Ultrathin Cu9S5 Nanosheets with Sulfur Vacancy for Multimodal Tumor Therapy.

Multimodal tumor therapy with nanotechnology is an effective and integrative strategy to overcome the limitations of therapeutic efficacy and possible side effects associated with monotherapy. However, the construction of multimodal treatment nanoplatforms often involves various functional components, leading to certain challenges, such as time-consuming synthesis processes, low product yield, and inadequate biocompatibility. To address these issues, we have developed a straightforward method for preparing ultrathin Cu9S5 nanosheets (NSs) with surface defects for photothermal/photodynamic/chemodynamic therapy. The ultrathin morphology of the Cu9S5 NSs (with 2-3 nm) not only confers excellent biocompatibility but also enables broad-spectrum absorption with a remarkable photothermal conversion efficiency (58.96%) under 1064 nm laser irradiation. Moreover, due to the presence of a S vacancy, these Cu9S5 NSs exhibit favorable enzyme-like properties, including reactive oxygen species generation and glutathione consumption, particularly under laser irradiation. The efficacy of related tumor therapy and antibacterial treatment is significantly enhanced by the synergistic activation of photothermal/photodynamic/chemodynamic therapy through 1064 nm laser irradiation, as demonstrated by both in vitro and in vivo experiments. This study presents a novel strategy for multimodal tumor therapy with the prepared ultrathin Cu9S5 NSs, which holds promising pathways for photodynamic therapy in the NIR-II region.

Insulin-like growth factor binding protein 7 promotes acute kidney injury by alleviating poly ADP ribose polymerase 1 degradation.

The novel biomarker, insulin-like growth factor binding protein 7 (IGFBP7), is used clinically to predict different types of acute kidney injury (AKI) and has drawn significant attention as a urinary biomarker. However, as a secreted protein in the circulation of patients with AKI, it is unclear whether IGFBP7 acts as a key regulator in AKI progression, and if mechanisms underlying its upregulation still need to be determined. Here we found that IGFBP7 is highly expressed in the blood and urine of patients and mice with AKI, possibly via a c-Jun-dependent mechanism, and is positively correlated with kidney dysfunction. Global knockout of IGFBP7 ameliorated kidney dysfunction, inflammatory responses, and programmed cell death in murine models of cisplatin-, kidney ischemia/reperfusion-, and lipopolysaccharide-induced AKI. IGFBP7 mainly originated from kidney tubular epithelial cells. Conditional knockout of IGFBP7 from the kidney protected against AKI. By contrast, rescue of IGFBP7 expression in IGFBP7-knockout mice restored kidney damage and inflammation. IGFBP7 function was determined in vitro using recombinant IGFBP7 protein, IGFBP7 knockdown, or overexpression. Additionally, IGFBP7 was found to bind to poly [ADP-ribose] polymerase 1 (PARP1) and inhibit its degradation by antagonizing the E3 ubiquitin ligase ring finger protein 4 (RNF4). Thus, IGFBP7 in circulation acts as a biomarker and key mediator of AKI by inhibiting RNF4/PARP1-mediated tubular injury and inflammation. Hence, over-activation of the IGFBP7/PARP1 axis represents a promising target for AKI treatment.

Targeted delivery of edaravone by liposomes for the treatment of ischemic stroke.

Aim: To construct an edaravone-encapsulated liposomes (EDV-LIPs) formulation against acute ischemic stroke. Methods: EDV-LIPs were prepared by the film dispersion method. The biosafety was evaluated both in vitro and in vivo by flow cytometry and the histological staining method. Biodistribution and therapeutic effect of EDV-LIPs against acute ischemic stroke was investigated by fluorescent imaging, the behavior test, laser speckle imaging and triphenyltetrazolium chloride staining. Results: The nanoliposomes had a long circulation time and could accumulate in the brain lesion region in ischemic stroke rats. EDV-LIPs show good biosafety. EDV-LIPs could restore more cerebral blood flow, reduce infarct volume and decrease neuronal apoptosis. Conclusion: EDV-LIPs provide an effective alternative for drug-targeted delivery against acute ischemic stroke.

Folic acid modified Fe3O4 nanoclusters by a one-step ultrasonic technique for drug delivery and MR imaging.

Multifunctional nanoclusters based on Fe3O4 nanoparticles for magnetic resonance imaging (MRI) and drug delivery are reported here. At first, oleic acid (OA)-coated Fe3O4 nanoparticles were prepared. Then block copolymer Pluronic F127 or folic acid (FA) conjugated-Pluronic F127 was used to modify the hydrophobic nanoparticles to become hydrophilic Fe3O4@F127 nanoclusters via facile ultrasonic treatment. During this process, drug molecules can also be introduced into the nanoclusters and therefore the targeted drug delivery system was formed. Next, we verified the feasibility of the nanoclusters as drug delivery vehicles and magnetic contrast agents. The nanoclusters have an average size of 200 nm and remained stable in water for long periods. Folic acid-modified nanoclusters showed an enhanced intracellular uptake into HepG2 cells by using both cellular iron amount analysis and flow cytometry analysis. Besides, Fe3O4@F127@FA nanoclusters showed good compatibility in the tested concentration range and good sensitivity in T 2-weighted MRI. The magnetic nanoclusters combined with drug delivery properties have greatly increased the significance in the diagnosis and therapy of diseases, which are suitable for systematical administration of hydrophobic drugs and simultaneously MRI diagnosis.

Comparison of the eighth version of the American Joint Committee on Cancer manual to the seventh version for colorectal cancer: A retrospective review of our data.

AIM: To analyze the survival trends in colorectal cancer (CRC) based on the different classifications recommended by the seventh and eighth editions of the American Joint Committee on Cancer staging system (AJCC-7th and AJCC-8th). METHODS: The database from our institution was queried to identify patients with pathologically confirmed stage 0-IV CRC diagnosed between 2006 and 2012. Data from 2080 cases were collected and 1090 cases were evaluated through standardized inclusion and exclusion criteria. CRC was staged by AJCC-7th and then restaged by AJCC-8th. Five-year disease-free survival (DFS) and overall survival (OS) were compared. SPSS 21.0 software was used for all data. DFS and OS were compared and analyzed by Kaplan-Meier and Log-rank test. RESULTS: Linear regression and automatic linear regression showed lymph node positive functional equations by tumor-node-metastasis staging from AJCC-7th and tumor-node-metastasis staging from AJCC-8th. Neurological invasion, venous infiltration, lymphatic infiltration, and tumor deposition put forward stricter requirements for pathological examination in AJCC-8th compared to AJCC-7th. After re-analyzing our cohort with AJCC-8th, the percentage of stage IVB cases decreased from 2.8% to 0.8%. As a result 2% of the cases were classified under the new IVC staging. DFS and OS was significantly shorter (P = 0.012) in stage IVC patients compared to stage IVB patients. CONCLUSION: The addition of stage IVC in AJCC-8th has shown that peritoneal metastasis has a worse prognosis than distant organ metastasis in our institution's CRC cohort. Additional datasets should be analyzed to confirm these findings.

[Effect of CD8(+)CD28(-) suppressor T cells induced by dendritic cell with major histocompatibility complex 1 expression RNA interference on immune tolerance in rat intestinal transplantation].

OBJECTIVE: To investigate the effect of CD8(+)CD28(-) suppressor T cells(Ts) induced by dendritic cell(DC) with major histocompatibility complex 1(MHC-1) expression RNA interference on immune tolerance in rat intestinal transplantation. METHODS: The expression level of CD8(+)CD28(-)Ts were successfully induced by DC with MHC-1 expression interfered by RNA interference technique under the stimulator of allograft antigen. Orthotopic intestinal transplantation was performed in 36 rats by modified three cuffs method. The recipients were randomly divided into three groups(12 rats in each group):group A was experimental group with CD8(+)CD28(-) Ts being administrated, mixed T cells were injected in group B, while in group C, NS were administrated. On the first day and the seventh day posttransplant, the 36 rats of the 3 groups were administrated through vena dorsalis penis respectively. Six rats were selected randomly from each group and the animals were sacrificed on the 14 th day postoperatively, serum levels of TGF-beta, IFN-gamma and the values of Na(+)-K(+)-ATPase activity of the intestinal graft were assayed and the intestinal pathologic morphology, intestinal allograft survival were observed concerning the remainders. RESULTS: On the 14 th day after operation, the expression levels of TGF-beta and IFN-gamma in group A were significantly up-regulated as compared with those in group B and group C(P<0.05). Na(+)-K(+)-ATPase activity in group A was(6.3+/-1.0) kU/g, much higher than the levels of group B(3.6+/-0.9)kU/g and group C(2.9+/-1.3) kU/g and the differences were significant(P<0.05). The data suggested preliminarily that pathological scores of intestinal graft in group A were lower than those in group B and group C. The survival time of the recipients in group A was 32.0 days, much longer than that in group B (17.5 days, P<0.05) and group C(21.0 days, P<0.05). CONCLUSION: CD8(+)CD28(-) Ts induced by DC with MHC-1 expression RNA interference can alleviate acute rejection and lead to immune tolerance in rat intestinal transplantation.

[Operative techniques and common complications of modified orthotopic intestinal transplantation in rats].

OBJECTIVE: To investigate operative techniques, treatment and precaution of common complications of orthotopic intestinal transplantation in the rats. METHODS: Orthotopic intestinal transplantation was performed in 120 rats by modified three cuffs method. The causes, treatment and precaution of common complications were analyzed retrospectively. RESULTS: The 7-day survival rate of recipients was 82.5% and the 30-day survival rate was 68.3%. The average volume of bleeding in the recipient operation was less than 1 ml. The result obtained from the above 99 recipients was satisfactory. The main reasons of final failure and death were as follows: anastomotic bleeding(5 rats), portal vein thrombus(2 rats), arterial thrombus(4 rats), air embolism(1 rat), infection of abdominal cavity(4 rats), aspiration pneumonitis (2 rats), anesthetic accident(2 rats) and kinking of graft intestine(1 rat). CONCLUSIONS: The sophisticated surgical technique and the delicate surgical manipulation are the prerequisite of preventing operational complication. Improving operative techniques and being familiar with the common complications can reduce the occurrence of complications and increase operative successful rate.