E/e' Ratio and Diastolic Function Between Deep Vein Catheterization and Internal Fistula Treatment in Patients with Chronic Kidney Disease.

Objective: To examine the relationship between diastolic function and the ratio of early diastolic mitral inflow to early diastolic mitral annular velocity (E/e') in patients with chronic renal disease who had deep vein catheterization and internal fistula. Methods: The clinical data of 50 uremia patients treated at The Affiliated Dongyang Hospital of Wenzhou Medical University from January 2020 to January 2022 were retrospectively analyzed. To assess the differences in E/e' ratio and patients' diastolic function between the two groups, they were split into two teams according to the various therapy modalities: the internal fistula team (n = 42) and the deep vein catheterization team (n = 8). Results: After treatment, the left ventricular end-diastolic diameter (LVd), E peak, a peak and E/A value, the volume and area of four chambers of the left ventricle (LV), the volume and area of two chambers of LV in both groups were significantly lower than those before treatment (P < .001). After treatment, the LVd left ventricular end-systolic diameter (LVs), the four-chamber volume of LV, and the two-chamber volume and area of LV in patients with internal fistula were significantly lower than those in patients with deep vein catheterization (P < .001). After treatment, E peak, A peak and E/A value, e' interventricular septum, E/e' value of interventricular septum, e' lateral wall, and E of lateral wall in patients with internal fistula group. Conclusion: Both deep vein catheterization and internal fistula treatment can improve the diastolic function and reduce the pulmonary pressure of uremic patients to a certain extent, but internal fistula treatment is better than deep vein catheterization in reducing LVd, LVs, LV four-chamber volume, LV two-chamber volume and area, and the effects of both in improving the E/e ratio of patients are not obvious.

Comparison of machine learning models based on multi-parametric magnetic resonance imaging and ultrasound videos for the prediction of prostate cancer.

Objective: To establish machine learning (ML) prediction models for prostate cancer (PCa) using transrectal ultrasound videos and multi-parametric magnetic resonance imaging (mpMRI) and compare their diagnostic performance. Materials and methods: We systematically collated the data of 383 patients, including 187 with PCa and 196 with benign lesions. Of them, 307 patients (150 with PCa and 157 with benign lesions) were randomly selected to train and validate the ML models, 76 patients were used as test set. B-Ultrasound videos (BUS), mpMRI T2 sequence (T2), and ADC sequence (ADC) were obtained from all patients. We extracted 851 features of each patient in the BUS, T2, and ADC groups and used a t-test, the Mann-Whitney U test, and LASSO regression to screen the features. Support vector machine (SVM), random forest (RF), adaptive boosting (ADB), and gradient boosting machine (GBM) models were used to establish radiomics models. In addition, we fused the features screened via LASSO regression from three groups as new features and rebuilt ML models. The performance of the ML models in diagnosing PCa in the BUS, T2, ADC, and fusion groups was compared using the area under the ROC curve (AUC), sensitivity, specificity, and accuracy. Results: In the test cohort, the AUC of each model in the ADC group was higher than that of in the.BUS and T2 groups. Among the models, the RF model had the best diagnostic performance, with an AUC of 0.85, sensitivity of 0.78 (0.61-0.89), specificity of 0.84 (0.69-0.94), and accuracy of 0.83 (0.66-0.93). The SVM model in both the BUS and T2 groups performed best. Based on the features screened in the BUS, T2, and ADC groups fused to construct the models, the SVM model was found to perform best, with an AUC of 0.87, sensitivity of 0.73 (0.56-0.86), specificity of 0.79 (0.63-0.90), and accuracy of 0.77 (0.59-0.89). The difference in the results was statistically significant (p<0.05). Conclusion: The ML prediction models had a good diagnostic ability for PCa. Among them, the SVM model in the fusion group showed the best performance in diagnosing PCa. These prediction models can help radiologists make better diagnoses.

Electric Fields Regulate In Vitro Surface Phosphatidylserine Exposure of Cancer Cells via a Calcium-Dependent Pathway.

Cancer is the second leading cause of death worldwide after heart disease. The current treatment options to fight cancer are limited, and there is a critical need for better treatment strategies. During the last several decades, several electric field (EF)-based approaches for anti-cancer therapies have been introduced, such as electroporation and tumor-treating fields; still, they are far from optimal due to their invasive nature, limited efficacy and significant side effects. In this study, we developed a non-contact EF stimulation system to investigate the in vitro effects of a novel EF modality on cancer biomarkers in normal (human astrocytes, human pancreatic ductal epithelial -HDPE-cells) and cancer cell lines (glioblastoma U87-GBM, human pancreatic cancer cfPac-1, and MiaPaCa-2). Our results demonstrate that this EF modality can successfully modulate an important cancer cell biomarker-cell surface phosphatidylserine (PS). Our results further suggest that moderate, but not low, amplitude EF induces p38 mitogen-activated protein kinase (MAPK), actin polymerization, and cell cycle arrest in cancer cell lines. Based on our results, we propose a mechanism for EF-mediated PS exposure in cancer cells, where the magnitude of induced EF on the cell surface can differentially regulate intracellular calcium (Ca2+) levels, thereby modulating surface PS exposure.

Massive gastrointestinal haemorrhage caused by pancreatic pseudocyst complicated with Dieulafoy's disease in a child: A case report and review of the literature.

Background: Pancreatic pseudocyst (PPC) with massive gastrointestinal bleeding is rare, especially in children. Inadvertent intraoperative examination and damage to the gastric mucosa and malformed blood vessels by the fluid content of PPC can lead to massive bleeding, which may endanger the patient's life. Case presentation: Here, we present a case of an 8-year-old boy who was diagnosed with a massive gastrointestinal haemorrhage caused by PPC complicated with Dieulafoy's disease. At his first admission, his complaint was being hit to the stomach by the handlebar while riding bicycle 24 h before admission. After being hospitalized, he was diagnosed with pancreatic injury by abdominal CT. Conservative treatment lasted for 1 month in the Department of Pediatric Surgery. Then, a pancreatic pseudocyst was formed. Under the guidance of ultrasonic endoscopy, cyst puncture and drainage of pseudocysts through the gastric wall were performed. Unexplained hematemesis occurred 8 days after surgery. Emergency gastroscopy was performed, and abnormal submucosal vascular haemorrhage was found at the gastric fundus. Gastric Dieulafoy's disease was diagnosed. The boy underwent gastroscopic titanium clipping of abnormal arteries. He had no complications during the 3-month follow-up. Then, the patient returned to the hospital, and the stent was removed under endoscopy. No bleeding was found, and the patient was discharged. The patient recovered smoothly and was followed up for half a year without any complications, and hematological indicators were normal. Conclusion: Endoscopic ultrasonography-guided gastric puncture and internal drainage of cysts is a safe and effective surgical method for the treatment of pancreatic pseudocysts. However, at the same time, it is necessary to thoroughly and carefully explore the stomach cavity to prevent adverse consequences caused by a missed diagnosis of gastric Dieulafoy's disease or other abnormal abnormalities.

Bioinformatics analysis to obtain critical genes regulated in subcutaneous adipose tissue after bariatric surgery.

Bariatric surgery (BS) is a dependable method for managing obesity and metabolic diseases, however, the regulatory processes of lipid metabolism are still not well elucidated. Differentially expressed genes (DEGs) were analysed through three transcriptomic datasets of GSE29409, GSE59034 and GSE72158 from the GEO database regarding subcutaneous adipose tissue (SAT) after BS, and 37 DEGs were identified. The weighted gene co-expression network analysis (WGCNA), last absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine-recursive feature elimination (SVM-RFE) algorithms further screened four key genes involved in the regulation of STMN2, SFRP4, APOE and MXRA5. The GSE53376 dataset was used to further confirm the differential expression of SFRP4, APOE and MXRA5 in the postoperative period. GSEA analysis reveals activation of immune-related regulatory pathways after surgery. Finally, the silencing of MXRA5 was found by experimental methods to affect the expression of PPARγ and CEBPα during the differentiation of preadipocytes, as well as to affect the formation of lipid droplets. In conclusion, SAT immunoregulation was mobilized after BS, while MXRA5 was involved in the regulation of lipid metabolism.

Axl Expression in Renal Mesangial Cells Is Regulated by Sp1, Ap1, MZF1, and Ep300, and the IL-6/miR-34a Pathway.

Axl receptor tyrosine kinase expression in the kidney contributes to a variety of inflammatory renal disease by promoting glomerular proliferation. Axl expression in the kidney is negligible in healthy individuals but upregulated under inflammatory conditions. Little is known about Axl transcriptional regulation. We analyzed the 4.4 kb mouse Axl promoter region and found that many transcription factor (TF)-binding sites and regulatory elements are located within a 600 bp fragment proximal to the translation start site. Among four TFs (Sp1, Ap1, MZF1, and Ep300) identified, Sp1 was the most potent TF that promotes Axl expression. Luciferase assays confirmed the siRNA results and revealed additional mechanisms that regulate Axl expression, including sequences encoding a 5'-UTR mini-intron and potential G-quadruplex forming regions. Deletion of the Axl 5'-UTR mini-intron resulted in a 3.2-fold increases in luciferase activity over the full-length UTR (4.4 kb Axl construct). The addition of TMPyP4, a G-quadruplex stabilizer, resulted in a significantly decreased luciferase activity. Further analysis of the mouse Axl 3'-UTR revealed a miRNA-34a binding site, which inversely regulates Axl expression. The inhibitory role of miRNA-34a in Axl expression was demonstrated in mesangial cells using miRNA-34a mimicry and in primary kidney cells with IL-6 stimulated STAT3 activation. Taken together, Axl expression in mouse kidney is synergistically regulated by multiple factors, including TFs and secondary structures, such as mini-intron and G-quadruplex. A unique IL6/STAT3/miRNA-34a pathway was revealed to be critical in inflammatory renal Axl expression.

Phosphatidylserine: The Unique Dual-Role Biomarker for Cancer Imaging and Therapy.

Cancer is among the leading causes of death worldwide. In recent years, many cancer-associated biomarkers have been identified that are used for cancer diagnosis, prognosis, screening, and early detection, as well as for predicting and monitoring carcinogenesis and therapeutic effectiveness. Phosphatidylserine (PS) is a negatively charged phospholipid which is predominantly located in the inner leaflet of the cell membrane. In many cancer cells, PS externalizes to the outer cell membrane, a process regulated by calcium-dependent flippases and scramblases. Saposin C coupled with dioleoylphosphatidylserine (SapC-DOPS) nanovesicle (BXQ-350) and bavituximab, (Tarvacin, human-mouse chimeric monoclonal antibodies) are cell surface PS-targeting drugs being tested in clinical trial for treating a variety of cancers. Additionally, a number of other PS-selective agents have been used to trigger cytotoxicity in tumor-associated endothelial cells or cancer cells in pre-clinical studies. Recent studies have demonstrated that upregulation of surface PS exposure by chemodrugs, radiation, and external electric fields can be used as a novel approach to sensitize cancer cells to PS-targeting anticancer drugs. The objectives of this review are to provide an overview of a unique dual-role of PS as a biomarker/target for cancer imaging and therapy, and to discuss PS-based anticancer strategies that are currently under active development.

RNA modification writers influence tumor microenvironment in gastric cancer and prospects of targeted drug therapy.

Background: RNA adenosine modifications are crucial for regulating RNA levels. N6-methyladenosine (m6A), N1-methyladenosine (m1A), adenosine-to-inosine RNA editing, and alternative polyadenylation (APA) are four major RNA modification types. Methods: We evaluated the altered mRNA expression profiles of 27 RNA modification enzymes and compared the differences in tumor microenvironment (TME) and clinical prognosis between two RNA modification patterns using unsupervised clustering. Then, we constructed a scoring system, WM_score, and quantified the RNA modifications in patients of gastric cancer (GC), associating WM_score with TME, clinical outcomes, and effectiveness of targeted therapies. Results: RNA adenosine modifications strongly correlated with TME and could predict the degree of TME cell infiltration, genetic variation, and clinical prognosis. Two modification patterns were identified according to high and low WM_scores. Tumors in the WM_score-high subgroup were closely linked with survival advantage, CD4- T-cell infiltration, high tumor mutation burden, and cell cycle signaling pathways, whereas those in the WM_score-low subgroup showed strong infiltration of inflammatory cells and poor survival. Regarding the immunotherapy response, a high WM_score showed a significant correlation with PD-L1 expression, predicting the effect of PD-L1 blockade therapy. Conclusion: The WM_scoring system could facilitate scoring and prediction of GC prognosis.

Shp2 suppresses fat accumulation in white adipose tissue by activating Wnt/ß-catenin signaling following vertical sleeve gastrectomy in obese rats with type-2 diabetes.

Adipogenesis and fat accumulation are closely associated with the development of obesity. Sleeve gastrectomy (SG) is an effective treatment for obesity and associated metabolic disorders. Leptin is downregulated after SG and Src homology phosphatase 2 (Shp2) has an important role in leptin signaling. The role of Shp2 in SG and the mechanisms of fat reduction following SG were further investigated in the current study. Sham and SG operations were performed on obese type-2 diabetes model Sprague-Dawley rats. Primary pre-adipocytes were isolated from the inguinal white adipose tissue (ingWAT) of the rats. Shp2 expression in ingWAT pre-adipocytes was silenced using small interfering RNA transfection. Shp2 function was inhibited using the specific inhibitor, SHP099. In addition, Shp2 was overexpressed using lentivirus. Gene and protein expression analysis was performed after adipocyte differentiation. Furthermore, Shp2-overexpressing ingWAT pre-adipocytes treated with the ß-catenin inhibitor, PNU-74654, were also used for gene and protein expression analysis. Adipogenic markers, including triglycerides, peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (Cebpα), adiponectin, fatty acid-binding protein 4 and leptin, were examined. Compared with the sham, triglyceride, leptin, PPARγ and Cebpα levels were significantly reduced in the ingWAT from the SG group. Shp2 expression levels were reduced following leptin treatment. Moreover, genetic analysis demonstrated depot-specific adipogenesis following Shp2 silencing or inhibition in ingWAT pre-adipocytes. Conversely, Shp2 overexpression decreased the expression of adipogenic markers by enhancing ß-catenin expression. PNU-74654 treatment abolished the downregulation of adipogenic markers caused by Shp2 overexpression. SG decreased leptin levels in ingWAT, which in turn upregulated Shp2, and Shp2 suppressed fat accumulation and adipogenic differentiation by activating the Wnt/ß-catenin signaling pathway. Overall, this may represent a potential mechanism of fat reduction in SG, and Shp2 may serve as a potential therapeutic target for the treatment of obesity and type-2 diabetes.

The Effects of Antral Preservation and Antral Resection on Body Composition, Glycemic Control and Bone Mineral Density Following Vertical Sleeve Gastrectomy in C57BL/6J Mice with Obesity and Type 2 Diabetes.

PURPOSE: Sleeve gastrectomy (SG) is the most currently popular operation for obesity and related metabolic disorders. The aim of this study was to compare the effect of antrum preservation SG (AP-SG) and antrum resection SG (AR-SG) on the body composition, glycemic control and bone mineral density (BMD) in mice. METHODS: Sham, AP-SG and AR-SG operation were performed on obese and T2D C57BL/6J mice (8 in each group). Body weight, food intake, and fasting glucose (FG) levels were measured at the 0, 2, 4, 6 and 8 weeks post-operatively. Oral glucose tolerance test (OGTT) was performed preoperatively and at the eighth postoperative week. The body fat content and total body BMD were evaluated by dual-energy x-ray absorptiometry. After being euthanized, the femurs were harvested and analyzed by micro-CT. RESULTS: The improvements in body weight, food intake, FG, glycemic control and body fat were statistically significant following AP-SG and AR-SG. Both AP-SG and AR-SG groups decreased total body BMD and regional BMD in the distal femur compared to the sham group. No significant difference of FG was observed in AP-SG and AR-SG group postoperatively, but AR-SG showed significantly superior OGTT glucose AUC than AP-SG. Except for a lower BMD, AR-SG achieved superior outcomes in body fat and glycemic control than AP-SG. CONCLUSION: Antrum resection SG shows a lower percentage of body fat and better glycemic control than antrum preservation SG. However, antrum resection SG has a higher risk of having a lower bone mass. Further human clinical trials are needed to confirm this finding.

Construction of a circRNA-miRNA-mRNA network based on differentially co-expressed circular RNA in gastric cancer tissue and plasma by bioinformatics analysis.

BACKGROUND: Increasing evidence implicates circular RNAs (circRNAs) have been involved in human cancer progression. However, the mechanism remains unclear. In this study, we identified novel circRNAs related to gastric cancer and constructed a circRNA-miRNA-mRNA network. METHODS: Microarray datasets GSE83521 and GSE93541 were obtained from the Gene Expression Omnibus (GEO). Then, we used computational biology to identify circRNAs that were differentially expressed in both GC tissue and plasma compared to normal controls; then, we detected the expression of the selected circRNAs in gastric cell lines by quantitative real-time polymerase chain reaction (qRT-PCR). We also identified circRNA-related candidate miRNAs and their target genes with online tools. Combining the predicted miRNAs and target mRNAs, a competing endogenous RNA regulatory network was established. Functional and pathway enrichment analyses were performed, and interactions between proteins were predicted by using String and Cytoscape. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to elucidate the possible functions of these differentially expressed circRNAs. The regulatory network constructed using the microarray datasets (GSE83521 and GSE93541) contained three differentially co-expressed circRNAs (DECs). A circRNA-miRNA-mRNA network was constructed based on 3 circRNAs, 43 miRNAs and 119 mRNAs. RESULTS: GO and KEGG analysis showed that the regulation of apoptotic signaling pathway and PI3K-Akt signaling pathway were highest degrees of enrichment respectively. We established a protein-protein interaction (PPI) network consisting of 165 nodes and 170 edges and identified hub genes by using MCODE plugin in Cytoscape. Furthermore, a core circRNA-miRNA-mRNA network was constructed based on hub genes. Hsa_circ_0001013 was finally determined to play an important role in the pathogenesis of GC according to the core circRNA-miRNA-mRNA network. CONCLUSIONS: We propose a new circRNA-miRNA-mRNA network that is associated with the pathogenesis of GC. The network may become a new molecular biomarker and could be used to develop potential therapeutic strategies for gastric cancer.

SapC-DOPS as a Novel Therapeutic and Diagnostic Agent for Glioblastoma Therapy and Detection: Alternative to Old Drugs and Agents.

Glioblastoma multiforme (GBM), the most common type of brain cancer, is extremely aggressive and has a dreadful prognosis. GBM comprises 60% of adult brain tumors and the 5 year survival rate of GBM patients is only 4.3%. Standard-of-care treatment includes maximal surgical removal of the tumor in combination with radiation and temozolomide (TMZ) chemotherapy. TMZ is the "gold-standard" chemotherapy for patients suffering from GBM. However, the median survival is only about 12 to 18 months with this protocol. Consequently, there is a critical need to develop new therapeutic options for treatment of GBM. Nanomaterials have unique properties as multifunctional platforms for brain tumor therapy and diagnosis. As one of the nanomaterials, lipid-based nanocarriers are capable of delivering chemotherapeutics and imaging agents to tumor sites by enhancing the permeability of the compound through the blood-brain barrier, which makes them ideal for GBM therapy and imaging. Nanocarriers also can be used for delivery of radiosensitizers to the tumor to enhance the efficacy of the radiation therapy. Previously, high-atomic-number element-containing particles such as gold nanoparticles and liposomes have been used as radiosensitizers. SapC-DOPS, a protein-based liposomal drug comprising the lipid, dioleoylphosphatidylserine (DOPS), and the protein, saposin C (SapC), has been shown to be effective for treatment of a variety of cancers in small animals, including GBM. SapC-DOPS also has the unique ability to be used as a carrier for delivery of radiotheranostic agents for nuclear imaging and radiotherapeutic purposes. These unique properties make tumor-targeting proteo-liposome nanocarriers novel therapeutic and diagnostic alternatives to traditional chemotherapeutics and imaging agents. This article reviews various treatment modalities including nanolipid-based delivery and therapeutic systems used in preclinical and clinical trial settings for GBM treatment and detection.

Targeting of elevated cell surface phosphatidylserine with saposin C-dioleoylphosphatidylserine nanodrug as individual or combination therapy for pancreatic cancer.

Pancreatic cancer is one of the deadliest of cancers with a five-year survival of roughly 8%. Current therapies are: surgery, radiation and chemotherapy. Surgery is curative only if the cancer is caught very early, which is rare, and the latter two modalities are only marginally effective and have significant side effects. We have developed a nanosome comprised of the lysosomal protein, saposin C (SapC) and the acidic phospholipid, dioleoylphosphatidylserine (DOPS). In the acidic tumor microenvironment, this molecule, SapC-DOPS, targets the phosphatidylserine cancer-biomarker which is predominantly elevated on the surface of cancer cells. Importantly, SapC-DOPS can selectively target pancreatic tumors and metastases. Furthermore, SapC-DOPS has exhibited an impressive safety profile with only a few minor side effects in both preclinical experiments and in phase I clinical trials. With the dismal outcomes for pancreatic cancer there is an urgent need for better treatments and SapC-DOPS is a good candidate for addition to the oncologist's toolbox.

Autophagy mediated lipid catabolism facilitates glioma progression to overcome bioenergetic crisis.

BACKGROUND: Activation of mTORC1 plays a significant role in cancer development and progression. However, the metabolic mechanisms to sustain mTORC1 activation of cancer cells within stressed environments are still under-appreciated. We recently revealed high autophagy activity in tumour cells with mTORC1 hyper-activation. Nevertheless, the functions and mechanisms of autophagy in regulating mTORC1 in glioma are not studied. METHODS: Using glioma patient database and human glioma cells, we assessed the mechanisms and function of selective autophagy to sustain mTORC1 hyper-activation in glioma. RESULTS: We revealed a strong association of altered mRNA levels in mTORC1 upstream and downstream genes with prognosis of glioma patients. Our results indicated that autophagy-mediated lipid catabolism was essential to sustain mTORC1 activity in glioma cells under energy stresses. We found that autophagy inhibitors or fatty acid oxidation (FAO) inhibitors in combination with 2-Deoxy-D-glucose (2DG) decreased energy production and survival of glioma cells in vitro. Consistently, inhibition of autophagy or FAO inhibitors with 2DG effectively suppressed the progression of xenografted glioma with hyper-activated mTORC1. CONCLUSIONS: This study established an autophagy/lipid degradation/FAO/ATP generation pathway, which might be used in brain cancer cells under energy stresses to maintain high mTORC1 signalling for tumour progression.

Reuse of Molecules for Glioblastoma Therapy.

Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor. The current standard of care for GBM is the Stupp protocol which includes surgical resection, followed by radiotherapy concomitant with the DNA alkylator temozolomide; however, survival under this treatment regimen is an abysmal 12-18 months. New and emerging treatments include the application of a physical device, non-invasive 'tumor treating fields' (TTFs), including its concomitant use with standard of care; and varied vaccines and immunotherapeutics being trialed. Some of these approaches have extended life by a few months over standard of care, but in some cases are only available for a minority of GBM patients. Extensive activity is also underway to repurpose and reposition therapeutics for GBM, either alone or in combination with the standard of care. In this review, we present select molecules that target different pathways and are at various stages of clinical translation as case studies to illustrate the rationale for their repurposing-repositioning and potential clinical use.

miR-130a-3p, a Preclinical Therapeutic Target for Crohn's Disease.

BACKGROUND: Crohn's disease [CD] is a chronic, relapsing and incurable inflammatory disorder. Micro RNAs [miRNAs], which modulate gene expression by binding to mRNAs, may make significant contributions to understanding the complex pathobiology and aetiology of CD. This study aimed to investigate the therapeutic role and mechanism of miR-130a-3p in CD. METHODS: Differentially expressed miRNAs in colon tissues of CD patients and normal controls [NCs] were screened using an miRNA microarray and then validated by quantitative reverse transcriptase-PCR [qRT-PCR]. The functional role of miR-130a-3p in the pathogenesis of CD was then demonstrated by in vitro and in vivo studies. The target genes of miR-130a-3p and the associated signalling pathways were identified using bioinformatics analysis and experimental verification of the interactions between the target predicted by the algorithms and dysregulated mRNAs. The therapeutic role of miR-130a-3p in trinitro-benzene-sulfonic acid [TNBS]-induced colitis models was further investigated. RESULTS: Our data demonstrated that miR-130a-3p is the most significantly upregulated miRNA and that miR-130a knockout significantly protects mice against TNBS-induced colitis. Gain- and loss-of-function studies indicated that miR-130a-3p promotes CD development by targeting ATG16L1 via the NF-κB pathway. Furthermore, an miR-130a-3p inhibitor significantly suppressed NLRP3 inflammasome activity by inducing autophagy in a mouse macrophage cell line [RAW264.7]. Therapeutically, an miR-130a-3p inhibitor effectively ameliorated the severity of TNBS-induced colitis. CONCLUSION: Our study reveals that miR-130a-3p promotes CD progression via the ATG16L1/NF-κB pathway and serves as a potential preclinical therapeutic target in CD.

A barrier against reactive oxygen species: chitosan/acellular dermal matrix scaffold enhances stem cell retention and improves cutaneous wound healing.

BACKGROUND: Stem cell therapies have gained great attention for providing novel solutions for treatment of various injuries and diseases due to stem cells' self-renewal, ability to differentiate into various cell types, and favorite paracrine function. Nevertheless, the low retention of transplanted stem cell still limits their clinical applications such as in wound healing in view of an induced harsh microenvironment rich in reactive oxygen species (ROS) during inflammatory reactions. METHODS: Herein, a novel chitosan/acellular dermal matrix (CHS/ADM) stem cell delivery system is developed, which is of great ROS scavenging activity and significantly attenuates inflammatory response. RESULT: Under ROS microenvironment, this stem cell delivery system acts as a barrier, effectively scavenging an amount of ROS and protecting mesenchymal stem cells (MSCs) from the oxidative stress. It notably regulates intracellular ROS level in MSCs and reduces ROS-induced cellular death. Most importantly, such MSCs delivery system significantly enhances in vivo transplanted stem cell retention, promotes the vessel growth, and accelerates wound healing. CONCLUSIONS: This novel delivery system, which overcomes the limitations of conventional plain collagen-based delivery system in lacking of ROS-environmental responsive mechanisms, demonstrates a great potential use in stem cell therapies in wound healing.

Biotherapy of Brain Tumors with Phosphatidylserine-Targeted Radioiodinated SapC-DOPS Nanovesicles.

Glioblastoma multiforme (GBM), a common type of brain cancer, has a very poor prognosis. In general, viable GBM cells exhibit elevated phosphatidylserine (PS) on their membrane surface compared to healthy cells. We have developed a drug, saposin C-dioleoylphosphatidylserine (SapC-DOPS), that selectively targets cancer cells by honing in on this surface PS. To examine whether SapC-DOPS, a stable, blood-brain barrier-penetrable nanovesicle, could be an effective delivery system for precise targeted therapy of radiation, we iodinated several carbocyanine-based fluorescent reporters with either stable iodine (127I) or radioactive isotopes (125I and 131I). While all of the compounds, when incorporated into the SapC-DOPS delivery system, were taken up by human GBM cell lines, we chose the two that best accumulated in the cells (DiI (22,3) and DiD (16,16)). Pharmacokinetics were conducted with 125I-labeled compounds and indicated that DiI (22,3)-SapC-DOPS had a time to peak in the blood of 0.66 h and an elimination half-life of 8.4 h. These values were 4 h and 11.5 h, respectively, for DiD (16,16)-SapC-DOPS. Adult nude mice with GBM cells implanted in their brains were treated with 131I-DID (16,16)-SapC-DOPS. Mice receiving the radionuclide survived nearly 50% longer than the control groups. These data suggest a potential novel, personalized treatment for a devastating brain disease.

Enhanced Efficacy of Combination of Gemcitabine and Phosphatidylserine-Targeted Nanovesicles against Pancreatic Cancer.

Phosphatidylserine (PS) is often externalized in viable pancreatic cancer cells and is therapeutically targetable using PS-selective drugs. One of the first-line treatments for advanced pancreatic cancer disease, gemcitabine (GEM), provides only marginal benefit to patients. We therefore investigated the therapeutic benefits of combining GEM and the PS-targeting drug, saposin C-dioleoylphosphatidylserine (SapC-DOPS), for treating pancreatic ductal adenocarcinoma (PDAC). Using cell-cycle analyses and a cell surface PS-based sorting method in vitro, we observed an increase in surface PS as cells progress through the cell cycle from G1 to G2/M. We also observed that GEM treatment preferentially targets G1 phase cells that have low surface PS, resulting in an increased median surface PS level of PDAC cells. Inversely, SapC-DOPS preferentially targets high surface PS cells that are predominantly in the G2/M phase. Finally, combination therapy in subcutaneous and orthotopic PDAC tumors in vivo with SapC-DOPS and GEM or Abraxane (Abr)/GEM (one of the current standards of care) significantly inhibits tumor growth and increases survival compared with individual treatments. Our studies confirm a surface PS and cell cycle-based enhancement of cancer cytotoxicity following SapC-DOPS treatment in combination with GEM or Abr/GEM. Thus, PDAC patients treated with Abr/GEM may benefit from concurrent administration of SapC-DOPS.