Characterization and verification of CAF-relevant prognostic gene signature to aid therapy in bladder cancer.

Cancer-associated fibroblasts (CAFs) are significantly involved in determining the patient's prognosis and response to bladder cancer (BLCA) therapy. CAFs can induce epithelial-mesenchymal transformation (EMT) as well as complex interaction with immune cells. Hence, it is imperative to identify potential markers for enhancing our understanding of CAFs in BLCA progression and immune regulation. A variety of algorithms and analyses were employed in the study, leading to the development of a novel prognostic feature for CAFs-Stromal-EMT (CSE)-prognostic feature. This feature was constructed based on the genes MFAP5, PCOLCE2, and JUN. Furthermore, we revealed that patients with higher CSE risk scores responded to immunotherapy better compared to those with lower. Finally, we verified two CSE-related genes using in vitro experiments. Our results suggested that the CSE-prognostic feature could predict the prognosis and evaluate the response of patients to immune and chemotherapies. This would aid clinicians in designing treatment strategies for patients with BLCA.

Functional hemostatic hydrogels: design based on procoagulant principles.

Uncontrolled hemorrhage results in various complications and is currently the leading cause of death in the general population. Traditional hemostatic methods have drawbacks that may lead to ineffective hemostasis and even the risk of secondary injury. Therefore, there is an urgent need for more effective hemostatic techniques. Polymeric hemostatic materials, particularly hydrogels, are ideal due to their biocompatibility, flexibility, absorption, and versatility. Functional hemostatic hydrogels can enhance hemostasis by creating physical circumstances conducive to hemostasis or by directly interfering with the physiological processes of hemostasis. The procoagulant principles include increasing the concentration of localized hemostatic substances or establishing a physical barrier at the physical level and intervention in blood cells or the coagulation cascade at the physiological level. Moreover, synergistic hemostasis can combine these functions. However, some hydrogels are ineffective in promoting hemostasis or have a limited application scope. These defects have impeded the advancement of hemostatic hydrogels. To provide inspiration and resources for new designs, this review provides an overview of the procoagulant principles of hemostatic hydrogels. We also discuss the challenges in developing effective hemostatic hydrogels and provide viewpoints.

Assessing the Relationship Between Gut Microbiota and Posttransplant Diabetes Mellitus.

OBJECTIVES: The incidence of diabetes significantly increases after kidney transplant, and the associated gut microbiota are closely related to diabetes. However, the gut microbiota of recipients with diabetes after kidney transplant remain unexplored. MATERIALS AND METHODS: Feces samples from recipients with diabetes 3 months after kidney transplant were collected and analyzed using high-throughput 16S rRNA gene sequencing. RESULTS: Our study included 45 transplant recipients: 23 posttransplant diabetes mellitus recipients, 11 recipients without diabetes mellitus, and 11 recipients with preexisting diabetes mellitus. No significant differences in intestinal flora richness and α diversity were observed among the 3 groups. However, principal coordinate analysis based on UniFrac distance revealed significant differences in ß diversity. At the phyla level, the abundance of Proteobacteria in posttransplant diabetes mellitus recipients decreased (P = .028), whereas that of Bactericide (P = .004) increased. At the class level, the abundance of Gammaproteobacteria (P = .037) decreased, whereas thatofBacteroidia (P=.004)increased.Attheorderlevel, the abundanceof Enterobacteriales (P = .039)decreased, whereasBacteroidales (P=.004)increased.Atthe family level, the abundance of Enterobacteriaceae (P = .039) and Peptostreptococcaceae (P = .008) decreased, whereas Bacteroidaceae (P = .010) increased. At the genus level,the abundance of Lachnospiraceae incertae sedis (P = .008) decreased, whereas Bacteroides (P = .010) increased. Furthermore, KEGG analysis identified 33 pathways, among which the biosynthesis of unsaturated fatty acids was closely related to gut microbiota and posttransplant diabetes mellitus. CONCLUSIONS: To our knowledge, this is the first comprehensive analysis of the gut microbiota from posttransplant diabetes mellitus recipients. The microbial composition of stool samples of post- transplant diabetes mellitus recipients was significantly different from recipients without diabetes and with preexisting diabetes. The number of bacteria producing short-chain fatty acids decreased, whereas pathogenic bacteria increased.

Progress of polymer-based strategies in fungal disease management: Designed for different roles.

Fungal diseases have posed a great challenge to global health, but have fewer solutions compared to bacterial and viral infections. Development and application of new treatment modalities for fungi are limited by their inherent essential properties as eukaryotes. The microorganism identification and drug sensitivity analyze are limited by their proliferation rates. Moreover, there are currently no vaccines for prevention. Polymer science and related interdisciplinary technologies have revolutionized the field of fungal disease management. To date, numerous advanced polymer-based systems have been developed for management of fungal diseases, including prevention, diagnosis, treatment and monitoring. In this review, we provide an overview of current needs and advances in polymer-based strategies against fungal diseases. We high light various treatment modalities. Delivery systems of antifungal drugs, systems based on polymers' innate antifungal activities, and photodynamic therapies each follow their own mechanisms and unique design clues. We also discuss various prevention strategies including immunization and antifungal medical devices, and further describe point-of-care testing platforms as futuristic diagnostic and monitoring tools. The broad application of polymer-based strategies for both public and personal health management is prospected and integrated systems have become a promising direction. However, there is a gap between experimental studies and clinical translation. In future, well-designed in vivo trials should be conducted to reveal the underlying mechanisms and explore the efficacy as well as biosafety of polymer-based products.

Endovascular Treatment of Transplant Renal Artery Stenosis: A Single-Center Retrospective Cohort Study.

OBJECTIVES: Endovascular therapy is the most common treatment for transplant renal artery stenosis; however, its long-term outcomes remain controversial, with no uniform standard for percutaneous transluminal angioplasty versus percutaneous transluminal stenting. MATERIALS AND METHODS: We retrospectively analyzed 26 patients with transplant renal artery stenosis who underwent endovascular therapy. We evaluated long-term efficacy of endovascular therapy and the reasonable choice of treatment. RESULTS: Serum creatinine increased significantly at onset of transplant renal artery stenosis (113.88 ± 37.573 before vs 279.31 ± 94.98 µmol/L during stenosis; P1 < .001), and endovascular therapy had a good short-term effect (279.31 ± 94.98 during stenosis vs 139.54 ± 124.40 µmol/L at 2 weeks posttreatment; P2 = .002). Long-term efficacy of endovascular therapy was stable (139.54 ± 124.40 at 2 weeks posttreatment vs 150.69 ± 180.72 at 6 months vs 161.58 ± 174.49 µmol/L at last follow-up; P3 > .05). Blood pressure increased significantly at onset of transplant renal artery stenosis (126.65 ± 16.11 before vs 159.62 ± 25.84 mm Hg during stenosis; P1 < .001). Moreover, the short-term effect of endovascular therapy was good (159.62 ± 25.84 during stenosis vs 128.73 ± 14.22 mm Hg at 2 weeks posttreatment; P2 < .001). Long-term effects remained stable (128.73 ± 14.22 at 2 weeks posttreatment vs 131.15 ± 14.55 at 6 months vs 138.50 ± 16.82 mm Hg at last follow-up; P3 > .05). Peak systolic velocity decreased significantly after endovascular therapy (176.6 ± 67.93 during stenosis vs 114.24 ± 67.93 cm/s at 2 weeks posttreatment; P < .001). CONCLUSIONS: Endovascular therapy is effective in transplant renal artery stenosis treatment and has a low incidence of complications. Percutaneous transluminal angioplasty should be performed routinely during endovascular therapy. After dilation, if stenosis remains >25% or retracted, then percutaneous transluminal stenting is recommended. Otherwise, percutaneous transluminal angioplasty is preferred.

Identification of a New Prediction Model for Bladder Cancer Related to Immune Functions and Chemotherapy Using Gene Sets of Biological Processes.

Background: Biological processes serve crucial functions in the initiation and development of cancer. Therefore, we constructed and validated a model for bladder cancer (BLCA) with good predictive power for immunity, prognosis, and therapy. Methods: Using the expression of the gene sets based on biological processes, BLCA patients were divided into three clusters by consensus cluster analysis. By performing LASSO regression analysis twice, key genes were selected, and the biological processes-related genes' (BPRG) score was calculated. Differences in immune infiltration, tumor microenvironment, tumor mutation burden, immunotherapy, and sensitivity towards chemotherapy were analyzed between two groups divided by BPRG score. Results: Good accuracy was observed for the three clusters. They showed different prognoses and levels of immune cell infiltration. The selected key genes were mainly enriched in immune-related pathways. The high-BPRG score group was related to poor prognosis, higher immune cell infiltration, interstitial scores, and increased tumor mutation. Moreover, the effects of immunotherapy were good, and those of chemotherapy were poor. Conclusion: Overall, key genes may be involved in various complex immune regulation processes. Therefore, the quantification and verification of the BPRG score are expected to facilitate the understanding of the immunosuppressive microenvironment in BLCA and guide the choice of chemotherapeutic drugs and immunotherapeutic regimens and help predict the prognoses of patients with BLCA.

Homocysteine (HCY) levels in patients with atrial fibrillation (AF): A meta-analysis.

PURPOSE: Atrial fibrillation (AF) is one of the most common persistent arrhythmia, and its complications include cerebral embolism, arterial embolism and heart failure. Some studies have found that elevated Homocysteine (HCY) levels is a new risk factor for AF. Currently, there is no meta-analysis to explore whether the HCY levels is related to AF. Therefore, a meta-analysis was conducted to evaluate the relationship between the HCY levels and AF, in order to draw the attention of clinicians to the HCY levels. METHODS: A meta-analysis was performed in the study to evaluated the association between the HCY levels and AF. In order to identify eligible original articles, The EMBASE, PubMed, and web of science were systematically searched until November 2020. All data were analyzed with Review Manager 5.3. The meta-analysis results were evaluated depending on standardized mean differences (SMD) with 95% confidence intervals (CI). Moreover, the subgroup analysis and sensitivity analysis were also analyzed. RESULTS: The HCY levels was significantly associated with AF (WMD = 0.81, 95% CI: 0.58 to 1.03; P < .00001). In the analysis, there was a medium degree of heterogeneity (I2 = 73%). Subgroup analysis showed that female < 60, BMI≥25, BMI <25, age ≥60 and publication year ≥2010 were identified as possible sources of heterogeneity. Sensitivity analysis showed that the main results remained unchanged after omitting any single study or converting the random effects model (REM) to fixed effects model (FEM). CONCLUSIONS: The meta-analysis showed that there is a significant correlation between the HCY levels and AF, and the role of HCY in AF patients should not be ignored in clinical.

Modified Circumcision Using the Disposable Circumcision Suture Device in Children: A Randomized Controlled Trial.

OBJECTIVE: To evaluate and compare the surgical outcomes and complications of the modified circumcision using disposable circumcision suture device (device group) and the conventional dorsal slit circumcision (conventional group) in children. METHODS: A total of 284 patients were randomized to either device group or conventional group. All patients were preoperatively assessed and evaluated at 4 weeks after surgery. The perioperative data and postoperative outcomes were compared between the 2 groups. RESULTS: No statistical differences were observed in the average age and indications between the 2 groups preoperatively (P > .05). Compared with the conventional group, patients in the device group were shorter mean operative time, less blood loss, lower intraoperative and postoperative pain score, faster incision healing time and a higher satisfaction rate of penile cosmetic appearance (P < .01). Similarly, the incidences of complication were significantly lower in the device group than in the conventional group (4.3% vs 12.3%, P < .05). CONCLUSIONS: The modified circumcision using disposable circumcision suture device is a simple, safe, faster, and effective procedure and may become the attractive alternative to the conventional technique for the children, with a relatively lower complication rate and better cosmetic results. With the improvement of disposable circumcision suture device, the modified circumcision using disposable circumcision suture device has the potential to be widely used in the world.

High efficiency green OLEDs based on homoleptic iridium complexes with steric phenylpyridazine ligands.

A series of steric phenylpyridazine based homoleptic iridium(iii) complexes (1-3) have been synthesized with novel one-pot methods. Single X-ray structural analyses are conducted on complexes 1 and 2 to reveal their coordination arrangement. These complexes exhibit a very strong green phosphorescence emission with high quantum yields of over 64%. The relationship between photophysical properties and the substituent nature of the complexes is discussed by density functional theory (DFT) and time-dependent DFT. Self-quenching is significantly reduced for these complexes in solid even at very high concentrations because the sterically hindered bicyclo [2.2.2] oct-2-ene and m-substituted CF3 spacers in the phosphor molecules lead to minimum bimolecular interactions. Accordingly, the electroluminescence device based on complex 3 exhibits a maximum luminous efficiency of 64.1 cd A-1 with a high EQE of 25.2% at a high doping concentration of 15 wt%. Meanwhile, when neat 3 was adopted as the emitting layer, the non-doped green device gives a state-of-the-art EQE as high as 15.2% (40.1 cd A-1) along with CIE coordinates of (0.346, 0.599).

Further evidence for sustained systemic inflammation in xenograft recipients (SIXR).

INTRODUCTION: In pig-to-baboon heart/artery patch transplantation models, adequate costimulation blockade prevents a T-cell response. After heart transplantation, coagulation dysfunction (thrombocytopenia, reduced fibrinogen, increased D-dimer) and inflammation (increased C-reactive protein [CRP]) develop. We evaluated whether coagulation dysfunction and/or inflammation can be detected following pig artery patch transplantation. METHODS: Baboons received heart (n = 8) or artery patch (n = 16) transplants from genetically engineered pigs and a costimulation blockade-based regimen. Heart grafts functioned for 15-130 days. Artery recipients were euthanized after 28-84 days. Platelet counts, fibrinogen, D-dimer, and CRP were measured. RESULTS: Thrombocytopenia and reduced fibrinogen developed only in recipients of hearts not expressing a coagulation-regulatory protein (n = 4), but not in other heart or patch recipients. However, in heart recipients (n = 8), there were sustained increases in D-dimer (<0.5 to 1.9 ug/ml [P < 0.01]) and CRP (0.26-2.2 mg/dl [P < 0.01]). In recipients of artery patches, there were also sustained increases in D-dimer (<0.5 to 1.4 ug/ml [P < 0.01]) and CRP (0.26 to 1.5 mg/dl [P < 0.001]). An IL-6R antagonist suppressed the increase in CRP, but not D-dimer. CONCLUSION: The pig artery patch model has proved valuable for determining immunosuppressive regimens that prevent sensitization to pig antigens. This model also provides information on the sustained systemic inflammation in xenograft recipients (SIXR). An IL-6R antagonist may help suppress this response.

Pig kidney graft survival in a baboon for 136 days: longest life-supporting organ graft survival to date.

The longest survival of a non-human primate with a life-supporting kidney graft to date has been 90 days, although graft survival > 30 days has been unusual. A baboon received a kidney graft from an α-1,3-galactosyltransferase gene-knockout pig transgenic for two human complement-regulatory proteins and three human coagulation-regulatory proteins (although only one was expressed in the kidney). Immunosuppressive therapy was with ATG+anti-CD20mAb (induction) and anti-CD40mAb+rapamycin+corticosteroids (maintenance). Anti-TNF-α and anti-IL-6R were administered. The baboon survived 136 days with a generally stable serum creatinine (0.6 to 1.6 mg/dl) until termination. No features of a consumptive coagulopathy (e.g., thrombocytopenia, decreased fibrinogen) or of a protein-losing nephropathy were observed. There was no evidence of an elicited anti-pig antibody response. Death was from septic shock (Myroides spp). Histology of a biopsy on day 103 was normal, but by day 136, the kidney showed features of glomerular enlargement, thrombi, and mesangial expansion. The combination of (i) a graft from a specific genetically engineered pig, (ii) an effective immunosuppressive regimen, and (iii) anti-inflammatory agents prevented immune injury and a protein-losing nephropathy, and delayed coagulation dysfunction. This outcome encourages us that clinical renal xenotransplantation may become a reality.

Experimental hepatocyte xenotransplantation--a comprehensive review of the literature.

Hepatocyte transplantation (Tx) is a potential therapy for certain diseases of the liver, including hepatic failure. However, there is a limited supply of human livers as a source of cells and, after isolation, human hepatocytes can be difficult to expand in culture, limiting the number available for Tx. Hepatocytes from other species, for example, the pig, have therefore emerged as a potential alternative source. We searched the literature through the end of 2014 to assess the current status of experimental research into hepatocyte xenoTx. The literature search identified 51 reports of in vivo cross-species Tx of hepatocytes in a variety of experimental models. Most studies investigated the Tx of human (n = 23) or pig (n = 19) hepatocytes. No studies explored hepatocytes from genetically engineered pigs. The spleen was the most common site of Tx (n = 23), followed by the liver (through the portal vein [n = 6]) and peritoneal cavity (n = 19). In 47 studies (92%), there was evidence of hepatocyte engraftment and function across a species barrier. The data provided by this literature search strengthen the hypothesis that xenoTx of hepatocytes is feasible and potentially successful as a clinical therapy for certain liver diseases, including hepatic failure. By excluding vascular structures, hepatocytes isolated from genetically engineered pig livers may address some of the immunological problems of xenoTx.

Pig-to-baboon heterotopic heart transplantation--exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens.

BACKGROUND: Three costimulation blockade-based regimens have been explored after transplantation of hearts from pigs of varying genetic backgrounds to determine whether CTLA4-Ig (abatacept) or anti-CD40mAb+CTLA4-Ig (belatacept) can successfully replace anti-CD154mAb. METHODS: All pigs were on an α1,3-galactosyltransferase gene-knockout/CD46 transgenic (GTKO.CD46) background. Hearts transplanted into Group A baboons (n=4) expressed additional CD55, and those into Group B (n=3) expressed human thrombomodulin (TBM). Immunosuppression included anti-thymocyte globulin with anti-CD154mAb (Regimen 1: n=2) or abatacept (Regimen 2: n=2) or anti-CD40mAb+belatacept (Regimen 3: n=2). Regimens 1 and 2 included induction anti-CD20mAb and continuous heparin. One further baboon in Group B (B16311) received a modified Regimen 1. Baboons were followed by clinical/laboratory monitoring of immune/coagulation parameters. At biopsy, graft failure, or euthanasia, the graft was examined by microscopy. RESULTS: Group A baboons survived 15 to 33 days, whereas Group B survived 52, 99, and 130 days, respectively. Thrombocytopenia and reduction in fibrinogen occurred within 21 days in Group A, suggesting thrombotic microangiopathy (TM), confirmed by histopathology. In Group B, with follow-up for >4 m, areas of myofiber degeneration and scarring were seen in two hearts at necropsy. A T-cell response was documented only in baboons receiving Regimen 2. CONCLUSIONS: The combination of anti-CD40mAb+belatacept proved effective in preventing a T-cell response. The expression of TBM prevented thrombocytopenia and may possibly delay the development of TM and/or consumptive coagulopathy.

Are there advantages in the use of specific pathogen-free baboons in pig organ xenotransplantation models?

Baboons have natural antibodies against pig antigens. We have investigated whether there are differences in anti-non-Gal pig antibody levels between baboons maintained under specific pathogen-free (SPF) conditions and those housed under conventional conditions (non-SPF) that might be associated with improved outcome after pig-to-baboon organ transplantation. Baboons (n = 40) were housed indoors (SPF n = 8) or in indoor/outdoor pens (non-SPF n = 32) in colonies of similar size and structure. Non-SPF colonies harbor a number of pathogens common to non-human primate species, whereas many of these pathogens have been eliminated from the SPF colony. Complete blood cell counts (CBC), blood chemistry, and anti-non-Gal IgM and IgG levels were monitored. There were no significant differences in CBC or blood chemistry between SPF and non-SPF baboons. Anti-non-Gal IgM levels were significantly lower in the SPF baboons than in the non-SPF baboons (MFI 7.1 vs. 8.8, P < 0.05). One SPF and two non-SPF baboons had an MFI >20; if these three baboons are omitted, the mean MFIs were 4.8 (SPF) vs. 7.5 (non-SPF) (P < 0.05). Anti-non-Gal IgG was minimal in both groups (MFI 1.0 vs. 1.0). As their levels of anti-non-Gal IgM are lower, baboons maintained under SPF conditions may be beneficial for xenotransplantation studies as the initial binding of anti-pig IgM to an α1,3-galactosyltransferase gene-knockout pig organ may be less, thus resulting in less complement and/or endothelial cell activation. However, even under identical SPF conditions, an occasional baboon will express a high level of anti-non-Gal IgM, the reason for which remains uncertain.