Cetuximab versus nimotuzumab for the treatment of advanced nasopharyngeal carcinoma: A network meta-analysis.

PURPOSE: We conducted a network meta-analysis to evaluate the efficacy and toxicity of cetuximab and nimotuzumab in the treatment of advanced nasopharyngeal carcinoma (NPC). METHODS: A systematic literature search was performed though Pubmed, Embase, Cochran Library, China National Knowledge Infrastructure (CNKI), Chinese Biomedical (CBM) and Wanfang databases. Totally, 19 randomized controlled trials (RCTs) (n=1201) met the study selection criteria and were incorporated in this network meta-analysis. RESULTS: Compared with cetuximab, the results of network meta-analysis indicated that nimotuzumab may achieve higher complete remission rate (CRR) or overall remission rate (ORR) of the primary tumor, but no difference was noticed in 1- and 2-year overall survival (OS) rate and certain toxicities such as myelosuppression, radiodermatitis, mucositis and gastrointestinal reactions. Although nimotuzumab increased the 3-year OS rate, compared with cetuximab, this result needs to be interpreted cautiously because of the studies' heterogeneity. CONCLUSION: Even though we didn't find significant difference between cetuximab and nimotuzumab in terms of survival outcomes, nimotuzumab is more advantageous in short-term efficacy.

STAT3 ameliorates cognitive deficits via regulation of NMDAR expression in an Alzheimer's disease animal model.

Background: Abnormal tau accumulation in the brain has a positively correlation with neurodegeneration and memory deterioration, but the mechanism underlying tau-associated synaptic and cognitive impairments remains unclear. Our previous work has found that human full length tau (hTau) accumulation activated signal transducer and activator of transcription-1 (STAT1) to suppress N-methyl-D-aspartate receptors (NMDARs) expression, followed by memory deficits. STAT3 also belongs to STAT protein family and is reported to involve in regulation of synaptic plasticity and cognition. Here, we investigated the role of STAT3 in the cognitive deficits induced by hTau accumulation. Methods:In vitro studies HEK293 cells were used. EMSA, Luciferase reporter assay, and Immunoprecipitation were applied to detect STAT3 activity. In vivo studies, AAV virus were injected into the hippocampal CA3 region of C57 mice. Western blotting, quantitative real-time polymerase chain reaction, and immunofluorescence were applied to examine the level of synaptic proteins. Electrophysiological analysis, behavioral testing and Golgi impregnation were used to determine synaptic plasticity and memory ability recovery after overexpressing STAT3 or non-acetylated STAT1. Results: Our results showed that hTau accumulation acetylated STAT1 to retain STAT3 in the cytoplasm by increasing the binding of STAT1 with STAT3, and thus inactivated STAT3. Overexpressing STAT3 or non-acetylated STAT1 ameliorated hTau-induced synaptic loss and memory deficits by increasing the expression of NMDARs. Conclusions: Taken together, our study indicates that hTau accumulation impaired synaptic plasticity through STAT3 inactivation induced suppression of NMDARs expression, revealing a novel mechanism for hTau-associated synapse and memory deficits.

STAT3 ameliorates cognitive deficits by positively regulating the expression of NMDARs in a mouse model of FTDP-17.

In tauopathies, memory impairment positively strongly correlates with the amount of abnormal tau aggregates; however, how tau accumulation induces synapse impairment is unclear. Recently, we found that human tau accumulation activated Signal Transduction and Activator of Transcription-1 (STAT1) to inhibit the transcription of synaptic N-methyl-D-aspartate receptors (NMDARs). Here, overexpressing human P301L mutant tau (P301L-hTau) increased the phosphorylated level of Signal Transduction and Activator of Transcription-3 (STAT3) at Tyr705 by JAK2, which would promote STAT3 translocate into the nucleus and activate STAT3. However, STAT3 was found mainly located in the cytoplasm. Further study found that P301L-htau acetylated STAT1 to bind with STAT3 in the cytoplasm, and thus inhibited the nuclear translocation and inactivation of STAT3. Knockdown of STAT3 in STAT3flox/flox mice mimicked P301L-hTau-induced suppression of NMDARs expression, synaptic and memory impairments. Overexpressing STAT3 rescued P301L-hTau-induced synaptic and cognitive deficits by increasing NMDARs expression. Further study proved that STAT3 positively regulated NMDARs transcription through direct binding to the specific GAS element of NMDARs promoters. These findings indicate that accumulated P301L-hTau inactivating STAT3 to suppress NMDARs expression, revealed a novel mechanism for tau-associated synapse and cognition deficits, and STAT3 will hopefully serve as a potential pharmacological target for tauopathies treatment.

Inflammation-dependent ISG15 upregulation mediates MIA-induced dendrite damages and depression by disrupting NEDD4/Rap2A signaling.

BACKGROUND: Maternal immune activation (MIA) is an independent risk factor for psychiatric disorders including depression spectrum in the offsprings, but the molecular mechanism is unclear. Recent studies show that interferon-stimulated gene-15 (ISG15) is involved in inflammation and neuronal dendrite development; here we studied the role of ISG15 in MIA-induced depression and the underlying mechanisms. METHODS: By vena caudalis injecting polyinosinic: polycytidylic acid (poly I:C) into the pregnant rats to mimic MIA, we used AAV or lentivirus to introduce or silence ISG15 expression. Synaptic plasticity was detected by confocal microscope and Golgi staining. Cognitive performances of the offspring were measured by Open field, Forced swimming and Sucrose preference test. RESULTS: We found that MIA induced depression-like behaviors with dendrite impairments in the offspring with ISG15 level increased in the offsprings' brain. Overexpressing ISG15 in the prefrontal cortex of neonatal cubs (P0) could mimic dendritic pathology and depressive like behaviors, while downregulating ISG15 rescued these abnormalities in the offsprings. Further studies demonstrated that MIA-induced upregulation of inflammatory cytokines promoted ISG15 expression in the offspring' brain which suppressed Rap2A ubiquitination via NEDD4 and thus induced Rap2A accumulation, while upregulating NEDD4 abolished ISG15-induced dendrite impairments. CONCLUSIONS: These data reveal that MIA impedes offsprings' dendrite development and causes depressive like behaviors by upregulating ISG15 and suppressing NEDD4/Rap2A signaling. The current findings suggest that inhibiting ISG15 may be a promising intervention of MIA-induced psychiatric disorders in the offsprings.

Therapeutic Effect of Modified Yinchenhao Tang on Cholestatic Liver Disease in Rats / 中国实验方剂学杂志

Objective::To investigate the protective effect of modified Yinchenhao Tang on α-isothiocyanate(ANIT)-induced cholestatic liver disease (CSLD). Method::Wistar rats were randomly divided into 7 groups: blank control group, model control group, compound Glycyrrhizin capsules group(22.5, 45 mg·kg-1), modified Yinchenhao Tang low, middle and high dose groups(4.1, 8.1, 16.2 g·kg-1). A model of cholestatic liver injury was prepared by intragastric administration of ANIT (100 mg·kg-1). Glycyrrhizin capsules and modified Yinchenhao Tang were administered intragastrically on the second day of modeling for 4 consecutive days. And bile duct intubation was performed on the fifth day to measure the bile flow rate of the rats, and serum was taken to test the total bilirubin(TBIL), direct bilirubin(DBIL), indirect bilirubin(IBIL), alanine aminotransferase(ALT) and total bile acid(TBA) serological indicators of each group. Pathological changes of liver tissues were observed by hematoxylin-eosin (HE) staining. The expression levels of G protein-coupled bile acid receptor(TGR5), nucleotide binding oligomerization domain-like receptor 3(NLRP3) and cysteinyl aspartate specific proteinase-1(Caspase-1) proteins in the iver tissues were detected by Western blot. Result::Compared with the blank control group, bile flow rate in the model group decreased significantly(P<0.01). TBIL, DBIL, IBIL, ALT and TBA level in serum were significantly increased(P<0.01), liver tissue lesions were severe, and significantly increased the expression of liver tissue TGR5 and Caspase-1.Compare with model group, the compound Glycyrrhizin capsules group had no significant effect on bile flow rate and TBIL, DBIL, IBIL, ALT and TBA level in serum. Bile flow rate increased and TBIL, DBIL, IBIL, ALT and TBA level in serum decreased significantly in modified Yinchenhao Tang high dose group. The compound Glycyrrhizin capsules group and modified Yinchenhao Tang group have different extents of improvement the pathological changes of the lung tissues, and the protein expression of TGR5 and Caspase-1 were significantly decreased in the liver tissue(P<0.01). Conclusion::Modified Yinchenhao Tang can effectively treat CSLD in rats, and its mechanism may be related to bile acid and bile acid receptor TGR5-mediated inflammatory factors.

Falls incidence and its influencing factors among the rural community elderly aged 65 years and above in Chongqing City / 公共卫生与预防医学

Objective To investigate the current situation and risk factors of falls in the rural community elderly aged 65 years and above in Chongqing City, and to provide references for developing preventive measures. Methods The multistage cluster random sampling method was used to select several rural communities in Chongqing City from September to December, 2019, and then the elderly aged 65 years and above who lived in the communities for one year were chosen to serve as the surveyed subjects. A self designed questionnaire (sociodemographic factors, exercise status, illness and medication status and fall to related information) was used to collect the data regarding falls occurring in the last year. The chi-square test and multi factor multi-variant logistic regression analysis were utilized to analyze the data, the used software was SPSS 25.0. Results A total of 801 rural community elderly people in Chongqing City were surveyed．The average age was (71.64±5.85) years old. 7.12% of elderly need cane or walker. 6.87% of them self-reported their health was poor. 42.57% of elderly seldom have the habit of exercise. The prevalence of heart disease, diabetes, osteoporosis, arthritis, cataract, deafness self-reported was 8.99%、8.11%、17.48%、25.97%、13.73% and 6.24% respectively. Totally 104 elderly people experienced 128 falls in the past 12 months, and the incidence rates of falls and falling times were 12.84% and 15.98% respectively．The multi-variant logistic regression analysis showed that poor heath status self-reported（OR=4.04，95% , CI：1.71-9.52）, diabetes （OR=2.68，95% CI： 1.41-5.12）, osteoporosis （OR=1.91 , 95% CI：1.16-3.15）, arthritis （OR=2.60 , 95% CI：1.65-4.11） and non self-care（OR=2.44，95% CI：1.16-5.16） were the risk factors for falls in the rural community elderly. Conclusions The incidence rate of falls in the rural community elderly aged 65 years and above in Chongqing City was low．It is necessary to formulate comprehensive intervention measures for the risk factors of fall so as to reduce the incidence rate of falls in the elderly.

High dose nanocrystallization of etoposide and its blood-brain barrier permeability in vitro / 中国药理学与毒理学杂志

OBJECTIVE To improve the poor water solubility and evaluating poor acitivity of etoposide (VP-16) by preparing VP-16 nanoparticle suspension (VP-16 NP) and its penetration through the blood-brain barrier (BBB).METHODS VP-16 NP was prepared with the anti-solution exchange method.The shape structure and diameter were observed with transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and dynamic light scattering (DLS), respectively. The drug release profiles of the VP-16 powder and VP-16 NP were measured.The effect of VP-16 NP on the growth of KB cells was observed via MTT assay. In addition, primary brain microvascular endothelial cells from 1stto 2nd generation of SD rats at two weeks of age were used to construct an in vitro BBB model.The classic 4 h leak test,trans-epithelial electrical resistance (TEER) test and fluorescein disodium salt(FLU)perme?ability test were conducted to verify whether the in vitro BBB model was successfully established.RESULTS VP-16 NP was a solid sphere with a size of 140 nm detected by TEM,SEM and DLS.The cumulative release rate of VP-16 NP was 3 times that of VP-16 powder. The results of MTT colorimetric assay showed that VP-16 powder had no inhibitory effect on KB cells,while VP-16 NP could effectively inhibit KB cells. In the 4 h leakage experiment, the top and bottom chambers of the Transwell cell model could maintain a liquid surface distance of >0.5 cm,indicating that the in vitro BBB model was initially formed.The effective resistance value of the TEER experiment was 223 Ω·cm2,indicating that the in vitro BBB model was basically established. In FLU permeability experiments, the permeability coefficients were respectively (0.33±0.04)×10-3,(0.42±0.07)×10-3,and (0.52±0.06)×10-3cm·min-1at 15,30 and 60 min, indicating that the model had low permeability.The above three experiments suggested that the BBB in vitro model was successfully constructed. On this basis, the in vitro BBB model was used to evaluate the penetration of VP-16 NP at a permeability coefficient of (1.87±0.03)×10-3cm·min-1at 30 min,showing high permeability.VP-16 NP showed better penetration of BBB.CONCLUSION VP-16 NP is success?fully prepared,which increases the release rate of the drug,enhances the killing effect of the cells,and shows good penetration through the in vitro BBB model evaluation.

Synthesis of hydrogel polymer coated ZnO nanoparticles and their decontaminating effect against soman in vitro / 中国药理学与毒理学杂志

OBJECTIVE To evaluate the decontamination capability of hydrogel polymer coated ZnO nanoparticles (ZnO NP-gel) against soman. METHODS ZnO NP was synthetized using chemical precipitation method and modified with 4-pentenoic acid,and then polymerized with comonomers to obtain ZnO NP-gel. The transmission electron microscope (TEM), scanning electron microscope (SEM) and particle size instrument were used to observe the internal structure,micromorphology,particle size and zeta potential of these materials. An infrared spectroscope (IR) was used to analyze their chemical bond structure,while X-ray diffraction (XRD) was used to analyze the diffraction pattern.The content of soman was determined by benzidine chromogenic reaction. ZnO NP(1 g·L-1), ZnO NP-gel (1 g·L-1) and distilled water were mixed with soman(52.2 mg·L-1),stood for 30 min,and then filtered before filtrate was subcutaneously injected into mice (40 μL·g-1) to observe the symptoms of poisoning and death. RESULTS SEM and TEM showed that ZnO NP-gel had a block structure, the zeta potential of which was (-7.89 ± 0.04) mV. The results of IR indlicated that ZnO NP-gel had stronger absorption peaks at 754 and 618 cm-1, and XRD revealed that these materials had a sharp peak at 2θ=8.06738°. The decontamination efficiency of ZnO NP-gel was higher than that of ZnO NP group at the same concen?tration (n=3, P<0.05), and the time for decontamination of 50% soman was shortened by four times. The mice were injected subcutaneously with the soman solution treated with ZnO NP-gel, which caused no convulsion or death. CONCLUSION ZnO NP-gel can perform the double function of fast adsorption and catalysis of soman,and the decontamination ability of which could be improved through polymer modification.

In vitro antibacterial activity of cefdinir against isolates of respiratory tract pathogens in children / 中华儿科杂志

<p><b>OBJECTIVE</b>To study the in vitro antibacterial activity of cefdinir against clinical isolates of respiratory tract pathogens in Children.</p><p><b>METHODS</b>MIC values of cefdinir against 380 strains were determined with E-test method and compared with those of cefaclor.</p><p><b>RESULTS</b>All penicillin-susceptible Streptococcus pneumoniae (PSSP) strains were also susceptible to cefdinir and cefaclor. Both cefdinir and cefaclor were not active against penicillin-resistant SP (PRSP). Against penicillin-intermediate SP (PISP) the susceptibility rates of cefdinir and cefaclor were 70.1% and 57.4%, respectively. The activity of cefdinir and cefaclor against beta-lactamases negative Hemophilus influenzae (HI) was excellent, but the susceptibility rates of cefdinir and cefaclor against beta-lactamases positive HI were 85.0% and 70.0%, respectively with MIC(90) of 1.5 mg/L vs. 256.0 mg/L. Cefdinir presented higher activities and lower MIC values than cefaclor against Moraxella catarrhalis (MC), Group A streptococcus (GAS), methicillin susceptible staphylococcus aureus (MSSA), and extended spectrum beta-lactamases (ESBLs) negative Escherichia coli (E. coli) or Klebsiella pneumoniae (K. pn). Both cefdinir and cefaclor were not susceptible to ESBLs positive E. coli and K. pn.</p><p><b>CONCLUSIONS</b>Cefdinir exhibits excellent activity against PSSP, PISP, HI, as well as MC, GAS, MSSA and ESBLs negative E. coli or K. pn.</p>