The Dual Role of the NFATc2/galectin-9 Axis in Modulating Tumor-Initiating Cell Phenotypes and Immune Suppression in Lung Adenocarcinoma.

Tumor-initiating cells (TICs) resilience and an immunosuppressive microenvironment are aggressive oncogenic phenotypes that contribute to unsatisfactory long-term outcomes in lung adenocarcinoma (LUAD) patients. The molecular mechanisms mediating the interaction between TICs and immune tolerance have not been elucidated. The role of Galectin-9 in oncogenesis and immunosuppressive microenvironment is still unknown. This study explored the potential role of galectin-9 in TIC regulation and immune modulation in LUAD. The results show that galectin-9 supports TIC properties in LUAD. Co-culture of patient-derived organoids and matched peripheral blood mononuclear cells showed that tumor-secreted galectin-9 suppressed T cell cytotoxicity and induced regulatory T cells (Tregs). Clinically, galectin-9 is upregulated in human LUAD. High expression of galectin-9 predicted poor recurrence-free survival and correlated with high levels of Treg infiltration. LGALS9, the gene encoding galectin-9, is found to be transcriptionally regulated by the nuclear factor of activated T cells 2 (NFATc2), a previously reported TIC regulator, via in silico prediction and luciferase reporter assays. Overall, the results suggest that the NFATc2/galectin-9 axis plays a dual role in TIC regulation and immune suppression.

A Novel Fluorescence Sensor for Iodide Detection Based on the 1,3-Diaryl Pyrazole Unit with AIE and Mechanochromic Fluorescence Behavior.

A D-A type of luminophore, TPA-CDP, was designed and synthesized by using triphenylamine (TPA) as D (electron donor), 1,3-diaryl pyrazole with cyano groups (CDP) as A (electron acceptor) and employing a cyanovinyl segment as a recognition group. Firstly, TPA-CDP demonstrates effective fluorescence quenching as a sensor for I- by the nucleophilic addition reaction of the cyanovinyl segment with a high level of sensitivity, selectivity and a low determination limit of 4.43 µM. Interestingly, TPA-CDP exhibited an AIE phenomenon with the fw value reaching 50%. In addition, TPA-CDP displayed distinct mechanochromic fluorescence behavior with 70 nm red shift, which was observed over four repeated cycles. Furthermore, the mechanochromic fluorescence behavior of TPA-CDP, as observed in powder XRD experiments, was found to be associated with the morphological transition from a crystalline state to an amorphous state. These results confirm the significant potential of CDP as a powerful electron-deficient component in the creation of D-A-type mechanochromic fluorescence materials and biosensors for detecting I-.

Relationship between cancer stem cell-related SNPs and survival outcomes in patients with primary lung cancer.

BACKGROUND: Cancer stem cells may be the source of cancer-causing mutant cells and are closely related to the prognosis of cancer. Our study aimed to investigate the potential association between single-nucleotide polymorphisms (SNPs) of cancer stem cell-related genes and the prognosis of lung cancer patients. METHODS: The SNP loci were genotyped by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS), and the overall survival of subjects was analyzed by log-rank test after stratifying and adjusting their demographic data, clinical data, and genotypes. The correlation between survival time and quality of life of lung cancer under codominant, dominant, recessive, and additive genetic models was analyzed by the Cox regression model. The association between SNP polymorphism and the prognosis of lung cancer was analyzed by Stata16.0 software, and their heterogeneity was tested. Interaction analysis was performed using R software (version 4.2.0). RESULTS: Stratified analysis unveiled that rs3740535 had recessive AA genotype and additive GG genotype; Rs3130932 dominant GT + GG genotype, additive TT genotype; Rs13409 additive TT genotype; Rs6815391 recessive CC genotype and additional TT genotype were associated with increased risk of lung cancer death. Rs3130932 recessive GG genotype was associated with a reduced risk of lung cancer death. CONCLUSION: Rs3740535, rs3130932, rs13409, and rs6815391 are associated with the overall survival of lung cancer patients and may be valuable for the prognosis of lung cancer patients.

Fabrication of surface ion imprinting rice husk-based polymer for selective detection and efficient adsorption of Cu2+ in lake water.

With the deepening of the concept of recycling economy and green chemistry, selective detection and capture of Cu2+ from lake water by biosorbent are of great significance. Herein, the Cu2+ ion-imprinted polymers (RH-CIIP) with organosilane containing hydroxyl and Schiff base groups (OHSBG) as ion-receptor, fluorescent chromophores and cross-linking agent, and Cu2+ as template ion, were fabricated via surface ion imprinting technology by employing mesoporous silica MCM-41 (RH@MCM-41) as supporter. The RH-CIIP could be exploited as a fluorescent sensor for Cu2+ with high selective compared with Cu2+ non-imprinted polymers (RH-CNIP). Additionally, the LOD was calculated to be 5.62 µg/L, which is far below WHO standard for Cu2+ in drinking water of 2 mg/L, and more lower than the reported methods. Moreover, the RH-CIIP can also be utilized as an adsorbent for the effective elimination of Cu2+ from lake water with the adsorption capacity of 87.8 mg/g. Besides, the kinetic features of adsorption were well defined by the pseudo-second-order model and the sorption isotherm was in agreement with the Langmuir model. Meanwhile, the interaction of RH-CIIP and Cu2+ was investigated using theoretical calculations and XPS. Finally, RH-CIIP was able to remove almost 99 % Cu2+ in lake water samples that satisfied the drink water standard.

An end-to-end tracking method for polyp detectors in colonoscopy videos.

Deep learning based computer-aided diagnosis technology demonstrates an encouraging performance in aspect of polyp lesion detection on reducing the miss rate of polyps during colonoscopies. However, to date, few studies have been conducted for tracking polyps that have been detected in colonoscopy videos, which is an essential and intuitive issue in clinical intelligent video analysis task (e.g. lesion counting, lesion retrieval, report generation). In the paradigm of conventional tracking-by-detection system, detection task for lesion localization is separated from the tracking task for cropped lesions re-identification. In the multi object tracking problem, each target is supposed to be tracked by invoking a tracker after the detector, which introduces multiple inferences and leads to external resource and time consumption. To tackle these problems, we proposed a plug-in module named instance tracking head (ITH) for synchronous polyp detection and tracking, which can be simply inserted into object detection frameworks. It embeds a feature-based polyp tracking procedure into the detector frameworks to achieve multi-task model training. ITH and detection head share the model backbone for low level feature extraction, and then low level feature flows into the separate branches for task-driven model training. For feature maps from the same receptive field, the region of interest head assigns these features to the detection head and the ITH, respectively, and outputs the object category, bounding box coordinates, and instance feature embedding simultaneously for each specific polyp target. We also proposed a method based on similarity metric learning. The method makes full use of the prior boxes in the object detector to provide richer and denser instance training pairs, to improve the performance of the model evaluation on the tracking task. Compared with advanced tracking-by-detection paradigm methods, detectors with proposed ITH can obtain comparative tracking performance but approximate 30% faster speed. Optimized model based on Scaled-YOLOv4 detector with ITH illustrates good trade-off between detection (mAP 91.70%) and tracking (MOTA 92.50% and Rank-1 Acc 88.31%) task at the frame rate of 66 FPS. The proposed structure demonstrates the potential to aid clinicians in real-time detection with online tracking or offline retargeting of polyp instances during colonoscopies.

Simultaneous Recognition of Atrophic Gastritis and Intestinal Metaplasia on White Light Endoscopic Images Based on Convolutional Neural Networks: A Multicenter Study.

INTRODUCTION: Patients with atrophic gastritis (AG) or gastric intestinal metaplasia (GIM) have elevated risk of gastric adenocarcinoma. Endoscopic screening and surveillance have been implemented in high incidence countries. The study aimed to evaluate the accuracy of a deep convolutional neural network (CNN) for simultaneous recognition of AG and GIM. METHODS: Archived endoscopic white light images with corresponding gastric biopsies were collected from 14 hospitals located in different regions of China. Corresponding images by anatomic sites containing AG, GIM, and chronic non-AG were categorized using pathology reports. The participants were randomly assigned (8:1:1) to the training cohort for developing the CNN model (TResNet), the validation cohort for fine-tuning, and the test cohort for evaluating the diagnostic accuracy. The area under the curve (AUC), sensitivity, specificity, and accuracy with 95% confidence interval (CI) were calculated. RESULTS: A total of 7,037 endoscopic images from 2,741 participants were used to develop the CNN for recognition of AG and/or GIM. The AUC for recognizing AG was 0.98 (95% CI 0.97-0.99) with sensitivity, specificity, and accuracy of 96.2% (95% CI 94.2%-97.6%), 96.4% (95% CI 94.8%-97.9%), and 96.4% (95% CI 94.4%-97.8%), respectively. The AUC for recognizing GIM was 0.99 (95% CI 0.98-1.00) with sensitivity, specificity, and accuracy of 97.9% (95% CI 96.2%-98.9%), 97.5% (95% CI 95.8%-98.6%), and 97.6% (95% CI 95.8%-98.6%), respectively. DISCUSSION: CNN using endoscopic white light images achieved high diagnostic accuracy in recognizing AG and GIM.

Patterns of mental health problems before and after easing COVID-19 restrictions: Evidence from a 105248-subject survey in general population in China.

BACKGROUND: The COVID-19 pandemic has alarming implications for individual and population level mental health. Although the future of COVID-19 is unknown at present, more countries or regions start to ease restrictions. The findings from this study have provided the empirical evidence of prevalence and patterns of mental disorders in Chinese general population before and after easing most COVID-19 restrictions, and information of the factors associated with these patterns. METHODS: A cross-sectional population-based online survey was carried out from February to March 2020 in the general population across all provinces in China. The 12-item General Health Questionnaire (GHQ-12) was incorporated in the survey. Latent class analyses were performed to investigate the patterns of mental disorders and multinomial logistic regressions were used to examine how individual and regional risk factors can predict mental disorder patterns. RESULTS: Four distinctive patterns of mental health were revealed in the general population. After the ease of most COVID-19 restrictions, the prevalence of high risk of mental disorders decreased from 25.8% to 20.9% and prevalence of being high risk of unhappiness and loss of confidence decreased from 10.1% to 8.1%. However, the prevalence of stressed, social dysfunction and unhappy were consistently high before and after easing restrictions. Several regional factors, such as case mortality rate and healthcare resources, were associated with mental health status. Of note, healthcare workers were less likely to have mental disorders, compared to other professionals and students. CONCLUSIONS: The dynamic management of mental health and psychosocial well-being is as important as that of physical health both before and after the ease of COVID-19 restrictions. Our findings may help in mental health interventions in other countries and regions while easing COVID-19 restrictions.

Heparin/poly-l-lysine nanoplatform with growth factor delivery for surface modification of cardiovascular stents: The influence of vascular endothelial growth factor loading.

The rapid re-endothelialization of the vascular stent surface is desirable for preventing thrombosis or reducing restenosis. Many biological factors that promote the biological behavior of endothelial cells have been used for the surface modification of stents. Vascular endothelial growth factor (VEGF), which plays an important role in angiogenesis, induces strong vascular growth. In this study, we investigated different VEGF concentrations (50 to 500 ng/ml) to determine the optimum concentration for biocompatibility. First, VEGF-loaded heparin/poly-l-lysine (Hep-PLL) nanoparticles were created by electrostatic interactions. Then, the VEGF-loaded nanoparticles were immobilized on dopamine-coated 316 L stainless steel (SS) surfaces. The physical and chemical properties of the modified surface were characterized and the biocompatibility was evaluated in vitro. The results indicated that the VEGF-loaded nanoparticles were immobilized successfully on the 316LSS surface, as evidenced by the results of Alcian Blue staining and water contact angle (WCA) measurements. The low platelet adhesion and activation indicated that the modified surfaces had good blood compatibility. The modified surfaces showed a good inhibitory effect on smooth muscle cells, indicating that they inhibited tissue hyperplasia. In addition, the modified surfaces significantly promoted endothelial cell adhesion, proliferation, migration, and biological activity, especially VEGF concentration was 350 ng/ml (NPV350). The optical VEGF concentration of the surface modified Hep-PLL nanoparticles was 350 ng/ml. The proposed method shows promise for potential applications for cardiovascular devices.

Ad.mda-7 (IL-24) selectively induces apoptosis in hepatocellular carcinoma cell lines, suppresses metastasis, and enhances the effect of doxorubicin on xenograft tumors.

Overexpression of the melanoma differentiation associated gene-7 (MDA-7)/IL-24 in vitro generally results in the growth suppression and induction of apoptosis of diverse human tumor cells. In this study, we investigated the effects of overexpression of the MDA-7/IL-24 gene in human hepatocellular carcinoma (HCC) cells in vitro and in vivo. Adenovirus-mediated overexpression of MDA-7 facilitated the MDA-7/IL-24-induced apoptosis and G2/M arrest in HCC cells, but not in the normal liver cell line L02, and the effect was independent of the p53 status. Inhibition of metastasis and angiogenesis was correlated with decreasing expression of STAT3, P-STAT3, MMP-2, VEGF, and TGF-beta genes, regulated by STAT3 in MHCCLM6 cells. We also showed that Ad.mda-7 combined with doxorubicin (ADM) had significantly enhanced antitumor and antimetastatic effects in vivo, accompanied by the downregulation of VEGF, MMP-2, and TGF-beta genes and the upregulation of E-cadherin genes. These data suggested that MDA-7/IL-24 induces its selective antitumor properties in HCC cells by promoting apoptosis independent of p53 status, inhibiting subcutaneous tumor growth and metastasis, and increasing the effect of chemotherapeutic agents. MDA-7/IL-24 represents a new class of cancer suppressor genes that may be useful in the targeted therapy of HCC.

[Mda-7-carrying replication-defective adenovirus selectively kills hepatocellular carcinoma cells by facilitating release of proapoptotic protein from mitochondria].

OBJECTIVE: To investigate the mechanism that mda-7/IL-24 selectively kills hepatocellular carcinoma (HCC) HepG2 cells in vitro. METHODS: HCC cell line HepG2 and normal liver cell line L02 were infected with Ad.mda-7. The expression of mda-7/IL-24 was detected by RT-PCR and ELISA, respectively. The apoptotic effects were confirmed by Hoechst staining and flow cytometry assay, respectively. Furthermore, Bcl-2 family proteins, cytochrome C, Smac/DIABLO and caspase-9 were determined by Western blot. RESULTS: The exogenous mda-7/IL-24 gene was expressed in HepG2 and L02 cells infected with Ad.mda-7. Ad.mda-7 induced apoptosis in HepG2 but not in L02 cells in vitro. The induction of tumor cell apoptosis is correlated with the increasing expression of Bax and decreasing expression of Bcl-2 and Bcl-xL genes, then facilitated the releasing of cytochrome C and Smac/DIABLO from mitochondria to cytoplasm and increasing the expression of caspase-9, eventually, resulted in apoptosis. CONCLUSION: Ad.mda-7 selectively induces growth inhibition and apoptosis in hepatocellular carcinoma HepG2 cells but not in normal L02 hepatocytes in vitro, and the mechanism might involve the decrease of Bcl-2 and Bcl-xL and increase of Bak expression, facilitating the release of cytochrome C and Smac/DIABLO from mitochondria in HCC cells.

[Melanoma differentiation associated gene-7 and interleukin-24 selectively induces growth arrest and apoptosis in hepatocellular carcinoma cell lines in vitro].

OBJECTIVE: To investigate the effect of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) on the hepatocellular carcinoma cell lines and normal liver cell line in vitro. METHODS: Hepatocellular carcinoma cell lines HepG2, SMMC7721, Hep3B, MHCC97L, M6 and normal liver cell line L02 were infected with Ad.mda-7. The gene expression of mda-7/IL-24 in these cell lines was confirmed by RT-PCR and ELISA assay. MTT assay and flow cytometry were used to study tumor cell proliferation and cell cycle in vitro. Hoechst staining and cytometry assay after Annexin-V and PI staining were studied to indicate the apoptosis effect. RESULTS: It was confirmed by RT-PCR that the exogenous mda-7/IL-24 gene expressed in all of these cells. The mda-7/IL-24 protein product was confirmed by assaying the supernatant with ELISA. MTT and apoptosis test indicated mda-7/IL-24 can induce the hepatocellular carcinoma cell lines growth suppression, apoptosis in vitro but not in normal liver cell line L02, cell cycle test revealed mda-7/IL-24 can block cancer cell lines in G2/M but not in L02. CONCLUSIONS: mda-7/IL-24 selectively induces growth suppression, apoptosis in hepatocellular carcinoma lines but not in normal liver cell in vitro.

[Adenovirus vector expressing MDA-7/IL-24 selectively induces growth arrests and apoptosis in human hepatocellular carcinoma cell lines independent of the state of p53 gene].

OBJECTIVE: To investigate the effect of melanoma differentiation associated gene-7/interleukin 24 (MDA/IL-24) on human hepatocellular carcinoma cell lines HepG2, MHCC97L and Hep3B and normal liver cell line L02 with a different p53 state. METHODS: The MDA-7/IL-24 gene was transfected into human hepatocellular carcinoma cell lines HepG2, MHCC97L and Hep3B and hepatocyte line L02 with a replication-incompetent adenovirus vector. The mRNA expression of MDA7/IL-24 in HepG2, MHCC97L, Hep3B and L02 cells was confirmed using RT-PCR. Protein expression was confirmed using ELISA assay. MTT assay and flow cytometry were used to study tumor cell proliferation and cell cycle in vitro. Hoechst and flow cytometry assay after annexin-V and PI staining were performed to indicate the apoptosis effect. RESULTS: Exogenous MDA-7/IL-24 gene was expressed in HepG2, MHCC97L, Hep3B and L02 cells. The protein product of MDA-7/IL-24 was confirmed in the supernatant. MTT assay and apoptosis test indicated MDA-7/IL-24 could induce growth suppression and apoptosis of HepG2, MHCC97L and Hep3B but could not in L02. Cell cycle test revealed MDA-7/IL-24 could block those cancer cells in G2/M but not in the normal cell L02. CONCLUSION: MDA-7/IL-24 selectively induces growth suppression and apoptosis in hepatocellular carcinoma lines HepG2, MHCC97L and Hep3B in vitro independent of the state of p53 gene but not in normal liver cell L02. This indicates MDA-7/IL-24 can be a perfect gene for gene therapy in hepatocellular carcinoma.