Identification of exosomal miR-484 role in reprogramming mitochondrial metabolism in pancreatic cancer through Wnt/MAPK axis control.

The microRNAs (miRNAs) are potent regulators of tumorigenesis in various cancers, especially pancreatic cancer. The abnormal expression of miRNAs can be observed in tumor cells. Noteworthy, miRNAs could be transferred by exosomes as small extracellular vesicles in regulation of carcinogenesis. This research focused on exploring the roles and mechanisms of exosomal miR-484, derived from human bone marrow mesenchymal stem cells (hBMSCs), in the context of molecular interactions and regulation of mitochondrial metabolism. Exosomes were isolated for the examination of miR-484 expression. The impacts of hBMSCs-derived exosomal miR-484 on pancreatic cancer cells were studied using various assays. Evaluation of mitochondrial function and metabolism was performed. Wnt/MAPK pathway-related protein expression was assessed, and an in vivo tumor xenograft model was utilized to examine the functions. Our findings demonstrated a decreased miR-484 expression in pancreatic cancer cells. However, hBMSCs-derived exosomal miR-484 inhibited the proliferation and migration of these cells, while inducing apoptosis. Moreover, miR-484 led to an upsurge in reactive oxygen species production, a decrease in ATP levels, and a disruption in mitochondrial metabolism. In vivo analyses showed that hBMSCs-derived exosomal miR-484 lessened tumor size and weight, while also suppressing the expression of mitochondrial biomarkers. Further, there was a decline in ß-catenin and p-p38 protein levels both in vitro and in vivo. The addition of LiCl restored the disrupted mitochondrial metabolism. Conclusively, our results suggest that hBMSCs-derived exosomal miR-484 mitigates the malignant transformation and mitochondrial metabolism of pancreatic cancer by deactivating the Wnt/MAPK pathway.

A Strong Adhesive Biological Hydrogel for Colon Leakage Repair and Abdominal Adhesion Prevention.

Colon leakage is one of the most severe complications in abdominal trauma or surgery cases. It can lead to severe abdominal infection and abdominal adhesions, resulting in prolonged hospital stays and increased mortality. In this study, a photosensitive hydrogel is proposed, which can swiftly form a strong adhesion coating on the damaged colon after UV irradiation, to realize quick cure and suture-free repair of colon leakage. The newly developed biological gel consists of hyaluronic acid methacryloyl (HAMA) and hyaluronic acid o-nitroso benzaldehyde (HANB) in the optimal ratio of 3: 1, which exerts both the rapid photocuring properties of HAMA and the strong tissue adhesion properties of HANB. HAMA/HANB shows excellent adhesion stability on wet surfaces, presenting controllable mechanical properties, ductility, adhesion stability, and chemical stability; it also evades foreign body response, which relieves the degree of abdominal adhesion. The underlying mechanism for HAMA/HANB promoting wound healing in colon leakage involves the reconstruction of the colon barrier, as well as the regulation of the immune reaction and neovascularization. In all, HAMA/HANB is a promising alternative suture-free approach for repairing colon leakage; it has a reliable healing effect and is expected to be extended to clinical application for other organ injuries.

Microbiota Regulates Pancreatic Cancer Carcinogenesis through Altered Immune Response.

The microbiota is present in many parts of the human body and plays essential roles. The most typical case is the occurrence and development of cancer. Pancreatic cancer (PC), one of the most aggressive and lethal types of cancer, has recently attracted the attention of researchers. Recent research has revealed that the microbiota regulates PC carcinogenesis via an altered immune response. Specifically, the microbiota, in several sites, including the oral cavity, gastrointestinal tract, and pancreatic tissue, along with the numerous small molecules and metabolites it produces, influences cancer progression and treatment by activating oncogenic signaling, enhancing oncogenic metabolic pathways, altering cancer cell proliferation, and triggering chronic inflammation that suppresses tumor immunity. Diagnostics and treatments based on or in combination with the microbiota offer novel insights to improve efficiency compared with existing therapies.

A Machine-Learning-Based Bibliometric Analysis of Cell Membrane-Coated Nanoparticles in Biomedical Applications over the Past Eleven Years.

Cell membrane encapsulation is a growing concept in nanomedicine, for it achieves the purpose of camouflage nanoparticles, realizing the convenience for drug delivery, bio-imaging, and detoxification. Cell membranes are constructed by bilayer lipid phospholipid layers, which have unique properties in cellular uptake mechanism, targeting ability, immunomodulation, and regeneration. Current medical applications of cell membranes include cancers, inflammations, regenerations, and so on. In this article, a general bibliometric overview is conducted of cell membrane-coated nanoparticles covering 11 years of evolution in order to provide researchers in the field with a comprehensive view of the relevant achievements and trends. The authors analyze the data from Web of Science Core Collection database, and extract the annual publications and citations, most productive countries/regions, most influential scholars, the collaborations of journals and institutions. The authors also divided cell membranes into several subgroups to further understand the application of different cell membranes in medical scenarios. This study summarizes the current research overview in cell membrane-coated nanoparticles and intuitively provides a direction for future research.

GelNB molecular coating as a biophysical barrier to isolate intestinal irritating metabolites and regulate intestinal microbial homeostasis in the treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic, immune-mediated inflammatory disease characterized by the destruction of the structure and function of the intestinal epithelial barrier. Due to the poor remission effect and severe adverse events associated with current clinical medications, IBD remains an incurable disease. Here, we demonstrated a novel treatment strategy with high safety and effective inflammation remission via tissue-adhesive molecular coating. The molecular coating is composed of o-nitrobenzaldehyde (NB)-modified Gelatin (GelNB), which can strongly bond with -NH2 on the intestinal surface of tissue to form a thin biophysical barrier. We found that this molecular coating was able to stay on the surface of the intestine for long periods of time, effectively protecting the damaged intestinal epithelium from irritations of external intestinal metabolites and harmful flora. In addition, our results showed that this coating not only provided a beneficial environment for cell migration and proliferation to promote intestinal repair and regeneration, but also achieved a better outcome of IBD by reducing intestinal inflammation. Moreover, the in vivo experiments showed that the GelNB was better than the classic clinical medication-mesalazine. Therefore, our molecular coating showed potential as a promising strategy for the prevention and treatment of IBD.

Cell membrane-coated human hair nanoparticles for precise disease therapies.

Precision medicine is the ultimate goal for current disease therapies, including tumor and infection. The lack of specific targeted drugs for liver cancer and the lack of specific anti-infective drugs in the treatment of diabetic foot ulcer with infection (DFI) are the representative obstacles in those 2 major diseases currently plaguing human beings. Inventing natural biocompatible polymers derived from natural materials is one of the main development directions of current bio-medical materials. Though previous studies have demonstrated the potential application values of human black hair-derived nanoparticles (HNP) in cancer, methicillin-resistant Staphylococcus aureus (MRSA) infection, and thrombosis scenarios treatments, it still has not solved the problem of low local therapeutic concentration and general targeting ability. Here, we firstly modified the HNP with membrane encapsulations, which endowed these dual-pure natural bio-fabricated materials with better targeting ability at the disease sites with no reduction in photothermal therapy (PTT) effect. HNP coated by red blood cell membrane loaded with DSPE-PEG-cRGD peptide for the therapeutic application of liver cancer greatly prolonged in vivo circulation time and enhanced local targeting efficacy as well as low toxicity; HNP coated by the murine macrophage cell membrane (RAWM) for the DFIs treatment greatly promoted the adhesive ability of HNP on the bacteria and thereby improved the killing effect. Briefly, the appropriate cell membranes camouflaged HNP nanomedicine has the characteristics of excellent photothermal effect, an all-natural source with excellent biocompatibility and easy access, which is expected to have huge potential in both benign and malignant diseases.

Synthesis of Strong Adhesive Hydrogel, Gelatin O-Nitrosobenzaldehyde.

Adhesive materials have become popular biomaterials in the field of biomedical and tissue engineering. In our previous work, we presented a new material - gelatin o-nitrosobenzaldehyde (gelatin-NB) - which is mainly used for tissue regeneration and has been validated in animal models of corneal injury and inflammatory bowel disease. This is a novel hydrogel formed by modifying biological gelatin with o-nitrosobenzaldehyde (NB). Gelatin-NB was synthesized by activating the carboxyl group of NB-COOH and reacting with gelatin through 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS). The obtained compound was purified to generate the final product, which can be stably stored for at least 18 months. NB has a strong adhesion to -NH2 on the tissue, which can form many C = N bonds, thus increasing the adhesion of gelatin-NB to the tissue interface. The preparation process comprises steps for the synthesis of the NB-COOH group, modification of the group, synthesis of gelatin-NB, and purification of the compound. The goal is to describe the specific synthesis process of gelatin-NB in detail and to demonstrate the application of gelatin-NB to damage repair. Moreover, the protocol is presented to further strengthen and expand the nature of the material produced by the scientific community for more applicable scenarios.

ESR1 Regulates the Obesity- and Metabolism-Differential Gene MMAA to Inhibit the Occurrence and Development of Hepatocellular Carcinoma.

Obesity is often regarded as a factor that promotes tumorigenesis, but the role of obesity in promoting hepatocellular carcinoma (HCC) is still controversial. We compared the trend change of 14 obesity-related genes in the formation and development of HCC in normal, adjacent, and HCC tissues. Mendelian randomization (MR) analysis was used to verify the relationship between obesity and HCC occurrence. Metabolism of cobalamin-associated A (MMAA) was discovered as an obesity- and metabolism-differential gene, and its function in HCC was tested in vitro and in vivo. Finally, we explored how obese female patients with an originally high expression of female estrogen receptor (ESR1) directly upregulated MMAA to interfere with the progression of HCC. Fourteen obesity-related genes were downregulated in adjacent and tumoral tissues compared with normal liver tissues, which indicated that obesity may be inversely related to the occurrence of HCC and was consistent with the results of MR analysis. We also discovered that MMAA is a metabolic gene closely related to the occurrence and development of HCC by mining the TCGA database, and it functioned an anti-tumor-promoting role in HCC by damaging the mitochondrial function and preserving the redox balance. We further verified that obese females with a high expression of ESR1 can regulate MMAA to protect HCC from progression. This study elucidates that obesity might be a protective factor for female HCC patients, as they originally highly expressed ESR1, which could upregulate MMAA to suppress tumor growth and participate in metabolic reprogramming.

Platelet-Vesicles-Encapsulated RSL-3 Enable Anti-Angiogenesis and Induce Ferroptosis to Inhibit Pancreatic Cancer Progress.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers. It is characterized by stromal richness, lack of blood supply and special metabolic reprogramming in the tumor microenvironment, which is difficult to treat and easy to metastase. Great efforts have been made to develop new drugs which can pass through the stroma and are more effective than traditional chemotherapeutics, such as ferroptosis inducers-Erastin and RSL-3. As current anti-angiogenic therapy drugs alone are suboptimal for PDAC, novel vascular disruption agents in combination with ferroptosis inducers might provide a possible solution. Here, we designed human platelet vesicles (PVs) to camouflage RSL-3 to enhance drug uptake rate by tumor cells and circulation time in vivo, deteriorating the tumor vessels and resulting in tumor embolism to cut the nutrient supply as well as causing cell death due to excessive lipid peroxidation. The RSL-3@PVs can also cause the classic ferroptosis-related change of mitochondrial morphology, with changes in cellular redox levels. Besides that, RSL-3@PVs has been proved to have great biological safety profile in vitro and in vivo. This study demonstrates the promising potential of integrating PVs and RSL-3 as a combination therapy for improving the outcome of PDAC.

Noncoding RNAs link metabolic reprogramming to immune microenvironment in cancers.

Altered metabolic patterns in tumor cells not only meet their own growth requirements but also shape an immunosuppressive microenvironment through multiple mechanisms. Noncoding RNAs constitute approximately 60% of the transcriptional output of human cells and have been shown to regulate numerous cellular processes under developmental and pathological conditions. Given their extensive action mechanisms based on motif recognition patterns, noncoding RNAs may serve as hinges bridging metabolic activity and immune responses. Indeed, recent studies have shown that microRNAs, long noncoding RNAs and circRNAs are widely involved in tumor metabolic rewiring, immune cell infiltration and function. Hence, we summarized existing knowledge of the role of noncoding RNAs in the remodeling of tumor metabolism and the immune microenvironment, and notably, we established the TIMELnc manual, which is a free and public manual for researchers to identify pivotal lncRNAs that are simultaneously correlated with tumor metabolism and immune cell infiltration based on a bioinformatic approach.

Injectable exosome-functionalized extracellular matrix hydrogel for metabolism balance and pyroptosis regulation in intervertebral disc degeneration.

Exosome therapy is a promising therapeutic approach for intervertebral disc degeneration (IVDD) and achieves its therapeutic effects by regulating metabolic disorders, the microenvironment and cell homeostasis with the sustained release of microRNAs, proteins, and transcription factors. However, the rapid clearance and disruption of exosomes are the two major challenges for the application of exosome therapy in IVDD. Herein, a thermosensitive acellular extracellular matrix (ECM) hydrogel coupled with adipose-derived mesenchymal stem cell (ADSC) exosomes (dECM@exo) that inherits the superior properties of nucleus pulposus tissue and ADSCs was fabricated to ameliorate IVDD. This thermosensitive dECM@exo hydrogel system can provide not only in situ gelation to replenish ECM leakage in nucleus pulposus cells (NPCs) but also an environment for the growth of NPCs. In addition, sustained release of ADSC-derived exosomes from this system regulates matrix synthesis and degradation by regulating matrix metalloproteinases (MMPs) and inhibits pyroptosis by mitigating the inflammatory response in vitro. Animal results demonstrated that the dECM@exo hydrogel system maintained early IVD microenvironment homeostasis and ameliorated IVDD. This functional system can serve as a powerful platform for IVD drug delivery and biotherapy and an alternative therapy for IVDD.

Whole-exon sequencing insights into pancreatic synovial sarcoma: a case report.

More than 30 cases of synovial sarcoma are sequenced on all organs of cBioPortal database, but it has not yet been reported before. Here, we reported a case of a 66-year-old male patient with an upper abdominal pain for half a month and a previous history of oral cancer. During this hospitalization, the patient underwent laparoscopic exploration followed by open pancreaticoduodenectomy. The histopathological diagnosis was pancreatic synovial sarcoma (PSS), and we further performed whole exome sequencing for this patient. We found that there are many copy number variations (CNV) of exon gene in all the 24 chromosomes, of which chr1, chr2, chr4 have the most exon gene amplification and chr21, chr22, chrY have the most exon gene deletion. Besides, GO (Gene Ontology) analysis showed that many driver-genes are related to chromosome or chromatin organization while KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis demonstrated that many driver-genes are enriched in the cancer-related pathways. Furthermore, we found mutations or CNV of the five vital driver-genes in the results of sequencing, including arid1a, arid1b, tp53, cdkn2a and asxl1. Of them, arid1a and arid1b in exon 1 are both in-frame mutations. By exploring the pathogenic genes of PSS, we have found some vital gene mutations and better understood the pathogenesis to promote the targeted treatment of primary PSS.

Development of an Aerobic Glycolysis Index for Predicting the Sorafenib Sensitivity and Prognosis of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a deadly tumor with high heterogeneity. Aerobic glycolysis is a common indicator of tumor growth and plays a key role in tumorigenesis. Heterogeneity in distinct metabolic pathways can be used to stratify HCC into clinically relevant subgroups, but these have not yet been well-established. In this study, we constructed a model called aerobic glycolysis index (AGI) as a marker of aerobic glycolysis using genomic data of hepatocellular carcinoma from The Cancer Genome Atlas (TCGA) project. Our results showed that this parameter inferred enhanced aerobic glycolysis activity in tumor tissues. Furthermore, high AGI is associated with poor tumor differentiation and advanced stages and could predict poor prognosis including reduced overall survival and disease-free survival. More importantly, the AGI could accurately predict tumor sensitivity to Sorafenib therapy. Therefore, the AGI may be a promising biomarker that can accurately stratify patients and improve their treatment efficacy.

Cancer and COVID-19 Susceptibility and Severity: A Two-Sample Mendelian Randomization and Bioinformatic Analysis.

The clinical management of patients with COVID-19 and cancer is a Gordian knot that has been discussed widely but has not reached a consensus. We introduced two-sample Mendelian randomization to investigate the causal association between a genetic predisposition to cancers and COVID-19 susceptibility and severity. Moreover, we also explored the mutation landscape, expression pattern, and prognostic implications of genes involved with COVID-19 in distinct cancers. Among all of the cancer types we analyzed, only the genetic predisposition to lung adenocarcinoma was causally associated with increased COVID-19 severity (OR = 2.93, ß = 1.074, se = 0.411, p = 0.009) with no obvious heterogeneity (Q = 17.29, p = 0.24) or symmetry of the funnel plot. In addition, the results of the pleiotropy test demonstrated that instrument SNPs were less likely to affect COVID-19 severity via approaches other than lung adenocarcinoma cancer susceptibility (p = 0.96). Leave-one-out analysis showed no outliers in instrument SNPs, whose elimination rendered alterations in statistical significance, which further supported the reliability of the MR results. Broad mutation and differential expression of these genes were also found in cancers, which may provide valuable information for developing new treatment modalities for patients with both cancer and COVID-19. For example, ERAP2, a risk factor for COVID-19-associated death, is upregulated in lung squamous cancer and negatively associated with patient prognosis. Hence, ERAP2-targeted treatment may simultaneously reduce COVID-19 disease severity and restrain cancer progression. Our results highlighted the importance of strengthening medical surveillance for COVID-19 deterioration in patients with lung adenocarcinoma by showing their causal genetic association. For these patients, a delay in anticancer treatment, such as chemotherapy and surgery, should be considered.

N6-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating ß-catenin signaling.

BACKGROUND AND AIMS: Accumulating evidence suggests that the primary and acquired resistance of hepatocellular carcinoma (HCC) to sorafenib is mediated by multiple molecular, cellular, and microenvironmental mechanisms. Understanding these mechanisms will enhance the likelihood of effective sorafenib therapy. METHODS: In vitro and in vivo experiments were performed and clinical samples and online databases were acquired for clinical investigation. RESULTS: In this study, we found that a circular RNA, circRNA-SORE, which is up-regulated in sorafenib-resistant HCC cells, was necessary for the maintenance of sorafenib resistance, and that silencing circRNA-SORE substantially increased the efficacy of sorafenib-induced apoptosis. Mechanistic studies determined that circRNA-SORE sequestered miR-103a-2-5p and miR-660-3p by acting as a microRNA sponge, thereby competitively activating the Wnt/ß-catenin pathway and inducing sorafenib resistance. The increased level of circRNA-SORE in sorafenib-resistant cells resulted from increased RNA stability. This was caused by an increased level of N6-methyladenosine (m6A) at a specific adenosine in circRNA-SORE. In vivo delivery of circRNA-SORE interfering RNA by local short hairpin RNA lentivirus injection substantially enhanced sorafenib efficacy in animal models. CONCLUSIONS: This work indicates a novel mechanism for maintaining sorafenib resistance and is a proof-of-concept study for targeting circRNA-SORE in sorafenib-treated HCC patients as a novel pharmaceutical intervention for advanced HCC.

Classification and mutation prediction based on histopathology H&E images in liver cancer using deep learning.

Hepatocellular carcinoma (HCC) is the most common subtype of liver cancer, and assessing its histopathological grade requires visual inspection by an experienced pathologist. In this study, the histopathological H&E images from the Genomic Data Commons Databases were used to train a neural network (inception V3) for automatic classification. According to the evaluation of our model by the Matthews correlation coefficient, the performance level was close to the ability of a 5-year experience pathologist, with 96.0% accuracy for benign and malignant classification, and 89.6% accuracy for well, moderate, and poor tumor differentiation. Furthermore, the model was trained to predict the ten most common and prognostic mutated genes in HCC. We found that four of them, including CTNNB1, FMN2, TP53, and ZFX4, could be predicted from histopathology images, with external AUCs from 0.71 to 0.89. The findings demonstrated that convolutional neural networks could be used to assist pathologists in the classification and detection of gene mutation in liver cancer.

A retrospective pilot study to examine the feasibility of real-time navigation for laparoscopic liver resections in intrahepatic cholangiocarcinoma using fusion indocyanine green fluorescence imaging.

BACKGROUND AND OBJECTIVES: Recently, PINPOINT, a novel laparoscopic fusion indocyanine green fluorescence imaging (IGFI) system has become available for laparoscopic liver resection. This study aims to characterize fluorescence patterns of intrahepatic cholangiocarcinoma (ICC) using the negative counterstaining method in laparoscopic anatomical hepatectomies of ICC. METHODS: Eleven consecutive patients, diagnosed with intrahepatic cholangiocarcinoma and underwent laparoscopic liver resection between April 2017 and December 2018, were retrospectively reviewed. A laparoscopic IGFI navigation system was used to characterize fluorescence patterns of ICC with intraoperative liver segment demarcation by means of negative counterstaining. RESULTS: Fusion IGFI of ICC was successfully obtained from all 11 patients from the surgical specimens. The fluorescence patterns of ICC can be categorized into rim-type fluorescence and segmental fluorescence, depending on tumor growth. In eight patients, indocyanine green fluorescence imaging was used to identify the hepatic lobes or segments by negative counterstaining. In six cases, a valid and persistent demarcation was achieved intraoperatively. CONCLUSION: Laparoscopic IGFI system could identify different types of ICC lesions and may facilitate real-time navigation for laparoscopic anatomic liver resection of ICC.

Fabrication of liver microtissue with liver decellularized extracellular matrix (dECM) bioink by digital light processing (DLP) bioprinting.

As one of the most effective treatments of end-stage liver disease, liver transplantation still suffers from a shortage of donor organs or a low degree of engraftment. Thus, alternatives to liver transplantation, such as liver support systems, have to be extensively explored. In this study, a novel liver microtissue with an inner gear-like structure, which achieved a larger body surface area, was designed and manufactured to improve hepatic functional restoration. The liver-specific bioinks were developed by combining photocurable methacrylated gelatin (GelMA) with liver decellularized extracellular matrix (dECM), and human-induced hepatocytes (hiHep cells) were encapsulated to form cell-laden bioinks. The mechanical properties, swelling, and cytocompatibility of GelMA/dECM bioinks were carefully characterized before 3D printing. Then, the digital light process (DLP)-based bioprinting was used to fabricate the liver microtissue, and liver dECM was found to improve both the printability and cell viability of GelMA bioinks. hiHep cells were also found to spread farther and have better hepatocyte-specific functions (albumin secretion and urea) in the liver microtissue when liver dECM was added to the GelMA bioinks. Our results provide a promising liver dECM-based cell-laden bioink for liver microtissue fabrication, which would be a potential liver tissue engineering product to help restore hepatic functions.

Laparoscopic radical resection of gastric cancer and metachronous colon cancer-a case report.

Due to the favorable prognosis of gastric cancer (GC), the incidence of second primary cancer (SPC) accompanied with GC has increased. Here, we reported a case of a 69-year-old male patient with metachronous GC and colon cancer, who had undergone laparoscopic radical resection of distal GC 4 years ago. During this hospitalization, the patient underwent laparoscopic radical resection of left hemicolectomy for metachronous colon cancer. Few literatures have reported that patients with metachronous GC and colon cancer can receive laparoscopic surgery successfully. The patient recovered well and was discharged on day 10 post-operation. The pathologic specimen was identified as metachronous colon cancer. We concluded that GC patients need regular standard follow-up programs after undergoing operations. For multiple primary cancers (MPCs), treatments need to be individualized and comprehensive. Laparoscopic surgery is recommended as an appropriate option.