Elevated Levels of Naturally-Occurring Autoantibodies Against the Extracellular Domain of p75NTR Aggravate the Pathology of Alzheimer's Disease / 神经科学通报·英文版

The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aβ neurotoxicity and promotes Aβ clearance in Alzheimer's disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.

Advance in the chemotherapy resistance of retinoblastoma / 国际眼科杂志(Guoji Yanke Zazhi)

Retinoblastoma(RB)is the most common intraocular malignant tumor of children. Chemotherapy is a preferred method in RB treatment, which includes intravenous chemotherapy, intra-arterial chemotherapy and intravitreal chemotherapy. However, the occurrence of chemotherapy resistance often leads to the failure of eye-preserving treatment in RB patients. Therefore, exploring the mechanism of the occurrence of chemotherapy resistance and searching for new strategies and combined medicines for RB treatment are of great clinical significance. This article reviews that RB cells obtain chemotherapy resistance through ATP binding cassette protein(ABC transporter), non-coding RNA, epigenetics modification, autophagy, epithelial mesenchymal transformation, extracellular matrix changes and other ways, and the potential therapeutic targets for chemotherapy resistance are also summarized, in the hope of providing some references for further research on chemotherapy resistance of RB.

Clinicopathological characteristics of gastric SMARCA4-deficient undifferentiated/rhabdoid carcinoma / 中华病理学杂志

Objective: To investigate the clinicopathological features and immunohistochemical phenotypes of gastric SMARCA4-deficient undifferentiated carcinoma, and to discuss the daily diagnostics of this entity and analyze its prognosis. Methods: The cases of gastric SMARCA4-deficient undifferentiated carcinoma diagnosed at the Department of Pathology, Peking University Cancer Hospital, China from January 2010 to August 2022 were collected. The histological sections were reviewed, the immunohistochemical results and clinicopathological features were analyzed, and relevant literature was reviewed. Results: Pure foci of undifferentiated carcinoma were seen in 7 cases, and 1 case was accompanied by a moderately differentiated tubular adenocarcinoma component. Undifferentiated carcinoma foci showed similar sheet-like or solid diffuse growth pattern, medium-sized tumor cells characterized by 1-2 nucleoli, and abundant cytoplasm and rhabdoid appearance. The average patient age was 65±8 years. Six patients were male and 2 were female. Immunohistochemical staining showed that undifferentiated carcinoma of all 8 tumors were negative for SMARCA4 (BRG1). Among 7 patients who underwent SMARCA2 (BRM) and SMARCB1 (INI1) staining, 4 cases showed loss of BRM expression, 2 cases showed weakly positive staining, and 1 case was diffusely positive, but all 7 cases were diffusely strong positive for INI1. The neuroendocrine marker, synaptophysin, was weakly positive in 5 cases, while CgA and CD56 were negative in 8 cases. Ki-67 index was more than 70%. Two cases were mismatch repair deficient and showed the loss of MLH1/PMS2 expression, while 1 case showed only MSH2 loss. PD-L1 staining showed that combined positive score (CPS)≥1 in 4 cases (CPS ranging from 1 to 55) and CPS<1 in the other 3 cases. Four patients had clinical stage Ⅳ disease. Two of them died within 3 months after diagnosis. Conclusions: Gastric SMARCA4-deficient undifferentiated carcinoma/rhabdoid carcinoma is a rare group of highly malignant tumors with a poor prognosis. Loss of the core subunit of SWI/SNF complex may be associated with the development of dedifferentiated histological pattern and aggressive tumor progression, which may be more frequently accompanied with mismatch repair deficiency.

Main components from cultivated and wild Nardostachyos Radix et Rhizoma by LC-MS and GC-MS / 中国中药杂志

In this study, ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry(UPLC-Q-TOF-MS) and gas chromatography-mass spectrometry(GC-MS) were combined with non-targeted metabonomic analysis based on multivariate statistics analysis, and the content of five indicative components in nardosinone was determined and compared by UPLC. The main chemical components of Nardostachyos Radix et Rhizoma with imitative wild cultivation and wild Nardostachyos Radix et Rhizoma were comprehensively analyzed. The results of multivariate statistical analysis based on liquid chromatography-mass spectrometry(LC-MS) and GC-MS were consistent. G1 and G2 of the imitative wild cultivation group and G8-G19 of the wild group were clustered into category 1, while G7 of the wild group and G3-G6 of the imitative wild cultivation group were clustered into category 2. After removing the outlier data of G1, G2, and G7, G3-G6 of the imitative wild cultivation group were clustered into one category, and G8-G19 of the wild group were clustered into the other category. Twenty-six chemical components were identified according to the positive and negative ion modes detected by LC-MS. The content of five indicative components(VIP>1.5) was determined using UPLC, revealing that chlorogenic acid, isochlorogenic acid A, isochlorogenic acid C, linarin, nardosinone, and total content in the imitative wild cultivation group were 1.85, 1.52, 1.26, 0.90, 2.93, and 2.56 times those in the wild group, respectively. OPLS-DA based on GC-MS obtained 10 diffe-rential peaks. Among them, the relative content of α-humulene and aristolene in the imitative wild cultivation group were extremely significantly(P<0.01) and significantly(P<0.05) higher than that in the wild group, while the relative content of 7 components such as 5,6-epoxy-3-hydroxy-7-megastigmen-9-one, γ-eudesmol, and juniper camphor and 12-isopropyl-1,5,9-trimethyl-4,8,13-cyclotetrade-catriene-1,3-diol was extremely significantly(P<0.01) and significantly(P<0.05) lower than that in the wild group, respectively. Therefore, the main chemical components of the imitative wild cultivation group and wild group were basically the same. However, the content of non-volatile components in the imitative wild cultivation group was higher than that in the wild group, and the content of some volatile components was opposite. This study provides scientific data for the comprehensive evaluation of the quality of Nardostachyos Radix et Rhizoma with imitative wild cultivation and wild Nardostachyos Radix et Rhizoma.

CircFhit Modulates GABAergic Synaptic Transmission via Regulating the Parental Gene Fhit Expression in the Spinal Dorsal Horn in a Rat Model of Neuropathic Pain / 神经科学通报·英文版

Effective treatments for neuropathic pain are lacking due to our limited understanding of the mechanisms. The circRNAs are mainly enriched in the central nervous system. However, their function in various physiological and pathological conditions have yet to be determined. Here, we identified circFhit, an exon-intron circRNA expressed in GABAergic neurons, which reduced the inhibitory synaptic transmission in the spinal dorsal horn to mediate spared nerve injury-induced neuropathic pain. Moreover, we found that circFhit decreased the expression of GAD65 and induced hyperexcitation in NK1R+ neurons by promoting the expression of its parental gene Fhit in cis. Mechanistically, circFhit was directly bound to the intronic region of Fhit, and formed a circFhit/HNRNPK complex to promote Pol II phosphorylation and H2B monoubiquitination by recruiting CDK9 and RNF40 to the Fhit intron. In summary, we revealed that the exon-intron circFhit contributes to GABAergic neuron-mediated NK1R+ neuronal hyperexcitation and neuropathic pain via regulating Fhit in cis.

Clinical Significance of Low Expression of LncRNA CASC15 in Acute Myeloid Leukemia with NPM1 Mutations / 中国实验血液学杂志

AbstractObjective: To identify the expression and methylation patterns of lncRNA CASC15 in bone marrow (BM) samples of acute myeloid leukemia (AML) patients, and further explore its clinical significance.@*METHODS@#Eighty-two de novo AML patients and 18 healthy donors were included in the study. Meanwhile, seven public datasets from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were included to confirm the expression and methylation data of CASC15. Receiver operating characteristic (ROC) curve analysis was applied to determine the discriminative capacity of CASC15 expression to identify AML. The patients were divided into CASC15high group and CASC15low group by X-tile method, and the prognostic value of CASC15 was identified by Kaplan-Meier method and univariate and multivariate Cox regression analysis.@*RESULTS@#The expression level of CASC15 was significantly decreased in BM cells of AML patients compared with healthy donors (P<0.001). ROC curve analysis suggested that CASC15 expression might be a potential biomarker to discriminate AML from controls. The expression of CASC15 was high at the early stage of hematopoiesis, and reached a peak at the stage of multipotent progenitors differentiation, then decreased rapidly, and was at a range of low level fluctuations in the subsequent process. Among FAB subtypes, CASC15 expression in M0 was significantly higher than that in M1-M7. Clinically, CASC15low patients were more likely to have NPM1 mutations than CASC15high patients (P=0.048), while CASC15high patients had a significantly higher frequency of IDH1 and RUNX1 mutations (P=0.021 and 0.014, respectively). Moreover, CASC15low group had a shorter overall survival (OS) in patients with NPM1 mutations. Furthermore, multivariate analysis confirmed that CASC15 expression was a significant independent risk factor for OS in NPM1 mutated AML patients. In addition, CASC15 methylation level in BM samples of AML patients was significantly decreased compared with healthy donors. Patients with CASC15 high methylation had poor OS and disease-free survival.@*CONCLUSION@#The expression of CASC15 is decreased in AML, and low CASC15 expression may predict adverse prognosis in AML patients with NPM1 mutations. Moreover, CASC15 methylation level in AML is significantly decreased, and high CASC15 methylation may predict poor prognosis in AML.

Detection of NPM1 Mutation in Acute Myeloid Leukemia by Droplet Digital PCR and Its Clinical Application Value / 中国实验血液学杂志

OBJECTIVE@#To establish the droplet digital PCR (ddPCR) assay for the detection of NPM1 type A mutation in patients with acute myeloid leukemia (AML), and to evaluate its specificity, sensitivity and its value in clinical application.@*METHODS@#NPM1 mutant and wildtype plasmids were used to verify the performance of ddPCR. Both ddPCR and Sanger sequencing were used to detect the bone marrow samples of 87 AML patients, which were confirmed by next generation sequencing (NGS). Moreover, NPM1 mutation burden was dynamically monitored in five patients by ddPCR.@*RESULTS@#The limit of blank (LOB) of ddPCR established for NPM1 mutation detection was 1.1 copies/μl, and the limit of detection (LOD) was 2.43 copies/μl, which had good linearity. Among the 87 newly diagnosed AML patients, ddPCR identified seventeen cases positive for NPM1 mutation (19.5%)， which was consistent with Sanger sequencing. NGS confirmed 12 positive cases, including 8 of type A mutations, 2 of type D mutations, and 2 of rare type mutations. The results of dynamic monitoring of NPM1 mutation burden in 5 patients showed that the NPM1 mutation burden decreased obviously even close to 0, when patients achieve complete remission after chemotherapy. However, the mutation burden was increased again at the time of relapse.@*CONCLUSION@#In this study, we established a ddPCR method for detection of NPM1 mutation with good sensitivity and repeatability, which can be used for screening NPM1 mutation in newly diagnosed AML patients and for minimal residual disease monitoring after remission in positive AML patients to guide treatment.

Analysis of clinical phenotype and genotype of Chinese children with disorders of sex development / 中华儿科杂志

Objective: To explore the heterogeneity and correlation of clinical phenotypes and genotypes in children with disorders of sex development (DSD). Methods: A retrospective study of 1 235 patients with clinically proposed DSD in 36 pediatric medical institutions across the country from January 2017 to May 2021. After capturing 277 DSD-related candidate genes, second-generation sequencing was performed to analyzed the heterogeneity and correlation combined with clinical phenotypes. Results: Among 1 235 children with clinically proposed DSD, 980 were males and 255 were females of social gender at the time of initial diagnosis with the age ranged from 1 day of age to 17.92 years. A total of 443 children with pathogenic variants were detected through molecular genetic studies, with a positive detection rate of 35.9%. The most common clinical phenotypes were micropenis (455 cases), hypospadias (321 cases), and cryptorchidism (172 cases) and common mutations detected were in SRD5A2 gene (80 cases), AR gene (53 cases) and CYP21A2 gene (44 cases). Among them, the SRD5A2 mutation is the most common in children with simple micropenis and simple hypospadias, while the AMH mutation is the most common in children with simple cryptorchidism. Conclusions: The SRD5A2 mutation is the most common genetic variant in Chinese children with DSD, and micropenis, cryptorchidism, and hypospadias are the most common clinical phenotypes. Molecular diagnosis can provide clues about the biological basis of DSD, and can also guide clinicians to perform specific clinical examinations. Target sequence capture probes and next-generation sequencing technology can provide effective and economical genetic diagnosis for children with DSD.

Diffuse midline gliomas with H3K27 alteration in children: a clinicopathological analysis of forty-one cases / 中华病理学杂志

Objective: To investigate the clinicopathological features of pediatric diffuse midline glioma with H3K27 alteration and to analyze their relationship with prognosis. Methods: Forty-one cases of childhood diffuse midline glioma with H3K27 alteration were collected at Children's Hospital of Fudan University (39 cases) and Xi'an Children's Hospital (2 cases), from July 2016 to July 2020. The clinical manifestations, imaging data, histopathology, immunohistochemical phenotype and molecular genetics features, tumor size, site and histological grading were evaluated. Results: Among the 41 cases, 21 were males and 20 females, the age of onset was 3-14 years, the average and median age was 7.6 years and 7.0 years, respectively. The tumor sites were brain stem (n=36) and other locations (n=5). The clinical manifestations were dizziness, gait disturbance, and limb weakness, etc. The MRI features were variable. The histology varied from low-grade to high-grade glioma with neuron differentiation. Immunohistochemistry showed that the tumor cells expressed H3K27M, GFAP, and Olig2. Genetic study showed that 76% (16/21) of tumors had H3F3A gene mutation, mostly accompanied by TP53 (62%, 13/21) missense mutation; five tumors (24%, 5/21) had HIST1H3B gene mutation, accompanied by missense mutations in ACVR1 and PI3K pathway-related gene PIK3CA (4/5) and PIK3R1 (1/5) mutations. The prognosis was dismal with only one alive and others died. The average and median overall survival time was 7 months and 4 months, respectively. Cox multivariate regression analysis showed that age, tumor location, radiologically maximum tumor diameter, histologic grading, and surgical methods were not significantly associated with overall survival rate (P>0.05). Conclusions: Pediatric diffuse midline gliomas with H3K27 alteration have unique clinicopathological and genetic characteristics. The prognosis is poor. The tumor location and histopathologic grading are not related to prognosis. New specific drugs and comprehensive treatment are needed to improve the prognosis.

Evaluation of the effectiveness of malaria control health education among overseas enterprise employees / 中国血吸虫病防治杂志

Objective To evaluate the effectiveness of health education on knowledge, attitude and practice (KAP) relating to malaria control among overseas enterprise employees. Methods In September 2019, on-site malaria control health education was conducted among all Chinese employees of a China-funded mining enterprise in the Democratic Republic of Congo. The KAP questionnaire for malaria control was generated on the Questionstar website, and the participants were subjected to two questionnaire surveys prior to and 14 months after health education. After the questionnaires were recovered, all valid questionnaires were divided into 4 groups, including the baseline group (the questionnaires filled out by respondents who received health education and participated in two questionnaire surveys before health education), the loss-to-follow-up group (the questionnaires filled out by respondents who received health education but only participated in the questionnaire survey after health education), the retest group (the questionnaires filled out by respondents who received health education and participated in two questionnaire surveys after health education) and the new group (questionnaires filled out by respondents who did not receive health education and only participated in the questionnaire survey after health education) according to subjects’ receiving health education and participation in two questionnaire surveys. The correct rate of malaria control knowledge, the proportion to good attitudes towards malaria control and the proportion of good practices towards malaria control were compared between the baseline group and the loss-to-follow-up group, between the baseline group and the retest group, and between the retest group and the new group. Results A total of 110 and 142 valid questionnaires were recovered during the two surveys, and the recovery rates were 90.9% and 70.3%, respectively. There were 77, 77, 33, and 65 valid questionnaires recovered from the baseline group, the loss-to-follow-up group, the retest group, and the new group, respectively. There were no significant differences in respondents’ gender, age and educational levels between the baseline group and the loss-to-follow-up group (all P values > 0.05), and there were no significant differences between the two groups in terms of the mean score of malaria control knowledge (Z = 2.011, P > 0.05), the mean score of attitudes towards malaria control (t = −0.787, P > 0.05) and the mean score of practices towards malaria control (t = −0.787, P > 0.05). There were significant differences between the retest group and the baseline group in terms of the mean score of malaria control knowledge (10.83 vs. 9.79; Z = −4.017, P < 0.05), the mean score of attitudes towards malaria control (29.48 vs. 28.61; Z = −1.981, P < 0.05) and the mean score of practices towards malaria control (6.43 vs. 5.91; Z = −2.499, P < 0.05). There were no significant differences between the retest group and the new group in terms of gender, age or education levels (all P values > 0.05), and a higher mean score of malaria control knowledge was found in the retest group than in the new group (10.83 vs. 9.81; Z = −2.962, P < 0.05), while no significant differences were seen in the mean score of attitudes towards malaria control (29.48 vs. 30.17; Z = −1.158, P > 0.05) and the mean score of practices towards malaria control (6.43 vs. 6.37; Z = −0.048, P > 0.05) between the two groups. Conclusion Malaria control health education may significantly improve the understanding of malaria control knowledge, positive attitudes towards malaria control and the compliance of practices towards malaria control among overseas enterprise employees.

Tryptophan and tumor immunity / 药学学报

As an essential amino acid, tryptophan (Trp) has various physiological functions and is of great significance in the metabolic process of tumors. In the human body, tryptophan is mainly transformed through kynurenine metabolic pathway, which not only promotes the inherent malignant properties of tumor cells, but also leads to immune-suppressive tumor microenvironment. Changes in tryptophan metabolism often occur in tumors, accompanied by abnormal gene expression of tryptophan-related enzymes, among which indoleamine 2,3-bioxygenase (IDO)-related gene expression and tryptophan 2,3-dioxygenase (TDO)-related gene changes are the most significant. A large number of clinical trials on IDO inhibitors, TDO inhibitors and combination therapy have been carried out. This paper reviewed the tryptophan metabolic pathway, regulation of IDO (TDO), kynurenine (KYN) and other related genes in tumor cells, and outlined the development of therapeutic schedule targeting tryptophan-related genes. The new progress provides new ideas for the further exploration of tumor treatment options.

The immunomodulatory effect of lactic acid within the tumor microenvironment / 药学学报

Tumor cells leads to enhanced glucose uptake and the conversion of a larger fraction of pyruvate into lactate even under the circumstance of abundant oxygen. This phenomenon of aerobic glycolysis is known as the Warburg effect. Lactic acid, as an important tool for tumor cells to modify the tumor microenvironment, promotes the process of tumor invasion and metastasis, and contributes to tumor development by inducing and recruiting immunosuppression-related cells and molecules. Lactic acid could efflux out of the cancer cells via the monocarboxylate transporters to prevent intracellular acidification. Lactate can inhibit the cytolytic activity of T cells and natural killer (NK) cells, promoting the differentiation of tolerogenic interleukin 10 (IL-10)-producing dendritic cells. Moreover, the lactate-derived lactylation of histone lysine residues can promote macrophage polarization toward the M2-like phenotype, suppressing the immune response within the tumor microenvironment. In this review, we discuss the role of lactate as an immunosuppressor molecule that contributes to tumor evasion from the aspects of lactic acid metabolism and its effect on immune cells. And we explore the possibility of targeting potential targets in lactate metabolism for tumor treatment. At last, we proposed a tumor immunotherapy strategy by inhibiting the pathway of aerobic glycolysis and proteins associated with the production and transport of lactic acid.

Protection Mechanism of Addition and Subtraction Therapy of Danshenyin Combined with Wendantang for Myocardial Ischemia in Patients with Stable Angina / 中国实验方剂学杂志

Objective:To observe the efficacy of addition and subtraction therapy of Danshenyin combined with Wendantang in the treatment to stable angina pectoris （SAP） with stagnation of phlegm and blood stasis， and to explore its protection mechanism for myocardial ischemia. Method:One hundred and thirty-two patients were randomly divided into control group and observation group equally. Finished the 63 cases study both in control group and observation group after dropout， loss of follow-up and withdrawal. Patients in control group and observation group got antianginal drugs and the treatment of drug therapy to control the risk factors. All patients were treated with anti-angina drugs and risk factors control drugs. Patients in control group got Danlou Tablets by oral administration， 5 tablets/time， 3 times/day. Patients in observation group got dispensing decoction pieces of Danshenyin and Wendantang 1 dose/day. The treatment continued for 3 months in both groups. Scores of angina attack were graded every week. Before and after treatment， electrocardiogram treadmill exercise test was made to evaluate myocardial ischemia of coronary heart disease， and scores of phlegm stasis block syndrome and Seattle Angina questionnaire （SAQ） were graded for TCM symptoms and quality of life. Levels of hemorheology index， interleukin-6 （IL-6）， tumor necrosis factor-<italic>α</italic> （TNF-<italic>α</italic>）， intercellular adhesion molecule-1 （ICAM-1）， Cystatin C （CysC）， homocysteine （Hcy）， ischemic modified albumin （IMA） and macrophage migration inhibitory factor were detected. In addition， safety was evaluated. Result:After treatment， scores of times， duration， degree of angina pectoris， nitroglycerin dosage of angina pectoris and nitroglycerin dosage in the observation group were lower than those in the control group （<italic>P</italic><0.01）. Total exercise time， duration of ST depression for 1.0 mm， occurrence time of stable angina pectoris， metabolic equivalent and scores of Duke in the observation group were more than those in the control group （<italic>P</italic><0.01）. Score of stagnation of phlegm and blood stasis in the observation group was lower than that in the control group （<italic>P</italic><0.01）， while score of SAQ was higher than that in the control group （<italic>P</italic><0.01）. Levels of IL-6， TNF-<italic>α</italic>， ICAM-1， CysC， IMA， Hcy， MIF， whole blood viscosity （low cut， high cut）， whole blood reducing viscosity， plasma viscosity， platelet aggregation rate and fibrinogen （FIB） in the observation group were lower than those in the control group （<italic>P</italic><0.01）. Effect of angina pectoris in observation group was superior to that in control group （<italic>Z</italic>=2.091， <italic>P</italic><0.01）. No adverse reactions related to Danshenyin combined with Wendantang were found. Conclusion:Addition and subtraction therapy of Danshenyin combined with Wendantang based on the routine western medicine treatment can control the attack of angina pectoris， relieve the symptoms of phlegm and stasis block syndrome， and improve the quality of life for patients with SAP， showing superior clinical efficacy and safety. In addition， it can improve the hemorheology of patients， inhibit the inflammatory reaction， reduce the stenosis or obstruction of lumen in order to improve the degree of myocardial ischemia.

Validation of VR in pediatric anesthesia emergency during standardized residency training / 中华医学教育探索杂志

Objective:To explore the effect of virtual reality (VR) on the emergency management of pediatric anesthesia.Methods:Four kinds of perioperative critical events were selected as VR training content, and the training objects were 60 residents who took part in the standardized residency training in Ninth People's Hospital of Shanghai Jiao Tong University School of Medicine. Through theoretical examination and questionnaire survey, the training effect and the anxiety of residents after critical events were evaluated. The data were input into Graphpad Prism 5 software, and the quantitative data conforming to normal distribution were expressed as (mean ± standard deviation), and compared by nonparametric test and t test of two independent samples between groups. Qualitative data were expressed in terms of rate, and the 2× k trend chi-square test was used to compare the scores of the two groups. Results:All the residents took part in the theoretical assessment of the management of pediatric anesthesia emergencies. Compared with the offline theoretical teaching, the average scores of the students who underwent VR training were higher, and the incidence of anxiety was significantly reduced.Conclusion:VR simulation teaching in the department of anesthesiology can fully arouse the enthusiasm of residents and make them overcome the fear of dealing with pediatric anesthesia emergencies.

Penetration enhancer for pharmacy prepared compound terbinafine ointment / 药学实践杂志

Objective To screen and identify the penetration enhancer in pharmacy prepared compound terbinafine ointment. Methods In vitro percutaneous penetration test was conducted with vertical Franz diffusion pool. The SD rat's abdomen skin was used for permeable membrane and 60% polyethylene glycol 400-40% saline for receiving liquid to analyze different osmotic promoters. Results The permeability of compound terbinafine ointment was significantly higher with 10% propylene glycol than 15% propylene glycol. The compound terbinafine ointment with 10% propylene glycol was also better than 3% azone in permeability. Conclusion 10% propylene glycol was selected to be the penetration promoter for pharmacy prepared compound terbinafine ointment, which improved the solubility of the drug in the skin.

Application of an autoregressive integrated moving average model in prediction of cardiovascular disease mortality / 上海预防医学

Objective:To use autoregressive integrated moving average （ARIMA） model for predicting the mortality of cardiovascular diseases in residents in Yushui District， Jiangxi Province， and to provide basis for developing the prevention and control strategies as well as to promote the continuous optimization of chronic disease prevention and treatment demonstration area. Methods:Based on the cardiovascular death monitoring data of residents in Yushui District， Jiangxi Province from 2014 to 2018， Econometrics View 9.0 software was used to construct the ARIMA seasonal adjustment model to predict the monthly cardiovascular death in this area. Results:The monthly death rate of cardiovascular diseases in Yushui showed a long-term rising trend， with an apparent seasonal pattern （a peak of cardiovascular death from December to January each year）. After the original sequence was subjected to first-order difference and first-order seasonal difference， the difference sequence showed good stationarity （P<0.05）. All the theoretical models were listed and their model parameters were calculated respectively. After statistical test （P<0.05）， 7 alternative models for seasonal adjustment of ARIMA were selected. Among them， ARIMA（1，1，1）（1，1，1）12 is the optimal model selected in this study （R2=0.749， Adjustment R2=0.724， AIC=8.454， SC=8.633， HQ=8.515）.And its residual sequence was tested by white noise test （P>0.05）， indicating that the prediction effect was good. Conclusion:ARIMA（1，1，1）（1，1，1） 12 model can accurately simulate the long-term trend and seasonal pattern of cardiovascular disease death in Yushui， and make a scientific prediction of the trend and monthly distribution of cardiovascular disease death in the next three years.

Simultaneous determination of three components in pharmacy compounded terbinafine ointment by HPLC method / 药学实践杂志

Objective To establish a method to assay 3 active components in pharmacy compounded terbinafine ointment simultaneously. Methods High performance liquid chromatography (HPLC) equipped with the ZORBAX SB-C8 (4.6 mm×250 mm, 5 μm) was used for the assay. The mobile phase was methanol-0.1% phosphoric acid (70∶30). The flow rate was 1.0 ml/min with the 248 nm detection wavelength, 10 μl injection volume and 30 ℃ column temperature. Results A good linear relationship was observed in the range of 20.4-204.0 µg/ml for terbinafine hydrochloride(r=0.999 7), 40.4-404.0 µg/ml for mupirocin(r=0.999 8), 2.02-20.20 µg/ml for mometasone furoate(r=0.999 7). The average recovery of each detected component in terbinafine ointment was 99.39%, 99.21%, 99.97% with the RSD 0.82%, 0.59%, 0.81%(n=9). Conclusion This method is simple, rapid and accurate. It can be used to detect the content of terbinafine, mupirocin and mometasone furoate in pharmacy compounded terbinafine ointment.

The assay of voriconazole in plasma from patients with hepatic insufficiency by UPLC-MS/MS / 药学实践杂志

Objective To establish an UPLC-MS/MS method of voriconazole assay in human plasma for clinical therapeutic drug monitoring. Methods The plasma samples were treated with methanol to precipitate protein and the supernatants were assayed by UPLC-MS/MS. The chromatographic column was InertSustain C18 HP (3.0 mm×100 mm, 3 μm) with the mobile phase of water and acetonitrile solution (15:85) at 35 ℃ and 0.3 ml/min flow rate. ESI was used for Mass Spectrum in positive ion MRM mode with target ions m/z: 350.9/282.2(voriconazole) and m/z: 307.0/238.0(fluconazole). Results The linear range of voriconazole was 0.1–20 μg/ml (r=0.999 5）. The lower limit of quantitation was 0.1 μg/ml. The extraction recovery was higher than 90%. RSDs of inter-day and intra-day were all lower than 10%. The plasma concentrations measured by this method were in the range of 0.97 to 18.7 μg/ml from 10 patients with hepatic insufficiency who were treated with voriconazole. Conclusion The established method was fast, accurate and sensitive。It can be applied for the therapeutic drug monitoring of voriconazole，and provided a good base for rationalized medication treatment in patients with hepatic insufficiency.

Desmethylbellidifolin protects against chronic alcoholic fatty liver disease by regulating Akt-mTORC1 pathway mediated autophagy / 中国药理学与毒理学杂志

OBJECTIVE To investigate the protective effect and potential mechanism of desmethylbellidifolin (DMB) in chronic alcoholic fatty liver disease. METHODS C57BL/6 mice were randomly divided into five groups. Control, meta?doxine and DMB group (high dose and low dose) mice were fed with Lieber-DeCarli liquid diet containing 5％alcohol for six weeks. Pair-fed group mice were fed with a liquid diet containing the same calories. After treatment, serum GOT, GPT, TG and hepatic T-CHO, TG, GSH, GSH-Px, SOD and CAT levels were measured. Ectopic liver lipid deposition was determined by oil red O and hematoxylin-eosin (HE) staining. Lipid metabolism and autophagy related genes expression were determined by real-time PCR and Western blotting. Electron microscope and laser scanning confocal microscope were used to detect autophagosome and autophagy flux. RESULTS DMB treatment markedly reduced serum TG, GOT and GPT levels in alcohol-induced mice, as well as hepatic levels of T-CHO, TG and MDA, while increased the GSH, GSH-Px, SOD and CAT levels in the liver. Oil red O and HE staining showed that the alcohol-induced lipid accumulation and hepatocyte morphology changes were significantly improved by DMB treatment. Mecha?nistically, the expression of stearoyl-CoA desaturase 1 and fatty acid synthase were significantly decreased, while lipoly?sis related hormone-sensitive lipase was elevated in mouse liver by DMB treatment. In addition, DMB could inhibit the phosphorylation of Akt and mTORC1, and activate autophagy process by inducing autophagy related genes expression, such as LC3, ATG5 and ATG7. Moreover, treatment with DMB notably increased the number of autolysosome and promote the autophagy flux, which may therefore induce the lipolysis and oxidation of lipids and prevent the alcohol-induced excessive lipid accumulation in the liver. CONCLUSION DMB exerts a protective role in alcoholic fatty liver dis?ease by regulating the Akt-mTORC1 pathway mediated autophagy activation.

Expression of p-AKT and p-mTOR in pediatric Burkitt lymphoma and their correlation with prognosis / 中华病理学杂志

To evaluate the expression of p-AKT and p-mTOR, the key proteins in PI3K/AKT/mTOR pathway in pediatric Burkitt lymphoma (BL), and to investigate the clinical and prognostic significance. Fifty-eight cases of pediatric BL and thirty cases of reactive hyperplastic lymphadenitis (RH) were collected at Children's Hospital of Fudan University from September 2011 to July 2018. Paraffin sections of tissues were immune stained for p-AKT and p-mTOR, and the expression was assessed and correlated with the clinical features and prognosis. A total of 58 cases were diagnosed and 6 cases lost the follow-up. Of the remaining 52 BL patients including 43 males and 9 females, the median age was 5 years (range: 2 to 14 years). Regarding to the correlation between the two biomarkers, Spearman test showed that p-mTOR was positively associated with the expression of p-AKT (0.759, 0.001). Of all BL patients, the positive rates of p-AKT and p-mTOR were 62.1% (36/58) and 60.3%(35/58) respectively, both significantly higher than control group (0.011, 0.035 respectively). The presence of p-AKT was significantly associated with higher lactate dehydrogenase (LDH≥573 IU/L) level in patients of the disease (0.006), while p-mTOR was increased both in the higher LDH and lower ratio of albumin to globulin (A/G) group (0.006, 0.034 respectively). Expression of p-AKT and p-mTOR did not show any statistical correlation with sex, age, St.jude stage, tumor size, B-symptom present or not, number of extra-nodal sites or international prognostic index (IPI) (0.05). Fifty-two patients had a median follow-up of 40 months (range: 5-87 months). Univariate analysis showed that p-AKT expression was significant in predicting both inferior OS (5-year estimate, 72.7% . 94.7%, (2)=4.123, 0.042) and PFS (5-year estimate, 66.7% . 94.7%, (2)=5.822, 0.016). The 5-year OS rate was 71.0% (22/31) for the p-mTOR positive cohort of patients compared to 95.2% (17/21) for p-mTOR negative group ((2)=4.881, 0.027); however, there was no statistical significance in 5-year PFS rate (0.05). Especially, the 5-year OS and PFS rate of p-AKT/p-mTOR double-positive group were significantly lower than negative control group (including absence of single p-AKT or p-mTOR expression, and absence of both) (OS: 69.0% . 95.7%, (2)=6.285, 0.012; PFS: 65.5% . 91.3%, (2)=5.405, 0.020). The results of multivariate COX proportional risk regression analysis indicated that p-AKT/p-mTOR double-positive, higher LDH and IPI score 3-5 were independent prognostic factors for both OS and PFS, and the bulky tumor (>10 cm) for PFS of pediatric BL. The expression of p-AKT and p-mTOR may be a potential reference for diagnosis and the independent prognostic indicators of pediatric BL.