Assessment of the Added Value of Intravoxel Incoherent Motion Diffusion-Weighted MR Imaging in Identifying Non-Diabetic Renal Disease in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Identification of non-diabetic renal disease (NDRD) in patients with type 2 diabetes mellitus (T2DM) may help tailor treatment. Intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) is a promising tool to evaluate renal function but its potential role in the clinical differentiation between diabetic nephropathy (DN) and NDRD remains unclear. PURPOSE: To investigate the added role of IVIM-DWI in the differential diagnosis between DN and NDRD in patients with T2DM. STUDY TYPE: Prospective. POPULATION: Sixty-three patients with T2DM (ages: 22-69 years, 17 females) confirmed by renal biopsy divided into two subgroups (28 DN and 35 NDRD). FIELD STRENGTH/SEQUENCE: 3 T/ T2 weighted imaging (T2WI), and intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI). ASSESSMENT: The parameters derived from IVIM-DWI (true diffusion coefficient [D], pseudo-diffusion coefficient [D*], and pseudo-diffusion fraction [f]) were calculated for the cortex and medulla, respectively. The clinical indexes related to renal function (eg cystatin C, etc.) and diabetes (eg diabetic retinopathy [DR], fasting blood glucose, etc.) were measured and calculated within 1 week before MRI scanning. The clinical model based on clinical indexes and the IVIM-based model based on IVIM parameters and clinical indexes were established and evaluated, respectively. STATISTICAL TESTS: Student's t-test; Mann-Whitney U test; Fisher's exact test; Chi-squared test; Intraclass correlation coefficient; Receiver operating characteristic analysis; Hosmer-Lemeshow test; DeLong's test. P < 0.05 was considered statistically significant. RESULTS: The cortex D*, DR, and cystatin C values were identified as independent predictors of NDRD in multivariable analysis. The IVIM-based model, comprising DR, cystatin C, and cortex D*, significantly outperformed the clinical model containing only DR, and cystatin C (AUC = 0.934, 0.845, respectively). DATA CONCLUSION: The IVIM parameters, especially the renal cortex D* value, might serve as novel indicators in the differential diagnosis between DN and NDRD in patients with T2DM. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Highly Efficient Circularly Polarized Luminescence from Chiral Au13 Clusters Stabilized by Enantiopure Monodentate NHC Ligands.

Chiral Au nanoclusters have promising application prospects in chiral sensing, asymmetric catalysis, and chiroptics. However, enantiopure superatomic homogold clusters with crystallographic structures emitting bright circularly polarized luminescence (CPL) remain challenging. In this study, we designed chiral N-heterocyclic carbenes (NHCs), and for the first time enantioselectively synthesized a pair of monovalent cationic superatomic Au13 clusters. This new enantiomeric pair of clusters has a quasi-C2 symmetric core and exhibited CPL with an unprecedent solution-state quantum yield (QY) of 61 % among those of the atomically precise Au nanoclusters. DFT calculations provided insights into the circular dichroism behavior, and revealed the origin of CPL from superatomic Au clusters. This work opens a new avenue for developing novel homochiral nanoclusters using chiral NHC ligands and provides fundamental understanding of the origin of the chiroptics of metal clusters.

Associations between the 1438A/G, 102T/C, and rs7997012G/A polymorphisms of HTR2A and the safety and efficacy of antidepressants in depression: a meta-analysis.

The correlations between hydroxytryptamine receptor 2A (HTR2A) gene polymorphisms (1438A/G, 102T/C, and rs7997012G/A) and the safety and efficacy of antidepressants in depression patients were constantly reported, but conclusions are debatable. This meta-analysis ascertained forty-two studies on the efficacy (including response and remission) and side-effect issued before February 2020. Pooled analyses indicated significant associations of 1438A/G polymorphism (16 studies, 1931 subjects) and higher response within dominant model (OR: 1.40, 95% CI: 1.12-1.76); rs7997012G/A polymorphism (nine studies, 1434 subjects) and higher remission in overall models (dominant model: OR: 1.30, 95% CI: 1.01-1.66; recessive model: OR: 2.20, 95% CI: 1.53-3.16; homozygote model: OR: 2.73, 95% CI: 1.78-4.17); 102T/C polymorphism (eight studies, 804 subjects) and reduced risk of side-effect within recessive (OR: 0.57, 95% CI: 0.4-0.83) and homozygote models (OR: 0.54, 95% CI: 0.29-0.99). For depression patients, genotyping of HTR2A polymorphisms is a promising tool for estimating the outcome and side-effect of antidepressants.

A Smart "Sense-and-Treat" Nanoplatform Based on Semiconducting Polymer Nanoparticles for Precise Photothermal-Photodynamic Combined Therapy.

Integrated theranostic nanoplatforms with biomarker recognition and photothermal- and photodynamic (PTT/PDT) therapy is in high demand but remains challenging. Herein, a "sense-and-treat" nanoplatform based on semiconducting polymer nanoparticles (SPNs) for ratiometric bioimaging of phospholipase D (PLD) activity and PTT/PDT combined therapy was proposed. Semiconducting polymer nanoparticles (PSBTBT NPs) serve not only as photothermal agents but also as fluorescent quenchers of Rhodamine B (Rhod B) through a PLD-cleavable linker. Chlorin e6 (Ce6) was used as a photodynamic agent and fluorescence reference. The obtained nanoplatform (PSBTBT-Ce6@Rhod NPs) showed high PDT efficiency and photothermal performance upon single laser irradiation. The PTT/PDT combined therapy achieved more efficient tumor inhibition results as compared with single treatments. In addition, the overexpressed biomarker PLD in tumor tissue will cleave Rhod, leading to the fluorescence recovery of Rhod B and thus allowing the activatable fluorescence imaging of tumor and targeted phototherapy.

Molecular cloning and expression analysis of CD79a and CD79b in rainbow trout (Oncorhynchus mykiss) after bacterial, parasitic, and viral infection.

CD79a and CD79b heterodimers are important components that consist of B cell receptor compound, which play a crucial role in transduction activation signal of the antigen binding BCR, and B cell development and antibody production. In order to investigate the characters and potential functions of CD79a and CD79b in rainbow trout (Oncorhynchus mykiss), we firstly cloned and analyzed the expression of CD79a and CD79b and found that the cDNA sequences of CD79a and CD79b both contained open reading frame of 711 and 645 bp in length for encoding the protein of 237 and 215 amino acid residues, respectively. The predicted amino acid sequences from trout were highly conserved with those of other teleost fishes in structure. Phylogenetic tree was constructed to analyze the evolutionary relationship between the trout and other known species, the result indicated that CD79a and CD79b of trout clustered at high bootstrap values with Salmo salar. Moreover, three trout infection models with F. columnare G4, I. multifiliis and infectious hematopoietic necrosis virus (IHNV) were constructed, which resulted in morphological changes and serious lesions in skin and gills. Importantly, the high expression of CD79a and CD79b occurred in skin, gills, and followed by head kidney in response to bacterial, parasitic, and viral infection, as its expression was closely related to that of Igs. Our findings indicated that CD79a and CD79b play vital roles in both systemic and mucosal immune responses of rainbow trout during bacterial, parasitic, and viral infection, which will contribute to explore the roles of CD79 subunits in B cell signaling during ontogeny and disease.

Phytoactinopolyspora mesophila sp. nov., isolated from a saline-alkaline soil.

A novel moderately halophilic, filamentous actinobacterium, designated as XMNu-373T, was isolated from a saline-alkaline soil sample collected from the Mongolia Plateau, Dongwu County, Inner Mongolia Autonomous Region, PR China. The isolate grew optimally at 28‒37 °C, pH 7.0‒8.0 and with 2-5 % (w/v) NaCl. The substrate mycelia fragmented into rod-like elements, and the white aerial mycelia formed spore chains at maturity. The predominant menaquinone was MK-9(H4). The polar lipids were diphosphatidylglycerol, three unidentified phosphoglycolipids, an unidentified aminophospholipid, two phosphatidylinositol mannosides, four unidentified phospholipids, phosphatidylglycerol and two unidentified lipids. The major cellular fatty acids were iso-C16 : 0, anteiso-C17 : 0 and anteiso-C15 : 0. The genomic DNA G+C content was 66.2 mol%. It shared high 16S rRNA gene sequence similarities to Phytoactinopolyspora halotolerans YIM 96448T (96.1 %) and Phytoactinopolyspora endophytica EGI 60009T (96.0 %). Phylogenetic trees based on 16S rRNA gene sequences revealed that strain XMNu-373T resided in the clade of family Jiangellaceae, and it formed a monophyletic branch distinct from four other recognized type species in the subclade of the genus Phytoactinopolyspora. On the basis of polyphasic taxonomic evidence, strain XMNu-373T represents a novel species of the genus Phytoactinopolyspora, for which the name Phytoactinopolyspora mesophila sp. nov. is proposed. The type strain is XMNu-373T (=JCM 33740T=CGMCC 4.7654T).

Endothelin-1 Stimulates Vasoconstriction Through Rab11A Serine 177 Phosphorylation.

RATIONALE: Large-conductance calcium-activated potassium channels (BK) are composed of pore-forming BKα and auxiliary ß1 subunits in arterial smooth muscle cells (myocytes). Vasoconstrictors, including endothelin-1 (ET-1), inhibit myocyte BK channels, leading to contraction, but mechanisms involved are unclear. Recent evidence indicates that BKα is primarily plasma membrane localized, whereas the cellular location of ß1 can be rapidly altered by Rab11A-positive recycling endosomes. Whether vasoconstrictors regulate the multisubunit composition of surface BK channels to stimulate contraction is unclear. OBJECTIVE: Test the hypothesis that ET-1 inhibits BK channels by altering BKα and ß1 surface trafficking in myocytes, identify mechanisms involved, and determine functional significance in myocytes of small cerebral arteries. METHODS AND RESULTS: ET-1, through activation of PKC (protein kinase C), reduced surface ß1 abundance and the proximity of ß1 to surface BKα in myocytes. In contrast, ET-1 did not alter surface BKα, total ß1, or total BKα proteins. ET-1 stimulated Rab11A phosphorylation, which reduced Rab11A activity. Rab11A serine 177 was identified as a high-probability PKC phosphorylation site. Expression of a phosphorylation-incapable Rab11A construct (Rab11A S177A) blocked the ET-1-induced Rab11A phosphorylation, reduction in Rab11A activity, and decrease in surface ß1 protein. ET-1 inhibited single BK channels and transient BK currents in myocytes and stimulated vasoconstriction via a PKC-dependent mechanism that required Rab11A S177. In contrast, NO-induced Rab11A activation, surface trafficking of ß1 subunits, BK channel and transient BK current activation, and vasodilation did not involve Rab11A S177. CONCLUSIONS: ET-1 stimulates PKC-mediated phosphorylation of Rab11A at serine 177, which inhibits Rab11A and Rab11A-dependent surface trafficking of ß1 subunits. The decrease in surface ß1 subunits leads to a reduction in BK channel calcium-sensitivity, inhibition of transient BK currents, and vasoconstriction. We describe a unique mechanism by which a vasoconstrictor inhibits BK channels and identify Rab11A serine 177 as a modulator of arterial contractility.

Polyoxometalate-Decorated g-C3 N4 -Wrapping Snowflake-Like CdS Nanocrystal for Enhanced Photocatalytic Hydrogen Evolution.

Photocatalytic hydrogen evolution technology is recognized as a promising approach to relieving the growing energy crisis. Therefore, the development of a stable high-performance photocatalyst has long been the focus of research. In this work, quaternary composite materials involving a snowflake-like CdS nanocrystal wrapped by different amounts of polyoxometalate-decorated g-C3 N4 and polypyrrole (GPP@CdS) have been synthesized as photocatalysts for hydrogen production under visible-light irradiation. It has been revealed that the best composite (40 % GPP@CdS composite) exhibits hydrogen production activity of 1321 µmol, which exceeds that of CdS by a factor of more than two, and can be used in at least seven cycles with negligible loss of activity. The enhanced photocatalytic performance has been primarily attributed to the efficient synergy of CdS, g-C3 N4 , polypyrrole (PPy), and the polyoxometalate Ni4 (PW9 )2 . It should be noted that the introduction of PPy and g-C3 N4 into the title composite simultaneously promotes electron/hole pair separation and photocatalytic stability, whereas Ni4 (PW9 )2 serves as an efficient electron modulator and extra catalytic active site.

[Resveratrol increases sirtuin 1 expression in peripheral blood mononuclear cells of premature infants and inhibits the oxidative stress induced by hyperoxia in vivo].

OBJECTIVE: To explore the effect of resveratrol on the levels of sirtuin 1 (SIRT1) and reactive oxygen species (ROS) in peripheral blood mononuclear cells (PBMCs) of premature infants exposed to hyperoxia. METHODS: Peripheral blood and isolated PBMCs from premature infants (gestational age<32 weeks) without oxygen supplement were collected and were randomly assigned into four groups: control, air+resveratrol, hyperoxia, and hyperoxia+resveratrol. The PBMCs were cultured in vitro for 48 hours, then the ROS content in PBMCs was measured by laser scanning confocal microscopy. Malondialdehyde (MDA) content in the medium was measured by the whole spectrum spectrophotometer. SIRT1 positioning was assessed by immunofluorescence. SIRT1 expression levels in PBMCs were measured by Western bolt. RESULTS: Compared with the control group, the level of SIRT1 in the air+resveratrol group increased significantly (P<0.05). The levels of ROS and MDA and the SIRT1 transposition rate in the hyperoxia group increased significantly, while the expression level of SIRT1 decreased significantly compared with the control group (P<0.05). The levels of ROS and MDA and the SIRT1 transposition rate decreased significantly (P<0.05), and the expression level of SIRT1 increased significantly in the hyperoxia+resveratrol group (P<0.05). CONCLUSIONS: Resveratrol can increase SIRT1 expression in PBMCs and inhibit SIRT1 shuttle from nucleus to cytoplasm in order to increase the ability of antioxidative stress in premature infants exposed to hyperoxia, thereby reducing the oxidative stress injury in premature infants.

Copper-organic cationic ring with an inserted arsenic-vanadium polyanionic cluster for efficient catalytic Cr(VI) reduction using formic acid.

Polyanionic cluster [ß-As8V14O42(H2O)](4-) is well embedded in a large porous eight-membered cationic ring of the copper ligand, giving a stable host-guest supramolecular system. The assembly exhibits an efficient heterogeneous catalytic performance for the reduction of Cr(VI) using formic acid at ambient temperature.

A simple LC-MS/MS method for quantitative analysis of underivatized neurotransmitters in rats urine: assay development, validation and application in the CUMS rat model.

Many amino acid neurotransmitters in urine are associated with chronic stress as well as major depressive disorders. To better understand depression, an analytical LC-MS/MS method for the simultaneous determination of 11 underivatized neurotransmitters (4-aminohippurate, 5-HIAA, glutamate, glutamine, hippurate, pimelate, proline, tryptophan, tyramine, tyrosine and valine) in a single analytical run was developed. The advantage of this method is the simple preparation in that there is no need to deconjugate the urine samples. The quantification range was 25-12,800 ng mL(-1) with >85.8% recovery for all analytes. The nocturnal urine concentrations of the 11 neurotransmitters in chronic unpredictable mild stress (CUMS) model rats and control group (n = 12) were analyzed. A series of significant changes in urinary excretion of neurotransmitters could be detected: the urinary glutamate, glutamine, hippurate and tyramine concentrations were significantly lower in the CUMS group. In addition, the urinary concentrations of tryptophan as well as tyrosine were significantly higher in chronically stressed rats. This method allows the assessment of the neurotransmitters associated with CUMS in rat urine in a single analytical run, making it suitable for implementation as a routine technique in depression research.

[Silencing of Pin1 suppresses hyperoxia-induced apoptosis of A549 cells].

OBJECTIVE: To explore the effect of silence of Pin1 expression on hyperoxia-induced apoptosis in alveolar epithelial cells A549. METHODS: A549 cells were divided into four groups: control, hyperoxia, negative lentivirus and Pin1-shRNA hyperoxia. The hyperoxia group was exposed to a mixture of 95%O2 and 5%CO2 for 10 minutes. Then cells were cultured in a closed environment. After 24 hours, the changes of morphology were observed under an inverted microscope. Cell apoptosis was detected by flow cytometry (FCM). The expression of X-linked inhibitor of apoptosis protein (XIAP) and Caspase-9 were detected by immunohistochemistry. The production of reactive oxygen species (ROS) and cellular mitochondria membrane potential (△Ψm) were determined by fluorescence microscopy. RESULTS: Under the inverted microscope, the A549 cells grew slowly and the changes in morphology of the cells were most obvious in the hyperoxia and negative lentivirus groups. The changes in morphology of A549 cells were obviously improved in the Pin1-shRNA hyperoxia group. The FCM results showed that the apoptosis rate of A549 cells increased, Caspase-9 expression increased, XIAP expression decreased, mitochondrial ROS production increased and mitochondrial membrane potential decreased in the hyperoxia and negative lentivirus groups compared with the control group (P<0.05). Compared with the hyperoxia and negative lentivirus groups, the apoptosis rate of A549 cells decreased, Caspase-9 expression decreased, XIAP expression increased, mitochondrial ROS production decreased and mitochondrial membrane potential increased in the Pin1-shRNA hyperoxia group (P<0.05), although the levels of the indexes did not reach to those of the control group. CONCLUSIONS: Silencing of Pin1 could suppress hyperoxia-induced apoptosis of A549 cells.

[Roles of PKCß/P66Shc oxidative stress signal pathway in mediating hyperoxia-induced ROS production in alveolar epithelial cells].

OBJECTIVE: To explore the roles of PKCß/P66Shc oxidative stress signal pathway in mediating hyperoxia-induced reactive oxgen species (ROS) production in alveolar epithelial cells (A549) and the protective effects of PKCß inhibitor on hyperoxia-induced injuries of alveolar epithelial cells. METHODS: A549 cells were cultured in vitro and randomly divided into three groups: control, hyperoxia and PKCß inhibitor LY333531 treatment. The hyperoxia group was exposed to a mixture of O2 (950 mL/L) and CO2 (50 mL/L) for 10 minutes and then cultured in a closed environment. The LY333531 group was treated with PKCß inhibitor LY333531 of 10 µmol/L for 24 hours before hyperoxia induction. Cells were collected 24 hours after culture and the levels of PKCß, Pin1, P66Shc and P66Shc-Ser36 were detected by Western blot. The intracellular translocation of P66Shc, the production of ROS and cellular mitochondria membrane potential were measured using the confocal microscopy. RESULTS: Compared with the control group, the levels of PKCß, Pin1, P66Shc and P-P66Shc-Ser36 in A549 cells 24 hours after culture increased significantly in the hyperoxia group. These changes in the hyperoxia group were accompanied with an increased translocation rate of P66Shc from cytoplasm into mitochondria, an increased production of mitochondrial ROS, and a reduced mitochondrial membrane potential. Compared with the hyperoxia group, the levels of Pin1, P66Shc and P66Shc-Ser36 in A549 cells, the translocation rate of P66Shc from cytoplasm into mitochondria and the production of mitochondrial ROS decreased significantly, while the mitochondrial membrane potential increased significantly in the LY333531 treatment group. However, there were significant differences in the above mentioned measurements between the LY333531 treatment and control groups. CONCLUSIONS: Hyperoxia can increase the expression of PKCß in alveolar epithelial cells and production of mitochondrial ROS and decrease mitochondrial membrane potential. PKCß inhibitor LY333531 can partially disrupt these changes and thus alleviate the hyperoxia-induced alveolar epithelial cell injury.

An unusual metallic oxygen cluster consisting of a {AlMo12O40(MoO2)}.

A novel aluminum-containing, bimolybdenum-capped Keggin-type polyoxomolybate cluster of the {AlMo12O40(MoO2)2} anion has been synthesized and characterized. This is the first experimentally determined Keggin-type {AlMo12O40} polyoxoanion. The polyoxometalate crystal exhibits high selectivity toward the heterogeneous catalytic oxidation of cyclohexanol to cyclohexanone.

Spindle apparatus coiled-coil protein 1 (SPDL1) serves as a novel prognostic biomarker in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) has a poor prognosis, an ineffective diagnosis, and a high degree of aggressiveness. Therefore, novel therapeutic targets for TNBC urgently need to be identified. METHODS: Through a series of bioinformatics analyses, including analysis of differential gene expression, protein-protein interaction (PPI) network, univariate cox regression, immune infiltration, pathway enrichment, etc, as well as auxiliary immunohistochemistry (IHC) and protein quantitativae analysis, to explore prognostic marker for TNBC. RESULTS: In TNBC tissues, we found that SPDL1 (CCDC99) was considerably overexpressed at both the mRNA and protein levels compared to that in normal and non-TNBC tissues. Additionally, we found that SPDL1-high expression was strongly linked to poor prognosis in TNBC patients. Excessive SPDL1 expression was positively correlated with tumor growth and strongly linked to the cell cycle, DNA replication, and the p53 signaling pathway. In addition, CIBERSORT analysis revealed that SPDL1 can affect the tumor immune microenvironment (TME) in TNBC, encourage the development of TNBC and act as a potential prognostic biomarker for TNBC. Patients with SPDL1-high expression were more sensitive to AZD8055. Notably, we discovered that SPDL1 is highly expressed in the majority of malignancies and may have an impact on the pancancer prognosis. CONCLUSIONS: SPDL1 can serve as a novel prognostic marker for TNBC and pancancer patients.

Construction of n-type homogeneous to improve interfacial carrier transfer for enhanced photoelectrocatalytic hydrolysis.

Photoelectrocatalyzed hydrogen production plays an important role in the path to carbon neutrality. The construction of heterojunctions provides an ideal example of an oxygen precipitation reaction. In this work, the performance of the n-n type heterojunction CeBTC@FeBTC/NIF in the photoelectronically coupled catalytic oxygen evolution reaction (OER) reaction is presented. The efficient transfer of carriers between components enhances the catalytic activity. Besides, the construction of heterojunctions optimizes the energy level structure and increases the absorption of light, and the microstructure forms holes with a blackbody effect that also enhances light absorption. Consequently, CeBTC@FeBTC/NIF has excellent photoelectric coupling catalytic properties and requires an overpotential of only 300 mV to drive a current density of 100 mA cm-2 under illumination. More importantly, the n-n heterojunction was found to be effective in enhancing charge and photogenerated electron migration by examining the carrier density of each component and carrier diffusion at the interface.

Construction of novel Ag(0)-containing silver nanoclusters by regulating auxiliary phosphine ligands.

Controlled synthesis of metal clusters through minor changes in surface ligands holds significant interest because the corresponding entities serve as ideal models for investigating the ligand environment's stereochemical and electronic contributions that impact the corresponding structures and properties of metal clusters. In this work, we obtained two Ag(0)-containing nanoclusters (Ag17 and Ag32) with near-infrared emissions by regulating phosphine auxiliary ligands. Ag17 and Ag32 bear similar shells wherein Ag17 features a trigonal bipyramid Ag5 kernel while Ag32 has a bi-icosahedral interpenetrating an Ag20 kernel. Ag17 and Ag32 showed a near-infrared emission (NIR) of around 830 nm. Benefiting from the rigid structure, Ag17 displayed a more intense near-infrared emission than Ag32. This work provides new insight into the construction of novel superatomic silver nanoclusters by regulating phosphine ligands.

Assessment of Ki-67 proliferation index in prognosis prediction in patients with nonmetastatic clear cell renal cell carcinoma and tumor thrombus.

PURPOSE: To determine the optimal cut-off value of Ki-67 for predicting the survival of patients with clear cell renal cell carcinoma (ccRCC) and tumor thrombus and to explore the correlation between Ki-67 expression and pathological features. PATIENTS AND METHODS: We retrospectively analyzed Ki-67 immunohistochemical staining of ccRCC and tumor thrombus resected from February 2006 to February 2022. The survival rate was evaluated using the Kaplan-Meier method. The optimal cut-off value of the Ki-67 expression for predicting survival was determined by the minimum P-value method. Clinicopathological data were compared based on Ki-67 status (low versus high expression). Univariate and multivariate Cox regression analysis was used to explore independent predictors. RESULTS: A total of 202 patients (median age, 58 years [IQR, 52-65 years], 147 men) with ccRCC and tumor thrombus were included in the study. The optimal cut-off value of Ki-67 for predicting survival was 30%. 159 (78.7%) and 43 (21.3%) patients were included in the low-expression and high-expression groups. Patients with Ki-67 high expression had significantly worse recurrence-free survival (P < 0.001) and cancer-specific survival (P < 0.001). Ki-67 high expression was associated with adverse pathological features, including tumor necrosis, ISUP nuclear grade, sarcomatoid differentiation, perirenal fat invasion, renal pelvis invasion, and inferior vena cava wall invasion (all P < 0.050). Ki-67 expression ≥ 30% (P = 0.016), tumor side (P = 0.003), diabetes (P = 0.040), blood loss (P = 0.016), inferior vena cava wall invasion (P = 0.016), and sarcomatoid differentiation (P = 0.014) were independent predictors of cancer-specific survival. CONCLUSION: The optimal cut-off level of Ki-67 in predicting the prognosis of ccRCC and tumor thrombus was 30%. The high expression of Ki-67 was associated with the aggressive pathological phenotype and poor prognosis.

Comparative Bioavailability and Tolerability of a Single 2-mg Dose of 2 Repaglinide Tablet Formulations in Fasting, Healthy Chinese Male Volunteers: An Open-Label, Randomized-Sequence, 2-Period Crossover Study.

BACKGROUND: Repaglinide, an oral insulin secretagogue, was the first meglitinide analogue to be approved for use in patients with type 2 diabetes mellitus. OBJECTIVE: In our study, the bioavailability and tolerability of the proposed generic formulation with the established reference formulation of repaglinide 2 mg were compared in a fasting, healthy Chinese male population. METHODS: This 2-week, open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in 22 healthy native Han Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 2-mg dose of the test or reference formulation, followed by a 7-day washout period and administration of the alternate formulation. After an overnight fast, subjects received a single oral dose of repaglinide (2 mg). Blood samples were drawn at predetermined time points (0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, and 6.0 hours). All plasma concentrations of repaglinide were measured by LC-MS/MS. The observed Cmax, Tmax, t1/2, and AUC were assessed. The formulations were to be considered bioequivalent if the ln-transformed ratios of Cmax and AUC were within the predetermined bioequivalence range of 80% to 125% established by the State Food and Drug Administration of the People's Republic of China. Tolerability was assessed throughout the study via subject interview, vital signs, and blood sampling. RESULTS: The mean (SD) age of the subjects was 24.2 (2.3) years; their mean (SD) weight was 62.6 (5.8) kg, their mean (SD) height was 172 (5.7) cm, and their mean (SD) body mass index was 21.0 (1.1). The mean (SD) Cmax for repaglinide with the test and reference formulations were 20.0 (5.1) and 18.7 (8.7) ng/mL. The AUC0-t for the test formulation was 46.3 (15.1) and AUC0-∞ was 47.9 (16.5) ng(•)h/mL. With the reference formulation, the corresponding values were 46.4 (26.1) and 49.0 (31.3) ng(•)h/mL. The mean (SD) Tmax values with the test and reference formulations were 1.2 (0.7) hours and 1.5 (0.8) hours and the mean (SD) values t1/2 values were 1.0 (0.3), and 0.9 (0.3) hours, respectively. The ln-transformed ratios of Cmax, AUC0-t, and AUC0-∞ were 113.6:1, 105.6:1, and 104.7:1. The corresponding 90% CIs were 99.8 to 129.2, 93.4 to 119.5, and 91.8 to 119.5, respectively. CONCLUSIONS: This single-dose study found that the test and reference formulations of repaglinide met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. Both formulations appeared to be well tolerated. ClinicalTrials.gov identifier: 2012L01684.

Comparative bioavailability and tolerability of single and multiple doses of 2 diclofenac sodium sustained-release tablet formulations in fasting, healthy chinese male volunteers.

BACKGROUND: Diclofenac is a nonsteroidal anti-inflammatory drug used for the treatment of patients with osteoarthritis. OBJECTIVES: Our primary objective was to compare bioavailability and tolerability of a generic sustained-release tablet with the established reference sustained-release tablet of diclofenac sodium in a fasting, healthy Chinese male population. METHODS: A randomized, open-label, single- and multiple-dose study design was used. After the single dose, volunteers received diclofenac sodium sustained-release tablet once daily for 5 days. In the single-dose phase, blood samples were collected from 0 to 36 hours after drug administration. In the multiple-dose phase, samples were obtained before drug administration at 8:00 am on Days 3 and 4 to determine Cmin,ss of diclofenac sodium; on Day 5, samples were collected from 0 to 36 hours. Adverse events were monitored via subject interview, vital signs, and blood sampling. RESULTS: Twenty-four Chinese male volunteers were enrolled. The pharmacokinetic parameters (mean [SD]) for diclofenac after single dose of 75 and 100 mg were: Cmax 473.5 [179.5] and 546.6 [154.9] ng/mL; AUC0-∞ 3841.2 [1402.3], and 5019.1 [2,314.0] ng·h/mL; Tmax 4.9 [2.4], and 4.3 [2.2] hours; t1/2 5.9 [2.5], and 6.0 [2.2] hours. Mean [SD] values after multiple doses of 75 and 100 mg were: Cmax,ss 525.6 [127.4] and 650.5 [167.0] ng/mL, Cmin,ss 33.9 [20.9] and 62.9 [34.9] ng/mL, AUCss 4316.3 [633.0] and 5335.1 [1291.9] ng·h/mL, Cav,ss 179.8 [26.4] and 222.3 [53.8] ng/mL, Tmax 5.1 [1.8] and 4.5 [0.9] hours and t1/2 5.2 [2.9] and 5.5 [2.8] hours, respectively. CONCLUSIONS: This diclofenac sodium 75 mg tablet has features compatible with the 100 mg sustained-release tablet and appeared to be well tolerated. ClinicalTrials.gov identifier: 2010L01969.