93, 95% CI = 1.09-3.44, p = 0.025; PFS: HR = 1.31, 95% CI = 1.06-1.63, p = 0.012), and sarcopenia (OS: HR = 1.25, 95% CI = 1.03-1.51, p = 0.022; PFS: HR = 1.25, 95% CI = 1.03-1.51, p = 0.022), were significantly associated with OS and PFS in melanoma patients treated with ICIs. However, these markers did not show a significant association with treatment-related adverse events. Interestingly, no significant correlation was found between visceral fat index (VFI) (OS: HR = 0.71, 95% CI = 0.29-1.76, p = 0.462; PFS: HR = 0.98, 95% CI = 0.93-1.02, p = 0.274) and OS or PFS in melanoma patients under ICIs treatment. Conclusion: Body composition was found to be associated with decreased treatment response and lower long-term efficacy in patients with melanoma undergoing immune checkpoint inhibitor (ICI) therapy. However, it is important to note that body composition did not appear to contribute to increased incidence of adverse events in these patients.

Bilateral endogenous Candida albicans endophthalmitis following COVID-19 infection and intravenous antibiotics use: A case report.

Key Clinical Message: Endogenous fungal endophthalmitis tends to occur in immunocompromised patients, including COVID-19 infection. For high-risk populations, timely tissue biopsy, fungal culture, and susceptibility testing can facilitate early diagnosis and treatment, thereby improving the prognosis. Abstract: While endogenous fungal endophthalmitis is a rare condition, its incidence has recently been on the rise. A 48-year-old male presented with complaints of acute visual loss in his right eye for 2 weeks. He had a history of COVID-19 infection, confirmed by a positive nucleic acid test, and was treated with intravenous antibiotics and glucocorticoids a week before the episode. A comprehensive eye examination revealed significant inflammatory cells floating in the anterior chamber and considerable cloudiness in the vitreous of the right eye, while few vitreous cells were visualized in the left eye. After pars plana vitrectomy (PPV) was performed in the right eye, a vitreous biopsy revealed an intravitreal infection of Candida albicans, which was susceptible to fluconazole. Endogenous fungal endophthalmitis occurs in patients with various underlying systemic conditions, such as those with diabetes, organ transplantation recipients, individuals undergoing chemotherapy, users of corticosteroids and immunosuppressants, AIDS patients, and those engaged in intravenous drug use. In high-risk populations associated with intravenous antibiotics, the timely identification of one or more well-defined oval yellow-white chorioretinal lesions, especially in the posterior pole of the retina, can contribute to an early diagnosis through tissue biopsy, fungal culture, and susceptibility testing. This approach enables targeted antifungal therapy, thereby improving the prognosis of visual function for the patient.

Comprehensive analysis of scRNA-Seq and bulk RNA-Seq data reveals dynamic changes in tumor-associated neutrophils in the tumor microenvironment of hepatocellular carcinoma and leads to the establishment of a neutrophil-related prognostic model.

BACKGROUND: Analysis of hepatocellular carcinoma (HCC) single-cell sequencing data was conducted to explore the role of tumor-associated neutrophils in the tumor microenvironment. METHODS: Analysis of single-cell sequencing data from 12 HCC tumor cores and five HCC paracancerous tissues identified cellular subpopulations and cellular marker genes. The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases were used to establish and validate prognostic models. xCELL, TIMER, QUANTISEQ, CIBERSORT, and CIBERSORT-abs analyses were performed to explore immune cell infiltration. Finally, the pattern of tumor-associated neutrophil roles in tumor microenvironmental components was explored. RESULTS: A total of 271 marker genes for tumor-associated neutrophils were identified based on single-cell sequencing data. Prognostic models incorporating eight genes were established based on TCGA data. Immune cell infiltration differed between the high- and low-risk groups. The low-risk group benefited more from immunotherapy. Single-cell analysis indicated that tumor-associated neutrophils were able to influence macrophage, NK cell, and T-cell functions through the IL16, IFN-II, and SPP1 signaling pathways. CONCLUSION: Tumor-associated neutrophils regulate immune functions by influencing macrophages and NK cells. Models incorporating tumor-associated neutrophil-related genes can be used to predict patient prognosis and immunotherapy responses.

Effectiveness and safety of human type 5 recombinant adenovirus (H101) in malignant tumor with malignant pleural effusion and ascites: A multicenter, observational, real-world study.

BACKGROUND: The aim of this study was to analyze the effectiveness and safety of H101 in Chinese patients with malignant pleural effusion and ascites (MPE/MA) in the real world. METHODS: This multicenter, observational, real-world study recruited patients with MPE/MA caused by malignant tumor receiving H101-containing treatment between January 2020 and June 2022. Effectiveness was evaluated by overall remission rate (ORR), and safety was evaluated based on adverse events (AEs). Subgroup analysis was performed on patients grouped according to tumor type, the volume of MPE and MA, and dosage of H101. RESULTS: A total of 643 eligible patients were enrolled, and 467 received H101 monotherapy and 176 received H101 combined with chemotherapy. The ORR of total patients was60.3% with 388 case of PR. In the H101 monotherapy group, the decrease of MPE or MA was achieved in 282 (60.4%, PR) patients, 176 (37.7%, NC) patients showed no change in volume of MPE or MA, and nine (1.9%, PD) patients showed an increase, yielding an ORR of 60.4% (282/467). The ORR for the combination therapy group was 60.2% (106/176), with 106 cases of PR, 69 cases of NC and one case of PD. Subgroup analyses based on tumor type, volume of MPE and MA, and dosage of H101 all showed high ORR, approximately 60%. The main AEs associated with H101-containing regimens were fever, nausea and vomiting. No serious AEs occurred in both groups. CONCLUSION: Encouraging clinical benefits and manageable toxicity of H101 against MPE/MA were preliminarily observed in the real-world clinical setting, indicating that the H101-containing regimen is reliable, safe, and feasible, providing a novel and effective option for the treatment of this disease.

Functional characterization of porcine nucleophosmin (NPM1) gene in promoting the replication of Japanese encephalitis virus and induction of inflammatory cytokines.

Nucleophosmin (NPM1) is a multifunctional nucleolar protein that plays a role in cell cycle control, tumorigenesis, induction of the inflammatory cytokine, virus replication, as well as the cellular responses to a variety of stress stimuli. However, its physiological functions in pigs have not been well understood. Here, we cloned the porcine NPM1 (porNPM1) gene and analyzed the functions of the porNPM1 protein in pigs. The full-length porNPM1 gene encoded a 294-amino acid protein with 94.5%-99.3% sequence identity to its orthologues in mammals and was extensively expressed in various pig tissues at the mRNA level. The porNPM1 primarily localizes in the nucleus of ST cells, while it translocates from the nucleus to nucleoplasm upon UV irradiation or H2O2 treatment. Notably, JEV infection blocked the translocation of porNPM1 from the nucleolus to the nucleoplasm. Furthermore, porNPM1 interacted with the JEV C protein and facilitated JEV replication in ST cells. The overexpression and knockdown of porNPM1 respectively enhanced or impaired JEV replication, suggesting the important role of porNPM1 in JEV replication. Additionally, the purified ectodomain of porNPM1 induced the production of inflammatory cytokines (TNF-α, IL-6, and IL-8). Together, these data demonstrated that porNPM1 is involved in cellular stress stimuli, JEV replication, and induction of inflammatory cytokines.

Combining hyperspectral imaging techniques with deep learning to aid in early pathological diagnosis of melanoma.

BACKGROUND: Cutaneous melanoma, an exceedingly aggressive form of skin cancer, holds the top rank in both malignancy and mortality among skin cancers. In early stages, distinguishing malignant melanomas from benign pigmented nevi pathologically becomes a significant challenge due to their indistinguishable traits. Traditional skin histological examination techniques, largely reliant on light microscopic imagery, offer constrained information and yield low-contrast results, underscoring the necessity for swift and effective early diagnostic methodologies. As a non-contact, non-ionizing, and label-free imaging tool, hyperspectral imaging offers potential in assisting pathologists with identification procedures sans contrast agents. METHODS: This investigation leverages hyperspectral cameras to ascertain the optical properties and to capture the spectral features of malignant melanoma and pigmented nevus tissues, intending to facilitate early pathological diagnostic applications. We further enhance the diagnostic process by integrating transfer learning with deep convolutional networks to classify melanomas and pigmented nevi in hyperspectral pathology images. The study encompasses pathological sections from 50 melanoma and 50 pigmented nevus patients. To accurately represent the spectral variances between different tissues, we employed reflectance calibration, highlighting that the most distinctive spectral differences emerged within the 500-675 nm band range. RESULTS: The classification accuracy of pigmented tumors and pigmented nevi was 89% for one-dimensional sample data and 98% for two-dimensional sample data. CONCLUSIONS: Our findings have the potential to expedite pathological diagnoses, enhance diagnostic precision, and offer novel research perspectives in differentiating melanoma and nevus.

A meta-analysis examined the effect of topical vancomycin application in decreasing sternal wound infections post cardiac surgery.

To assess the impact of topical vancomycin (TV) application in decreasing sternal wound infections (SWIs) post cardiac surgery (CS), we lead a meta-analysis. Twenty-three thousand seven hundred and forty five participants had CS at the outset of the investigations, according to a thorough evaluation of the literature done up to November 2022; 8730 of them used TV, while 15 015 were controls. To assess the effectiveness of TV application in lowering SWIs following CS, odds ratios (OR) with 95% confidence intervals (CIs) were computed with dichotomous technique with a fixed- or random-effect model. The TV had significantly lower SWIs post CS (OR, 0.34; 95% CI, 0.20-0.57; P < .001), and deep SWIs post CS (OR, 0.26; 95% CI, 0.11-0.65; P = .004) compared with control as shown in Figures 2 and 3. Yet, there was no significant difference found amongst TV and control in superficial SWIs post CS (OR, 0.30; 95% CI, 0.07-1.30; P = .011). The TV had significantly lower SWIs, and deep SWIs post CS, and no significant difference was found in superficial SWIs post CS compared with control. The low number of included studies in this meta-analysis for superficial SWIs calls for precaution when analysing the outcomes.

LncRNA LINC01197 inhibited the formation of calcium oxalate-induced kidney stones by regulating miR-516b-5p/SIRT3/FOXO1 signaling pathway.

Long non-coding RNA (lncRNA) plays a key role in the regulation of calcium oxalate (CaOx) crystals-induced kidney stone formation and deposition. The purpose of this study is to study the effect of lncRNA LINC01197 on CaOx-induced kidney stone formation and the underlying mechanism. Crystal cell adhesion in HK-2 cells was evaluated by analyzing Ca2+ concentration. Apoptosis was detected by flow cytometry. The RT-qPCR and western blot were used to detect the mRNA and protein expression. Patients with kidneys stones showed down-regulated LINC01197 and SIRT3 expression, and up-regulated miR-516b-5p expression. LINC01197 knockdown promoted CaOx-induced cell adherence and cell apoptosis, increased Bax, decreased Bcl-2 expression. Luciferase reporter assay showed that SIRT3 expression was promoted by LINC01197 competing binds to miR-516b-5p. In addition, LINC01197 expression was promoted by SIRT3/FOXO1 overexpression, and could be reversed by FOXO1 knockdown. In conclusion, the present study revealed that lncRNA LINC01197 inhibited CaOx-induced kidney stones formation by regulating the miR-516b-5p/SIRT3/FOXO1 signaling pathway.

Factors Influencing the Incidence of Pneumonia after Coronary Artery Bypass Grafting.

OBJECTIVE: This study aimed to explore and analyze the factors affecting the incidence of pneumonia after coronary artery bypass grafting (CABG) to provide reference for the prevention of such situation. METHODS: A total of 500 patients who underwent CABG in a hospital were selected. From March 2019 to March 2022, 410 patients without pneumonia and 90 patients with pneumonia were divided into groups A and B. The influencing factors and pathogen composition of postoperative pneumonia were discussed and analyzed. RESULTS: Univariable analysis results showed that age, cardiac function grade, occurrence of smoking, operation time, tracheal intubation time, suspended red-blood-cell transfusion and hospital stay in group B were higher than those in group A. Multivariable logistic analysis results showed that operation time, smoking history, and tracheal intubation time were risk factors for pneumonia after CABG. Among the 90 patients with postoperative pneumonia, 90 had pathogens, 81 had Gram-negative bacteria, 4 had Gram-positive bacteria, and 5 had fungi. CONCLUSIONS: Patients after CABG were more likely to develop pneumonia. Operation time, smoking history, and tracheal intubation time were the risk factors of pneumonia after CABG. Most of these patients had Gram-negative bacteria. Patient intervention based on the influencing factors can effectively prevent the occurrence of postoperative pneumonia.

Ephedrine vs. phenylephrine effect on sublingual microcirculation in elderly patients undergoing laparoscopic rectal cancer surgery.

Background: The effects of anesthesia administration on sublingual microcirculation are unknown. It is unclear how sublingual microcirculation responds to ephedrine or phenylephrine administration. We hypothesized that microvascular perfusion is impaired under anesthesia. Materials and methods: We randomly divided 100 elderly patients undergoing laparoscopic rectal cancer surgery into phenylephrine and ephedrine groups in a 1:1 ratio. Ephedrine or phenylephrine was administered when MAP was < 80% for > 1 min. The heart rate (HR) and mean arterial pressure (MAP) were recorded every 5 min. Lactic acid was tested both pre- and postoperatively. The sublingual microcirculation characteristics of the microvascular flow index, the percentage of perfused vessels, the density of perfused vessels, and the heterogeneity index were monitored using a sidestream dark field imaging device. Results: Their MAP showed an evident decrease of > 20%. At this point, the HR, microvascular flow index, perfused vessel density, and proportion of perfused vessels decreased similarly in ephedrine and phenylephrine groups. Conversely, the heterogeneity index increased in both groups. After phenylephrine and ephedrine administration, ephedrine treatment significantly increased the proportion of perfused vessels, microvascular flow index, and HR compared with phenylephrine treatment. Conclusion: General anesthesia was associated with reduced MAP, HR, and sublingual microcirculation in elderly patients undergoing laparoscopic rectal cancer surgery. The results of ephedrine treatment were better than those of phenylephrine treatment in terms of HR, increased the proportion of perfused vessels, and microvascular flow index of sublingual microcirculation. Clinical trial registration: [www.ClinicalTrials.gov], identifier [ChiCTR-2000035959].

Development and validation of genomic and epigenomic signatures associated with tumor immune microenvironment in hepatoblastoma.

BACKGROUND: This study aimed to probe and verify aberrantly methylated and expressed genes in hepatoblastoma and to analyze their interactions with tumor immune microenvironment. METHODS: Aberrantly methylated and expressed genes were obtained by comprehensively analyzing gene expression and DNA methylation profiles from GSE81928, GSE75271 and GSE78732 datasets. Their biological functions were predicted by the STRING and Metascape databases. CIBERSORT was utilized for inferring the compositions of tumor-infiltrating immune cells (TIICs) in each sample. Correlation between hub genes and immune cells was then analyzed. Hub genes were validated in hepatoblastoma tissues via western blot or immunohistochemistry. After transfection with sh-NOTUM, migration and invasion of HuH-6 and HepG2 cells were investigated. The nude mouse tumorigenesis model was constructed. RESULTS: Totally, 83 aberrantly methylated and expressed genes were determined in hepatoblastoma, which were mainly involved in metabolic and cancer-related pathways. Moreover, their expression was liver-specific. 13 hub genes were screened, which were closely related to immune cells in hepatoblastoma tissues. Among them, it was confirmed that AXIN2, LAMB1 and NOTUM were up-regulated and SERPINC1 was down-regulated in hepatoblastoma than normal tissues. NOTUM knockdown distinctly weakened migration and invasion of HuH-6 and HepG2 cells and tumor growth in vivo. CONCLUSIONS: This study identified aberrantly methylated and expressed signatures that were in relation to immune microenvironment in hepatoblastoma. Targeting NOTUM hub gene could suppress migration and invasion of hepatoblastoma cells. Thus, these aberrantly methylated and expressed genes might act as therapeutic agents in hepatoblastoma therapy.

Progress in the development of small molecular inhibitors of the Bruton's tyrosine kinase (BTK) as a promising cancer therapy.

Bruton tyrosine kinase (BTK) is a key kinase in the B cell antigen receptor signal transduction pathway, which is involved in the regulation of the proliferation, differentiation and apoptosis of B cells. BTK has become a significant target for the treatment of hematological malignancies and autoimmune diseases. Ibrutinib, the first-generation BTK inhibitor, has made a great contribution to the treatment of B cell malignant tumors, but there are still some problems such as resistance or miss target of site mutation. Therefore, there is an imperative need to develop novel BTK inhibitors to overcome these problems. Besides, proteolysis targeting chimera (PROTAC) technology has been successfully applied to the development of BTK degradation agents, which has opened a fresh way for the BTK targeted treatment. This paper reviews the biological function of BTK, the discovery and development of BTK targeted drugs as a promising cancer therapy. It mainly reviews the binding sites and structural characteristics of BTK, structure-activity relationships, activity and drug resistance of BTK inhibitors, as well as potential treatment strategies to overcome the resistance of BTK, which provides a reference for the rational design and development of new powerful BTK inhibitors.

Discovery of N-aryl sulphonamide-quinazoline derivatives as anti-gastric cancer agents in vitro and in vivo via activating the Hippo signalling pathway.

Hippo signalling pathway plays a crucial role in tumorigenesis and cancer progression. In this work, we identified an N-aryl sulphonamide-quinazoline derivative, compound 9i as an anti-gastric cancer agent, which exhibited potent antiproliferative ability with IC50 values of 0.36 µM (MGC-803 cells), 0.70 µM (HCT-116 cells), 1.04 µM (PC-3 cells), and 0.81 µM (MCF-7 cells), respectively and inhibited YAP activity by the activation of p-LATS. Compound 9i was effective in suppressing MGC-803 xenograft tumour growth in nude mice without obvious toxicity and significantly down-regulated the expression of YAP in vivo. Compound 9i arrested cells in the G2/M phase, induced intrinsic apoptosis, and inhibited cell colony formation in MGC-803 and SGC-7901 cells. Therefore, compound 9i is to be reported as an anti-gastric cancer agent via activating the Hippo signalling pathway and might help foster a new strategy for the cancer treatment by activating the Hippo signalling pathway regulatory function to inhibit the activity of YAP.

Discovery of 1,2,4-triazine dithiocarbamate derivatives as NEDDylation agonists to inhibit gastric cancers.

NEDDylation process regulates multiple physiological functions and signaling pathways, which are still in an equilibrium that favors the survival and proliferation of tumor cells. Unlike inhibitors, NEDDylation agonists are rarely studied. In this work, novel 1,2,4-triazine-dithiocarbamate derivatives were synthesized and evaluated for antiproliferative activity against MGC-803, PC-3 and EC-109 cells. Among them, compound K3 displayed the most potent activity MGC-803, PC-3 and EC-109 cells with IC50 values of 2.35, 5.71 and 10.1 µM, respectively, which were more potent than 5-FU. Further cellular mechanisms suggested that compound K3 inhibited the cell viability, induced proliferation inhibition, arrested cell cycle at G2/M phase and induced cell apoptosis in MGC-803 and HGC-27 cells. Importantly, compound K3 could interact with NAE1 to promote the NEDDylation of MGC-803 and HGC-27 cells. The promotion of NEDDylation resulted in the degradation of c-IAP and YAP/TAZ, which leads to the induction of cell apoptosis and inhibition of proliferation in MGC-803 and HGC-27 cells. Therefore, as a NEDDylation agonist, compound K3 could effectively inhibit gastric cancer cells. Here, we reported NEDDylation promotion induced by compound K3, which could inhibit the cancer cell lines MGC-803 and HGC-27 and induce the cancer cell apoptosis via prompting the degradation of c-IAP and YAP/TAZ.

Design, Synthesis, and Anticancer Activity Studies of Novel Quinoline-Chalcone Derivatives.

The chalcone and quinoline scaffolds are frequently utilized to design novel anticancer agents. As the continuation of our work on effective anticancer agents, we assumed that linking chalcone fragment to the quinoline scaffold through the principle of molecular hybridization strategy could produce novel compounds with potential anticancer activity. Therefore, quinoline-chalcone derivatives were designed and synthesized, and we explored their antiproliferative activity against MGC-803, HCT-116, and MCF-7 cells. Among these compounds, compound 12e exhibited a most excellent inhibitory potency against MGC-803, HCT-116, and MCF-7 cells with IC50 values of 1.38, 5.34, and 5.21 µM, respectively. The structure-activity relationship of quinoline-chalcone derivatives was preliminarily explored in this report. Further mechanism studies suggested that compound 12e inhibited MGC-803 cells in a dose-dependent manner and the cell colony formation activity of MGC-803 cells, arrested MGC-803 cells at the G2/M phase and significantly upregulated the levels of apoptosis-related proteins (Caspase3/9 and cleaved-PARP) in MGC-803 cells. In addition, compound 12e could significantly induce ROS generation, and was dependent on ROS production to exert inhibitory effects on gastric cancer cells. Taken together, all the results suggested that directly linking chalcone fragment to the quinoline scaffold could produce novel anticancer molecules, and compound 12e might be a valuable lead compound for the development of anticancer agents.

Discovery of Novel Diarylamide N-Containing Heterocyclic Derivatives as New Tubulin Polymerization Inhibitors with Anti-Cancer Activity.

Tubulin has been regarded as an attractive and successful molecular target in cancer therapy and drug discovery. Vicinal diaryl is a simple scaffold found in many colchicine site tubulin inhibitors, which is also an important pharmacophoric point of tubulin binding and anti-cancer activity. As the continuation of our research work on colchicine binding site tubulin inhibitors, we designed and synthesized a series of diarylamide N-containing heterocyclic derivatives by the combination of vicinal diaryl core and N-containing heterocyclic skeletons into one hybrid though proper linkers. Among of these compounds, compound 15b containing a 5-methoxyindole group exhibited the most potent inhibitory activity against the tested three human cancer cell lines (MGC-803, PC-3 and EC-109) with IC50 values of 1.56 µM, 3.56 µM and 14.5 µM, respectively. Besides, the SARs of these compounds were preliminarily studied and summarized. The most active compound 15b produced the inhibition of tubulin polymerization in a dose-dependent manner and caused microtubule network disruption in MGC-803 cells. Therefore, compound 15b was identified as a novel tubulin polymerization inhibitor targeting the colchicine binding site. In addition, the results of molecular docking also suggested compound 15b could tightly bind into the colchicine binding site of ß-tubulin.

Drug Discovery Targeting Focal Adhesion Kinase (FAK) as a Promising Cancer Therapy.

FAK is a nonreceptor intracellular tyrosine kinase which plays an important biological function. Many studies have found that FAK is overexpressed in many human cancer cell lines, which promotes tumor cell growth by controlling cell adhesion, migration, proliferation, and survival. Therefore, targeting FAK is considered to be a promising cancer therapy with small molecules. Many FAK inhibitors have been reported as anticancer agents with various mechanisms. Currently, six FAK inhibitors, including GSK-2256098 (Phase I), VS-6063 (Phase II), CEP-37440 (Phase I), VS-6062 (Phase I), VS-4718 (Phase I), and BI-853520 (Phase I) are undergoing clinical trials in different phases. Up to now, there have been many novel FAK inhibitors with anticancer activity reported by different research groups. In addition, FAK degraders have been successfully developed through "proteolysis targeting chimera" (PROTAC) technology, opening up a new way for FAK-targeted therapy. In this paper, the structure and biological function of FAK are reviewed, and we summarize the design, chemical types, and activity of FAK inhibitors according to the development of FAK drugs, which provided the reference for the discovery of new anticancer agents.

CircRNA expression profiling and bioinformatics analysis indicate the potential biological role and clinical significance of circRNA in influenza A virus-induced lung injury.

Circular RNA (circRNA) plays an important role in the regulation of multiple biological processes. However, circRNA profiling and the potential biological role of circRNA in influenza A virus (IAV)-induced lung injury have not been investigated. In the present study, circRNA expression profiles in lung tissues from mice with and without IAV-induced lung injury were analyzed using high-throughput sequencing, and differentially expressed circRNAs were verified by quantitative PCR. The gene homology of candidate circRNAs was investigated and the expression of plasma circRNAs from patients with IAV-induced acute respiratory distress syndrome (ARDS) was detected. The target microRNAs (miRNAs) of circRNAs were predicted. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. In total, 781 circRNAs were differentially expressed between ARDS mice and control (467 were up-regulated and 314 were down-regulated). Moreover, the candidate circRNAs (Slco3a1, Nfatc2, Wdr33, and Dmd) expression showed the same trend with the sequencing results. The isoforms of circRNA Slco3a1 and Wdr33 were highly conserved between humans and mice. Plasma circRNA Slco3a1 and Wdr33 presented differential expression in patients with IAV-induced ARDS compared to control. The circRNAmiRNA interaction network and GO and KEGG analyses indicated the potential biological role of circRNAs in the development of IAV-induced lung injury. Taken together, a large number of differentially expressed circRNAs were identified in our study. CircRNA Slco3a1 and Wdr33 had significantly different expression in specimens from mice and humans, and showed a potential biological role in IAV-induced lung injury by bioinformatics analysis.