Pairwise machine learning-based automatic diagnostic platform utilizing CT images and clinical information for predicting radiotherapy locoregional recurrence in elderly esophageal cancer patients.

OBJECTIVE: To investigate the feasibility and accuracy of predicting locoregional recurrence (LR) in elderly patients with esophageal squamous cell cancer (ESCC) who underwent radical radiotherapy using a pairwise machine learning algorithm. METHODS: The 130 datasets enrolled were randomly divided into a training set and a testing set in a 7:3 ratio. Clinical factors were included and radiomics features were extracted from pretreatment CT scans using pyradiomics-based software, and a pairwise naive Bayes (NB) model was developed. The performance of the model was evaluated using receiver operating characteristic (ROC) curves and decision curve analysis (DCA). To facilitate practical application, we attempted to construct an automated esophageal cancer diagnosis system based on trained models. RESULTS: To the follow-up date, 64 patients (49.23%) had experienced LR. Ten radiomics features and two clinical factors were selected for modeling. The model demonstrated good prediction performance, with area under the ROC curve of 0.903 (0.829-0.958) for the training cohort and 0.944 (0.849-1.000) for the testing cohort. The corresponding accuracies were 0.852 and 0.914, respectively. Calibration curves showed good agreement, and DCA curve confirmed the clinical validity of the model. The model accurately predicted LR in elderly patients, with a positive predictive value of 85.71% for the testing cohort. CONCLUSIONS: The pairwise NB model, based on pre-treatment enhanced chest CT-based radiomics and clinical factors, can accurately predict LR in elderly patients with ESCC. The esophageal cancer automated diagnostic system embedded with the pairwise NB model holds significant potential for application in clinical practice.

GNA15 facilitates the malignant development of thyroid carcinoma cells via the BTK-mediated MAPK signaling pathway.

G protein subunit alpha 15 (GNA15) is recognized as an oncogene for some cancers, however, its role in thyroid carcinoma (TC) is elusive and is investigated in this study. Concretely, bioinformatics was employed to analyze the GNA15 expression profile in TC. The effect of GNA15 on TC cell functions was examined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, and Transwell assays. Expressions of extracellular regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 were determined using Western blot. The involvement of Bruton tyrosine kinase (BTK) in the mechanism of GNA15 was investigated by BTK knockdown and rescue assay. GNA15 presented an overexpression pattern in TC samples, which facilitated the viability, proliferation, migration, and invasion of TC cells; GNA15 silencing led to converse results. Ratios of p-ERK/ERK, p-JNK/JNK, and p-p38/p38 were upregulated by GNA15 overexpression. The BTK deficiency weakened the aforementioned behaviors of TC cells and blocked the MAPK signaling pathway, however, these effects were counteracted by GNA15 overexpression. Collectively, GNA15 contributes to the malignant development of TC cells by binding to BTK and thus activating the MAPK signaling pathway.

Asiaticoside Down-Regulates HIF-1α to Inhibit Proliferation, Migration, and Angiogenesis in Thyroid Cancer Cells

Background: Thyroid cancer (TC), the most prevalent endocrine malignancy, has been subjected to various treatment methods. However, the efficacy of asiaticoside (AC) for treating TC remains uncertain. Aims: To explore the impact of AC on TC and determine its potential mechanisms of action. Study Design: In vitro and in vivo cell line study. Methods: We evaluated the effects of AC on human TC cell lines, namely TPC-1 and FTC-133. Both in vitro and in vivo experimental validations were conducted. Results: AC significantly diminished the viability and proliferation of TC cells based on the CCK-8 assay and Edu staining findings. Migration and invasion assays revealed that AC effectively curtailed the migration and invasiveness of TC cells. The tube formation assay demonstrated that AC substantially impeded TC cell-induced angiogenesis. Western blot assay revealed that AC significantly reduced the expression levels of TRAF6, HIF-1α, and VEGFA, indicating that AC could potentially exert its anticancer effect by inhibiting the TRAF6/HIF1α pathway. Our in vivo experiments, which involved administering AC to BALB/c nude mice injected with TPC-1 cells, demonstrated significant inhibition of tumor growth and reduction in the expression of Ki-67, TRAF6, HIF-1α, and VEGFA. Conclusion: Our study highlights the significant inhibitory effect of AC on TC, offering fresh insights and potential drug candidates for TC treatment.

Comparison the effects of progestin-primed ovarian stimulation (PPOS) protocol and GnRH-a long protocol in patients with normal ovarian reserve function.

OBJECTIVE: To compare the effects of progestin-primed ovarian stimulation (PPOS) protocol and GnRH-a long protocol in infertility patients with normal ovarian reserve function undergoing invitro fertilization and embryo transfer. METHODS: A retrospective cohort study was conducted to analyze the clinical data of 2013 cycles of patients with normal ovarian reserve function who underwent invitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) in the Department of Human Reproductive Center, Renmin Hospital, Hubei University of Medicine from January 2018 and June 2020. The PPOS protocol group included 679 cycles and GnRH-along protocol group included 1334 cycles, the pregnancy outcomes were compared between the two groups. RESULTS: The duration of Gn used and total Gn used dosage in the PPOS protocol group were less than those in the GnRH-along protocol group (Duration of Gn used: 10.05 ± 1.48 vs 11.90 ± 1.85 d, p < 0.001; Total Gn used dosage: 1944.49 ± 533.61 vs 2661.34 ± 987.97 IU, p < 0.001); The LH levels were significantly higher on HCG trigger day in PPOS protocol compared to GnRH-a long protocol (2.8 ± 1 ± 1.07 vs 1.01 ± 0.62 IU/L, p < 0.001), the E2 levels on HCG trigger day in PPOS protocol group was lower than that in the GnRH-a long protocol group (2135.92 ± 1387.00 vs 2417.01 ± 1010.70 pg/mL, p < 0. 001). The number of oocytes retrieved in the PPOS protocol group was lower than that in the GnRH-along protocol group (8.03 ± 2.86 vs 9.47 ± 2.64, p < 0.001). No significant differences were found in pregnancy outcome including clinical pregnancy rate, early miscarriage rate and ectopic pregnancy rate between the two group (p > 0.05); In addition, no severe OHSS occurred in the PPOS protocol group during ovulation induction, while 11 patients of severe ovarian hyperstimulation syndrome (OHSS) occurred in GnRH-a long protocol group (p < 0.001). CONCLUSION: The clinical efficacy of PPOS protocol combining embryo cryopreservation is comparable to that of GnRH-a long protocol in patients with normal ovarian reserve function, and the PPOS protocol is able to reduce the incidence of severe OHSS significantly.

Gas-Dependent Active Sites on Cu/ZnO Clusters for CH3OH Synthesis.

This study describes an instantaneously gas-induced dynamic transition of an industrial Cu/ZnO/Al2O3 catalyst. Cu/ZnO clusters become "alive" and lead to a promotion in reaction rate by almost one magnitude, in response to the variation of the reactant components. The promotional changes are functions of either CO2-to-CO or H2O-to-H2 ratio which determines the oxygen chemical potential thus drives Cu/ZnO clusters to undergo reconstruction and allows the maximum formation of Cu-Zn2+ sites for CH3OH synthesis.

The follicular-phase depot GnRH agonist protocol results in a higher live birth rate without discernible differences in luteal function and child health versus the daily mid-luteal GnRH agonist protocol: a single-centre, retrospective, propensity score matched cohort study.

BACKGROUND: The gonadotropin-releasing hormone agonist (GnRH-a) has been used in in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles for a long time. This paper evaluates the efficacy and safety of two commonly used protocols (follicular-phase depot GnRH-a protocol and daily mid-luteal long GnRH-a protocol) in normal responders undergoing IVF/ICSI using propensity score matching (PSM) analysis. METHODS: A total of 6,816 infertile women treated within the period from January 2016 to September 2020 were stratified into cohorts. A total of 2,851 patients received the long-acting group (depot GnRH-a protocol), and 1,193 used the short-acting group (long GnRH-a protocol) after the data-selection process. PSM was utilized for sampling by up to 1:1 nearest neighbour matching to adjust the numerical difference and balance the confounders between groups. The primary outcome was the live birth rate (LBR). Multivariable logistic analysis was used to evaluate the difference between these two protocols in relation to the LBR. RESULT(S): In this study, 1:1 propensity score matching was performed to create a perfect match of 964 patients in each group. After matching, the blastocyst formation rates, oestradiol (E2) value on Day hCG + 9, progesterone (P) value on Day hCG + 9, implantation rates, clinical pregnancy rates, and LBR were more favourable in the depot GnRH-a protocol than in the long GnRH-a protocol (P < 0.05). However, the moderate or severe OHSS rates were higher in the depot group than in the long group (P < 0.001). There were no significant differences in endometrial thickness, luteal support medication, early pregnancy loss rates, mid- and late-term pregnancy loss rates, or foetal malformation rates between the two protocols. CONCLUSION(S): Compared with the daily short-acting GnRH agonist protocol, the follicular-phase depot GnRH-a protocol might improve LBRs in normogonadotropic women without discernible differences in luteal function and child health.

Prognosis and Risk Factors of Recurrence in HBV-Related Small Hepatocellular Carcinoma After Stereotactic Body Radiation Therapy.

Objective: The role of stereotactic body radiation therapy (SBRT) for treating small hepatocellular carcinoma (sHCC) has gained increasing recognition. However, the prognosis and risk factors for recurrence in patients with sHCC remain unclear. This study investigated the risk factors for the recurrence of hepatitis B virus (HBV)-related sHCC after SBRT. Methods: A total of 240 HBV-related sHCC patients treated with SBRT between March 2011 and March 2020 were retrospectively analyzed. The cumulative probability of recurrence was calculated according to the Kaplan-Meier method. Univariate and multivariate analyses were performed with Cox proportional hazard models. Results: Recurrent hepatocellular carcinoma developed in 134 (55.8%) patients at a median time of 27 months after SBRT. The one- and two-year rates of recurrence were 20.9 and 45.0%, respectively. The median follow-up time was 30 months. The Cox multivariate analysis indicated that age (P = 0.029, HR [1.019, 1.002-1.037]), tumor size (P = 0.012, HR [1.227, 1.045-1.440]), and aspartate aminotransferase-to-platelet ratio index (APRI) (P = 0.005, HR [1.911, 1.221-2.989]) were independent risk factors for recurrence. Conclusion: Patients receiving SBRT for HBV-related sHCC may be at greater risk of recurrence if they have a high APRI score combined with advanced age and large tumor size.

Downregulation of miR-519d-3p is Associated with Poor Outcomes and Facilitates Tumor Progression in Papillary Thyroid Cancer by Regulating FOXQ1.

MicroRNA-519d-3p (miR-519d-3p) has emerged as a tumor suppressor in several human cancers. But whether miR-519d-3p is involved in papillary thyroid cancer (PTC) remains elusive. In this study, we investigated the potential relevance of miR-miR-519d-3p in PTC. A retrospective study of 119 PTCs was carried out. The RT-qPCR analysis was used to measure the expression of miR-519d-3p and FOXQ1 in PTC tissues and cells. Chi-square test, Kaplan-Meier curve analysis, and multivariate Cox regression analyses were performed to assess the clinical and prognostic value of miR-519d-3p in PTC. Then cellular experiments were used to explore its biological effects on PTC cells. Finally, the Pearson correlation coefficient, dual-luciferase reporter assay, and rescue experiments were used to analyze the association between miR-519d-3p and FOXQ1. miR-519d-3p was significantly downregulated in PTC tissues and cell lines. The decreased expression of miR-519d-3p was associated with reduced overall survival and progression-free survival of patients. The proliferative, migratory, and invasive abilities of cells were blocked or elevated after upregulation or downregulation of miR-519d-3p, while FOXQ1 reversed these cellular behaviors caused after upregulation or knockdown of miR-519d-3p. In conclusion, miR-519d-3p was downregulated in PTC and associated with OS and PFS of patients. MiR-519d-3p may be a tumor-inhibiting miRNA in PTC, and that miR-519d-3p/FOXQ1 axis mediated PTC tumor progression from cell proliferation, migration, and invasion in PTC cells.

Significant combination of Aß aggregation inhibitory and neuroprotective properties in silico, in vitro and in vivo by bis(propyl)-cognitin, a multifunctional anti-Alzheimer's agent.

Inhibition of Aß aggregation and neurotoxicity has been developed as an attractive therapeutic strategy to combat Alzheimer's disease (AD). Bis(propyl)-cognitin (B3C) is a multifunctional dimer derived from tacrine. Herein, the anti-aggregation and disassembly effects of B3C on Aß, together with the neuroprotective effects and underlying mechanisms of B3C against Aß-induced neurotoxicity were investigated in silico, in vitro and in vivo. Data from Thioflavin-T fluorescence and atomic force microscopy assays indicated that B3C (1-10 µM), but not its monomer tacrine, greatly inhibited the formation of Aß fibrils and disaggregated pre-formed mature Aß fibrils. Comparative molecular dynamics simulation results revealed a possible binding mode that prevented Aß fibrils formation, showing that B3C favorably bound to Aß via hydrophobic interactions. Additionally, B3C was able to block the neurotoxicity caused by Aß fibrils in cultured PC12 cells. Very encouragingly, B3C (0.3 and 0.45 mg/kg) markedly alleviated the cognitive impairments in rats insulted by intra-hippocampal injection of Aß1-42 fibrils, more potently than tacrine (1 and 2 mg/kg). Furthermore, mechanistic studies demonstrated that B3C reversed the inhibition of phospho-GSK3ß at Ser9 site in vitro and in vivo caused by Aß, suggesting the neuroprotection of B3C was achieved through the inhibition of GSK3ß pathway. These findings indicate that B3C could serve as an effective inhibitor of Aß aggregation and neurotoxicity, and provide novel molecular insights into the potential application of B3C in AD prevention and treatment.

Multifunctional memantine nitrate significantly protects against glutamate-induced excitotoxicity via inhibiting calcium influx and attenuating PI3K/Akt/GSK3beta pathway.

Overactivation of N-methyl-D-aspartate (NMDA) receptors has been associated with neurodegenerative disorders such as Alzheimer's disease (AD), cerebral vascular disorders and amyotrophic lateral sclerosis (ALS). We have previously designed and synthesized a series of memantine nitrate and some of them have shown vessel dilatory effects and neuroprotective effects; however, the detailed mechanisms have not been elucidated. In this study, we further demonstrated that memantine nitrate-06 (MN-06), one of the novel compounds derived from memantine, possessed significant neuroprotective effects against glutamate-induced excitotoxicity in rat primary cerebellar granule neurons (CGNs). Pretreatment of MN-06 reversed the activation of GSK3b and the suppression of phosphorylated Akt induced by glutamate. In addition, the neuroprotective effects of MN-06 could be abolished by LY294002, the specific phosphatidylinositol 3-kinase (PI3-K) inhibitor. Ca2+ imaging shown that pretreatment of MN-06 prevented Ca2+ influx induced by glutamate. Moreover, MN-06 might inhibit the NMDA-mediated current by antagonizing NDMA receptors, which was further confirmed by molecular docking simulation. Taken together, MN-06 protected against glutamate-induced excitotoxicity by blocking calcium influx and attenuating PI3-K/Akt/GSK-3b pathway, indicating that MN-06 might be a potential drug for treating neurodegenerative disorders.

Isorhynchophylline ameliorates cognitive impairment via modulating amyloid pathology, tau hyperphosphorylation and neuroinflammation: Studies in a transgenic mouse model of Alzheimer's disease.

Isorhynchophylline (IRN) has been demonstrated to have distinct anti-Alzheimer's disease (AD) activity in several animal models of AD. In this study, we aimed at evaluating the preventive effect of IRN on the cognitive deficits and amyloid pathology in TgCRND8 mice. Male TgCRND8 mice were administered with IRN (20 or 40 mg/kg) by oral gavage daily for 4 months, followed by assessing the spatial learning and memory functions with the Radial Arm Maze (RAM) test. Brain tissues were determined immunohistochemically or biochemically for changes in amyloid pathology, tau hyperphosphorylation and neuroinflammation. Our results revealed that IRN (40 mg/kg) significantly ameliorated cognitive deficits in TgCRND8 mice. In addition, IRN (40 mg/kg) markedly reduced the levels of Aß40, Aß42 and tumor necrosis factor (TNF-α), interleukin 6 (IL-6) and IL-1ß, and modulated the amyloid precursor protein (APP) processing and phosphorylation by altering the protein expressions of ß-site APP cleaving enzyme-1 (BACE-1), phosphorylated APP (Thr668), presenilin-1 (PS-1) and anterior pharynx-defective-1 (APH-1), as well as insulin degrading enzyme (IDE), a major Aß-degrading enzyme. IRN was also found to inhibit the phosphorylation of tau at the sites of Thr205 and Ser396. Immunofluorescence showed that IRN reduced the Aß deposition, and suppressed the activation of microglia (Iba-1) and astrocytes (GFAP) in the cerebral cortex and hippocampus of TgCRND8 mice. Furthermore, IRN was able to attenuate the ratios of p-c-Jun/c-Jun and p-JNK/JNK in the brains of TgCRND8 mice. IRN also showed marked inhibitory effect on JNK signaling pathway in the Aß-treated rat primary hippocampus neurons. We conclude that IRN improves cognitive impairment in TgCRND8 transgenic mice via reducing Aß generation and deposition, tau hyperphosphorylation and neuroinflammation through inhibiting the activation of JNK signaling pathway, and has good potential for further development into pharmacological treatment for AD.

Strong Metal-Support Interactions between Copper and Iron Oxide during the High-Temperature Water-Gas Shift Reaction.

The commercial high-temperature water-gas shift (HT-WGS) catalyst consists of CuO-Cr2 O3 -Fe2 O3 , where Cu functions as a chemical promoter to increase the catalytic activity, but its promotion mechanism is poorly understood. In this work, a series of iron-based model catalysts were investigated with in situ or pseudo in situ characterization, steady-state WGS reaction, and density function theory (DFT) calculations. For the first time, a strong metal-support interaction (SMSI) between Cu and FeOx was directly observed. During the WGS reaction, a thin FeOx overlayer migrates onto the metallic Cu particles, creating a hybrid surface structure with Cu-FeOx interfaces. The synergistic interaction between Cu and FeOx not only stabilizes the Cu clusters, but also provides new catalytic active sites that facilitate CO adsorption, H2 O dissociation, and WGS reaction. These new fundamental insights can potentially guide the rational design of improved iron-based HT-WGS catalysts.

Bis(propyl)-cognitin potentiates rehabilitation of treadmill exercise after a transient focal cerebral ischemia, possibly via inhibiting NMDA receptor and regulating VEGF expression.

Combination therapies may have greater efficacy compared with monotherapy in treating stroke. We investigated the molecular mechanisms by which the combination of bis(propyl)-cognitin, an uncompetitive antagonist of NMDA receptor, and treadmill exercise promote rehabilitation after ischemic stroke. Rats were distributed into 3 treatment groups: infarct/bis(propyl)-cognitin(drug only group, DO); infarct/treadmill exercise(exercise only group, EO); infarct/bis(propyl)-cognitin + treadmill exercise (drug + exercise group, DE). The DE group had further separated to 3 sub-groups to investigate the effects achieved by different time for drug administration (60 min before stroke (DE-60 m), 15 min (DE+15 m) and 60 min (DE+60 m) after stroke). Although all infarct groups improved over time, the combination of bis(propyl)-cognitin and treadmill exercise effectively enhanced motor recovery during 14-day intervention. Early drug intervention has a best recovery result, the DE+15 m group with drug intervention at 15-min after stroke had better motor recovery than DE+60 m, DO, EO and control groups. Both bis(propyl)-cognitin and treadmill exercise significantly elevated brain VEGF expression and decreased brain infarct volume at 14 day post-ischemia. Our study reveals that bis(propyl)-cognitin potentiated rehabilitation of treadmill exercise after ischemic stroke, possibly via regulating brain VEGF expression, indicating that the combination of NMDA receptor antagonists and exercise might be useful for stroke rehabilitation.

Simultaneous removal of SO2 and NOx from flue gas by wet scrubbing using a urea solution.

Nitrogen oxides (NOx) and sulfur dioxide (SO2) are major air pollutants, so simultaneously removing them from gases emitted during fossil fuel combustion in stationary systems is important. Wet denitrification using urea is used for a wide range of systems. Additives have strong effects on wet denitrification using urea, and different mechanisms are involved and different effects found using different additives. In this study, the effects of different additives, initial urea concentrations, reaction temperatures, initial pH values, gas flow rates, and reaction times on the simultaneous desulfurization and denitrification efficiencies achieved using wet denitrification using urea were studied in single factor experiment. The optimum reaction conditions for desulfurization and denitrification were found. Desulfurization and denitrification efficiencies of 97.5% and 96.3%, respectively, were achieved at a KMnO4 concentration 5 mmol/L, a reaction temperature of 70°C, initial urea solution pH 8, a urea concentration of 9%, and a gas flow rate of 40 L/h. The concentrations of the desulfurization and denitrification reaction products in the solution were determined. NOx was mainly transformed into N2, and the NO3- and NO2- concentrations in the solution became very low. The reactions involved in SO2 and NOx removal using urea were analyzed from the thermodynamic viewpoint. Increasing the temperature was not conducive to the reactions but increased the rate constant, so an optimum temperature was determined. The simultaneous desulfurization and denitrification kinetics were calculated. The urea consumption and NO2- , NO3- , and SO42- generation reactions were all zero order. The NO3- generation rate was greater than the NO2- generation rate. The simultaneous desulfurization and denitrification process and mechanism were studied. The results provide reference data for performing flue gas desulfurization and denitrification in factories.

Downregulation of CDH16 in Papillary Thyroid Cancer and Its Potential Molecular Mechanism Analysed by qRT-PCR, TCGA and in silico Analysis.

OBJECTIVE: Thyroid cancer has the highest prevalence among the cancer types that affect the endocrine system; however, its molecular mechanisms are not yet determined. Cadherin-16 (CDH16) plays an important role in the tumorigenesis of human cancers, but its influence on papillary thyroid cancer (PTC) is poorly investigated. This study aimed to explore the role of CDH16 in PTC. METHODS: We performed quantitative real-time polymerase chain reaction to investigate CDH16 expression in PTC. The clinical significance of CDH16 expression in PTC was then evaluated using The Cancer Genome Atlas (TCGA) database. Bioinformatics analysis was also conducted to determine the potential molecular mechanisms of CDH16. RESULTS: CDH16 was remarkably downregulated in PTC tumors compared with that in corresponding normal thyroid tissues in the local and TCGA cohorts. This downregulation was associated with unfavorable clinicopathological features, including histological type, high tumor stage, aggressive lymph node metastasis (LNM), and advanced clinical stage. In addition, logistic analyses revealed that the reduced expression of CDH16 can aggravate the risk of LNM in PTC. Bioinformatics analysis indicated that the co-expressed CDH16 genes mainly participated in signaling the cancer-related pathways. CONCLUSION: CDH16 is involved in PTC progression and acts as an LNM-related gene in PTC.

Tacrine(10)-Hupyridone Prevents Post-operative Cognitive Dysfunction via the Activation of BDNF Pathway and the Inhibition of AChE in Aged Mice.

Post-operative cognitive dysfunction (POCD) could cause short-term or long-term cognitive disruption lasting weeks or months after anesthesia and surgery in elderly. However, no effective treatment of POCD is currently available. Previous studies indicated that the enhancement of brain-derived neurotrophic factor (BDNF) expression, and the elevation the cholinergic system, might be effective to prevent POCD. In this study, we have discovered that tacrine(10)-hupyridone (A10E), a novel acetylcholinesterase (AChE) inhibitor derived from tacrine and huperzine A, could prevent surgery-induced short-term and long-term impairments of recognition and spatial cognition, as evidenced by the novel object recognition test and Morris water maze (MWM) tests, in aged mice. Moreover, A10E significantly increased the expression of BDNF and activated the downstream Akt and extracellular regulated kinase (ERK) signaling in the surgery-treated mice. Furthermore, A10E substantially enhanced choline acetyltransferase (ChAT)-positive area and decreased AChE activity, in the hippocampus regions of surgery-treated mice, indicating that A10E could prevent surgery-induced dysfunction of cholinergic system, possibly via increasing the synthesis of acetylcholine and the inhibition of AChE. In conclusion, our results suggested that A10E might prevent POCD via the activation of BDNF pathway and the inhibition of AChE, concurrently, in aged mice. These findings also provided a support that A10E might be developed as a potential drug lead for POCD.

In Situ Growth of CuS/SiO2-Based Multifunctional Nanotherapeutic Agents for Combined Photodynamic/Photothermal Cancer Therapy.

A scalable and low-cost strategy is developed to fabricate a novel CuS/SiO2-based nanotherapeutic agent for dual-model imaging-guided photothermal/photodynamic combined therapy. In this design, mesoporous silica nanoparticles (MSNs) with CuS bundled in the channel are obtained in aqueous solution via in situ growth route for the first time. Furthermore, to achieve a more efficient therapy, photosensitizer (complex Ir-2) and bovine serum albumin are sequentially assembled via layer-by-layer method. The as-prepared complex Ir-2 presents a remarkably high 1O2 generation (ΦΔ = 1.3) under light illumination to offer effective photodynamic cell killing, and MSN/CuS exhibits high photothermal conversion efficiency (η = 31.7%) under illumination by 808 nm light to offer hyperthermia tumor ablation. In vitro and in vivo analyses show that the as-obtained nanotherapeutic agents exhibit excellent performance in tumor therapy even under irradiation with low power because of the high yield of 1O2 combined with the high photothermal conversion efficiency. Additionally, the nanotherapeutic agents are readily visualized in vivo via near-infrared fluorescence and thermal imaging. More importantly, based on the strategy of in situ growth and layer-by-layer assembly developed in this study, the development of other "all-in-one" multifunctional theranostic platform with high efficiency can be predictable.

miR-27b-3p is Involved in Doxorubicin Resistance of Human Anaplastic Thyroid Cancer Cells via Targeting Peroxisome Proliferator-Activated Receptor Gamma.

Chemotherapy is one of the most effective forms of cancer treatment. It has been widely used in the treatment of various malignant tumours. To investigate molecular mechanisms responsible for the chemoresistance of anaplastic thyroid cancer (ATC), we established the doxorubicin (Dox) resistance of human ATC SW1736 and 8305C cells and named them SW1736/Dox and 8305C/Dox, respectively. We evaluated the expression of various micro-RNAs (miRNAs) between control and Dox-resistant ATC cells and found that the expression of miR-27b-3p was significantly increased in Dox-resistant ATC cells. Targeted inhibition of miR-27b can increase the sensitivity of SW1736/Dox and 8305C/Dox cells. Bioinformatics analysis revealed that miR-27b can directly target peroxisome proliferator-activated receptor gamma (PPARγ) within the 3' untranslated region (UTR). This was proved by the results that miR-27b-3p down-regulated the protein and mRNA levels of PPARγ. While the mutant in the core binding sites of PPARγ abolished miR-27b-3p-induced down-regulation of luciferase activity. Over-expression of PPARγ can increase the Dox sensitivity of SW1736/Dox and 8305C/Dox cells. Basic fibroblast growth factor (bFGF) might be involved in miR-27b-3p/PPARγ-regulated Dox resistance of ATC cells. The activation of p65 nuclear factor-κB (NF-κB) regulated the up-regulation of miR-27b-3p in Dox-resistant ATC cells. Collectively, our data revealed that miR-27b-3p/PPARγ is involved in the Dox resistance of human ATC cells. It suggested that targeted inhibition of miR-27b-3p might be helpful to overcome the drug resistance of ATC cells.

Polyphasic taxonomic characterisation of a novel strain as Pararhizobium haloflavum sp. nov., isolated from soil samples near a sewage treatment tank.

A Gram-stain negative, aerobic, motile and ovoid- to rod-shaped bacteria strain, designated XC0140T, was isolated from soil samples near the sewage treatment tank of a chemical factory in Zhejiang Province, China, and subjected to polyphasic taxonomic investigation. Strain XC0140T grew at 10-37 °C and pH 6.0-9.0 (optimum, 35 °C and pH 7.5) and with 0-17% (w/v) NaCl (optimum, 1%). According to phylogenetic analysis based on 16S rRNA gene sequences, strain XC0140T was assigned to the genus Pararhizobium with high 16S rRNA gene sequence similarity of 95.97% to "Pararhizobium helanshanense CCNWQTX14T", followed by Pararhizobium sphaerophysae CCNWGS0238T (95.95%). Chemotaxonomic analysis showed that strain XC0140T contains ubiquinone-10 as the predominant respiratory quinone and possessed summed feature 8 (comprising C18: 1 ω7c and/or ω6c), 11-methyl C18:1 ω7c, C18: 0 and C16: 0 as predominant forms of fatty acids. The polar lipids of strain XC0140T consisted of seven phospholipids (PL), two aminolipids (AL), one glycolipid (GL) and three unidentified lipids (L1, L2 and L3). The DNA G+C content was 62.7 mol%. Based on the polyphasic taxonomic characterization, strain XC0140T is considered to represent a novel species of the genus Pararhizobium, for which the name Pararhizobium haloflavum sp. nov. is proposed. (type strain XC0140T = MCCC 1K03228T = KCTC 52582T).

Indirubin Derivative 7-Bromoindirubin-3-Oxime (7Bio) Attenuates Aß Oligomer-Induced Cognitive Impairments in Mice.

Indirubins are natural occurring alkaloids extracted from indigo dye-containing plants. Indirubins could inhibit various kinases, and might be used to treat chronic myelocytic leukemia, cancer and neurodegenerative disorders. 7-bromoindirubin-3-oxime (7Bio), an indirubin derivative derived from indirubin-3-oxime, possesses inhibitory effects against cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3ß (GSK3ß), two pharmacological targets of Alzheimer's disease (AD). In this study, we have discovered that 2.3-23.3 µg/kg 7Bio effectively prevented ß-amyloid (Aß) oligomer-induced impairments of spatial cognition and recognition without affecting bodyweight and motor functions in mice. Moreover, 7Bio potently inhibited Aß oligomer-induced expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Furthermore, 7Bio significantly prevented the decreased expression of synapsin-1 and PSD-95, biomarkers of pre-synaptic and post-synaptic proteins in Aß oligomer-treated mice. The mean optical density (OD) with hyper-phosphorylated tau (pTau), glial fibrillary acidic protein (GFAP) and CD45 positive staining in the hippocampus of 7Bio-treated mice were significantly decreased compared to those of Aß oligomer-treated mice. In addition, Western blotting analysis showed that 7Bio attenuated Aß oligomer-decreased expression of pSer9-GSK3ß. Those results suggested that 7Bio could potently inhibit Aß oligomer-induced neuroinflammation, synaptic impairments, tau hyper-phosphorylation, and activation of astrocytes and microglia, which may contribute to the neuroprotective effects of 7Bio. Based on these findings, we expected that 7Bio might be developed as a novel anti-AD lead compound.