Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation.

Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/ß inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.

Oleanolic acid alleviates obesity-induced skeletal muscle atrophy via the PI3K/Akt signaling pathway.

Oleanolic acid (OA) is a pentacyclic triterpene with reported protective effects against various diseases, including diabetes, hepatitis, and different cancers. However, the effects of OA on obesity-induced muscle atrophy remain largely unknown. This study investigated the effects of OA on skeletal muscle production and proliferation of C2C12 cells. We report that OA significantly increased skeletal muscle mass and improved glucose intolerance and insulin resistance. OA inhibited dexamethasone (Dex)-induced muscle atrophy in C2C12 myoblasts by regulating the PI3K/Akt signaling pathway. In addition, it also inhibited expression of MuRF1 and Atrogin1 genes in skeletal muscle of obese mice suffering from muscle atrophy, and increased the activation of PI3K and Akt, thereby promoting protein synthesis, and eventually alleviating muscle atrophy. Taken together, these findings suggest OA may have potential for the prevention and treatment of muscle atrophy.

Dynamic flux balance analysis of 1,3-propanediol production by clostridium butyricum fermentation.

To study the relationship between the yield of 1,3-propanediol (1,3-PDO) and the flux change of the Clostridium butyricum metabolic pathway, an optimized calculation method based on dynamic flux balance analysis was used by combining genome-scale flux balance analysis with a kinetic model. A more comprehensive and extensive metabolic pathway was obtained by optimization calculations. The primary extended branches include: the dihydroxyacetone node, which enters the pentose phosphate pathway; the α-oxoglutarate node, which has synthetic metabolic pathways for glutamic acid and amino acids; and the serine and homocysteine nodes, which produce cystathionine before homocysteine enters the methionine cycle pathway. According to the expanded metabolic network, the flux distribution of key nodes in the metabolic pathway and the relationship between the flux distribution ratio of nodes and the yield of 1,3-PDO were analyzed. At the dihydroxyacetone node, the flux of dihydroxyacetone converted to dihydroxyacetone phosphate was positively correlated with the yield of 1,3-PDO. As an important intermediate product, the flux change in the metabolic pathway of α-oxoglutarate reacting with amino acids to produce glutamic acid is positively correlated with the yield. When pyruvate was used as the central node to convert into lactic acid and α-oxoglutarate, the proportion of branch flux was negatively correlated with the yield of 1,3-PDO. These studies provide a theoretical basis for the optimization and further study of the metabolic pathway of C. butyricum.

MiR-222-3p suppresses C2C12 myoblast proliferation and differentiation via the inhibition of IRS-1/PI3K/Akt pathway.

Numerous studies have revealed the profound impact of microRNAs on regulating skeletal muscle development and regeneration. However, the biological function and regulation mechanism of miR-222-3p in skeletal muscle remains largely unknown. In this study, miR-222-3p was found to be abundantly expressed in the impaired skeletal muscles, indicating that it might have function in the development and regeneration process of the skeletal muscle. MiR-222-3p overexpression impeded C2C12 myoblast proliferation and myogenic differentiation, whereas inhibition of miR-222-3p got the opposite results. The dual-luciferase reporter assay showed that insulin receptor substrate-1 (IRS-1) was the target gene of miR-222-3p. We next found that knockdown of IRS-1 could obviously suppress C2C12 myoblast proliferation and differentiation. Additionally, miR-222-3p-induced repression of myoblast proliferation and differentiation was verified to be associated with a decrease in phosphoinositide 3-kinase (PI3K)-Akt signaling. Overall, we demonstrated that miR-222-3p inhibited C2C12 cells myogenesis via IRS-1/PI3K/Akt pathway. Therefore, miR-222-3p may be used as a therapeutic target for alleviating muscle loss caused by inherited and nonhereditary diseases.

Clinical efficacy and safety of Cox-maze IV procedure for atrial fibrillation in patients with aortic valve calcification.

Objective: Atrial fibrillation is associated with a high incidence of heart valve disease. There are few prospective clinical research comparing aortic valve replacement with and without surgical ablation for safety and effectiveness. The purpose of this study was to compare the results of aortic valve replacement with and without the Cox-maze IV procedure in patients with calcific aortic valvular disease and atrial fibrillation. Methods: We analyzed one hundred and eight patients with calcific aortic valve disease and atrial fibrillation who underwent aortic valve replacement. Patients were divided into concomitant Cox maze surgery (Cox-maze group) and no concomitant Cox-maze operation (no Cox-maze group). After surgery, freedom from atrial fibrillation recurrence and all-cause mortality were evaluated. Results: Freedom from all-cause mortality after aortic valve replacement at 1 year was 100% in the Cox-maze group and 89%, respectively, in the no Cox-maze group. No Cox-maze group had a lower rate of freedom from atrial fibrillation recurrence and arrhythmia control than those in the Cox-maze group (P = 0.003 and P = 0.012, respectively). Pre-operatively higher systolic blood pressure (hazard ratio, 1.096; 95% CI, 1.004-1.196; P = 0.04) and post-operatively increased right atrium diameters (hazard ratio, 1.755; 95% CI, 1.182-2.604; P = 0.005) were associated with atrial fibrillation recurrence. Conclusion: The Cox-maze IV surgery combined with aortic valve replacement increased mid-term survival and decreased mid-term atrial fibrillation recurrence in patients with calcific aortic valve disease and atrial fibrillation. Pre-operatively higher systolic blood pressure and post-operatively increased right atrium diameters are associated with the prediction of recurrence of atrial fibrillation.

Bone marrow mesenchymal stem cell-derived exosomes reduce insulin resistance and obesity in mice via the PI3K/AKT signaling pathway.

Obesity is a common chronic metabolic disease that induces chronic systemic inflammation in the body, eventually leading to related complications such as insulin resistance (IR), type 2 diabetes mellitus, and metabolic syndromes such as cardiovascular disease. Exosomes transfer bioactive substances to neighboring or distal cells through autosomal, paracrine, or distant secretion, regulating the gene and protein expression levels of receptor cells. In this study, we investigated the effect of mouse bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) on high-fat diet obese mice and mature 3T3-L1 adipocyte models of IR. BMSC-Exo treatment of obese mice promoted their metabolic homeostasis, including reduction of obesity, inhibition of M1-type proinflammatory factor expression, and improvement of insulin sensitivity. In vitro analysis revealed that BMSC-Exos improved IR and lipid droplet accumulation in mature 3T3-L1 adipocytes treated with palmitate (PA). Mechanistically, BMSC-Exos cause increased glucose uptake and improved IR in high-fat chow-fed mice and PA-acting 3T3-L1 adipocytes by activating the phosphoinositide 3-kinases/protein kinase B (PI3K/AKT) signaling pathway and upregulating glucose transporter protein 4 (GLUT4) expression. This study offers a new perspective for the development of treatments for IR in obese and diabetic patients.

Machine learning-based analysis of risk factors for atrial fibrillation recurrence after Cox-Maze IV procedure in patients with atrial fibrillation and chronic valvular disease: A retrospective cohort study with a control group.

Objectives: To evaluate the efficacy of the Cox-Maze IV procedure (CMP-IV) in combination with valve surgery in patients with both atrial fibrillation (AF) and valvular disease and use machine learning algorithms to identify potential risk factors of AF recurrence. Methods: A total of 1,026 patients with AF and valvular disease from two hospitals were included in the study. 555 patients received the CMP-IV procedure in addition to valve surgery and left atrial appendage ligation (CMP-IV group), while 471 patients only received valve surgery and left atrial appendage ligation (Non-CMP-IV group). Kaplan-Meier analysis was used to calculate the sinus rhythm maintenance rate. 58 variables were selected as variables for each group and 10 machine learning models were developed respectively. The performance of the models was evaluated using five-fold cross-validation and metrics including F1 score, accuracy, precision, and recall. The four best-performing models for each group were selected for further analysis, including feature importance evaluation and SHAP analysis. Results: The 5-year sinus rhythm maintenance rate in the CMP-IV group was 82.13% (95% CI: 78.51%, 85.93%), while in the Non-CMP-IV group, it was 13.40% (95% CI: 10.44%, 17.20%). The eXtreme Gradient Boosting (XGBoost), LightGBM, Category Boosting (CatBoost) and Random Fores (RF) models performed the best in the CMP-IV group, with area under the curve (AUC) values of 0.768 (95% CI: 0.742, 0.786), 0.766 (95% CI: 0.744, 0.792), 0.762 (95% CI: 0.723, 0.801), and 0.732 (95% CI: 0.701, 0.763), respectively. In the Non-CMP-IV group, the LightGBM, XGBoost, CatBoost and RF models performed the best, with AUC values of 0.738 (95% CI: 0.699, 0.777), 0.732 (95% CI: 0.694, 0.770), 0.724 (95% CI: 0.668, 0.789), and 0.716 (95% CI: 0.656, 0.774), respectively. Analysis of feature importance and SHAP revealed that duration of AF, preoperative left ventricular ejection fraction, postoperative heart rhythm, preoperative neutrophil-lymphocyte ratio, preoperative left atrial diameter and heart rate were significant factors in AF recurrence. Conclusion: CMP-IV is effective in treating AF and multiple machine learning models were successfully developed, and several risk factors were identified for AF recurrence, which may aid clinical decision-making and optimize the individual surgical management of AF.

Effect of electrophysiological mapping on non-transmural annulus ablation and atrial fibrillation recurrence prediction after 6 months of Cox-Maze IV procedure.

Objective: The objective of this study was to observe the safety and efficacy of electrophysiological mapping following the Cox-Maze IV procedure and to investigate whether a correlation exists between recurrence of atrial fibrillation (AF) with the completeness of bidirectional electrical isolation and the inducibility of AF immediately after the Cox-Maze IV procedure. Methods: Totally, 80 consecutive patients who suffered from aortic valve or mitral valve disease and persistent AF were randomly enrolled into the control group and electrophysiological mapping following the Cox-Maze IV group (Electrophysio-Maze group). In the Electrophysio-Maze group, patients underwent concomitant Cox-Maze procedure and following electrophysiological mapping of ablation lines in mitral isthmus, left atrial "box," and tricuspid annulus. If the bidirectional electrical isolation of tricuspid annulus ablation line is incomplete, whether to implement supplementary ablation will be independently decided by the operator. Before and after the Cox-Maze IV procedure, AF induction was performed. All patients in both groups were continuously followed-up and underwent electrocardiogram Holter monitoring after 6 months. Results: In total, 42 Electrophysio-Maze patients and 38 controls were enrolled. Compared with patients in the control group, there were shorter hospital stay, better cardiac remodeling changes, and higher relief from AF during the follow-up period of 6 months in the Electrophysio-Maze group. Within the Electrophysio-Maze group, the rate of incomplete the bidirectional electrical isolation of "box" ablation lines was zero, and the rate of incomplete bidirectional electrical isolation of mitral isthmus ablation line or tricuspid annulus ablation line was 23.8%. After two cases of successful complementary ablation on the tricuspid annulus ablation line, the final incomplete bidirectional electrical isolation of annulus ablation lines was 19.0%. There were correlations between late AF recurrence after 6 months with incomplete bidirectional electrical isolation of annulus ablation lines and AF induction immediately after the Cox-Maze IV procedure. Conclusion: Electrophysiological mapping following the Cox-Maze procedure is safe and effective. Electrophysiological mapping in the Cox-Maze procedure can find out the non-transmural annulus ablation lines by assessing the completeness of bidirectional electrical isolation of ablation lines, guide supplementary ablation, and predict AF recurrence after 6 months.

Bu Shen Yi Sui Capsules Promote Remyelination by Regulating MicroRNA-219 and MicroRNA-338 in Exosomes to Promote Oligodendrocyte Precursor Cell Differentiation.

Remyelination is a refractory feature of demyelinating diseases such as multiple sclerosis (MS). Studies have shown that promoting oligodendrocyte precursor cell (OPC) differentiation, which cannot be achieved by currently available therapeutic agents, is the key to enhancing remyelination. Bu Shen Yi Sui capsule (BSYSC) is a traditional Chinese herbal medicine over many years of clinical practice. We have found that BSYSC can effectively treat MS. In this study, the effects of BSYSC in promoting OPCs differentiation and remyelination were assessed using an experimental autoimmune encephalomyelitis (EAE) model in vivo and cultured OPCs in vitro. The results showed that BSYSC reduced clinical function scores and increased neuroprotection. The expression of platelet-derived growth factor receptor α (PDGFR-α) was decreased and the level of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) was increased in the brains and spinal cords of mice as well as in OPCs after treatment with BSYSC. We further found that BSYSC elevated the expression of miR-219 or miR-338 in the serum exosomes of mice with EAE, thereby suppressing the expression of Sox6, Lingo1, and Hes5, which negatively regulate OPCs differentiation. Therefore, serum exosomes of BSYSC-treated mice (exos-BSYSC) were extracted and administered to OPCs in which miR-219 or miR-338 expression was knocked down by adenovirus, and the results showed that Sox6, Lingo1, and Hes5 expression was downregulated, MBP expression was upregulated, OPCs differentiation was increased, and the ability of OPCs to wrap around neuronal axons was improved. In conclusion, BSYSC may exert clinically relevant effects by regulating microRNA (miR) levels in exosomes and thus promoting the differentiation and maturation of OPCs.

Chinese Medicine Formula Siwu-Yin Inhibits Esophageal Precancerous Lesions by Improving Intestinal Flora and Macrophage Polarization.

Siwu-Yin (SWY), a traditional Chinese medicinal formula, can replenish blood and nourish Yin. It was recorded in ancient Chinese medicine books in treating esophageal dysphagia, which has similar symptoms and prognosis with esophageal precancerous lesions and esophageal cancer. However, its effect has not been established in vivo. This study explores the antiesophageal cancer effect of SWY on rats with esophageal precancerous lesions. By performing 16S rRNA gene sequencing and metabolomics, it was suggested that SWY may improve the composition of intestinal flora of rats by regulating the synthesis and secretion of bile acids. In addition, flow cytometry results showed that SWY treatment modified tumor microenvironment by improving macrophage polarization and therefore inhibiting the occurrence of esophageal precancerous lesions.

Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model.

Chaperone-mediated autophagy (CMA) is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases. However, the mechanisms that regulate CMA are not fully understood. Here, using unbiased drug screening approaches, we discover Metformin, a drug that is commonly the first medication prescribed for type 2 diabetes, can induce CMA. We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/ß signaling that leads to phosphorylation of Ser85 of the key mediator of CMA, Hsc70, and its activation. Notably, we find that amyloid-beta precursor protein (APP) is a CMA substrate and that it binds to Hsc70 in an IKKα/ß-dependent manner. The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity. Importantly, we find that in the APP/PS1 mouse model of Alzheimer's disease (AD), activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aß plaque levels and reverses the molecular and behavioral AD phenotypes. Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/ß-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases, such as AD, where such therapeutic intervention could be beneficial.

Bu Shen Yi Sui Capsule Alleviates Neuroinflammation and Demyelination by Promoting Microglia toward M2 Polarization, Which Correlates with Changes in miR-124 and miR-155 in Experimental Autoimmune Encephalomyelitis.

BACKGROUND: Bu Shen Yi Sui capsule (BSYS) is a traditional Chinese medicine prescription that has shown antineuroinflammatory and neuroprotective effects in treating multiple sclerosis (MS) and its animal model of experimental autoimmune encephalomyelitis (EAE). Microglia play an important role in neuroinflammation. The M1 phenotype of microglia is involved in the proinflammatory process of the disease, while the M2 phenotype plays an anti-inflammatory role. Promoting the polarization of microglia to M2 in MS/EAE is a promising therapeutic strategy. This study is aimed at exploring the effects of BSYS on microglial polarization in mice with EAE. METHODS: The EAE model was established by the intraperitoneal injection of pertussis toxin and subcutaneous injection of myelin oligodendrocyte glycoprotein (MOG)35-55 in C57BL/6J mice. The mice were treated with BSYS (3.02 g/kg), FTY720 (0.3 mg/kg), or distilled water by intragastric administration. H&E and LFB staining, transmission electron microscopy, qRT-PCR, immunofluorescence, ELISA, fluorescence in situ hybridization, and western blotting were used to detect the histological changes in myelin, microglial M1/M2 polarization markers, and the expression of key genes involved in EAE. Results and Conclusions. BSYS treatment of EAE mice increased the body weight, decreased the clinical score, and reduced demyelination induced by inflammatory infiltration. BSYS also inhibited the mRNA expression of M1 microglial markers while increasing the mRNA level of M2 markers. Additionally, BSYS led to a marked decrease in the ratio of M1 microglia (iNOS+/Iba1+) and an obvious increase in the number of M2 microglia (Arg1+/Iba1+). In the EAE mouse model, miR-124 expression was decreased, and miR-155 expression was increased, while BSYS treatment significantly reversed this effect and modulated the levels of C/EBP α, PU.1, and SOCS1 (target genes of miR-124 and miR-155). Therefore, the neuroprotective effect of BSYS against MS/EAE was related to promoting microglia toward M2 polarization, which may be correlated with changes in miR-124 and miR-155 in vivo.

ARIH1 signaling promotes anti-tumor immunity by targeting PD-L1 for proteasomal degradation.

Cancer expression of PD-L1 suppresses anti-tumor immunity. PD-L1 has emerged as a remarkable therapeutic target. However, the regulation of PD-L1 degradation is not understood. Here, we identify several compounds as inducers of PD-L1 degradation using a high-throughput drug screen. We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation. Overexpression of ARIH1 suppresses tumor growth and promotes cytotoxic T cell activation in wild-type, but not in immunocompromised mice, highlighting the role of ARIH1 in anti-tumor immunity. Moreover, combining EGFR inhibitor ES-072 with anti-CTLA4 immunotherapy results in an additive effect on both tumor growth and cytotoxic T cell activation. Our results delineate a mechanism of PD-L1 degradation and cancer escape from immunity via EGFR-GSK3α-ARIH1 signaling and suggest GSK3α and ARIH1 might be potential drug targets to boost anti-tumor immunity and enhance immunotherapies.

Bioconversion of Raw Glycerol From Waste Cooking-Oil-Based Biodiesel Production to 1,3-Propanediol and Lactate by a Microbial Consortium.

Waste cooking oil (WCO) is a sustainable alternative to raw vegetable oils and fats for biodiesel production considering both environmental and economic benefits. Raw glycerol from WCO-based biodiesel production (GWCO) is difficult to utilize via biological method, as multiple toxic impurities have inhibitory effects on microbial growth especially for pure cultures. In this work, four microbial consortia were selected from activated sludge by 30 serial transfers under different conditions. The obtained consortia exhibited lower diversity and species difference with the transfers. The consortium LS30 exhibited unique advantages for bioconversion of GWCO to 1,3-propanediol (1,3-PDO) and lactate (LA). Moreover, the fermentation could be performed economically under microaerobic and non-sterile conditions. The consortium consisted of 57.97% Enterobacter and 39.25% Escherichia could effectively convert 60 g/L GWCO to 1,3-PDO and LA in batch fermentation. In addition, this consortium exhibited better tolerance to fatty acid-derived crude glycerol (100 g/L), which demonstrated that specific toxic impurities in GWCO did pose a great challenge to microbial growth and metabolism. In fed batch fermentation, 27.77 g/L 1,3-PDO and 14.68 g/L LA were achieved. Compared with the consortium, a long lag phase in cell growth associated with a decreased glycerol consumption was observed in four single-strain fermentations. Furthermore, neither the consortium DL38 with excellent glycerol tolerance nor consortium C2-2M with high yield of 1,3-PDO could effectively transform GWCO into valuable products. The results demonstrated that the selected microbial consortium has the advanced adaptability to the toxic impurities in GWCO compared with other reported consortia and isolated single strain. This process can contribute to added-value use of GWCO.

Mechanism of Lycium barbarum polysaccharides liposomes on activating murine dendritic cells.

Dendritic cells (DCs) are professional antigen-presenting cells (APC) that play a central role in the initiation and regulation of immune responses. We have previously demonstrated that Lycium barbarum polysaccharides liposomes (LBPL) as immune adjuvant elicits strong antigen-specific Th1 immune responses. The purpose of this study was to investigate underlying mechanism of liposomes promoting effect of Lycium barbarum polysaccharides (LBP) on activating DCs. LBP were loaded with high entrapment efficiency (86%) into liposomes using reverse phase evaporation. LBPL activation of phenotypic and functional maturation of DCs was explored through mechanistic studies of the TLR4-MyD88-NF-κB signaling pathway and amount of proinflammatory cytokines released. We found that LBPL indeed activated immature DCs and induced DCs maturation characterized by up-regulation of co-stimulatory molecules (MHCII, CD80, CD86), production of cytokines (IL-12p40, TNF-α), and enhancement of antigen uptake. Additionally, we demonstrated that liposomes could promote LBP up-regulation of TLR4, MyD88, TRAF6, NF-κB gene and protein expression.

Angelica sinensis polysaccharide encapsulated into PLGA nanoparticles as a vaccine delivery and adjuvant system for ovalbumin to promote immune responses.

Nanoparticles (NPs)-based vaccine delivery systems are widely used for their ability to control the release of antigens and promote immune responses against cancer or infectious diseases. In this study, the immunopotentiator Angelica sinensis polysaccharide (ASP) and model protein antigen ovalbumin (OVA) were encapsulated into Poly(lactic-co-glycolic acid) (PLGA) to formulate the novel NPs-based vaccine delivery system (ASP-PLGA/OVA). These formulations were subcutaneously administered to mice, then the magnitude and kinetics of antibody and cellular immune responses were assessed. The ASP-PLGA/OVA NPs were pherical in shape with smooth surfaces, approximately 225.2 nm in average size, negatively charged (around -11.27 mV), and the encapsulation efficiency of OVA at around 66.28%, respectively. Furthermore, ASP-PLGA/OVA NPs could keep stable at 4 °C over 30 days and provide a sustained and controlled release of OVA from the NPs. The results demonstrated that mice immunized with ASP-PLGA/OVA NPs could significantly enhance lymphocyte proliferation and improve the ratio of CD4+ to CD8+ T cells, thereby ASP-PLGA/OVA NPs could induce a strong cellular immune response. Moreover, the ASP-PLGA/OVA NPs could induce vigorous and long-term IgG immune responses with a mixed Th1 and Th2 responses and up-regulate the levels of Th-associated cytokines. These results suggested that ASP-PLGA/OVA NPs, which stimulated strong and continuous antibody responses and induced cellular immune responses, could potentially serve as an efficient and safe vaccine delivery and adjuvant system against infections and diseases.

Immunopotentiation of Polysaccharides of Atractylodes macrocephala Koidz-loaded nanostructured lipid carriers as an adjuvant.

The immunoregulation and immunopotentiation of Polysaccharides of Atractylodes macrocephala Koidz (PAMK) have been widely demonstrated. Nanostructured lipid carriers (NLC) have high drug loading capacity for lipophilic and hydrophilic drugs, and have good biocompatibility and high bioavailability. In this study, the effect of PAKM-NLC on the surface molecule expression of bone marrow-derived dendritic cells (BMDCs) in vitro was investigated by flow cytometry, and the cytokines secreted by dendritic cell supernatants were detected by ELISA. The results showed that compared with other control groups, PAMK-NLC could significantly increase the expression of CD80 and CD86 and promote the secretion of IL-1ß, IL-12, TNF-α and IFN-γ, indicating that PAMK-NLC have a more pronounced effect on the maturation and differentiation of BMDCs. In addition, effects of PAMK-NLC nanoparticles on OVA-immunized mice were explored. Compared with other control groups, PAMK-NLC-OVA can significantly promote the production of OVA-specific antibodies in serum, stimulate the secretion of cytokines, increase the proliferation rate of spleen lymphocytes after OVA re-stimulation, and induce stronger activation of CD3+CD4+ and CD3+CD8+ lymphocytes. As an adjuvant of OVA, PAMK-NLC has a better immunological enhancement effect than PAMK or blank NLC, and has good adjuvant activity.

Is chronic hepatitis B infection a protective factor for the progression of advanced pancreatic ductal adenocarcinoma? An analysis from a large multicenter cohort study.

PURPOSE: Whether the progression of advanced pancreatic ductal adenocarcinoma (PDAC) patients could be affected by HBV exposure remains to be determined. Therefore, we conducted this study to assess the effect of HBV infection on PDAC progression among a large cohort in China. METHODS: A multicenter cohort study was conducted to explore whether liver metastasis and overall survival in locally advanced and metastatic PDAC could be affected by HBV infection. In this study, we collected 1,526 advanced PDAC patients at three participating hospitals - Shanghai Cancer Center, Changhai Hospital and Ruijin Hospital from 2004 to 2013. The association between HBV status and advanced PDAC progression was then examined. RESULTS: In multivariable Logistic regression model, chronic hepatitis B(CHB) infection was inversely associated with synchronous liver metastasis compared to non HBV infection (OR 0.41, 95% CI 0.19-0.85) for stage IV patients. In a multivariable Cox model, CHB infection (HR=0.11, 95% CI 0.02-0.82) is considered as a protective factor of metachronous liver metastasis compared to Non HBV infection for stage III patients. For stage IV patients, CHB infection was inversely associated with overall survival compared to non HBV infection (HR 0.70, 95% CI 0.51-0.95). Inactive carrier(IC) and resolved HBV infection showed no significant association with survival compared to non HBV infection. CONCLUSION: This study indicated that CHB infection may serve as an independent factor which decrease synchronous or metachronous liver metastasis, and increase overall survival among advanced PDAC patients.

Value of Multimode Sonography for Assessment of Pelvic Lipomatosis Compared With Computed Tomography.

OBJECTIVES: To assess imaging features of pelvic lipomatosis with a multimode sonographic technique, including 2-dimensional (2D) grayscale sonography, 3-dimensional (3D) sonography, and transrectal sonography, and compare its diagnostic features with those of computed tomography (CT). METHODS: In this study, 7 patients with different clinical manifestations were incidentally discovered by 2D sonography and followed by 3D and transrectal sonography before CT was performed for comparison. The urinary tract morphologic characteristics, bladder shape, and amount and distribution of perivesical or perirectal fatty tissue in all 7 patients were evaluated by both imaging modalities. Ten healthy participants were recruited and imaged as a control group. RESULTS: The following sonographic features were shown in all 7 patients: (1) bilateral hydroureters and hydronephrosis on 2D sonography; (2) bladder shifting anteriorly and superiorly on 2D sonography; (3) nonvisualization of the prostate through the bladder window on transabdominal scanning and nonvisualization of the bladder when the prostate was scanned by transrectal sonography; (4) bladder elongation in the craniocaudal dimension, which appeared as a gourd or pear shape on 3D sonography; and (5) excessive fat accumulation between the prostate and rectum as well as in perivesical or perirectal regions on 2D and transrectal sonography. Computed tomography in these patients confirmed the sonographic findings, with evidence of hydronephrosis, bladder location shift and elongation, and excessive fitty tissue with extrinsic compression. CONCLUSIONS: This preliminary study has shown that the application of a multimode sonographic technique (ie, 2D, 3D, and transrectal sonography) can provide unique evidence and imaging features of pelvic lipomatosis, which are comparable with CT for making a suggestive diagnosis of pelvic lipomatosis. Thus, multimode sonography may be the modality of choice for assessment of patients with a suspicion of lipomatosis.