SCARB1-encoded circ _0029343 induces p73 splicing to promote growth and metastasis of hepatocellular carcinoma via miR-486-5p/SRSF3 axis.

Circular RNAs (circRNAs) exhibit essential regulation in the malignant development of hepatocellular carcinoma (HCC). This study aims to investigate the physiological mechanisms of circ_0029343 encoded by scavenger receptor class B member 1 (SCARB1) involved in the growth and metastasis of HCC. Differentially expressed mRNAs in HCC were obtained, followed by the prediction of target genes of differentially expressed miRNAs and gene ontology and kyoto encyclopedia of genes and genomes analysis on the differentially expressed mRNAs. Moreover, the regulatory relationship between circRNAs encoded by SCARB1 and differentially expressed miRNAs was predicted. In vitro cell experiments were performed to verify the effects of circ_0029343, miR-486-5p, and SRSF3 on the malignant features of HCC cells using the gain- or loss-of-function experiments. Finally, the effects of circ_0029343 on the growth and metastasis of HCC cells in xenograft mouse models were also explored. It was found that miR-486-5p might interact with seven circRNAs encoded by SCARB1, and its possible downstream target gene was SRSF3. Moreover, SRSF3 was associated with the splicing of various RNA. circ_0029343 could sponge miR-486-5p to up-regulate SRSF3 and activate PDGF-PDGFRB (platelet-derived growth factor and its receptor, receptor beta) signaling pathway by inducing p73 splicing, thus promoting the proliferation, migration, and invasion and inhibiting apoptosis of HCC cells. In vivo, animal experiments further confirmed that overexpression of circ_0029343 could promote the growth and metastasis of HCC cells in nude mice. circ_0029343 encoded by SCARB1 may induce p73 splicing and activate the PDGF-PDGFRB signaling pathway through the miR-486-5p/SRSF3 axis, thus promoting the growth and metastasis of HCC cells.

JMJD6-BRD4 complex stimulates lncRNA HOTAIR transcription by binding to the promoter region of HOTAIR and induces radioresistance in liver cancer stem cells.

BACKGROUND: Long non-coding RNA (lncRNA) HOTAIR acts importantly in liver cancer development, but its effect on radioresistance remains poorly understood. Here, our study probed into the possible impact of HOTAIR in radioresistance in liver cancer stem cells (LCSCs) and to elucidate its molecular basis. METHODS: Following sorting of stem and non-stem liver cancer cells, LCSCs were identified and subjected to RNA-seq analysis for selecting differentially expressed genes. Expression of HOTAIR was determined in liver cancer tissues and CSCs. The stemness, proliferation, apoptosis and radioresistance of LCSCs were then detected in response to altered expression of HOTAIR-LSD1-JMJD6-BRD4. RESULTS: Ectopic HOTAIR expression was found to promote radioresistance of LCSCs by maintaining its stemness. Mechanistic investigations indicated that HOTAIR recruited LSD1 to the MAPK1 promoter region and reduced the level of H3K9me2 in the promoter region, thus elevating ERK2 (MAPK1) expression. JMJD6-BRD4 complex promoted HOTAIR transcription by forming a complex and positively regulated ERK2 (MAPK1) expression, maintaining the stemness of LCSCs, and ultimately promoting their radioresistance in vitro and in vivo. CONCLUSION: Collectively, our work highlights the promoting effect of the JMJD6-BRD4 complex on the radioresistance of LCSCs through a HOTAIR-dependent mechanism.

Tumor suppressive lncRNA MEG3 binds to EZH2 and enhances CXCL3 methylation in gallbladder cancer.

Gallbladder cancer is a malignant tumor with a high mortality rate. Accumulating evidence supports that lncRNA MEG3 may halt the progression of gallbladder cancer, while the downstream mechanism is rarely studied. Thus, we aim to investigate the molecular basis of the tumor-suppressing role of lncRNA MEG3 in gallbladder cancer. The expression of lncRNA MEG3 and CXCL3 was measured in patient serum and cell lines of gallbladder cancer. The viability, apoptosis, migration, and invasion of gallbladder cancer cells were assessed following ectopic MEG3 expression, as detected by CCK-8, flow cytometry, and Transwell assays. The interaction among lncRNA MEG3, EZH2, and CXCL3 was explored through ChIP, RNA pull-down, and RIP assays. The effects of lncRNA MEG3 and CXCL3 on tumor growth were evaluated by a mouse xenograft model. lncRNA MEG3 was expressed at a low level in gallbladder cancer patient serum and cell lines, while CXCL3 was highly expressed. MEG3 overexpression repressed the malignant behaviors of gallbladder cancer cells and promoted their apoptosis. MEG3 was mainly localized in the nucleus. MEG3 bound to EZH2, and EZH2 catalyzed the H3K27 trimethylation of the CXCL3 promoter region. MEG3 downregulated CXCL3 by activating EZH2-mediated H3K27 trimethylation of CXCL3; MEG3 overexpression attenuated cancer cell malignant behaviors in vitro and suppressed tumor growth in vivo in gallbladder cancer by inhibiting CXCL3 expression. Altogether, our results indicate that lncRNA MEG3 impedes gallbladder cancer development via the EZH2-CXCL3 axis, offering potential biomarkers for gallbladder cancer management.

Mitochondrial DNA enables AIM2 inflammasome activation and hepatocyte pyroptosis in nonalcoholic fatty liver disease.

Mitochondria damage exacerbates NAFLD through trigerring AIM2 inflammasome activation and hepatocyte pyroptosis. This study provides novel insights into the underlying mechanisms of mitochondrial DNA synthesis in NAFLD and also suggests potential therapeutic targets for the treatment of NAFLD.

Research progress on neonatal Fc receptor and its application.

Neonatal Fc receptor (FcRn) is a specific receptor for immunoglobulin G (IgG) and albumin, which binds to them in a pH-dependent manner and prevents them from lysosomal degradation to keep a long plasma half-life. In addition, FcRn plays an important role in transmembrane transport of IgG and albumin and in antigen presentation. In autoimmune diseases, anti-FcRn antibody can promote the degradation of pathogenic IgG by competitive binding to FcRn. In infectious diseases, the half-life of drugs can be prolonged by increasing the affinity between therapeutic antibody and FcRn, while the combination of viral antigen and Fc fragment of IgG can cause local immune response of mucosa for disease prevention and treatment. In cancer, albumin as a carrier of anticancer drugs can achieve efficient drug delivery, and FcRn itself may be used as a predictor of the prognosis of cancer patients. This review details the functions of FcRn, highlights its role in autoimmune diseases, infectious diseases and cancer, as well as the mechanism of drug development based on FcRn, to provide a reference for the clinical application and drug development of FcRn.

Silencing of microRNA-135b inhibits invasion, migration, and stemness of CD24+CD44+ pancreatic cancer stem cells through JADE-1-dependent AKT/mTOR pathway.

BACKGROUND: Recent studies have emphasized determining the ability of microRNAs (miRNAs) as crucial regulators in the occurrence and development of pancreatic cancer (PC), which continues to be one of the deadliest malignancies with few effective therapies. The study aimed to investigate the functional role of miR-135b and its associated mechanism to unravel the biological characteristics of tumor growth in pancreatic cancer stem cells (PCSCs). METHODS: Microarray analyses were initially performed to identify the PC-related miRNAs and genes. The expression of miR-135b and PCSC markers in PC tissues and cells was determined by RT-qPCR and western blot analysis, respectively. The potential gene (JADE-1) that could bind to miR-135b was confirmed by the dual-luciferase reporter assay. To investigate the tumorigenicity, migration, invasion, and stemness of PC cells, several gain-of-function and loss-of-function genetic experiments were conducted. Finally, tumor formation in nude mice was conducted to confirm the results in vivo. RESULTS: miR-135b was highly-expressed in PC tissues and PCSCs, which was identified to specifically target JADE-1. The overexpression of miR-135b promoted proliferation, migration, and invasion of PCSC, inhibited cell apoptosis and increased the expression of stemness-related factors (Sox-2, Oct-4, Nanog, Aldh1, and Slug). Moreover, miR-135b could promote the expression of phosphorylated AKT and phosphorylated mTOR in the AKT/mTOR pathway. Additionally, miR-135b overexpression accelerated tumor growth in nude mice. CONCLUSIONS: Taken together, the silencing of miR-135b promotes the JADE-1 expression, which inactivates the AKT/mTOR pathway and ultimately results in inhibition of self-renewal and tumor growth of PCSCs. Hence, this study contributes to understanding the role of miR-135 in PCSCs and its underlying molecular mechanisms to aid in the development of effective PC therapeutics.

hsa_circ_001653 up-regulates NR6A1 expression and elicits gastric cancer progression by binding to microRNA-377.

NEW FINDINGS: What is the central question of this study? Does hsa_circ_001653 influence the development of gastric cancer (GC) and if so how? What is the main finding and its importance? Bioinformatics analysis revealed the presence of differentially expressed hsa_circ_001653 in GC and adjacent normal tissues, and this was strongly related to the pathology of patients with GC. Knockdown of hsa_circ_001653 suppressed the proliferation, invasion and migration of GC cells, while inducing cell apoptosis via miR-377-mediated NR6A1 inhibition. The effect of hsa_circ_001653 and miR-377 on tumour growth in GC was further confirmed in vivo. ABSTRACT: Gastric cancer (GC) is one of the leading causes of human mortality through malignant tumours. Circular RNAs (circRNAs) have been identified as binding to microRNAs (miRNAs) to modulate the progression of tumours. This study explores the role of hsa_circ_001653, a newly identified circRNA, in the development of GC. hsa_circ_001653 expression was measured in 86 paired normal and tumour tissues surgically resected from GC patients. Cross-talk between hsa_circ_001653 and microRNA-377 (miR-377)/nuclear receptor subfamily 6, group A, member 1 (NR6A1) was assessed using bioinformatics analysis, dual-luciferase reporter assay, Ago2 immunoprecipitation and western blot analysis. A series of functional experiments were carried out to elucidate the role of hsa_circ_001653 in GC cell proliferation, invasion, migration and apoptosis, and its underlying molecular mechanisms. Nude mice were inoculated with GC cells for in vivo analysis. hsa_circ_001653 was found to be an up-regulated circRNA in GC tissues and cells. Down-regulation of hsa_circ_001653 inhibited GC cell proliferation, migration and invasion, while stimulating cell apoptosis. hsa_circ_001653 was found to bind to miR-377, which targeted NR6A1 and repressed its expression. Inhibition of miR-377 and overexpression of NR6A1 restored the proliferation, migration and invasion in GC cells lacking hsa_circ_001653. Furthermore, inhibition of hsa_circ_001653 attenuated tumour growth in nude mice inoculated with GC cells. Collectively, the demonstration that hsa_circ_001653 exerts its anticancer effects by regulating the miR-377-NR6A1 axis increases our understanding of gastric cancer pathophysiology. The findings uncover new potential therapeutic targets for GC.

MiR-98 modulates macrophage polarization and suppresses the effects of tumor-associated macrophages on promoting invasion and epithelial-mesenchymal transition of hepatocellular carcinoma.

BACKGROUND: Tumor-associated macrophages (TAMs) are generally recognized as a promoter of tumor progression. miR-98 has been shown to suppress the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) cells. Here, we aim to investigate the role of miR-98-mediated macrophage polarization in HCC progression. METHODS: Human blood monocytes were isolated from healthy male donors and incubated with culture medium collected from HepG2 cells for 7 days. The phenotype of the macrophages was detected. The protein expression was detected by Western blot. Levels of cytokines secreted in culture medium were measured using the specific enzyme-linked immunosorbent assay kits. To explore the role of miR-98 in HCC-conditioned TAMs, HCC cells HepG2 and SMMC7721 were cultured with conditioned medium from HCC-conditioned TAMs that had been transfected with miR-98 mimic/inhibitor. Cell proliferation, migration and invasion assays were performed. RESULTS: HCC-conditioned TAMs possessed M2-like phenotype, including increased protein expression of CD163 and TNF-αlow, IL-1ßlow, TGF-ßhigh and IL-10high phenotype. HCC-conditioned TAMs also promoted proliferation, migration, invasion and EMT of HepG2 and SMMC7721 cells. Furthermore, miR-98 modulated macrophage polarization from M2 to M1 in HCC-conditioned TAMs, as evidenced by the alteration of M1- or M2-related cytokines. Moreover, miR-98 mimic significantly suppressed the HCC-conditioned TAMs-mediated promotion of cell migration, invasion and EMT in HepG2 and SMMC7721 cells compared with negative control, whereas miR-98 inhibitor exerted reversed effects. CONCLUSIONS: miR-98 may play a vital role in regulating macrophage polarization, thereby suppressing the TAMs-mediated promotion of invasion and EMT in HCC.

LOXL4 Shuttled by Tumor Cells-derived Extracellular Vesicles Promotes Immune Escape in Hepatocellular Carcinoma by Activating the STAT1/PD-L1 Axis.

Emerging evidence has validated that extracellular vesicles (EVs) regulate hepatocellular carcinoma (HCC) progression, while its role in HCC immune escape remains to be elucidated. This study investigates the role of EVs-encapsulated lysyl oxidase like-4 (LOXL4) derived from tumor cells in HCC immune escape. HCC-related microarray data sets GSE36376 and GSE87630 were obtained for differential analysis, followed by identifying the essential genes related to the prognosis of HCC patients. Bone marrow-derived macrophages were treated with EVs derived from mouse Hepa 1-6 cells and cocultured with CD8 + T cells to observe the CD8 + T-cell activity. At last, a mouse HCC orthotopic xenograft model was constructed to verify the effects of HCC cell-derived EVs on the immune escape of HCC cells and tumorigenicity in vivo by delivering LOXL4. It was found that ACAT1, C4BPA, EHHADH, and LOXL4 may be the essential genes related to the prognosis of HCC patients. On the basis of the TIMER database, there was a close correlation between LOXL4 and macrophage infiltration in HCC. Besides, STAT1 was closely related to LOXL4. In vitro experiments demonstrated that LOXL4 could induce programmed death-ligand 1 expression in macrophages and immunosuppression by activating STAT1. In vivo experiments also verified that HCC cell-derived EVs promoted the immune escape of HCC cells and tumorigenicity by delivering LOXL4. LOXL4 was delivered into macrophages via EVs to induce programmed death-ligand 1 by activating STAT1 and inhibiting the killing ability of CD8 + T cells to HCC cells, thus promoting immune escape in HCC.

Significance of the POSSUM scoring system in predicting morbidity and mortality in elderly patients after pancreatoduodenectomy.

BACKGROUND/AIMS: To explore the significance of POSSUM scoring system (Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity) in predicting morbidity and mortality in elderly Chinese patients undergoing pancreatoduodenectomy (PD). METHODOLOGY: Between January 2001 and January 2011, 396 patients underwent PD in our hospital; POSSUM and P-POSSUM score were retrospectively calculated for each patient and correlated with observed morbidity and mortality, respectively. RESULTS: The mortality and morbidity rates were 4.11% and 42.8%, respectively. The POSSUM showed "good fit" in morbidity prediction (p=0.103), it also showed "good fit" in mortality prediction but only in elderly patients (p=0.078). While in young patients, POSSUM showed "poor fit" in both morbidity (p=0.002) and mortality (p=0.012) prediction. CONCLUSIONS: The POSSUM showed significance in predicting morbidity and mortality in elderly Chinese patients, and is helpful in guiding surgical management decisions. A modified equation for POSSUM scoring system based on large-scale clinical PD data should be developed to achieve a better fit in low-risk patients.

Tumor-suppressor p53 specifically binds to miR-29c-3p and reduces ADAM12 expression in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is an extremely aggressive malignant tumor associated with high migratory and invasive potential. The present study intends to explore regulatory mechanism of p53/microRNA (miR)-29c-3p/A disintegrin and metalloproteinase 12 (ADAM12) axis in HCC based on clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology. METHODS: Putative miR-29c-3p binding sites on ADAM12 3'UTR were verified by a luciferase assay. The binding affinity of p53 to miR-29c-3p was assessed based on CRISPR/Cas9 technology to construct a p53 knockout (p53-/-) HCCLM3 cell line. Furthermore, the effect of p53/miR-29c-3p/ADAM12 was assessed on maligant phenotypes in vitro and tumor formation and metastasis in nude mice. RESULTS: ADAM12 was highly expressed but miR-29c-3p was poorly expressed in HCC. miR-29c-3p inhibited migratory and invasive abilities of HCC cells by targeting ADAM12 expression. p53 was found to target and upregulate miR-29c-3p, thus downregulating ADAM12 and conferring inhibitory effect on HCC cell activities. Moreover, ADAM12 knockout or p53 overexpression reduced HCC tumor formation and metastasis, which were reversed by further silencing of miR-29c-3p. CONCLUSION: The identification of the p53/miR-29c-3p/ADAM12 axis in migration and invasion of HCC may potentially further our understanding of mechanisms underpinning HCC, and also bear translational value as novel molecular targets.

Retinogenesis in a Dish: Bibliometric Analysis and Visualization of Retinal Organoids From 2011 to 2022.

Retinal organoid (RO) is the three-dimensional (3D) retinal culture derived from pluripotent or embryonic stem cells which recapitulates organ functions, which was a revolutionary milestone in stem cell technology. The purpose of this study is to explore the hotspots and future directions on ROs, as well as to better understand the fields of greatest research opportunities. Eligible publications related to RO from 2011 to 2022 were acquired from the Web of Science (WoS) Core Collection database. Bibliometric analysis was performed by using software including VOSviewer, CiteSpace, and ArcGIS. A total of 520 articles were included, and the number of annual publications showed a rapid increase with an average rate of 40.86%. The United States published the most articles (241/520, 46.35%) with highest total citation frequencies (5,344). University College London (UK) contributed the largest publication output (40/520, 7.69%) and received highest total citation frequencies. Investigative Ophthalmology & Visual Science was the most productive journal with 129 articles. Majlinda Lako contributed the most research with 32 articles, while Olivier Goureau has the strongest collaboration work. Research could be subdivided into four keyword clusters: "culture and differentiation," "morphogenesis and modeling," "gene therapy," and "transplantation and visual restoration," and evolution of keywords was identified. Last decade has witnessed the huge progress in the field of RO, which is a young and promising research area with extensive and in-depth studies. More attention should be paid to RO-related models and therapies based on specific retinal diseases, especially inherited retinopathies.

Extracellular Vesicle-Loaded Oncogenic lncRNA NEAT1 from Adipose-Derived Mesenchymal Stem Cells Confers Gemcitabine Resistance in Pancreatic Cancer via miR-491-5p/Snail/SOCS3 Axis.

It is becoming increasingly evident that key mechanisms of mesenchymal stem cell (MSC) efficacy appear to associate with paracrine activities, and the delivery of cargos through extracellular vesicles (EVs) controls the mechanistic actions of MSCs. Thus, this study clarified a possible mechanism by which EV-encapsulated NEAT1 from adipose-derived mesenchymal stem cells (ADSCs) might mediate gemcitabine resistance in pancreatic cancer (PCa). Microarray profile suggested a differentially expressed lncRNA NEAT1 in PCa, and we determined its expression in PCa cells. NEAT1 was found to be upregulated in PCa. The binding affinity among NEAT1, miR-491-5p, and Snail was identified through bioinformatic analysis and experimental validation. NEAT1 competitively bound to miR-491-5p to elevate Snail expression and diminish SOCS3 expression. PCa cells were cocultured with EVs extracted from ADSCs, followed by assessment of malignant phenotypes, tumorigenesis, and gemcitabine resistance of PCa cells using gain- or loss-of-function experiments. ADSC-derived EVs carrying NEAT1 promoted PCa cell proliferation, migration, and gemcitabine resistance in vitro and enhanced tumorigenicity in vivo by inhibiting miR-491-5p and SOCS3 and upregulating Snail. Collectively, the findings from our study found a new potential strategy for gemcitabine resistance in PCa by illustrating the mechanistic insights of oncogenic ADSC-derived EVs-loaded NEAT1 via regulating the miR-491-5p/Snail/SOCS3 axis.

Enhancer of zeste homolog 2 promotes hepatocellular cancer progression and chemoresistance by enhancing protein kinase B activation through microRNA-381-mediated SET domain bifurcated 1.

Metastasis and chemoresistance are the leading causes of death in patients with hepatocellular carcinoma (HCC). microRNAs (miRNAs or miRs) may be useful as diagnostic, therapeutic and prognostic markers for HCC. In this study, we set out to investigate the possible role of miR-381 in HCC development and chemoresistance along with the related mechanism. Microarray-based gene expression profiling was carried out to analyze the expression of SET domain bifurcated 1 (SETDB1) and histone methyltransferase enhancer of zeste homolog 2 (EZH2) followed by validation in clinical HCC tissues and cells. The potential binding between miR-381 and SETDB1 was found and verified. Then, the role of SETDB1 in HCC in relation to miR-381 and protein kinase B (AKT) pathway was explored through gain- and loss-of-function approaches. After expression determination of EZH2, SETDB1, miR-381, and AKT pathway-related factors, their reactions were analyzed and their functional roles in HCC progression and chemoresistance were investigated in vitro and in vivo. SETDB1 was aberrantly upregulated in clinical HCC tissues and cells. This upregulation activated AKT pathway by promoting its tri-methylation on K64. SETDB1 promoted the proliferation, migration and chemoresistance through the AKT pathway in HCC cells. In a xenograft mouse model, SETDB1 promoted HCC cell tumorigenesis in vivo by activating the AKT pathway. Furthermore, EZH2 suppressed miR-381 by catalyzing the activity of H3K27me3 on its promoter region. In conclusion, EZH2 suppressed miR-381 expression by promoting H3K27me3 activity on its promoter region to facilitate SETDB1 expression, thereby activating the AKT pathway to promote hepatocarcinogenesis and chemoresistance.

Suppression of histone deacetylase 1 by JSL-1 attenuates the progression and metastasis of cholangiocarcinoma via the TPX2/Snail axis.

Histone deacetylases (HDACs) are entwined with the pathogenesis of various cancers and potentially serve as promising therapeutic targets. Herein, we intend to explore the potential role of HDAC1 inhibitor (JSL-1) in the tumorigenesis and metastasis of cholangiocarcinoma (CC) and to highlight the molecular basis of its function. As shown by bioinformatics analysis and immunohistochemical detection, high HDAC1 expression was witnessed in CC tissues relative to matched controls from patients with cholecystitis. The molecular network that HDAC1 silencing reduced the enrichment of HDAC1 and Snail on the TPX2 promoter was identified using immunoprecipitation and chromatin immunoprecipitation assays. Both short hairpin RNA (shRNA)-mediated knockdown of HDAC1 and JSL-1 treatment exhibited anti-proliferative, anti-migration and anti-invasion effects on CC cells through downregulation of TPX2. The in vivo xenograft model was developed in nude mice. Consistently, the anti-tumorigenic and anti-metastatic properties of shRNA against HDAC1 and HDAC1 inhibitor were validated in the in vivo settings. Taken together, our data supported the notion that HDAC1 inhibitor retards the initiation and development of CC via mediating the TPX2/Snail axis, highlighting the anti-tumor molecular network functioned in CC.

Tumor-derived extracellular vesicles containing long noncoding RNA PART1 exert oncogenic effect in hepatocellular carcinoma by polarizing macrophages into M2.

AIM: We explored whether tumor-derived extracellular vesicles (EVs) could deliver long noncoding RNA (lncRNA) PART1 into macrophage to orchestrate macrophage polarization in the progression of hepatocellular carcinoma (HCC). METHOD: The expression patterns of PART1, microRNA (miR)-372-3p and TLR4 were detected by RT-qPCR in the HCC tissues and HCC cells. PART1 was silenced or overexpressed in HCC cells to assess its effects on the HCC cell process. EVs were isolated from PART1-overexpressed HCC cells, and co-cultured with macrophages, and gain- and loss-of-function assays were implemented in macrophages to evaluate their role in macrophage polarization. Relationship among PART1, miR-372-3p, and TLR4 was evaluated. Effect of EV-PART1 on tumorigenicity in vivo was detected by subcutaneous tumorigenicity test in nude mice. RESULT: PART1 and TLR4 were upregulated while miR-372-3p was downregulated in HCC tissues and cells. PART1 increased HCC cell proliferation, migration, invasion, and EMT. Mechanistically, PART1 bound to miR-372-3p to downregulate its expression, whereas TLR4 was negatively targeted by miR-372-3p in the macrophages. EVs containing PART1, TLR4 overexpression, or miR-372-3p inhibition induced M2 polarization of macrophages. Also, EVs containing PART1 promoted M2 polarization of macrophages and the occurrence of HCC by affecting miR-372-3p/TLR4 axis. CONCLUSION: HCC cell-derived EVs might up-regulate TLR4 by inhibiting miR-372-3p via PART1 delivery to promote macrophage M2 polarization in HCC.

Overview of global publications on machine learning in diabetic retinopathy from 2011 to 2021: Bibliometric analysis.

Purpose: To comprehensively analyze and discuss the publications on machine learning (ML) in diabetic retinopathy (DR) following a bibliometric approach. Methods: The global publications on ML in DR from 2011 to 2021 were retrieved from the Web of Science Core Collection (WoSCC) database. We analyzed the publication and citation trend over time and identified highly-cited articles, prolific countries, institutions, journals and the most relevant research domains. VOSviewer and Wordcloud are used to visualize the mainstream research topics and evolution of subtopics in the form of co-occurrence maps of keywords. Results: By analyzing a total of 1147 relevant publications, this study found a rapid increase in the number of annual publications, with an average growth rate of 42.68%. India and China were the most productive countries. IEEE Access was the most productive journal in this field. In addition, some notable common points were found in the highly-cited articles. The keywords analysis showed that "diabetic retinopathy", "classification", and "fundus images" were the most frequent keywords for the entire period, as automatic diagnosis of DR was always the mainstream topic in the relevant field. The evolution of keywords highlighted some breakthroughs, including "deep learning" and "optical coherence tomography", indicating the advance in technologies and changes in the research attention. Conclusions: As new research topics have emerged and evolved, studies are becoming increasingly diverse and extensive. Multiple modalities of medical data, new ML techniques and constantly optimized algorithms are the future trends in this multidisciplinary field.

The CXCR4-CXCL12 pathway facilitates the progression of pancreatic cancer via induction of angiogenesis and lymphangiogenesis.

BACKGROUND: This study reports the influence of CXCL12 and its receptor CXCR4 on the progression of pancreatic cancer and illuminates the correlation between the CXCL12/CXCR4 axis and the angiogenesis and lymphangiogenesis of pancreatic adenocarcinoma (PAC). METHODS: A total of 30 patients with pancreatic cancer participated in the current study. The expression of CXCL12 and CXCR4 in cancerous tissues, paracancerous tissues, normal pancreas, and lymph nodes surrounding the pancreas were investigated using real-time PCR and immunohistochemistry, respectively. In addition, we assessed microvessel density (MVD) and microlymphatic vessel density (MLVD) in tumor tissues using immunohistochemistry. RESULTS: CXCL12 expression in tumor tissues was significantly lower than that of paracancerous tissues, normal pancreas, and lymph nodes. In contrast, CXCR4 expression in cancerous tissues was considerably higher than that of normal pancreas. Additionally, a significant correlation between the expression pattern of the CXCL12/CXCR4 axis and clinicopathologic features, such as lymph node metastasis, was identified. Furthermore, we found that CXCL12 expression was significantly associated with MVD but not significantly associated with MLVD, while CXCR4 expression was significantly associated with MLVD but not significantly associated with MVD. CONCLUSIONS: The chemotactic interaction between CXCR4 and its ligand CXCL12 may be a critical event during the progression of pancreatic cancer. The underlying mechanism may be the induction of angiogenesis and lymphangiogenesis regulated by the interaction of CXCL12 and CXCR4.

[The study of the relationship between microlymphatic vessel density and lymph metastasis in hepatocellular carcinoma].

Not Abstract.

Human gene therapy: A scientometric analysis.

To provide a clear landscape, trends, and research frontiers of gene therapy, we systematically retrieved a total of 62,961 peer-viewed studies published between 1996 and 2020 from the Scopus, Web of Science, and 42,120 Inpadoc patent families from Derwent Innovation databases. Multiple bibliometric approaches suggest that gene therapy began to recover in 2013 after a period of significant decline. However, metrics in terms of authors and scholarly output growth, FWCI, annual citations, percentage of high-impact journal literature, and patent-citations per scholarly output are still weak at this stage, indicating a lack of research momentum. We also visualized gene therapy's knowledge structure by employing citation analysis, co-citation analysis, and co-word analysis, revealing its research hotspots and trends by text mining with Natural Language Processing. For the current predicament, we propose that the future success of gene therapy may depend on breakthroughs in more advanced and exhilarating technologies such as the CRISPR-Cas system, CAR-T cell therapies, and gene delivery vector technology. The results show that evidence-based bibliometrics allows the dissection of gene therapy to inform scientific planning and decision-making.