Effectiveness and safety of early lens extraction during par plana vitrectomy for proliferative diabetes retinopathy with mild cataract: a randomized clinical trial.

AIM: To evaluate the effectiveness and safety of early lens extraction during pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR) compared to those of PPV with subsequent cataract surgery. METHODS: This multicenter randomized controlled trial was conducted in three Chinese hospitals on patients with PDR, aged >45y, with mild cataracts. The participants were randomly assigned to the combined (PPV combined with simultaneously cataract surgery, i.e., phacovitrectomy) or subsequent (PPV with subsequent cataract surgery 6mo later) group and followed up for 12mo. The primary outcome was the change in best-corrected visual acuity (BCVA) from baseline to 6mo, and the secondary outcomes included complication rates and medical expenses. RESULTS: In total, 129 patients with PDR were recruited and equally randomized (66 and 63 in the combined and subsequent groups respectively). The change in BCVA in the combined group [mean, 36.90 letters; 95% confidence interval (CI), 30.35-43.45] was significantly better (adjusted difference, 16.43; 95%CI, 8.77-24.08; P<0.001) than in the subsequent group (mean, 22.40 letters; 95%CI, 15.55-29.24) 6mo after the PPV, with no significant difference between the two groups at 12mo. The overall surgical risk of two sequential surgeries was significantly higher than that of the combined surgery for neovascular glaucoma (17.65% vs 3.77%, P=0.005). No significant differences were found in the photocoagulation spots, surgical time, and economic expenses between two groups. In the subsequent group, the duration of work incapacity (22.54±9.11d) was significantly longer (P<0.001) than that of the combined group (12.44±6.48d). CONCLUSION: PDR patients aged over 45y with mild cataract can also benefit from early lens extraction during PPV with gratifying effectiveness, safety and convenience, compared to sequential surgeries.

TGF-ß1-Induced SOX18 Elevation Promotes Hepatocellular Carcinoma Progression and Metastasis Through Transcriptionally Upregulating PD-L1 and CXCL12.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is characterized by an immune-suppressive microenvironment, which contributes to tumor progression, metastasis, and immunotherapy resistance. Identification of HCC-intrinsic factors regulating the immunosuppressive microenvironment is urgently needed. Here, we aimed to elucidate the role of SYR-Related High-Mobility Group Box 18 (SOX18) in inducing immunosuppression and to validate novel combination strategies for SOX18-mediated HCC progression and metastasis. METHODS: The role of SOX18 in HCC was investigated in orthotopic allografts and diethylinitrosamine/carbon tetrachloride-induced spontaneous models by using murine cell lines, adeno-associated virus 8, and hepatocyte-specific knockin and knockout mice. The immune cellular composition in the HCC microenvironment was evaluated by flow cytometry and immunofluorescence. RESULTS: SOX18 overexpression promoted the infiltration of tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) while diminishing cytotoxic T cells to facilitate HCC progression and metastasis in cell-derived allografts and chemically induced HCC models. Mechanistically, transforming growth factor-beta 1 (TGF-ß1) upregulated SOX18 expression by activating the Smad2/3 complex. SOX18 transactivated chemokine (C-X-C motif) ligand 12 (CXCL12) and programmed death ligand 1 (PD-L1) to induce the immunosuppressive microenvironment. CXCL12 knockdown significantly attenuated SOX18-induced TAMs and Tregs accumulation and HCC dissemination. Antagonism of chemokine receptor 4 (CXCR4), the cognate receptor of CXCL12, or selective knockout of CXCR4 in TAMs or Tregs likewise abolished SOX18-mediated effects. TGFßR1 inhibitor Vactosertib or CXCR4 inhibitor AMD3100 in combination with anti-PD-L1 dramatically inhibited SOX18-mediated HCC progression and metastasis. CONCLUSIONS: SOX18 promoted the accumulation of immunosuppressive TAMs and Tregs in the microenvironment by transactivating CXCL12 and PD-L1. CXCR4 inhibitor or TGFßR1 inhibitor in synergy with anti-PD-L1 represented a promising combination strategy to suppress HCC progression and metastasis.

Research progress in improving sludge dewaterability: sludge characteristics, chemical conditioning and influencing factors.

Sludge from wastewater treatment processes with high water content and large volume has become an inevitable issue in environmental management. Due to the challenging dewatering properties of sludge, current mechanical dewatering methods are no longer sufficient to meet the escalating water content standards of sludge. This paper summarizes the characteristics of various sludge and raises reasons for the their dewaterability differences. Affected by extracellular polymeric substances, biological sludge is hydrophilic and negatively charged, which limits the dewatering degree. The rheological properties, flocs, ionic composition, and solid phase concentration of the sludge also influence the dewatering to some extent. For these factors, the chemical conditioning measures with simple operation and excellent effect improve its dewaterability, which mainly include flocculation/coagulation, acid/alkali treatment, advanced oxidation, surfactant treatment and combined treatment. There is a growing necessity to explore the development of new chemical conditioning agents, even though traditional agents continue to remain widely used. However, the development of these new agents should prioritize finding a balance between various factors such as efficiency, effectiveness, ease of operation, environmental safety, and cost-effectiveness. Electrochemical dewatering enhances solid-liquid separation, and its coupling with chemical conditioning is also an excellent means to further reduce water content. In addition, the improvement of press filter is an effective way, which is influenced by pressure, processing time, sludge cake thickness and pore structure, filter media etc. In general, it is essential to develop new conditioning agents and enhance mechanical filtration press technology based on a thorough understanding of various sludge properties. Concurrently, an in-depth study of the principles of mechanical pressure filtration will contribute to establishing a theoretical foundation for effective deep sludge dewatering and propel further advancements in this field.

HMGB1-mediated elevation of KLF7 facilitates hepatocellular carcinoma progression and metastasis through upregulating TLR4 and PTK2.

Background: Metastasis is a major cause of HCC-related deaths with no effective pharmacotherapies. Chronic inflammation promotes HCC dissemination, however, its underlying mechanisms are not fully understood. Here, we investigated the role of Krüppel-like factor 7 (KLF7) in inflammation-provoked HCC metastasis and proposed therapeutic strategies for KLF7-positive patients. Methods: The expression of KLF7 in human HCC specimens were examined by immunohistochemistry and quantitative real-time PCR. The luciferase reporter assays and chromatin immunoprecipitation assays were conducted to explore the transcriptional regulation related to KLF7. Orthotopic xenograft models and DEN/CCl4-induced HCC models were established to evaluate HCC progression and metastasis. Results: KLF7 overexpression promotes HCC metastasis through transactivating toll-like receptor 4 (TLR4) and protein tyrosine kinase 2 (PTK2) expression. High mobility group box 1 (HMGB1) upregulates KLF7 expression through the TLR4/advanced glycosylation end-product specific receptor (RAGE)-PI3K-AKT-NF-κB pathway, forming an HMGB1-KLF7-TLR4 positive feedback loop. The HMGB1-KLF7-TLR4/PTK2 axis is gradually activated during the progression of inflammation-HCC transition. Genetic depletion of KLF7 impedes HMGB1-mediated HCC progression and metastasis. The combined application of TLR4 inhibitor TAK-242 and PTK2 inhibitor defactinib alleviates HCC progression and metastasis induced by the HMGB1-KLF7 axis. In human HCCs, KLF7 expression is positively correlated with cytoplasmic HMGB1, p-p65, TLR4, and PTK2 levels, and patients positively co-expressing HMGB1/KLF7, p-p65/KLF7, KLF7/TLR4 or KLF7/PTK2 exhibit the worst prognosis. Conclusions: HMGB1-induced KLF7 overexpression facilitates HCC progression and metastasis by upregulating TLR4 and PTK2. Genetic ablation of KLF7 via AAV gene therapy and combined blockade of TLR4 and PTK2 represents promising therapy strategies for KLF7-positive HCC patients.

FGF19-mediated ELF4 overexpression promotes colorectal cancer metastasis through transactivating FGFR4 and SRC.

Background: Metastasis accounts for the high lethality of colorectal cancer (CRC) patients. Unfortunately, the molecular mechanism manipulating metastasis in CRC is still elusive. Here, we investigated the function of E74-like factor 4 (ELF4), an ETS family member, in facilitating CRC progression. Methods: The expression of ELF4 in human CRC samples and CRC cell lines was determined by quantitative real-time PCR, immunohistochemistry and immunoblotting. The migratory and invasive phenotypes of CRC cells were evaluated by in vitro transwell assays and in vivo metastatic models. The RNA sequencing was used to explore the downstream targets of ELF4. The luciferase reporter assays and chromatin immunoprecipitation assays were used to ascertain the transcriptional regulation related to ELF4. Results: We found elevated ELF4 was positively correlated with distant metastasis, advanced AJCC stages, and dismal outcomes in CRC patients. ELF4 expression was also an independent predictor of poor prognosis. Overexpression of ELF4 boosted CRC metastasis via transactivating its downstream target genes, fibroblast growth factor receptor 4 (FGFR4) and SRC proto-oncogene, non-receptor tyrosine kinase, SRC. Fibroblast growth factor 19 (FGF19) upregulated ELF4 expression through the ERK1/2/SP1 axis. Clinically, ELF4 expression had a positive correlation with FGF19, FGFR4 and SRC, and CRC patients who positively coexpressed FGF19/ELF4, ELF4/FGFR4, or ELF4/SRC exhibited the worst clinical outcomes. Furthermore, the combination of the FGFR4 inhibitor BLU-554 and the SRC inhibitor KX2-391 dramatically suppressed ELF4-mediated CRC metastasis. Conclusions: We demonstrated the essentiality of ELF4 in the metastatic process of CRC, and targeting the ELF4-relevant positive feedback circuit might represent a novel therapeutic strategy.

An integrative analysis revealing cuproptosis-related lncRNAs signature as a novel prognostic biomarker in hepatocellular carcinoma.

Background: Cuproptosis is a newly defined form of cell death, whether cuproptosis involved in hepatocellular carcinoma (HCC) remains elusive. Method: We obtained patients' RNA expression data and follow-up information from University of California Santa Cruz (UCSC) and The Cancer Genome Atlas (TCGA). We analyzed the mRNA level of Cuproptosis-related genes (CRGs) and performed univariate Cox analysis. Liver hepatocellular carcinoma (LIHC) was chosen for further investigation. Real-Time quantitative PCR (RT-qPCR), Western blotting (WB), Immunohistochemical (IHC), and Transwell assays were used to determine expression patterns and functions of CRGs in LIHC. Next, we identified CRGs-related lncRNAs (CRLs) and differentially expressed CRLs between HCC and normal cases. Univariate Cox analysis, least absolute shrinkage selection operator (LASSO) analysis and Cox regression analysis were used to construct the prognostic model. Univariate and multivariate Cox analysis was used to assess whether the risk model can act as an independent risk factor of overall survival duration. Different risk groups performed immune correlation analysis, tumor mutation burden (TMB), and Gene Set Enrichment Analysis (GSEA) analysis were performed in different risk groups. Finally, we assessed the performance of the predictive model in drug sensitivity. Results: CRGs expression levels have significant differences between tumor and normal tissues. High expression of Dihydrolipoamide S-Acetyltransferase (DLAT) correlated to metastasis of HCC cells and indicated poor prognosis for HCC patients. Our prognostic model consisted of four cuproptosis-related lncRNA (AC011476.3, AC026412.3, NRAV, MKLN1-AS). The prognostic model performed well in predicting survival rates. The results from Cox regression analysis suggested that risk score can serve as an independent prognostic element for survival durations. Survival analysis revealed that low risk patients have extended survival periods compared with those with high risk. The results of the immune analysis indicated that risk score has a positive correlation with B cell and CD4+ T cell Th2, while has a negative relationship with endothelial cell and hematopoietic cells. Besides, immune checkpoint genes have higher expression folds in the high-risk set than in the low-risk set. The high-risk group had higher rates of genetic mutation than the low-risk set while having a shorter survival time. GSEA revealed the signaling pathways enriched in the high-risk group were mostly immune-related, while metabolic-related pathways were enriched in the low-risk group. Drugs sensitivity analysis indicated that our model has the ability to predict the efficacy of clinical treatment. Conclusion: The Cuproptosis-related lncRNAs prognostic formula is a novel predictor of HCC patients' prognosis and drug sensitivity.

DeepFundus: A flow-cytometry-like image quality classifier for boosting the whole life cycle of medical artificial intelligence.

Medical artificial intelligence (AI) has been moving from the research phase to clinical implementation. However, most AI-based models are mainly built using high-quality images preprocessed in the laboratory, which is not representative of real-world settings. This dataset bias proves a major driver of AI system dysfunction. Inspired by the design of flow cytometry, DeepFundus, a deep-learning-based fundus image classifier, is developed to provide automated and multidimensional image sorting to address this data quality gap. DeepFundus achieves areas under the receiver operating characteristic curves (AUCs) over 0.9 in image classification concerning overall quality, clinical quality factors, and structural quality analysis on both the internal test and national validation datasets. Additionally, DeepFundus can be integrated into both model development and clinical application of AI diagnostics to significantly enhance model performance for detecting multiple retinopathies. DeepFundus can be used to construct a data-driven paradigm for improving the entire life cycle of medical AI practice.

Preparation of phosphoric acid modified antibiotic mycelial residues biochar: Loading of nano zero-valent iron and promotion on biogas production.

Antibiotic mycelial residues (AMRs), as recyclable hazardous waste, can realize efficient utilization by reasonable treatment. To solve the problems of undeveloped pore structure and low specific surface area existed in AMR biochar, this study first modified biochar by phosphoric acid (H3PO4) to prepare PBC (H3PO4-modified biochar). Then, PBC was used as carrier to load nano zero-valent iron (nZVI) for preparation of nZVI/PBC. Finally, the biochar materials were used to promote anaerobic digestion (AD) of corn straw. The results showed that H3PO4-modification can effectively improve the specific surface area, pore structure, and electron donating capacity of AMRs biochar. The using of PBC as carrier to load nZVI attenuated the agglomeration of nZVI particles. Both PBC and nZVI/PBC improved the AD process, with biogas yield enhanced by 29.63% and 29.26%, respectively. The nZVI/PBC exhibited higher ability in maintaining the stability of AD system and promotion of fiber degradation than PBC.

[T cell factor 3 (TCF3) is overexpressed in hepatocellular carcinoma and promotes their invasion and metastasis].

Objective To investigate the expression of T cell factor 3 (TCF3) in hepatocellular carcinoma (HCC), its correlation with the prognosis of HCC patients, and its effect on the invasion, migration, and metastasis of HCC cells. Methods The expression of TCF3 mRNA in HCC tissues was detected with tumor public databases and the expression of TCF3 protein in HCC specimens was detected by immunohistochemical staining. Correlation between TCF3 expression and HCC patients' prognosis was analyzed. Western blot analysis was used to detect the expression of TCF3 in different human HCC cell lines, and lentivirus infection was conducted to construct TCF3-upregulated and TCF3-downregulated HCC cell lines. The effect of TCF3 on the invasion and migration of HCC cells was assessed by in vitro TranswellTM assay, and in vivo intrahepatic tumor implantation models were established to evaluate the effect of TCF3 on the metastatic capacity of HCC cells. Results The expression of TCF3 mRNA was significantly higher in HCC tissues than that in normal liver tissues, and high expression of TCF3 mRNA was closely correlated with decreased overall survival rates of HCC patients. In 120 cases of HCC tissues, the protein level of TCF3 was significantly higher than that in adjacent nontumor tissues, and patients with positive TCF3 expression had a markedly decreased overall survival rate and a higher recurrence rate compared with patients with negative TCF3 expression. In vitro TranswellTM assay indicated that TCF3 upregulation promoted the invasion and migration of PLC/PRF/5 cells, whereas knockdown of TCF3 inhibited the invasion and migration abilities of HCCLM3 cells. Intrahepatic tumor implantation models showed that TCF3 upregulation promoted the metastasis of PLC/PRF/5 cells, while TCF3 knockdown weakened the metastatic capacity of HCCLM3 cells. Conclusion TCF3 expression is significantly upregulated in human HCC tissues, and high TCF3 expression predicts a poor prognosis of HCC patients. TCF3 markedly promotes the invasion, migration, and metastasis of HCC cells.

Development and validation of a deep learning system to screen vision-threatening conditions in high myopia using optical coherence tomography images.

BACKGROUND/AIMS: To apply deep learning technology to develop an artificial intelligence (AI) system that can identify vision-threatening conditions in high myopia patients based on optical coherence tomography (OCT) macular images. METHODS: In this cross-sectional, prospective study, a total of 5505 qualified OCT macular images obtained from 1048 high myopia patients admitted to Zhongshan Ophthalmic Centre (ZOC) from 2012 to 2017 were selected for the development of the AI system. The independent test dataset included 412 images obtained from 91 high myopia patients recruited at ZOC from January 2019 to May 2019. We adopted the InceptionResnetV2 architecture to train four independent convolutional neural network (CNN) models to identify the following four vision-threatening conditions in high myopia: retinoschisis, macular hole, retinal detachment and pathological myopic choroidal neovascularisation. Focal Loss was used to address class imbalance, and optimal operating thresholds were determined according to the Youden Index. RESULTS: In the independent test dataset, the areas under the receiver operating characteristic curves were high for all conditions (0.961 to 0.999). Our AI system achieved sensitivities equal to or even better than those of retina specialists as well as high specificities (greater than 90%). Moreover, our AI system provided a transparent and interpretable diagnosis with heatmaps. CONCLUSIONS: We used OCT macular images for the development of CNN models to identify vision-threatening conditions in high myopia patients. Our models achieved reliable sensitivities and high specificities, comparable to those of retina specialists and may be applied for large-scale high myopia screening and patient follow-up.

Development and validation of a survival model for esophageal adenocarcinoma based on autophagy-associated genes.

Autophagy is a highly conserved catabolic process which has been implicated in esophageal adenocarcinoma (EAC). We sought to investigate the biological functions and prognostic value of autophagy-related genes (ARGs) in EAC. A total of 21 differentially expressed ARGs were identified between EAC and normal samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were then applied for the differentially expressed ARGs in EAC, and the protein-protein interaction (PPI) network was established. Cox survival analysis and Lasso regression analysis were performed to establish a prognostic prediction model based on nine overall survival (OS)-related ARGs (CAPN1, GOPC, TBK1, SIRT1, ARSA, BNIP1, ERBB2, NRG2, PINK1). The 9-gene prognostic signature significantly stratified patient outcomes in The Cancer Genome of Atlas (TCGA)-EAC cohort and was considered as an independently prognostic predictor for EAC patients. Moreover, Gene set enrichment analysis (GSEA) analyses revealed several important cellular processes and signaling pathways correlated with the high-risk group in EAC. This prognostic prediction model was confirmed in an independent validation cohort (GSE13898) from The Gene Expression Omnibus (GEO) database. We also developed a nomogram with a concordance index of 0.78 to predict the survival possibility of EAC patients by integrating the risk signature and clinicopathological features. The calibration curves substantiated favorable concordance between actual observation and nomogram prediction. Last but not least, Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2), a member of the prognostic gene signature, was identified as a potential therapeutic target for EAC patients. To sum up, we established and verified a novel prognostic prediction model based on ARGs which could optimize the individualized survival prediction in EAC.

IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R.

Metastasis is the major reason for the high mortality of colorectal cancer (CRC) patients and its molecular mechanism remains unclear. Here, we report a novel role of Homeobox A13 (HOXA13), a member of the Homeobox (HOX) family, in promoting CRC metastasis. The elevated expression of HOXA13 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in two independent CRC cohorts. Overexpression of HOXA13 promoted CRC metastasis whereas downregulation of HOXA13 suppressed CRC metastasis. Mechanistically, HOXA13 facilitated CRC metastasis by transactivating ATP-citrate lyase (ACLY) and insulin-like growth factor 1 receptor (IGF1R). Knockdown of ACLY and IGFIR inhibited HOXA13-medicated CRC metastasis, whereas ectopic overexpression of ACLY and IGFIR rescued the decreased CRC metastasis induced by HOXA13 knockdown. Furthermore, Insulin-like growth factor 1 (IGF1), the ligand of IGF1R, upregulated HOXA13 expression through the PI3K/AKT/HIF1α pathway. Knockdown of HOXA13 decreased IGF1-mediated CRC metastasis. In addition, the combined treatment of ACLY inhibitor ETC-1002 and IGF1R inhibitor Linsitinib dramatically suppressed HOXA13-mediated CRC metastasis. In conclusion, HOXA13 is a prognostic biomarker in CRC patients. Targeting the IGF1-HOXA13-IGF1R positive feedback loop may provide a potential therapeutic strategy for the treatment of HOXA13-driven CRC metastasis.

CXCL12-mediated HOXB5 overexpression facilitates Colorectal Cancer metastasis through transactivating CXCR4 and ITGB3.

Background: Metastasis is the major reason for the high mortality of colorectal cancer (CRC). However, the molecular mechanism underlying CRC metastasis remains unclear. Here, we report a novel role of homeobox B5 (HOXB5), a member of the HOX family, in promoting CRC metastasis. Method: The expression of HOXB5 and its target genes were examined by immunohistochemistry in human CRC. Chromatin immunoprecipitation and luciferase reporter assays were performed to measure the transcriptional regulation of target genes by HOXB5. The metastatic capacities of CRC cells were evaluated by in vivo lung and liver metastatic models. Results: The elevated expression of HOXB5 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in CRC patients. HOXB5 expression was an independent and significant risk factor for the recurrence and survival in CRC patients. Overexpression of HOXB5 promoted CRC metastasis by transactivating metastatic related genes, C-X-C motif chemokine receptor 4 (CXCR4) and integrin subunit beta 3 (ITGB3). C-X-C motif chemokine ligand 12 (CXCL12), which is the ligand of CXCR4, upregulated HOXB5 expression through the extracellular regulated protein kinase (ERK)/ETS proto-oncogene 1, transcription factor (ETS1) pathway. The knockdown of HOXB5 decreased CXCL12-enhanced CRC metastasis. Furthermore, AMD3100, a specific CXCR4 inhibitor, significantly suppressed HOXB5-mediated CRC metastasis. HOXB5 expression was positively correlated with CXCR4 and ITGB3 expression in human CRC tissues, and patients with positive co-expression of HOXB5/CXCR4, or HOXB5/ITGB3 exhibited the worst prognosis. Conclusion: Our study implicates HOXB5 as a prognostic biomarker in CRC, and defines a CXCL12-HOXB5-CXCR4 positive feedback loop that plays an important role in promoting CRC metastasis.

Molecular mechanisms and clinical implications of miRNAs in drug resistance of colorectal cancer.

Systemic chemotherapy is identified as a curative approach to prolong the survival time of patients with colorectal cancer (CRC). Although great progress in therapeutic approaches has been achieved during the last decades, drug resistance still extensively persists and serves as a major hurdle to effective anticancer therapy for CRC. The mechanism of multidrug resistance remains unclear. Recently, mounting evidence suggests that a great number of microRNAs (miRNAs) may contribute to drug resistance in CRC. Certain of these miRNAs may thus be used as promising biomarkers for predicting drug response to chemotherapy or serve as potential targets to develop personalized therapy for patients with CRC. This review mainly summarizes recent advances in miRNAs and the molecular mechanisms underlying miRNA-mediated chemoresistance in CRC. We also discuss the potential role of drug resistance-related miRNAs as potential biomarkers (diagnostic and prognostic value) and envisage the future orientation and challenges in translating the findings on miRNA-mediated chemoresistance of CRC into clinical applications.

SOX18 promotes gastric cancer metastasis through transactivating MCAM and CCL7.

The therapeutic strategies for advanced gastric cancer (GC) remain unsatisfying and limited. Therefore, it is still imperative to fully elucidate the mechanisms underlying GC metastasis. Here, we report a novel role of SRY-box transcription factor 18 (SOX18), a member of the SOX family, in promoting GC metastasis. The elevated expression of SOX18 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in human GC. SOX18 expression was an independent and significant risk factor for the recurrence and survival in GC patients. Up-regulation of SOX18 promoted GC invasion and metastasis, whereas down-regulation of SOX18 decreased GC invasion and metastasis. Melanoma cell adhesion molecule (MCAM) and C-C motif chemokine ligand 7 (CCL7) are direct transcriptional targets of SOX18. Knockdown of MCAM and CCL7 significantly decreased SOX18-mediated GC invasion and metastasis, while the stable overexpression of MCAM and CCL7 reversed the decrease in cell invasion and metastasis that was induced by the inhibition of SOX18. A mechanistic investigation indicated that the upregulation of SOX18 that was mediated by the CCL7-CCR1 pathway relied on the ERK/ELK1 pathway. SOX18 knockdown significantly reduced CCL7-enhanced GC invasion and metastasis. Furthermore, BX471, a specific CCR1 inhibitor, significantly reduced the SOX18-mediated GC invasion and metastasis. In human GC tissues, SOX18 expression was positively correlated with CCL7 and MCAM expression, and patients with positive coexpression of SOX18/CCL7 or SOX18/MCAM had the worst prognosis. In conclusion, we defined a CCL7-CCR1-SOX18 positive feedback loop that played a pivotal role in GC metastasis, and targeting this pathway may be a promising therapeutic option for the clinical management of GC.

Interleukin 1ß-mediated HOXC10 Overexpression Promotes Hepatocellular Carcinoma Metastasis by Upregulating PDPK1 and VASP.

Rationale: Metastasis and recurrence are the primary reasons for the high mortality rate of human hepatocellular carcinoma (HCC) patients. However, the exact mechanism underlying HCC metastasis remains unclear. The Homeobox (HOX) family proteins, which are a highly conserved transcription factor superfamily, play important roles in cancer metastasis. Here, we report a novel role of HOXC10, one of the most upregulated HOX genes in human HCC tissues, in promoting HCC metastasis. Methods: The expression of HOXC10 and its functional targets was detected by immunohistochemistry in two independent human HCC cohorts. Luciferase reporter and chromatin immunoprecipitation assays were used to measure the transcriptional regulation of target genes by HOXC10. The effect of HOXC10-mediated invasion and metastasis were analyzed by Transwell assays and by an orthotopic metastasis model. Results: Elevated expression of HOXC10 was positively correlated with the loss of tumor encapsulation and with higher tumor-nodule-metastasis (TNM) stage and poor prognosis in human HCC. Overexpression of HOXC10 promoted HCC metastasis by upregulating metastasis-related genes, including 3-phosphoinositide-dependent protein kinase 1 (PDPK1) and vasodilator-stimulated phosphoprotein (VASP). Knockdown of PDPK1 and VASP inhibited HOXC10-enhanced HCC metastasis, whereas upregulation of PDPK1 and VASP rescued the decreased metastasis induced by HOXC10 knockdown. Interleukin-1ß (IL-1ß), which is the ligand of IL-1R1, upregulated HOXC10 expression through the c-Jun NH2-terminal kinase (JNK)/c-Jun pathway. HOXC10 knockdown significantly reduced IL-1ß-mediated HCC metastasis. Furthermore, Anakinra, a specific antagonist of IL-1R1, inhibited IL-1ß-induced HOXC10 upregulation and HCC metastasis. In human HCC tissues, HOXC10 expression was positively correlated with PDPK1, VASP and IL-1R1 expression, and patients with positive coexpression of HOXC10/PDPK1, HOXC10/VASP or IL-1R1/HOXC10 exhibited the poorest prognosis. Conclusions: Upregulated HOXC10 induced by IL-1ß promotes HCC metastasis by transactivating PDPK1 and VASP expression. Thus, our study implicates HOXC10 as a prognostic biomarker, and targeting this pathway may be a promising therapeutic option for the clinical prevention of HCC metastasis.

SOX13 promotes colorectal cancer metastasis by transactivating SNAI2 and c-MET.

Metastasis is a major cause of high recurrence and poor survival of patients with colorectal cancer (CRC), although the mechanisms associated with this process remain poorly understood. In this study, we report a novel mechanism by which SOX13 promotes CRC metastasis by transactivating SNAI2 and c-MET. SOX13 overexpression was significantly correlated with more aggressive clinicopathological features of CRC and indicated poor prognosis in two independent cohorts of CRC patients (cohort I, n = 363; cohort II, n = 390). Overexpression of SOX13-promoted CRC migration, invasion, and metastasis, whereas SOX13 downregulation caused the opposite effects. Further mechanistic investigation identified SNAI2 and MET as important target genes of SOX13 using serial deletion and site-directed mutagenesis luciferase reporter and chromatin immunoprecipitation (ChIP) assays, as well as functional complementation analyses. In addition, SOX13 was shown to be a direct target of HGF/STAT3 signaling, and the c-MET inhibitor crizotinib blocked the HGF/STAT3/SOX13/c-MET axis, significantly inhibiting SOX13-mediated CRC migration, invasion and metastasis. Moreover, in clinical CRC tissues, SOX13 expression was positively correlated with the expression of SNAI2, c-MET, and HGF. CRC patients with positive coexpression of SOX13/SNAI2, SOX13/c-MET, or HGF/SOX13 exhibited a worse prognosis. In summary, SOX13 is a promising prognostic biomarker in patients with CRC, and blocking the HGF/STAT3/SOX13/c-MET axis with crizotinib could be a new therapeutic strategy to prevent SOX13-mediated CRC metastasis.

Deep learning for detecting retinal detachment and discerning macular status using ultra-widefield fundus images.

Retinal detachment can lead to severe visual loss if not treated timely. The early diagnosis of retinal detachment can improve the rate of successful reattachment and the visual results, especially before macular involvement. Manual retinal detachment screening is time-consuming and labour-intensive, which is difficult for large-scale clinical applications. In this study, we developed a cascaded deep learning system based on the ultra-widefield fundus images for automated retinal detachment detection and macula-on/off retinal detachment discerning. The performance of this system is reliable and comparable to an experienced ophthalmologist. In addition, this system can automatically provide guidance to patients regarding appropriate preoperative posturing to reduce retinal detachment progression and the urgency of retinal detachment repair. The implementation of this system on a global scale may drastically reduce the extent of vision impairment resulting from retinal detachment by providing timely identification and referral.

Fibroblast Growth Factor 19-Mediated Up-regulation of SYR-Related High-Mobility Group Box 18 Promotes Hepatocellular Carcinoma Metastasis by Transactivating Fibroblast Growth Factor Receptor 4 and Fms-Related Tyrosine Kinase 4.

BACKGROUND AND AIMS: The poor prognosis of patients with hepatocellular carcinoma (HCC) is mainly attributed to its high rate of metastasis and recurrence. However, the molecular mechanisms underlying HCC metastasis need to be elucidated. The SRY-related high-mobility group box (SOX) family proteins, which are a group of highly conserved transcription factors, play important roles in cancer initiation and progression. Here, we report on a role of SOX18, a member of the SOX family, in promoting HCC invasion and metastasis. APPROACH AND RESULTS: The elevated expression of SOX18 was positively correlated with poor tumor differentiation, higher tumor-node-metastasis (TNM) stage, and poor prognosis. Overexpression of SOX18 promoted HCC metastasis by up-regulating metastasis-related genes, including fibroblast growth factor receptor 4 (FGFR4) and fms-related tyrosine kinase 4 (FLT4). Knockdown of both FGFR4 and FLT4 significantly decreased SOX18-mediated HCC invasion and metastasis, whereas the stable overexpression of FGFR4 and FLT4 reversed the decrease in cell invasion and metastasis that was induced by inhibition of SOX18. Fibroblast growth factor 19 (FGF19), which is the ligand of FGFR4, up-regulated SOX18 expression. A mechanistic investigation indicated that the up-regulation of SOX18 that was mediated by the FGF19-FGFR4 pathway relied on the phosphorylated (p)-fibroblast growth factor receptor substrate 2/p-glycogen synthase kinase 3 beta/ß-catenin pathway. SOX18 knockdown significantly reduced FGF19-enhanced HCC invasion and metastasis. Furthermore, BLU9931, a specific FGFR4 inhibitor, significantly reduced SOX18-mediated HCC invasion and metastasis. In human HCC tissues, SOX18 expression was positively correlated with FGF19, FGFR4, and FLT4 expression, and patients that coexpressed FGF19/SOX18, SOX18/FGFR4, or SOX18/FLT4 had the worst prognosis. CONCLUSIONS: We defined a FGF19-SOX18-FGFR4 positive feedback loop that played a pivotal role in HCC metastasis, and targeting this pathway may be a promising therapeutic option for the clinical management of HCC.