The multifaceted roles of small extracellular vesicles in metabolic reprogramming in the tumor microenvironments.

The link between metabolism and tumor progression has been extensively researched for a long time. With the increasing number of studies uncovering the multiple functions of metabolic reprogramming in tumor microenvironments, the regulatory network seems to become even more intricate at the same time. Small extracellular vesicles (sEV), as crucial mediators facilitating intercellular communications, exhibit significant involvement in regulating metabolic reprogramming within the complicated network of tumor microenvironments. sEV derived from tumor cells and those released by other cell populations such as tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) can mutually influence each other, giving rise to diverse complex feedback loops. This review includes multiple studies conducted in recent years to summarize the functions of sEV in altering metabolism in various cell types within tumor microenvironments. Additionally, it aims to highlight potential therapeutic targets based on the commonly observed mechanisms identified in different studies.

A Multi-Centric Comparative Study Between Endoscopy-Assisted Laparoscopic Surgery (EALS) vs Laparoscopic Surgery for the Treatment of Gastric Duplication Cysts in Children.

Purpose: To compare and analyze the therapeutic effects of endoscopy-assisted laparoscopic surgery (EALS) and laparoscopic surgery (LS) in the treatment of gastric duplication cysts (GDCs). Patients and Methods: We reviewed the clinical data of children with GDCs who underwent surgical treatment at Hubei Maternal and Child Health Hospital, Yijishan Hospital of Wannan Medical College, and Qingdao Women and Children's Medical Center from September 2014 to November 2022. Results: The study comprised 29 children with GDCs, including 14 in the EALS group and 15 in the LS group. There was no significant difference between the two groups in terms of age, sex, weight, and cyst size characteristics. There was a significant difference between the two groups in terms of average surgical time (P>0.05), which was 1.100 ± 0.833 hours in the EALS group and 1.933 ± 0.159 hours in the LS group. There was a significant difference between the two groups (P<0.05) in average intraoperative blood loss, which was 7.93 ± 3.81 milliliters in the EALS group and 11.80 ± 2.72 milliliters in the LS group. There was a significant difference between the two groups (P<0.05) in average postoperative fasting time, which was 73.79 ± 8.36 hours in the EALS group and 114.1 ± 9.24 hours in the LS group. There was a significant difference between the two groups (P<0.05) in average postoperative hospital stay, which was 10.21 ± 4.25 days in the EALS group and 14.47 ± 4.36 days in the LS group. Conclusion: EALS technology can not only shorten surgical time, accurately locate GDCs, reduce injuries, and decrease the probability of complications but also achieve treatment goals safely and reliably.

Dendritic Cell Vaccines: A Shift from Conventional Approach to New Generations.

In the emerging era of cancer immunotherapy, immune checkpoint blockades (ICBs) and adoptive cell transfer therapies (ACTs) have gained significant attention. However, their therapeutic efficacies are limited due to the presence of cold type tumors, immunosuppressive tumor microenvironment, and immune-related side effects. On the other hand, dendritic cell (DC)-based vaccines have been suggested as a new cancer immunotherapy regimen that can address the limitations encountered by ICBs and ACTs. Despite the success of the first generation of DC-based vaccines, represented by the first FDA-approved DC-based therapeutic cancer vaccine Provenge, several challenges remain unsolved. Therefore, new DC vaccine strategies have been actively investigated. This review addresses the limitations of the currently most adopted classical DC vaccine and evaluates new generations of DC vaccines in detail, including biomaterial-based, immunogenic cell death-inducing, mRNA-pulsed, DC small extracellular vesicle (sEV)-based, and tumor sEV-based DC vaccines. These innovative DC vaccines are envisioned to provide a significant breakthrough in cancer immunotherapy landscape and are expected to be supported by further preclinical and clinical studies.

Clathrin light chain A-enriched small extracellular vesicles remodel microvascular niche to induce hepatocellular carcinoma metastasis.

Small extracellular vesicles (sEVs) play a key role in exchanging cargoes between cells in tumour microenvironment. This study aimed to elucidate the functions and mechanisms of hepatocellular carcinoma (HCC) derived sEV-clathrin light chain A (CLTA) in remodelling microvascular niche. CLTA level in the circulating sEVs of HCC patients was analysed by enzyme-linked immunosorbent assay (ELISA). The functions of sEV-CLTA in affecting HCC cancerous properties were examined by multiple functional assays. Mass spectrometry was used to identify downstream effectors of sEV-CLTA in human umbilical vein endothelial cells (HUVECs). Tube formation, sprouting, trans-endothelial invasion and vascular leakiness assays were performed to determine the functions of sEV-CLTA and its effector, basigin (BSG) in HUVECs. BSG inhibitor, SP-8356, was tested in a mouse model of patient-derived xenografts (PDXs). Circulating sEVs of HCC patients had markedly enhanced CLTA levels than control individuals and were reduced in patients after surgery. HCC derived sEV-CLTA enhanced HCC cancerous properties, disrupted endothelial integrity and induced angiogenesis. Mechanistically, CLTA remodels microvascular niche by stabilizing and upregulating BSG. Last, SP-8356 alone or in combination with sorafenib attenuated PDXs growth. The study reveals the role of HCC derived sEV-CLTA in microvascular niche formation. Inhibition of CLTA and its mediated pathway may illuminate a new therapeutic strategy for HCC patients.

Single-incision laparoscopic appendectomy versus traditional three-hole laparoscopic appendectomy for acute appendicitis in children by senior pediatric surgeons: a multicenter study from China.

Objective: The aim of this study was to evaluate the clinical efficacy of single-incision laparoscopy appendectomy (SILA) and traditional three-hole laparoscopy appendectomy (THLA) for the treatment of acute appendicitis in children. Methods: The clinical data of children (<14 years old) who underwent laparoscopic appendectomy at Yijishan Hospital of Wannan Medical College, Hubei Provincial Maternal Health Hospital and Qingdao Women and Children's Medical Center from January 2019 to June 2022 were retrospectively analyzed. According to the operation method, the patients were assigned to the SILA group or the THLA group. The clinical data, including the efficacy, and the surgical details, including the complications, of the two surgical methods were compared. The personal information of the children and the time of disease onset were recorded. Results: In this study, the data of 588 patients, including 385 patients in the THLA group and 203 patients in the SILA group were collected. The baseline characteristics between the two groups of patients before surgery were comparable. There was no significant difference in the average operation time between the THLA group and the SILA group (56.31 ± 1.83 min vs. 57.48 ± 1.15 min, P > 0.05). There was also no significant difference in the average length of hospital stay between the THLA group and the SILA group (6.91 ± 0.24 days vs. 7.16 ± 0.36 days, P > 0.05). However, the FLACC scores of the SILA group (3.71 ± 0.78) were significantly lower than those of the THLA group (3.99 ± 0.56) on the second postoperative day, and the difference was significant (P < 0.05). The score of the questionnaire evaluating cosmetic appearance of the postoperative abdomen was significantly higher in the SILA group (15.81 ± 0.36) than in the THLA group (13.10 ± 0.24) (P < 0.05). There was no significant difference in the incidence of postoperative complications between the two groups (P > 0.05). Conclusion: SILA is more advantageous in terms of postoperative FLACC scores and cosmetic appearance in children than THLA. There was no significant difference in the incidence of complications or other aspects between the two surgical methods.

Small Extracellular Vesicle-Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a hypervascular malignancy by which its growth and dissemination are largely driven by the modulation of tumor-derived small extracellular vesicles (sEVs). Proteomic profiling of circulating sEVs of control individuals and HCC patients identifies von Willibrand factor (vWF) to be upregulated progressively along HCC stages. Elevated sEV-vWF levels are found in a larger cohort of HCC-sEV samples and metastatic HCC cell lines compared to their respective normal counterparts. Circulating sEVs of late-stage HCC patients markedly augment angiogenesis, tumor-endothelial adhesion, pulmonary vascular leakiness, and metastasis, which are significantly compromised by anti-vWF antibody. The role of vWF is further corroborated by the enhanced promoting effect of sEVs collected from vWF-overexpressing cells. sEV-vWF modulates endothelial cells through an elevated level of vascular endothelial growth factor A (VEGF-A) and fibroblast growth factor 2 (FGF2). Mechanistically, secreted FGF2 elicits a positive feedback response in HCC via the FGFR4/ERK1 signaling pathway. The co-administration of anti-vWF antibody or FGFR inhibitor significantly improves the treatment outcome of sorafenib in a patient-derived xenograft mouse model. This study reveals mutual stimulation between HCC and endothelial cells by tumor-derived sEVs and endothelial angiogenic factors, facilitating angiogenesis and metastasis. It also provides insights into a new therapeutic strategy involving blocking tumor-endothelial intercellular communication.

Dihydroartemisinin engages liver fatty acid binding protein and suppresses metastatic hepatocellular carcinoma growth.

Dihydroartemisinin non-covalently binds liver fatty acid binding protein (FABP1) with micromolar affinity, acts as a FABP1-dependent peroxisome proliferator-activated receptor alpha agonist and inhibits metastatic hepatocellular carcinoma growth.

An update on the role of complement in hepatocellular carcinoma.

As a main producer of complement, the environment in the liver is greatly affected by the complement system. Although the complement system is considered to have the ability of nonself discrimination, remarkable studies have revealed the tight association between improper complement activation in tumour initiation and progression. As complement activation predominantly occurs within the liver, the protumourigenic role of the complement system may contribute to the development of hepatocellular carcinoma (HCC). Improvement in the understanding of the molecular targets involved in complement-mediated tumour development, metastasis, and tumour-promoting inflammation in HCC would certainly aid in the development of better treatments. This minireview is focused on recent findings of the protumourigenic role of the complement system in HCC.

Long-term survival outcomes of pediatric adrenal malignancies: An analysis with the upstaged SEER registry during 2000-2019.

Objective: To investigate the clinicopathological characteristics and long-term survival outcomes of pediatric adrenal malignancies. Method: This study retrospectively analyzed children with pathologically confirmed pediatric adrenal malignancies from Surveillance, Epidemiology, and End Results Database from 2000 to 2019. Kaplan-Meier curve was used to assess the overall survival (OS) and cancer-special survival (CSS), and the Log-Rank method was used to calculate statistical differences. Cox proportional hazards model and Fine-and-Grey model were used to calculate the hazard ratio (HR) of all-cause mortality risk and the sub-distribution HR (sHR) of disease-specific mortality risk, respectively, and their corresponding 95% confidence intervals (CI). Results: 1601 children were included in the study in which 1335 (83.4%) neuroblastoma, 151 (9.4%) ganglioneuroblastoma, 89 (5.6%) adrenocortical carcinoma, and 26 (1.6%) were diagnosed with other types malignancies. Metastatic disease accounted for the largest proportion (69.3%), and the proportion of metastases diagnosed by neuroblastoma was higher than that of adrenocortical carcinoma and ganglioneuroblastoma (73.9% vs. 45.7% vs. 47.2%). The 5-year OS and CSS of all cohort were 69.5% and 70.5%, respectively. Adrenal cortical carcinoma had the worst prognosis, with 5-year OS and CSS of 52.5% and 53.1%, respectively. Patients in recent years had no better OS and CSS than in previous years at diagnosis. The tumor stage remained the main prognostic predictor. Compared to metastatic adrenal tumors, the risk of all-cause mortality (adjusted HR: 0.12, 95% CI: 0.06-0.25, P < 0.001) and the risk of disease-specific mortality (adjusted sHR: 0.11, 95% CI: 0.05-0.25, P<0.001) was significantly lower for patients with localized diseases. Additionally, higher age, adrenal cortical carcinoma, and lack of complete tumor resection are independent risk factors for poor prognosis. Furthermore, it was found that the prognosis of patients who received chemotherapy was worse than those who did not, mainly because the former mostly had metastasis at the presentation and complete resection of the tumor cannot be achieved. Conclusion: The clinicopathological characteristics of pediatric adrenal malignancies have not changed significantly in the past two decades, while the prognosis of patients has improved. Early diagnosis of disease and complete resection of local tumors are the keys to improving prognosis.

Manifestation of Urinary Tract Injury during Cervical Cancer Surgery Based on CT Urography Secretion Phase Images.

Methods: We grouped the patients who had undergone cervical cancer surgery in a hospital in this article and compared the nanodrug carrier system under CT imaging with traditional laparoscopy. The postoperative physical parameters of surgical patients are collected from cervical cancer patients of different degrees, and the parameters and prognostic health of patients after different operations are compared. Results: The results of the study show that the postoperative patient's body parameters of the nanodrug delivery system under the CT imaging technology used in this article are better than those of the traditional surgery group, and the average intraoperative blood loss is about 20% less than that of the traditional surgery. Postoperative complications occur. The situation is even lower, more than 30% lower than traditional surgery. Conclusion: This shows that the operation of the nanodrug delivery system based on CT imaging technology has broken through some of the limitations of the development of laparoscopic technology and has played an important role in the surgical treatment of cervical cancer.

[Research hotspots and trends of Hedysari Radix: based on CiteSpace knowledge map].

This study aims to summarize the research hotspots of Hedysari Radix and predict the research trend with bibliometric methods, which is expected to serve as a reference for future research. CiteSpace V 5.8.R2 was employed for visualization of the number, authors, author affiliations, journals, funds, and keywords of the Chinese and English articles on Hedysari Radix in China National Knowledge Infrastructure(CNKI) and Web of Science(WOS) from 2001 to 2021. A total of 693 Chinese articles and 167 English articles were finally included. According to the knowledge map, most of the articles were from China and the authors from China had a close cooperation with the related institutions in the United States and Australia. Gansu University of Chinese Medicine(288) and Lanzhou University(151) respectively came out on top of the author affiliations in the number of Chinese and English articles. The journals were mainly about Chinese medicine, mainly including Chinese Journal of Information on Traditional Chinese Medicine and Evidence-based Complementary and Alternative Medicine. Papers(191 in Chinese and 60 in English) funded by National Natural Science Foundation of China were the most. Keyword analysis suggested that the main research directions were pharmacological action and mechanism, component analysis, content determination, and industrialization of medicinal materials of Hedysari Radix and that the research hotspots were the prevention and treatment of diabetes and its complications, tumors, myocardial injury, liver fibrosis and other diseases with active components such as polysaccharides, ultrafiltrate, formononetin, and calycosin. The targets, signaling pathways, and genes related to the anti-tumor, heart protection, prevention and treatment of diabetes and its complications, and regulation of immunity should be further studied.

Actin-related protein 2/3 complex subunit 2-enriched extracellular vesicles drive liver cancer metastasis.

BACKGROUND: Extracellular vesicles (EVs) play pivotal roles in tumor growth, cancer metastasis and angiogenesis. Here, we aimed to identify proteins that contribute to the functionality of EVs derived from metastatic hepatocellular carcinoma (HCC) cells. METHODS: Proteins of EVs derived from metastatic HCC cells and normal liver cells were analyzed by mass spectrometry. Proteomic profiling identified actin-related protein 2/3 complex subunit 2 (ARPC2) to be highly expressed in EVs of metastatic HCC cells. The expression of ARPC2 in EVs and HCC tissues was examined using immunoblotting and TCGA database, respectively. The functional roles of EV-ARPC2 were investigated by knockout approach and various in vitro and in vivo assays. RESULTS: ARPC2 was highly expressed in EVs of metastatic cells but barely detected in non-metastatic HCC cells and normal liver cells. Immunogold labeling showed the presence of APRC2 on the surface of EVs. Analysis of TCGA database of liver cancer revealed ARPC2 overexpression was correlated with poor prognosis of patients. ARPC2 was knockout in metastatic HCC cells. EVs derived from knockout cells displayed compromised activity in enhancing cell growth, motility and metastasis compared to EVs of control cells. Pimozide, an inhibitor of APRC2, also inhibited the promoting effect of EVs of metastatic cells in lung colonization of tumor cells in mice. CONCLUSION: This study reveals previously unreported expression and function of ARPC2 in EVs. EVs with highly expressed ARPC2 enhance cancer cell growth and metastasis. ARPC2 may provide a prospective target for the novel treatment of HCC patients.

Patient pIgR-enriched extracellular vesicles drive cancer stemness, tumorigenesis and metastasis in hepatocellular carcinoma.

BACKGROUND & AIMS: Extracellular vesicles (EVs) play a pivotal role in connecting tumor cells with their local and distant microenvironments. Herein, we aimed to understand the role (on a molecular basis) patient-derived EVs play in modulating cancer stemness and tumorigenesis in the context of hepatocellular carcinoma (HCC). METHODS: EVs from patient sera were isolated, quantified and characterized. The EVs were vigorously tested, both in vitro and in vivo, through various functional assays. Proteomic analysis was performed to identify the functional components of EVs. The presence and level of polymeric immunoglobulin receptor (pIgR) in circulating EVs and tumor and non-tumorous tissues of patients with HCC were determined by ELISA, immunoblotting, immunohistochemistry and quantitative PCR. The functional role and underlying mechanism of EVs with enhanced pIgR expression were elucidated. Blockade of EV-pIgR with neutralizing antibody was performed in nude mice implanted with patient-derived tumor xenografts (PDTXs). RESULTS: Circulating EVs from patients with late-stage HCC (L-HCC) had significantly elevated pIgR expression compared to the EVs released by control individuals. The augmenting effect of L-HCC-EVs on cancer stemness and tumorigenesis was hindered by an anti-pIgR antibody. EVs enriched with pIgR consistently promoted cancer stemness and cancerous phenotypes in recipient cells. Mechanistically, EV-pIgR-induced cancer aggressiveness was abrogated by Akt and ß-catenin inhibitors, confirming that the role of EV-pIgR depends on the activation of the PDK1/Akt/GSK3ß/ß-catenin signaling axis. Furthermore, an anti-pIgR neutralizing antibody attenuated tumor growth in mice implanted with PDTXs. CONCLUSIONS: This study illustrates a previously unknown role of EV-pIgR in regulating cancer stemness and aggressiveness: EV-pIgR activates PDK1/Akt/GSK3ß/ß-catenin signaling cascades. The blockade of the intercellular communication mediated by EV-pIgR in the tumor microenvironment may provide a new therapeutic strategy for patients with cancer. LAY SUMMARY: The World Health Organization estimates that more than 1 million patients will die from liver cancer, mostly hepatocellular carcinoma (HCC), in 2030. Understanding the underlying mechanism by which HCC acquires aggressive attributes is crucial to improving the diagnosis and treatment of patients. Herein, we demonstrated that nanometer-sized extracellular vesicles released by tumors promote cancer stemness and tumorigenesis. Within these oncogenic vesicles, we identified a key component that functions as a potent modulator of cancer aggressiveness. By inhibiting this functional component of EVs using a neutralizing antibody, tumor growth was profoundly attenuated in mice. This hints at a potentially effective therapeutic alternative for patients with cancer.

TPI1-reduced extracellular vesicles mediated by Rab20 downregulation promotes aerobic glycolysis to drive hepatocarcinogenesis.

Rab GTPases are major mediators that ensure the proper spatiotemporal regulation of intracellular trafficking. Functional impairment and altered expression of Rab proteins have been revealed in various human cancers. There is an emerging evidence about the role of Rab proteins in the biogenesis of extracellular vesicles (EVs). In hepatocellular carcinoma (HCC), using RNA sequencing comparing expression profiles of adjacent non-tumorous tissues and HCC, Rab20 is identified to be the most frequently downregulated Rab member in HCC. Functionally, restoration of Rab20 in metastatic HCC cells results in the release of EVs with a diminished activity to promote cell growth, motility and metastasis. Conversely, EVs released from normal liver cells with Rab20 knockdown loses suppressive effect on HCC cell growth and motility. Proteomic profiling revealed the level of triosephosphate isomerase 1 (TPI1), a glycolytic enzyme, in EVs to be positively associated with Rab20 expression of the releasing cells. TPI1 targeted to be expressed in EVs released by Rab20 knockdown cells compromises the oncogenic activity of EVs. Besides, EVs released by TPI1 knockdown cells recapitulates the promoting effect of EVs derived from HCC cells with Rab20 underexpression. Aerobic glycolysis is beneficial to the survival and proliferation of tumour cells. Here, we observed that the enhanced cell growth and motility are driven by the enhanced aerobic glycolysis induced by EVs with reduced TPI1. The addition of glycolytic inhibitor blocks the promoting effect of EVs with reduced TPI1. Taken together, our study provides a mechanistic link among tumour cell-derived EVs and glucose metabolism in HCC with Rab20 deregulation.

Suppression of ACADM-Mediated Fatty Acid Oxidation Promotes Hepatocellular Carcinoma via Aberrant CAV1/SREBP1 Signaling.

Lipid accumulation exacerbates tumor development, as it fuels the proliferative growth of cancer cells. The role of medium-chain acyl-CoA dehydrogenase (ACADM), an enzyme that catalyzes the first step of mitochondrial fatty acid oxidation, in tumor biology remains elusive. Therefore, investigating its mode of dysregulation can shed light on metabolic dependencies in cancer development. In hepatocellular carcinoma (HCC), ACADM was significantly underexpressed, correlating with several aggressive clinicopathologic features observed in patients. Functionally, suppression of ACADM promoted HCC cell motility with elevated triglyceride, phospholipid, and cellular lipid droplet levels, indicating the tumor suppressive ability of ACADM in HCC. Sterol regulatory element-binding protein-1 (SREBP1) was identified as a negative transcriptional regulator of ACADM. Subsequently, high levels of caveolin-1 (CAV1) were observed to inhibit fatty acid oxidation, which revealed its role in regulating lipid metabolism. CAV1 expression negatively correlated with ACADM and its upregulation enhanced nuclear accumulation of SREBP1, resulting in suppressed ACADM activity and contributing to increased HCC cell aggressiveness. Administration of an SREBP1 inhibitor in combination with sorafenib elicited a synergistic antitumor effect and significantly reduced HCC tumor growth in vivo. These findings indicate that deregulation of fatty acid oxidation mediated by the CAV1/SREBP1/ACADM axis results in HCC progression, which implicates targeting fatty acid metabolism to improve HCC treatment. SIGNIFICANCE: This study identifies tumor suppressive effects of ACADM in hepatocellular carcinoma and suggests promotion of ß-oxidation to diminish fatty acid availability to cancer cells could be used as a therapeutic strategy.

Nidogen 1-Enriched Extracellular Vesicles Facilitate Extrahepatic Metastasis of Liver Cancer by Activating Pulmonary Fibroblasts to Secrete Tumor Necrosis Factor Receptor 1.

In hepatocellular carcinoma (HCC) patients with extrahepatic metastasis, the lung is the most frequent site of metastasis. However, how the lung microenvironment favors disseminated cells remains unclear. Here, it is found that nidogen 1 (NID1) in metastatic HCC cell-derived extracellular vesicles (EVs) promotes pre-metastatic niche formation in the lung by enhancing angiogenesis and pulmonary endothelial permeability to facilitate colonization of tumor cells and extrahepatic metastasis. EV-NID1 also activates fibroblasts, which secrete tumor necrosis factor receptor 1 (TNFR1), facilitate lung colonization of tumor cells, and augment HCC cell growth and motility. Administration of anti-TNFR1 antibody effectively diminishes lung metastasis induced by the metastatic HCC cell-derived EVs in mice. In the clinical perspective, analysis of serum EV-NID1 and TNFR1 in HCC patients reveals their positive correlation and association with tumor stages suggesting the potential of these molecules as noninvasive biomarkers for the early detection of HCC. In conclusion, these results demonstrate the interplay of HCC EVs and activated fibroblasts in pre-metastatic niche formation and how blockage of their functions inhibits distant metastasis to the lungs. This study offers promise for the new direction of HCC treatment by targeting oncogenic EV components and their mediated pathways.

Tumour extracellular vesicle-derived Complement Factor H promotes tumorigenesis and metastasis by inhibiting complement-dependent cytotoxicity of tumour cells.

The complement system is involved in the immunosurveillance of pathogens and tumour cells. Proteomic profiling revealed that extracellular vesicles (EVs) released by metastatic hepatocellular carcinoma (HCC) cells contained a significant number of complement proteins. Complement Factor H (CFH), an abundant soluble serum protein that inhibits the alternative complement pathway, was found to be highly expressed in EVs of metastatic HCC cell lines. Here, we investigated the functional role of EV-CFH and explored the therapeutic efficacy of targeting EV-CFH with an anti-CFH antibody in HCC. The results showed that EVs that are enriched in CFH promoted HCC cell growth, migration, invasiveness and enhanced liver tumour formation in mice. EV-CFH also promoted metastasis, which was significantly abrogated when treated with an anti-CFH antibody. These findings demonstrate an unexplored function of EV-CFH in protecting HCC cells by evading complement attack, thereby facilitating tumorigenesis and metastasis. Lastly, we demonstrated the therapeutic efficacy of an anti-CFH antibody in suppressing tumour formation in a syngeneic mouse model. This study suggests a new therapeutic strategy for HCC, by inhibiting EV-CFH with a tumour specific anti-CFH antibody.

Galectin-1 promotes hepatocellular carcinoma and the combined therapeutic effect of OTX008 galectin-1 inhibitor and sorafenib in tumor cells.

BACKGROUND: Galectins are beta-galactose specific binding proteins. In human cancers, including hepatocellular carcinoma (HCC), galectin-1 (Gal-1) is often found to be overexpressed. In order to combat the dismal diagnosis and death rates of HCC, gene silencing and targeted inhibition of Gal-1 was investigated for its improved therapeutic potential. METHODS: Cellular and secretory Gal-1 levels were analyzed using HCC clinical samples. The study of Gal-1 was carried by both knockdown and overexpression approaches. The stable clones were tested by in vitro assays and in vivo experiments. Mass spectrometry was used to identify downstream targets of Gal-1. The upstream regulator of Gal-1, microRNA-22 (miR-22) was characterized by functional assays. The therapeutic effect of inhibiting Gal-1 was also analyzed. RESULTS: Gal-1 overexpression was observed in HCC and correlated with aggressive clinicopathological features and poorer survival. The loss of Gal-1 resulted in hindered cell migration, invasion and anchorage independent growth. This was also observed in the animal models, in that when Gal-1 was knocked down, there were fewer lung metastases. Proteomic profiling of control and Gal-1 knockdown cells identified that the level of retention in endoplasmic reticulum 1 (RER1) was suppressed when Gal-1 level was reduced. The cell motility of Gal-1 knockdown cells was enhanced upon the rescue of RER1 expression. In HCC tissues, Gal-1 and RER1 expressions displayed a significant positive correlation. The upstream regulator of Gal-1, miR-22 was observed to be underexpressed in HCC tissues and negatively correlated with Gal-1. Silencing of miR-22 resulted in the upregulation of Gal-1 and enhanced cell growth, migration and invasion. However, such enhancement was abolished in cells treated with OTX008, an inhibitor of Gal-1. Combinational treatment of OTX008 and sorafenib significantly reduced tumor growth and size. CONCLUSIONS: Gal-1 overexpression was detected in HCC and this played a role in promoting tumorigenic processes and metastasis. The function of Gal-1 was found to be mediated through RER1. The correlations between miR-22, Gal-1 and RER1 expressions demonstrated the importance of miR-22 regulation on Gal-1/RER1 oncogenic activity. Lastly, the combinational treatment of OTX008 and sorafenib proved to be an improved therapeutic option compared to when administering sorafenib alone.

Current Status and Challenges of NRF2 as a Potential Therapeutic Target for Diabetic Cardiomyopathy.

Diabetic cardiomyopathy is one of the main causes of heart failure and death in patients with diabetes mellitus. Reactive oxygen species produced excessively in diabetes mellitus cause necrosis, apoptosis, ferroptosis, inflammation, and fibrosis of the myocardium as well as impair the cardiac structure and function. It is increasingly clear that oxidative stress is a principal cause of diabetic cardiomyopathy. The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (NRF2) activates the transcription of more than 200 genes in the human genome. Most of the proteins translated from these genes possess anti-oxidant, anti-inflammatory, anti-apoptotic, anti-ferroptotic, and anti-fibrotic actions. There is a growing body of evidence indicating that NRF2 and its target genes are crucial in preventing high glucose-induced oxidative damage in diabetic cardiomyopathy. Recently, many natural and synthetic activators of NRF2 are shown to possess promising therapeutic effects on diabetic cardiomyopathy in animal models of diabetic cardiomyopathy. Targeting NRF2 signaling by pharmacological entities is a potential approach to ameliorating diabetic cardiomyopathy. However, the persistent high expression of NRF2 in cancer tissues also protects the growth of cancer cells. This "dark side" of NRF2 increases the challenges of using NRF2 activators to treat diabetic cardiomyopathy. In addition, some NRF2 activators were found to have off-target effects. In this review, we summarize the current status and challenges of NRF2 as a potential therapeutic target for diabetic cardiomyopathy.