ROUX-en-Y gastric bypass surgery improves metabolic syndrome-related erectile dysfunction in mice via the IRS-1/PI3K/AKT/eNOS pathway.

Objective: Although many clinical studies have shown that ROUX-en-Y gastric bypass (RYGB) surgery significantly improves metabolic syndrome-related erectile dysfunction (MED), the role and mechanism are unclear. Aim: In this study we used a mouse model to explore how RYGB improves MED induced by a high-fat diet (HFD). Methods: We established a mouse model of metabolic syndrome by feeding an HFD for 16 weeks. The mice were randomly assigned to the standard chow diet (SCD), HFD, or RYGB groups. Body weight, fasting blood glucose, plasma insulin, and total plasma cholesterol were analyzed. Erectile responses were evaluated by determining the mean systolic blood pressure and the intracavernosal pressure (ICP). Penile histologic examination (Masson's trichrome and immunohistochemical stain) and Western blot were performed. Result: Compared with the SCD group, the ICP in the sham group was significantly lower, and the ICP of the RYGB was significantly increased. Masson's trichrome and immunohistochemical staining showed that the content of endothelium and smooth muscle in the corpus cavernosum of mice with MED was significantly reduced. Western blot analysis showed a significant decrease in α-smooth muscle actin and a significant increase in osteopontin in penile tissue in the sham group, which was improved by RYGB surgery. Furthermore, RYGB significantly increased IRS-1/PI3K/Akt/eNOS phosphorylation. Clinical Translation: In this study we explored the mechanism of bariatric surgery to improve erectile dysfunction associated with metabolic syndrome and provided a theoretical basis for clinical research. Strengths and Limitations: First, we did not investigate the mechanism by which RYGB affects the IRS-1/PI3K/Akt/eNOS signaling pathway. Second, the effect of the IRS-1/PI3K/Akt/eNOS signaling pathway on the function of corpus cavernosum endothelial cells and smooth muscle cells remains to be investigated in cellular studies. Conclusion: This study demonstrated that RYGB may not only improve metabolic parameters but also restore erectile function in MED patients. The mechanism of the therapeutic effect of RYGB may be reactivation of the IRS-1/PI3K/Akt/eNOS pathway.

Study on the effects and mechanisms of Wenzhong Bushen Formula in improving ovarian reserve decline in mice based on network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: The Wenzhong Bushen Formula (WZBSF) is a traditional Chinese medicine empirical formula known for its effects in tonifying qi, strengthening the spleen, warming the kidneys, promoting yang, regulating blood circulation, and balancing menstruation. Clinical evidence has demonstrated its significant efficacy in treating Diminished Ovarian Reserve (DOR) by improving ovarian reserves. However, the specific pharmacological mechanisms of WZBSF remain unclear. AIM OF THE STUDY: This study aims to investigate the mechanisms by which WZBSF improves ovarian reserve decline through network pharmacology and animal experiments. METHODS AND MATERIALS: WZBSF was analyzed using a dual UPLC-MS/MS and GC-MS platform. Effective components and targets of WZBSF were obtained from the TCMSP database and standardized using UniProt. Disease targets were collected from GeneCard, OMIM, PHARMGKB, and DisGeNET databases, with cross-referencing between the two sets of targets. A PPI protein interaction network was constructed using Cytoscape3.9.1 and STRING database, followed by KEGG and GO enrichment analysis using the Metascape database. Finally, an ovarian reserve decline model was established in mice, different doses of WZBSF were administered, and experimental validation was conducted through serum hormone detection, H&E staining, immunofluorescence (IF), immunohistochemistry (IHC), and Western blot analysis (WB). RESULTS: WZBSF shares 145 common targets with ovarian reserve decline. GO enrichment analysis revealed involvement in biological processes such as response to hormone stimulation and phosphatase binding, while KEGG analysis implicated pathways including the PI3K-AKT signaling pathway and FoxO signaling pathway. In mice with ovarian reserve decline, WZBSF restored weight gain rate, increased ovarian index, normalized estrous cycles, reversed serum hormone imbalances, restored various follicle counts, and improved ovarian morphology. Additionally, WZBSF reduced p-AKT and p-FOXO3a levels, preventing excessive activation of primordial follicles and maintaining ovarian reserve. CONCLUSION: WZBSF can ameliorate cyclophosphamide and busulfan-induced ovarian reserve decline, and its mechanism may be associated with the inhibition of the PI3K/AKT/FOXO3a signaling pathway.

Targeted co-delivery of resiquimod and a SIRPα variant by liposomes to activate macrophage immune responses for tumor immunotherapy.

Tumor-associated macrophages (TAMs) are the major immune cells infiltrating the tumor microenvironment (TME) and typically exhibit an immunosuppressive M2-like phenotype, which facilitates tumor growth and promotes resistance to immunotherapy. Additionally, tumor cells tend to express high levels of CD47, a "don't eat me" signal, that obstructs macrophage phagocytosis. Consequently, re-educating TAMs in combination with CD47 blockage is promising to trigger intense macrophage immune responses against tumors. As a toll-like receptor 7/8 agonist, resiquimod (R848) possesses the capacity to re-educate TAMs from M2 type to M1 type. We found that intratumoral administration of R848 synergistically improved the antitumor immunotherapeutic effect of CV1 protein (a SIRPα variant with high antagonism to CD47). However, the poor bioavailability and potential toxicity of this combo strategy remain a challenge. Here, a TAMs-targeted liposome (named: R-LS/M/CV1) co-delivering R848 and CV1 protein was constructed via decorating mannose on the liposomal surface. R-LS/M/CV1 exhibited high abilities of targeting, re-education and pro-phagocytosis of tumor cells to M2 macrophages in vitro. Intratumoral administration of R-LS/M/CV1 remarkedly eliminated tumor burden in the MC38 tumor model via repolarization of TAMs to M1 type, pro-phagocytosis of TAMs against tumors, and recruitment of tumor-infiltrating T cells. More encouragingly, due to the double targeting to TAMs and tumor cells of mannose and CV1 protein, R-LS/M/CV1 effectively accumulated at the tumor site, thereby not only remarkedly inhibiting tumors, but also exerting no hematological and histopathological toxicity when administered systemically. Our integrated strategy based on re-educating TAMs and CD47 blockade provides a promising approach to trigger macrophage immune responses against tumors for immunotherapy.

Molecular Dynamics Study of Silica Nanoparticles and CO2-Switchable Surfactants at an Oil-Water Interface.

Adsorbing CO2-sensitive surfactants on the surface of nanoparticles is an important strategy for preparing stimuli-responsive Pickering emulsions. However, the microscopic mechanisms are still limited, owing to a lack of intuitive understanding at the molecular level on the interactions between nanoparticle and switchable surfactants at the oil-water interface. We employed the molecular dynamics (MD) simulations to explore the mechanism behind the reversible emulsification/demulsification of a Pickering emulsion stabilized by silica nanoparticles (NPs) and CO2-switchable surfactants, named N-(3-(dimethylamino)propyl)alkyl amide (CPMA). MD results show that the protonated surfactant CPMAH+ has strong hydrophilicity, forming an adsorption layer at the oil-water interface. The ionic surfactants can be tightly adsorbed on NP surface through electrostatic interactions. Thus, the formed colloid particle has both hydrophobic and hydrophilic properties, which is a key factor in stabilizing emulsion. When CPMAH+ molecules were deprotonated to CPMA, the hydration activity of the headgroups reduced greatly, inducing a mixture with oil molecules. There are still a certain number of CPMA molecules residing at the oil-water interface due to the hydrophilic amine groups. The results from repeated simulations show that NP can either stay in the water phase or locate at the interface. Even NP was finally adsorbed on the interface and combined with CPMA or oil molecules, the adsorption configuration of CPMA on the NP surface was essentially different from that of CPMAH+. The potential of mean force confirmed that the combination between NP and CPMA is quite unstable due to the disappearance of electrostatic attraction. Different binding configurations and stability between NP and CPMA or CPMAH+ were the fundamental reason for the reversible emulsification/demulsification of Pickering emulsion.

Based on network pharmacology to explore the effect and mechanism of Yipibushen decoction in improving obese type 2 diabetes mellitus with oligoasthenotspermia.

ETHNOPHARMACOLOGICAL RELEVANCE: A traditional Chinese medicine experience compound known as Yipibushen (YPBS) decoction stimulates qi and nourishes yin, stimulates the kidney and solid essence, dissolves phlegm and eliminates stasis. YPBS decoction has proven to be successful in treating obese type 2 diabetes mellitus with oligoasthenotspermia in clinical settings. Nevertheless, the pharmacological mechanism is not understood. AIM OF THE STUDY: Investigating the mechanism of action of YPBS decoction in enhancing the obese type 2 diabetes mellitus with oligoasthenotspermia involved network pharmacology and animal validation techniques. METHODS AND MATERIALS: The YPBS Decoction' active components were found in the TCMSP database and their targets were identified using UniProtKB. Additionally, targets for the obese type 2 diabetes mellitus with oligoasthenotspermia were found in the GeneCard, DisGeNet, TTD and OMIM databases. The intersection of active ingredients, the obese type 2 diabetes mellitus with oligoasthenotspermia was chosen as the intersection target. The protein-protein interaction (PPI) network of the intersection target was built with the aid of Cytoscape 3.9.1, the core target of PPI was obtained through software analysis in R-project, GO enrichment and KEGG enrichment analysis was carried out on the core target. Finally, animal experiments were used to verify the intersection target. RESULTS: The research revealed 74 intersection targets of YPBS decoction active ingredients in the obese type 2 diabetes mellitus with oligoasthenotspermia. There were also 18 PPI core targets, GO enrichment analysis of PPI core targets involving response to oxidative stress, membrane raft, DNA-binding transcription regulator complex and other biological processes; KEGG involving endocrine resistance, PI3K/AKT signaling pathway, apoptosis and other signal pathways. In the obese type 2 diabetes mellitus with oligoasthenotspermia mice, animal studies have shown that YPBS decoction group could decrease blood glucose levels and improve insulin resistance; improve testicular function, enhance sperm count, sperm motility, sperm viability, and decrease the malformation rate. It could increase the levels of T-SOD and GSH-Px, and decrease the MDA level. In addition to this, it could improve the amount of testosterone hormone, and enhance the expression of PI3K, p-AKT and Bcl-2. CONCLUSION: By controlling the degree of oxidative stress and the PI3K/AKT/Bcl-2 pathway, YPBS decoction may enhance the obese type 2 diabetes mellitus with Oligoasthenotspermia, provide a scientific basis for clinical diagnosis and therapy.

Codelivery of TRAIL and Mitomycin C via Liposomes Shows Improved Antitumor Effect on TRAIL-Resistant Tumors.

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) constitutes a promising antitumor drug, tumor resistance to TRAIL has become a major obstacle in its clinical application. Mitomycin C (MMC) is an effective TRAIL-resistant tumor sensitizer, which indicates a potential utility of combination therapy. However, the efficacy of this combination therapy is limited owing to its short half-life and the cumulative toxicity of MMC. To address these issues, we successfully developed a multifunctional liposome (MTLPs) with human TRAIL protein on the surface and MMC encapsulated in the internal aqueous phase to codeliver TRAIL and MMC. MTLPs are uniform spherical particles that exhibit efficient cellular uptake by HT-29 TRAIL-resistant tumor cells, thereby inducing a stronger killing effect compared with control groups. In vivo assays revealed that MTLPs efficiently accumulated in tumors and safely achieved 97.8% tumor suppression via the synergistic effect of TRAIL and MMC in an HT-29 tumor xenograft model while ensuring biosafety. These results suggest that the liposomal codelivery of TRAIL and MMC provides a novel approach to overcome TRAIL-resistant tumors.

Liposome-Based Co-Immunotherapy with TLR Agonist and CD47-SIRPα Checkpoint Blockade for Efficient Treatment of Colon Cancer.

Antitumor immunity is an essential component of cancer therapy and is primarily mediated by the innate immune response, which plays a critical role in initiating and shaping the adaptive immune response. Emerging evidence has identified innate immune checkpoints and pattern recognition receptors, such as CD47 and Toll-like receptor 7 (TLR7), as promising therapeutic targets for cancer treatment. Based on the fusion protein Fc-CV1, which comprises a high-affinity SIRPα variant (CV1), and the Fc fragment of the human IgG1 antibody, we exploited a preparation which coupled Fc-CV1 to imiquimod (TLR7 agonist)-loaded liposomes (CILPs) to actively target CT26. WT syngeneic colon tumor models. In vitro studies revealed that CILPs exhibited superior sustained release properties and cell uptake efficiency compared to free imiquimod. In vivo assays proved that CILPs exhibited more efficient accumulation in tumors, and a more significant tumor suppression effect than the control groups. This immunotherapy preparation possessed the advantages of low doses and low toxicity. These results demonstrated that a combination of immune checkpoint blockade (ICB) therapy and innate immunity agonists, such as the Fc-CV1 and imiquimod-loaded liposome preparation utilized in this study, could represent a highly effective strategy for tumor therapy.

Metformin improves polycystic ovary syndrome in mice by inhibiting ovarian ferroptosis.

Background and objective: PCOS is a common metabolic disorder in women of reproductive age, which pathogenesis is very complex. The role of ferroptosis in PCOS is a novel finding, and the mechanistic studies are not clear. Metformin is a commonly used drug of PCOS but few studies on whether metformin can improve the follicle development and ovarian function in PCOS. We aims to use PCOS mouse model to study the effect of metformin on PCOS based on the ovarian function and explored the regulation of metformin in PCOS mice by intervening in ferroptosis pathway. Materials and methods: C57 BL/6J female mice aged 4-5 weeks were purchased and gavaged with letrozole (1 mg/kg/day) combined with high-fat diet for 21days to establish PCOS model, and control group was set up. After modeling, the mice were divided into PCOS model group and metformin treatment group (Met) (n=6).The Met group were gavaged metformin (200 mg/kg/day) for 28 days. The body weight, estrous cycle, glucose tolerance test (OGTT)and insulin resistance test (ITT) were monitored. Then, The mice were euthanized to collect serum and ovaries. Elisa was used to detect changes in related serum hormones (E2, LH, FSH, TP). Ovaries used for molecular biology experiments to detect changes in GPX4, SIRT3, AMPK/p-AMPK, and mTOR/p-mTOR by Western blot and qPCR. Results: Compared with the model group mice, body weight was significantly reduced, and their estrous cycle was restored in Met group. The results of OGTT and ITT showed an improvment of glucose tolerance and insulin resistance. Morphological results showed that after metformin treatment, polycystic lesions in ovaries were reduced, the ovarian function was restored, and the expressions of SIRT3 and GPX4 were elevated. WB results demonstrated that the expressions of p-mTOR and p-AMPK in ovaries were significantly reduced in Model group, but reversed in MET group. Conclusion: Our study confirmed metformin could not only improve body weight and metabolism disorders, but also improve ovarian dysfunction in PCOS mice.In addition, we explored metformin could regulate ferroptosis to improve PCOS via the SIRT3/AMPK/mTOR pathway. Our study complements the mechanisms by which metformin improves PCOS.

3D Printed Hybrid Aerogel Gauzes Enable Highly Efficient Hemostasis.

Hemostatic materials have played a significant role in mitigating traumatic injury by controlling bleeding, however, the fabrication of the desirable material's structure to enhance the accumulation of blood cells and platelets for highly efficient hemostasis is still a great challenge. In this work, directed assembly of poly(vinyl alcohol) (PVA) macromolecules covering the rigid Kevlar nanofiber (KNF) network during 3D printing process is utilized to fabricate hydrophilic, biocompatible, and mechanically stable KNF-PVA aerogel filaments for effective enriching blood components by fast water absorption. As such, KNF-PVA aerogel gauzes demonstrate remarkable water permeability (338 mL cm-2 s-1 bar-1 ), water absorption speed (as high as 9.64 g g-1 min-1 ) and capacity (more than ten times of self-weight), and ability to enrich micron-sized particles when contacting aqueous solution. All these properties favor efficient hemostasis and the resulting KNF-PVA aerogel gauzes significantly outperform the commercial product Quikclot Gauze (Z-Medica) during in vivo experiments with the rat liver laceration model, reducing the hemostasis time by half (60 ± 4 s) and the blood loss by two thirds (0.07 ± 0.01 g). These results demonstrate a robust strategy to design various aerogel gauzes for hemostasis applications.

Periurethral and Intravenous Injections of Adipose-Derived Stem Cells to Promote Local Tissue Recovery in a Rat Model of Stress Urinary Incontinence.

OBJECTIVE: To compare the effects of periurethral and intravenous injection of adipose-derived stem cells (ADSCs) on voiding function and tissue recovery in a stress urinary incontinence (SUI) rat model. METHODS: Sixty-four postpartum rats were randomly allocated to a normal group and the SUI model was established in 48 rats by vagina balloon dilation and bilateral ovariectomy. The SUI rats were randomized into 3 groups and received urethral injection of PBS (SUI group), periurethral injection of ADSCs (PU group), and intravenous injection of ADSCs (IV group) in 10 days after the ovariectomy. After 1, 7, and 14 days, ADSCs were tracked in urethra specimen. The urinary function of the remaining rats was analyzed at day 28, and urethral tissues were harvested for Western blotting and histochemical analyses. RESULTS: Alpha smooth muscle actin, myosin heavy chain, vascular endothelial growth factor, and neurofilament protein expression was increased in the IV and PU groups. Voiding function was also improved, with no significant differences between the IV and PU groups. The cell retention rate in rat urethral tissues was higher in the PU group than that in the IV group. Compared with the IV group, myosin heavy chain, vascular endothelial growth factor, neurofilament and transforming growth factor-ß1 (TGF-ß1)/Smad pathway protein expression levels were significantly higher in the PU group, while alpha smooth muscle actin expression was significantly lower (P < .05). CONCLUSION: Periurethral and intravenous injection of ADSCs induces different degrees of recovery of the urethral sphincter, cytokine secretion levels and cell retention rates in the urethral tissues in SUI rats, however, there was no significant difference in 2 methods.

[Metformin improves polycystic ovary syndrome and activates female germline stem cells in mice].

Polycystic ovary syndrome (PCOS) is a common disease caused by complex endocrine and metabolic abnormalities in women of childbearing age. Metformin is the most widely used oral hypoglycemic drug in clinic. In recent years, metformin has been used in the treatment of PCOS, but its mechanism is not clear. In this study, we aimed to investigate the effect of metformin on PCOS and its mechanism through PCOS mouse model. Female C57BL/6J mice aged 4-5 weeks were intragastrically given letrozole (1 mg/kg daily) combined with a high-fat diet (HFD) for 21 days to establish the PCOS model. After modeling, metformin (200 mg/kg daily) was intragastrically administered. One month later, the body weight and oral glucose tolerance test (OGTT) were measured. Hematoxylin eosin (H&E) staining was used to detect the pathological changes of ovary. The serum levels of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2 and testosterone (T) were measured by ELISA. The expression of DDX4/MVH was detected by immunohistochemistry. DDX4/MVH and PCNA were co-labeled by immunofluorescence. The protein levels of DDX4/MVH, PCNA, cyclin D2, AMPK and mTOR were detected by Western blot. The results showed that after metformin treatment, the body weights of PCOS mice were gradually returned to normal, glucose tolerance was significantly improved, serum E2 levels were increased, while AMH, LH, T levels and LH/FSH ratio were decreased. Ovarian polycystic lesions were reduced with reduced atresia follicles. Furthermore, the number of proliferative female germline stem cells (FGSCs) and levels of proliferation related proteins (PCNA, cyclin D2) were significantly increased, and the p-mTOR and p-AMPK levels were markedly up-regulated. These results suggest that metformin treatment not only improves hyperandrogenemia, glucose intolerance and polycystic ovarian lesions in PCOS, but also activates the function of FGSCs. The underlying mechanism may be related to the phosphorylation of AMPK and mTOR. These findings provide new evidence to use metformin in the treatment of PCOS and follicular development disorder.

Fusion of an EGFR-antagonistic affibody enhances the anti-tumor effect of TRAIL to EGFR positive tumors.

Tumor necrosis factor-related apoptosis ligand (TRAIL) is a promising antitumor agent candidate for its selective proapoptotic activity to various tumor cells. However, TRAIL showed limited efficacy in clinical trials despite of good tolerability. One important reason might be attributed to the poor tumor-homing ability of TRAIL. Herein, we designed an EGFR-targeting TRAIL (Z-TRAIL) by genetically fusing an EGFR-antagonistic affibody (ZEGFR:1907) to the N-terminus of TRAIL. Z-TRAIL was produced as a soluble protein with high yield in E. coli and it maintained the trimeric state of active TRAIL. Under the EGFR-binding mediated by ZEGFR:1907, Z-TRAIL showed a âˆ¼5 to 20-fold enhancement of cytotoxicity compared to TRAIL on tumor cells in vitro. Furthermore, fusion to ZEGFR:1907 endowed TRAIL with a âˆ¼1.8-fold increase of tumor uptake and a dramatical stronger apoptosis-inducing ability in the mice bearing EGFR-overexpressing A431 tumor xenografts. More importantly, Z-TRAIL exhibited significantly enhanced antitumor efficacy against whether EGFR high-expressing or low-expressing tumors than TRAIL in vivo. In addition, repeated injection of high-dose Z-TRAIL did not show obvious acute toxicity in mice. These results demonstrated that the newly engineered Z-TRAIL might be a promising agent for targeted therapy of EGFR-expressing tumors.

FDDM1 and FDDM2, Two SGS3-like Proteins, Function as a Complex to Affect DNA Methylation in Arabidopsis.

DNA methylation is an important epigenetic modification required for the specific regulation of gene expression and the maintenance of genome stability in plants and animals. However, the mechanism of DNA demethylation remains largely unknown. Here, we show that two SGS3-like proteins, FACTOR OF DNA DEMETHYLATION 1 (FDDM1) and FDDM2, negatively affect the DNA methylation levels at ROS1-dependend DNA loci in Arabidopsis. FDDM1 binds dsRNAs with 5' overhangs through its XS (rice gene X and SGS3) domain and forms a heterodimer with FDDM2 through its XH (rice gene X Homology) domain. A lack of FDDM1 or FDDM2 increased DNA methylation levels at several ROS1-dependent DNA loci. However, FDDM1 and FDDM2 may not have an additive effect on DNA methylation levels. Moreover, the XS and XH domains are required for the function of FDDM1. Taken together, these results suggest that FDDM1 and FDDM2 act as a heterodimer to positively modulate DNA demethylation. Our finding extends the function of plant-specific SGS3-like proteins.

Coupling EGFR-Antagonistic Affibody Enhanced Therapeutic Effects of Cisplatin Liposomes in EGFR-expressing Tumor Models.

Epidermal growth factor receptor (EGFR) is an efficient target for cancer therapy. In this study, a high-affinity EGFR-antagonistic affibody (ZEGFR) molecule coupled with cisplatin-loaded PEGylated liposomes (LS-DDP) was applied to actively target EGFR+ A431 tumor cells in vitro and in vivo. The LS-DDP coupled with ZEGFR (AS-DDP) had an average size of 140.01 ± 0.84 nm, low polydispersity, a zeta potential of -13.40 ± 0.8 mV, an acceptable encapsulation efficiency of 17.30 ± 1.35%, and released cisplatin in a slow-controlled manner. In vitro, AS-DDP demonstrated a higher amount of platinum intracellular uptake by A431 cells than LS-DDP. The IC50 value of AS-DDP (9.02 ± 1.55 µg/ml) was much lower than that of LS-DDP (16.44 ± 0.87 µg/ml), indicating that the anti-tumor effects of AS-DDP were remarkable due to the modification of ZEGFR. In vivo, the concentration of AS-DDP in the tumor site increased more than 1.76-fold, while an increase in apoptotic cells at 48 h compared to the LS-DDP was also observed, illustrating that AS-DDP possessed excellent tumor-targeting efficiency. As a result, the targeted nano-liposomes achieved greater tumor suppression. Therefore, selective targeting of LS-DDP coupled with ZEGFR enhanced the anti-tumor effects and appeared to be a promising strategy for the treatment of EGFR+ tumors.

Increasing the antitumor efficacy of doxorubicin liposomes with coupling an anti-EGFR affibody in EGFR-expressing tumor models.

Epidermal growth factor receptor (EGFR) is overexpressed in a wide range of solid tumors. In this study, we exploited a high-affinity EGFR-antagonistic affibody (ZEGFR) coupled to a doxorubicin loaded pegylated liposome (LS-Dox) for concurrent passive and active targeting of EGFR+ A431 tumor cells in vitro and in vivo. The in vitro studies revealed that the Dox liposomes coupled with ZEGFR (AS-Dox) showed a higher Dox uptake than LS-Dox in EGFR+ A431 cells but not in EGFR- B16F10 cells, resulting in a selectively enhanced cytotoxicity. In vivo, AS-Dox confirmed its long circulation time and efficient accumulation in tumors. This targeted chemotherapy achieved greater tumor suppression. Further, this low-dose but effective targeted treatment reduced systemic toxicity such as body weight loss and organ injury demonstrated by H&E staining. Thus, selective targeting of LS-Dox coupled with ZEGFR enhanced antitumor effects and improved systemic safety. These results demonstrated that LS-Dox coupled with ZEGFR might be developed as a potential tool for therapy of EGFR+ tumors.

Enhanced recovery after surgery for radical cystectomy with ileal urinary diversion: a multi-institutional, randomized, controlled trial from the Chinese bladder cancer consortium.

PURPOSE: Enhanced recovery after surgery (ERAS) has played an important role in recovery management for radical cystectomy with ileal urinary diversion (RC-IUD). This study is to evaluate ERAS compared with the conventional recovery after surgery (CRAS) for RC-IUD. METHODS: From October 2014 and July 2016, bladder cancer patients scheduled for curative treatment from 25 centers of Chinese Bladder Cancer Consortium were randomly assigned to either ERAS or CRAS group. Primary endpoint was the 30-day complication rate. Secondary endpoints included recovery of fluid and regular diet, flatus, bowel movement, ambulation, and length of stay (LOS) postoperatively. Follow-up period was 30-day postoperatively. RESULTS: There were 144 ERAS and 145 CRAS patients. Postoperative complications occurred in 25.7 and 30.3% of the ERAS and CRAS patients with 55 complications in each group, respectively (p = 0.40). There was no significant difference between groups in major complications (p = 0.82), or type of complications (p = 0.99). The ERAS group had faster recovery of bowel movements (median 88 versus 100 h, p = 0.01), fluid diet tolerance (68 versus 96 h, p < 0.001), regular diet tolerance (125 versus 168 h, p = 0.004), and ambulation (64 versus 72 h, p = 0.047) than the CRAS group, but similar time to flatus and LOS. CONCLUSIONS: ERAS did not increase 30-day complications compared with CRAS after RC. ERAS may be better than CRAS in terms of bowel movement, tolerance of fluid and regular diet, and ambulation.

Diagnostic significance of microRNAs as novel biomarkers for bladder cancer: a meta-analysis of ten articles.

BACKGROUND: Previous studies have revealed the importance of microRNAs' (miRNAs) function as biomarkers in diagnosing human bladder cancer (BC). However, the results are discordant. Consequently, the possibility of miRNAs to be BC biomarkers was summarized in this meta-analysis. METHODS: In this study, the relevant articles were systematically searched from CBM, PubMed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI). The bivariate model was used to calculate the pooled diagnostic parameters and summary receiver operator characteristic (SROC) curve in this meta-analysis, thereby estimating the whole predictive performance. STATA software was used during the whole analysis. RESULTS: Thirty-one studies from 10 articles, including 1556 cases and 1347 controls, were explored in this meta-analysis. In short, the pooled sensitivity, area under the SROC curve, specificity, positive likelihood ratio, diagnostic odds ratio, and negative likelihood ratio were 0.72 (95%CI 0.66-0.76), 0.80 (0.77-0.84), 0.76 (0.71-0.81), 3.0 (2.4-3.8), 8 (5.0-12.0), and 0.37 (0.30-0.46) respectively. Additionally, sub-group and meta-regression analyses revealed that there were significant differences between ethnicity, miRNA profiling, and specimen sub-groups. These results suggested that Asian population-based studies, multiple-miRNA profiling, and blood-based assays might yield a higher diagnostic accuracy than their counterparts. CONCLUSIONS: This meta-analysis demonstrated that miRNAs, particularly multiple miRNAs in the blood, might be novel, useful biomarkers with relatively high sensitivity and specificity and can be used for the diagnosis of BC. However, further prospective studies with more samples should be performed for further validation.

Therapeutic Potential of Adipose-derived Stem Cell-based Microtissues in a Rat Model of Stress Urinary Incontinence.

OBJECTIVE: To examine the potential and mechanism of 3-dimensional cultures of adipose-derived stem cells (ADSCs) in the treatment of stress urinary incontinence (SUI) in a rat model simulating menopause combined with preceding childbirth injury. MATERIALS AND METHODS: ADSCs were used to generate microtissues (MTs) with a hanging drop method. Forty-eight postpartum Sprague-Dawley rats were developed as SUI models after 4 hours of vagina dilation followed by bilateral ovariectomy. Ten rats that underwent sham ovariectomy without vagina dilation served as the control group. The SUI rats were divided into 3 groups and received urethral injection of phosphate-buffered saline, ADSCs, and MTs. Specimens were harvested for histology examination and ADSCs tracking at days 1, 3, 7, and 28 (n = 3) postinjection. At day 28, the remaining rats were examined for voiding function. Western blot, immunofluorescence, and immunohistochemistry staining were performed to examine histological changes and cytokine expression. RESULTS: The voiding function and histopathological structures were better recovered in the MT group than in the ADSC group. Compared with ADSCs, MTs express higher level of vascular endothelial growth factor and TNFα-stimulated gene/protein 6 in vitro, and represented a higher retention rate in vivo. CONCLUSION: Urethral injection of MTs better restored voiding function than ADSCs.

Polypyrrole/silver coaxial nanowire aero-sponges for temperature-independent stress sensing and stress-triggered Joule heating.

To obtain ideal sensing materials with nearly zero temperature coefficient resistance (TCR) for self-temperature-compensated pressure sensors, we proposed an Incipient Network Conformal Growth (INCG) technology to prepare hybrid and elastic porous materials: the nanoparticles (NPs) are first dispersed in solvent to form an incipient network, another component is then introduced to coat the incipient network conformally via wet chemical route. The conformal coatings not only endow NPs with high stability but also offer them additional structural elasticity, meeting requirements for future generations of portable, compressive and flexible devices. The resultant polypyrrole/silver coaxial nanowire hybrid aero-sponges prepared via INCG technology have been processed into a piezoresistive sensor with highly sensing stability (low TCR 0.86 × 10(-3)/°C), sensitivity (0.33 kPa(-1)), short response time (1 ms), minimum detectable pressure (4.93 Pa) after suffering repeated stimuli, temperature change and electric heating. Moreover, a stress-triggered Joule heater can be also fabricated mainly by the PPy-Ag NW hybrid aero-sponges with nearly zero temperature coefficient.

Current status of diagnosis and treatment of bladder cancer in China - Analyses of Chinese Bladder Cancer Consortium database.

OBJECTIVE: To investigate current status of diagnosis and treatment of bladder cancer in China. METHODS: A database was generated by Chinese Bladder Cancer Consortium (CBCC). From January 2007 to December 2012, 14,260 cases from 44 CBCC centers were included. Data of diagnosis, treatment and pathology were collected. RESULTS: The average age was 63.5 year-old and most patients were male (84.3%). The most common histologic types were urothelial carcinoma (91.4%), adenocarcinoma (1.8%), and squamous carcinoma (1.9%). According to 1973 and 2004 WHO grading system, 42.0%, 41.0%, and 17.0% of patients were grade 1, 2, and 3, and 16.0%, 48.7%, and 35.3% of patients were papillary urothelial neoplasms of low malignant potential, low, and high grade, respectively. Non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) were 25.2% and 74.1%, respectively (0.8% not clear). Carcinoma in situ was only 2.4%. Most patients were diagnosed by white-light cystoscopy with biopsy (74.3%). Fluorescence and narrow band imaging cystoscopy had additional detection rate of 1.0% and 4.0%, respectively. Diagnostic transurethral resection (TUR) provided detection rate of 16.9%. Most NMIBCs were treated with TUR (89.2%). After initial TUR, 2.6% accepted second TUR, and 45.7%, 69.9%, and 58.7% accepted immediate, induced, and maintenance chemotherapy instillation, respectively. Most MIBCs were treated with radical cystectomy (RC, 59.7%). Laparoscopic RCs were 35.1%, while open RC 63.4%. Extended and standard pelvic lymph node dissection were 7% and 66%, respectively. Three most common urinary diversions were orthotopic neobladder (44%), ileal conduit (31%), and ureterocutaneostomy (23%). Only 2.3% of patients accepted neo-adjuvant chemotherapy and only 18% of T3 and T4 patients accepted adjuvant chemotherapy. CONCLUSION: Disease characteristics are similar to international reports, while differences of diagnosis and treatment exist. This study can provide evidences for revisions of the guideline on bladder cancer in China.