Prediction of the Impact of CYP2C19 Polymorphism on Drug-Drug Interaction between Voriconazole and Tacrolimus Using Physiologically-Based Pharmacokinetic Modelling

Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole.

Prognosis and risk factors of brain metastases from limited-stage small cell lung cancer after complete resection / 中华放射肿瘤学杂志

Objective:To analyze the prognosis and risk factors for brain metastases (BM) in patients with limited-stage small cell lung cancer (LS-SCLC) after complete resection, aiming to identify those most likely to benefit from prophylactic cranial irradiation (PCI).Methods:Clinical data of 94 patients with LS-SCLC treated in Cangzhou Integrated Traditional Chinese and Western Medicine Hospital from January 2005 to December 2018 who underwent complete resection were retrospectively analyzed, including 31 cases treated with PCI and 63 without PCI. Prognostic factors and risk factors of BM were analyzed by Kaplan-Meier method. The differences between two groups were analyzed by log-rank test. Independent risk factors of overall survival (OS) and BM were assessed by multivariate Cox regression model.Results:The 2-year and 5-year OS rates were 80.6% and 61.3% in the PCI group, and 61.9% and 46.0% in the non-PCI group, respectively ( P=0.001). The 2-year and 5-year brain metastasis-free survival (BMFS) rates were 80.6% and 54.8% in the PCI group, and 57.1% and 42.9% in the non-PCI group, respectively ( P=0.045). The 2-year and 5-year progression-free survival (PFS) rates were 71.0% and 48.4% in the PCI group, and 49.2% and 34.9% in the non-PCI group, respectively ( P=0.016). PCI could improve OS in patients with pII/III stage LS-SCLC ( P=0.039, P=0.013), but the OS benefit in patients with pI stage LS-SCLC was not significant ( P=0.167). BM occurred in 3 patients (9.7%) in the PCI group, which was significantly lower than that in the non-PCI group ( n=17, 27.0%; P=0.044); there was no significant difference in the BM rate of patients with pI and pII stage LS-SCLC between PCI and non-PCI groups ( P=0.285, P=0.468); and the BM rate of patients with pIII stage LS-SCLC in the PCI group was significantly lower than that in the non-PCI group ( P=0.041). Multivariate analysis showed age ≥60 ( HR=2.803, P=0.001), BM ( HR=2.239, P=0.022), no PCI ( HR=0.341, P=0.004) and pathological stage pII/III ( HR=4.963, P=0.002) were the independent high-risk factors affecting OS; and pathological stage pII/III ( HR=11.665, P=0.007) was an independent high-risk factor affecting BM. Conclusions:LS-SCLC patients with pII-III stage have a higher risk of developing BM and poor prognosis after complete resection, and should receive PCI treatment. However, LS-SCLC patients with pI stage may not benefit significantly.

Research progress on stable gene transfection methods of Plasmodium falciparum / 中国热带医学

@#Abstract: Transfection of Plasmodium falciparum is helpful to study the function of its genes, such as drug resistance. However, transgenic manipulation has been very challenging, mainly due to the high A/T base sequence structure (A+T content of about 82%) and low transfection efficiency of the Plasmodium genome. Electroporation-based transfection of Plasmodium falciparum has been successfully applied in the study of certain genes, and electroporation by preloading is currently the preferred method for introducing foreign DNA into Plasmodium falciparum. The site-directed editing of Plasmodium genes mostly adopts the method of two-plasmid transfection. It is generally believed that successful transfection of Plasmodium requires a large amount of high-purity plasmid DNA and an accurate transfection system. In addition to the evaluation of the current commonly used electrotransfection methods, this paper also introduces a new transfection method, namely lyse-reseal erythrocytes for transfection (LyRET). This paper also review the role of factors such as plasmid DNA concentration, the use of transfection reagents, the setting of transfection parameters, the addition of fresh red blood cells, and the markers of successful transfection in improving the success rate and efficiency of Plasmodium transfection, in the hope of providing a reference for study in this field.

Remifentanil Down-regulates GIRK2 Expression in Rat Dorsal Root Ganglion and Spinal Dorsal Horn / 中山大学学报(医学科学版)

ObjectiveTo observe the changes in the expression and distribution of G protein-gated inwardly rectifying potassium channel subunit 2 （GIRK2） in the dorsal root ganglion （DRG） and spinal cord dorsal horn of rats with remifentanil-induced hyperalgesia. MethodsHyperalgesia was induced by intravenous infusion of remifentanil 4 μg/kg/min for 2 h in adult male SD rats. At 6th hour and on days 1， 3 and 5 following remifentanil treatment， we used immunofluorescence to examine the changes in the GIRK2 distribution and expression. Immunoblotting was used to detect GIRK2 expression of the total protein and membrane protein in DRG and spinal dorsal horn of rats. Behavioral testing was applied to evaluate the effect of intrathecal injection of GIRK2-specific agonist ML297 on thermal nociceptive threshold on day 1 after remifentanil infusion. Resultsmmunofluorescence results showed that GIRK2 was mainly co-localized with IB4-positive small neurons in DRG and nerve fibers in spinal dorsal horn. GIRK2 expression was significantly downregulated following remifentanil treatment. Immunoblotting results revealed that on day 1 following intravenous infusion of remifentanil， compared with those in the control group， GIRK2 expression levels of the total protein and membrane protein in DRG （0.47 ± 0.10 vs. 1.01 ± 0.17， P < 0.001； 0.47 ± 0.11 vs. 1.06 ± 0.12， P < 0.001） and spinal dorsal horn （0.52 ± 0.09 vs. 1.10 ± 0.08， P < 0.001； 0.54 ± 0.10 vs. 1.01 ± 0.13， P < 0.001） were all significantly decreased. The behavioral results showed that intrathecal ML297 effect on thermal withdrawal latency was significantly reduced following remifentanil treatment （P < 0.001）. ConclusionsRemifentanil might induce hyperalgesia via down-regulating GIRK2 expression in rat DRG and spinal cord dorsal horn.

Opinion on the definition of "occult hepatitis B virus infection" / 临床肝胆病杂志

The presence of replication-competent HBV DNA in the liver and/or serum of HBsAg-negative individuals is a sufficient and necessary condition for the diagnosis of occult hepatitis B virus infection (OBI). In recent years, Chinese scholars have proposed what is considered a more "rigorous" definition, i.e., on this basis, HBV window period (WP) infection is excluded, which corresponds to a serum HBV DNA level of below the lower limit of detection or a low positive value (< 200 IU/mL). As the definition of WP for HBV infection remains unclear and its duration is highly variable, "HBV DNA < 200 IU/mL" is not the only criterion in OBI patients. Therefore, it is believed that there is still a lack of sufficient basis and operability for the definition of OBI based on "the exclusion of HBV WP infection" and "HBV DNA < 200 IU/mL" as "rigorous" conditions for the diagnosis of OBI.

Effects of glabridin on malignant biological behaviors of lung adenocarcinoma A549 cells and its molecular mechanism / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探讨光甘草定对肺腺癌细胞A549恶性生物学行的影响及其分子机制。方法：常规方法培养A549细胞和人正常肺上皮细胞BEAS-2B，用不同浓度的光甘草定和或顺铂对其进行处理，通过结晶紫染色、CCK-8法检测光甘草定、顺铂对A549、BEAS-2B细胞增殖活力的影响，Transwell小室实验、细胞划痕实验检测光甘草定对A549细胞侵袭、迁移能力的影响，流式细胞术检测光甘草定对A549细胞凋亡的影响，3D超低黏附板培养法培养A549细胞后采用CCK-8法检测光甘草定对A549细胞增殖的影响，WB法检测光甘草定对A549细胞中上皮间质转化（EMT）相关蛋白表达的影响；构建A549细胞移植瘤模型后检测光甘草定、顺铂对移植瘤的生长以及移植瘤组织中EMT相关蛋白表达的影响。结果：光甘草定、顺铂呈剂量依赖性地显著抑制A549细胞的增殖（P<0.05或P<0.01）、细胞迁移（P<0.05或P<0.01）和侵袭能力（P<0.05或P<0.01），光甘草定能诱导A549细胞凋亡（P<0.01），抑制A549细胞中N-cadherin、snail和vimentin蛋白的表达，促进E-cadherin蛋白表达；光甘草定、顺铂均能抑制A549移植瘤的生长，抑制移植瘤组织中Ki67、N-cadherin、snail和vimentin蛋白的表达、促进E-cadherin蛋白的表达。结论：光甘草定可通过抑制A549细胞的增殖、迁移和侵袭，诱导A549细胞凋亡，其机制可能与其抑制细胞的EMT进程而产生抑癌作用有关。

Mechanism study of platelet derived growth factor receptor alpha on the bidirectional differentiation regulation of glioma-associated oncogene homolog 1-positive mesenchymal stem cells in mice / 中华口腔医学杂志

Objective: To investigate the role of platelet derived growth factor receptor alpha (PDGFRα) on bidirectional differentiation of glioma-associated oncogene homolog 1-positive mesenchymal stem cells (Gli1+-MSC). Methods: Breeding double reporter transgenic mice ROSAmT/mG/Gli1-CreERt2/PDGFRαfl (Experimental group) and ROSAmT/mG/Gli1-CreERt2 (Control group), 20 mice in each of the two groups at four weeks of age were selected, MSC were isolated from the mouse aortic epithelium. After tamoxifen inducement, the two groups of Gli1+-MSC were screened by green fluorescent protein (GFP) labeling and flow cytometry sorting. PDGFRα was conditionally knocked out in the experimental group, and the control group Gli1+-MSC expressed PDGFRα normally. The two groups of Gli1+-MSC were subjected to adipogenic induction and fibrogenic induction, the Western blotting was performed to detect PDGFRα, adipocyte markers [perilipin and CCAAT/enhancer binding protein alpha (C/EBPα)] and fibrogenic markers [alpha smooth muscle actin (α-SMA) and fibroblast-specific protein 1 (FSP-1)] and semi-quantitative analysis was performed. The degree of cellular adipose differentiation after bidirectional induction of Gli1+-MSC in both groups was observed by oil red O staining and analyzed semi-quantitatively. Results: After tamoxifen induction, Gli1+-MSC could be accurately isolated from flow cytometry by GFP labeling. Via adipogenic differentiation, the expression of PDGFRα in the experimental group (0.017±0.002) was significantly lower than that in the control group (0.184±0.012) (t=25.48，P=0.002). The protein expressions of perilipin (3.138±0.414) and C/EBPα (3.565±0.289) were significantly higher than those in the control group (2.312±0.218 and 2.179±0.103, respectively) (t=6.21，P=0.025；t=6.69，P=0.022). Thus, the knock-out of PDGFRα enhanced the adipogenic differentiation ability of Gli1+-MSC. After fibrogenesis induction, the protein expressions of PDGFRα, α-SMA and FSP-1 in the experimental group (0.030±0.001, 0.932±0.177 and 0.276±0.020, respectively) were significantly lower than those in the control group (0.439±0.006, 1.352±0.170 and 0.835±0.097, respectively) (t=149.40, P<0.001; t=66.38,P<0.001; t=11.41,P<0.08). This suggested that the knock-out of PDGFRα significantly inhibited Gli1+-MSC differentiation toward fibroblasts. After bidirectional induction, significantly less adipocyte formation was seen in the control group and more in the experimental group. Quantitative analysis showed that the amount of oil red O staining in the experimental group (0.461±0.042) was significantly higher than that in the control group (0.017±0.007) after bidirectional induction (t=23.20, P<0.01). Conclusions: PDGFRα plays an important role in the regulation of bidirectional differentiation of vascular adventitial Gli1+-MSC.

Efficacy of CLAE Chemotherapy Regimen Followed by Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed/Refractory Acute Leukemia / 中国实验血液学杂志

OBJECTIVE@#To observe the efficacy and safety of CLAE intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with relapsed/refractory acute leukemia (R/R AL).@*METHODS@#CLAE regimen [cladribine 5 mg/(m2·d), d 1-5; cytarabine 1.5 g/(m2·d), d 1-5; etoposide 100 mg/(m2·d), d 3-5] followed by allo-HSCT was used to treat 3 R/R AL patients. The patients received CLAE chemotherapy in relapsed or refractory status and underwent bone marrow puncture to judge myelodysplastic state. After an interval of 3 to 5 days, followed by preconditioning regimen for allo-HSCT [fludarabine 30 mg/(m2·d), d -7 to d -3; busulfan 0.8 mg/kg q6h, d -6 to d -3 or d -5 to d -2. If the bone marrow hyperplasia was not active and the blasts were less than 10%, busulfan should be used for 3 days. If the bone marrow hyperplasia was active and the blasts were more than 10%, busulfan should be used for 4 days]. Cyclosporin A, mycophenolate mofetil and short-term methotrexate were used for graft-versus-host disease (GVHD) prevention. After transplantation, the status of minimal residual disease (MRD) and bone marrow chimerism were regularly monitored in all 3 patients, and demethylation drugs or dasatinib were used to prevent recurrence 3 months after transplantation.@*RESULTS@#2 patients with t(11;19) translocation and relapse/refractory acute myeloid leukemia recurred within 6 months after induction of remission, and received intensive chemotherapy with CLAE regimen followed by haploidentical allo-HSCT and unrelated donor allo-HSCT, respectively. The two patients both relapsed 6 months after transplantation, then achieved complete remission by donor lymphocyte infusion, interferon, interleukin-2 and other methods, and disease-free survival was 2 years after transplantation. The other patient was chronic myelogenous leukemia who developed acute lymphoblastic leukemia during oral administration of tyrosine kinase inhibitor, accompanied by T315I and E255K mutations in ABL1 kinase region and additional chromosomal abnormalities. After morphological remission by induction chemotherapy, central nervous system leukemia was complicated. Intensive chemotherapy with CLAE regimen followed by sibling allo-HSCT was performed in the positive state of MRD. The patient relapsed 3 months after transplantation, and achieved remission after chimeric antigen receptor T-cell (CAR-T) therapy, however, he died 5 months after transplantation because of severe cytokine release syndrome (CRS) and GVHD.@*CONCLUSION@#CLAE regimen followed by allo-HSCT may be an effective salvage treatment option for R/R AL patients to prolong the overall survival.

Application of lateral supraclavicular incision in unilateral thyroid papillary carcinoma surgery / Incisão supraclavicular lateral em cirurgia de carcinoma papilífero unilateral de tireoide

Abstract Introduction The standard approach to thyroidectomy is a collar incision via the anterior neck, and the neck scar has always been a source of worry for patients. Acceptable wound cosmetology has become a focus for thyroid surgeons. Objective To verify the effectiveness and cosmetic results of thyroidectomy through a lateral supraclavicular incision. Methods 180 patients were randomly divided into two groups: a lateral supraclavicular approach and a conventional transcervical approach. The main outcomes included incision length, intraoperative blood loss, operative time, total drainage volume, hospitalization expense, early postoperative pain measured by visual analog scale, infection, and perceived cosmetic outcome. Results There were no statistical significances between the two groups in terms of age, gender, nodule size, intraoperative blood loss, operative time, total drainage volume, hospital expense and postoperative complications, whereas there were significant differences in terms of incision length (5.2 ± 1.04 cm vs. 6.9 ± 1.14 cm, p < 0.05). Conclusions The lateral supraclavicular incision is a safe and feasible approach for thyroidectomy. Compared with conventional approach, it provides a better cosmetic result.

Resumo Introdução A abordagem padrão para tireoidectomia é uma incisão em colar na face anterior do pescoço; a cicatriz no pescoço sempre foi uma fonte de preocupação para os pacientes; consequentemente, a cosmetologia aceitável da ferida tornou‐se um foco de atenção para os cirurgiões de cabeça e pescoço. Objetivos Verificar a eficácia e os resultados cosméticos da tireoidectomia por meio de incisão supraclavicular lateral. Método Foram divididos aleatoriamente 180 pacientes em dois grupos: um grupo supraclavicular lateral (Grupo LS) e outro transcervical convencional (Grupo TC). Os desfechos principais incluíram comprimento da incisão, perda de sangue intraoperatória, tempo cirúrgico, volume total de drenagem, despesas hospitalares, dor no pós‐operatório imediato medida através de escala visual analógica, infecção e resultado cosmético percebido. Resultados Não houve significância estatística entre os dois grupos em termos de idade, sexo, tamanho do nódulo, perda sanguínea intraoperatória, tempo cirúrgico, volume total de drenagem, custo hospitalar e complicações pós‐operatórias, mas houve diferença significante em termos de comprimento da incisão (5,2 ± 1,04 cm vs. 6,9 ± 1,14 cm, p < 0,05). Conclusão A incisão supraclavicular lateral é uma abordagem segura e viável para tireoidectomia. Em comparação com a abordagem convencional, oferece um melhor resultado cosmético.

PLCL1 regulates fibroblast-like synoviocytes inflammation via NLRP3 inflammasomes in rheumatoid arthritis

Abstract Background: Phospholipase C-like 1 (PLCL1), a protein that lacks catalytic activity, has similar structures to the PLC family. The aim of this research was to find the function and underlying mechanisms of PLCL1 in fibroblast-like synoviocyte (FLS) of rheumatoid arthritis (RA). Methods: In this study, we first analyzed the expression of PLCL1 in the synovial tissue of RA patients and K/BxN mice by immunohistochemical staining. Then silencing or overexpressing PLCL1 in FLS before stimulating by TNF-α. The levels of IL-6, IL-1β and CXCL8 in FLS and supernatants were detected by Western Blot (WB), Real-Time Quantitative PCR and Enzyme Linked Immunosorbent Assay. We used INF39 to specifically inhibit the activation of NLRP3 inflammasomes, and detected the expression of NLRP3, Cleaved Caspase-1, IL-6 and IL-1β in FLS by WB. Result: When PLCL1 was silenced, the level of IL-6, IL-1β and CXCL8 were down-regulated. When PLCL1 was overexpressed, the level of IL-6, IL-1β and CXCL8 were unregulated. The previous results demonstrated that the mechanism of PLCL1 regulating inflammation in FLS was related to NLRP3 inflammasomes. INF39 could counteract the release of inflammatory cytokines caused by overexpression of PLCL1. Conclusion: Result showed that the function of PLCL1 in RA FLS might be related to the NLRP3 inflammasomes. We finally confirmed our hypothesis with the NLRP3 inhibitor INF39. Our results suggested that PLCL1 might promote the inflammatory response of RA FLS by regulating the NLRP3 inflammasomes.

Investigation and analysis of HbA1c among voluntary blood donors in Hunan Province / 中国输血杂志

【Objective】 To understand the abnormalities of HbA1c in the blood donor population in order to improve blood quality and blood donor safety. 【Methods】 The qualified voluntary blood donors, from April 2021 to March 2022, were recruited from Yueyang Central Blood Station, Loudi Central Blood Station and Chenzhou Central Blood Station. The baseline data and HbA1c screening results of blood donors were collected for cross-sectional analysis. 【Results】 Among 1 397 eligible blood donors, 30.0% (419/1397) was in the prediabetes range (HbA1c 5.7%~6.4%) and 5.3% (74/1397) was in the diabetes range (HbA1c≥6.5%). Logistic regression analysis showed that age (OR=1.073, 95%CI: 1.058~1.088, P<0.05, BMI (OR=1.096, 95%CI: 1.060~1.133, P<0.05), gender (OR=2.392, 95%CI: 1.482~3.303, P<0.05, smoking (OR=2.216, 95%CI: 1.818~3.743, P<0.05), drinking (OR=3.615, 95%CI: 2.240~4.990, P<0.05), and education level (OR=0.077, 95%CI: 0.022~0.278, P<0.05) were the influencing factors of HbA1c in blood donors. 【Conclusion】 Among the blood donors in Hunan, 35.3% had abnormal HbA1c (diabetes and prediabetes). HbA1c screening of blood donors is helpful to improve the health management of blood donors, and may also help to improve the storage quality of red blood cells and reduce the occurrence of adverse reactions to blood transfusion in patients.

Grouping rules and implications of MS-DRG in the United States / 中华医院管理杂志

The United States is the first country to implement DRG payment in the world, and its MS-DRG(medical severity DRG)version has been used for reference by many countries and regions. In order to ensure the universal applicability of DRG grouping scheme and adapt to the clinical reality, the MS-DRG grouping scheme should follow such grouping rules as similarity of resource consumption, clinical similarity and easy management of DRG groups. This paper presented the evolution of MS-DRG and expounded on its grouping rules in detail, for reference in the amendment and improvement of grouping rules in CHS-DRG.

Establishment of a rapid risk assessment system for imported COVID-19 cases / 中华流行病学杂志

Objective: To develop a rapid risk assessment tool for imported COVID-19 cases and provide reference evidences for prevention and control of COVID-19 at ports. Methods: The information about COVID-19 pandemic and control strategies of 12 concerned countries was collected during July to August 2021, and 12 indexes were selected to assess the importation risk of COVID-19 by risk matrix. Results: The risk for imported COVID-19 cases from 12 countries to China was high or extremely high, and the risk from Russia and the USA was highest. Conclusions: The developed rapid risk assessment tool based on the risk matrix method can be used to determine the risk level of countries for imported COVID-19 cases to China at ports, and the risk of imported COVID-19 was high at Beijing port in August 2021.

Clinical characteristics and serum IgG, IgM antibody manifestations of patients infected with SARS-CoV-2 B.1.1.529 (Omicron) variant strain / 中国热带医学

@#Abstract: Objective　To analyze the clinical characteristics and changes of serum IgG, IgM antibodies in patients infected with the SARS-CoV-2 B.1.1.529 (Omicron) variant. Methods　The clinical data of 82 patients with SARS-CoV-2 B.1.1.529 variant was analyzed retrospectively. Based on the presence of pneumonia on chest CT, the patients were divided into pneumonia group and non-pneumonia group. Serum IgG, IgM antibodies were observed at 5 time points T1 (1~<4 d), T2 (4~<8 d), T3 (8~<15 d), T4 (15~<22 d) and T5 (22~<30 d) after admission. Results　Among the 82 patients infected with the SARS-CoV-2 B.1.1.529 variant strain, there were 62 cases of cough, 31 cases of fever, 33 cases of throat discomfort, 5 cases of muscle soreness and 3 cases of diarrhea. The serum IgG antibody levels at 5 time points were 50.22 (142.20) AU/mL, 326.50 (220.63) AU/mL, 368.23 (76.21) AU/mL, 368.65 (79) AU/mL, and 385.26 (113.10) AU/mL, respectively. The level of serum IgG antibody in the pneumonia group was lower than that of the non-pneumonia group at T1 and T4 time points, and the differences were statistically significant (P<0.05) , the positive rate of serum IgG antibody in the pneumonia group was lower than that of the non-pneumonia group at the T1 time point, and the difference was statistically significant (P<0.05) . The serum IgM antibody levels at 5 time points were 0.41 (0.81) AU/mL, 0.95 (1.62) AU/mL, 1.09 (2.42) AU/mL, 0.74 (3) AU/mL, and 0.81 (3.10) AU/mL respectively, and there was no significant difference between the two groups. Conclusion　The clinical symptoms of patients infected with the SARS-CoV-2 B.1.1.529 variant strain are mild. Serum IgG antibodies increased after infection, but there are some differences between the pneumonia group and the non-pneumonia group, whether serum IgG has a protective effect needs further research; the serum IgM antibodies do not increase highly after infection, there are some differences between individuals.

EGFR mutation, expression of PD-L1/Ki-67 and their correlation with clinical features in elderly NSCLC patients / 中华检验医学杂志

Objective:To investigate the mutation of epidermal growth factor receptor (EGFR), the expression of programmed death ligand 1 (PD-L1), cell proliferation-associated antigen (Ki-67) in elderly patients with non-small cell lung cancer (NSCLC), and their correlation with clinical feature such as gender, histological type and TNM stage.Methods:The tissue samples of 340 elderly NSCLC patients with definite histopathological diagnosis were collected from January 2020 to December 2020 in Huadong Hospital Affiliated to Fudan University, including 195 males and 145 females, age between 68.9±6.0 years. Patients were grouped according to clinical features such as gender, histological type and TNM stage. The expression of EGFR mutation, PD-L1 and Ki-67 were detected by Super-ARMS and immunohistochemistry. The correlation between tnem and clinical features was statistically analyzed, and the correlation between EGFR mutation and PD-L1/Ki-67 expression was further analyzed separately.Results:In elderly NSCLC patients′ tissues, the positive rate of EGFR mutation was 48.53% (165/340). L858R and 19del mutations were the most common types, which were 56.36% (93/165), 30.30% (50/165) respectively. The mutation rate of EGFR was higher in women, lung adenocarcinoma, well-differentiated, and low-stage patients, which were 65.52% (95/145), 53.77% (164/305), 56.75% (143/252), 52.53% (135/257) respectively. In addition, the positive rate of PD-L1 expression was higher in elderly patients with non-adenocarcinoma lung cancer and poorly differentiated adenocarcinoma, which were 37.14% (13/35), 24.53% (13/53) respectively. The negative rate of PD-L1 expression was higher in elderly patients with NSCLC in stage Ⅰ+Ⅱ, no lymph node metastasis and weakly positive Ki-67, which were 89.11% (229/257), 87.63% (248/283), 94.71% (197/208) respectively. Correlation analysis showed that EGFR mutation was negatively correlated with the expression of PD-L1 and Ki-67 (PD-L1: r=-0.22, P<0.001; Ki-67: r=-0.32, P<0.001). Conclusion:There is a negatively correlation between EGFR mutation and the expression of PD-L1 and Ki-67 in elderly NSCLC, suggesting that the combined detection of EGFR mutation and PD-L1 expression could provide the basis for precise targeted therapy for elderly NSCLC patients.

Application of 192Ir brachytherapy combined with external beam radiation and biliary stent in the treatment of unresectable hilar cholangiocarcinoma / 国际肿瘤学杂志

Objective:To evaluate the efficacy and safety of 192Ir brachytherapy combined with external beam radiation for the treatment of unresectable hilar cholangiocarcinoma. Methods:The clinical data of 26 patients with unresectable hilar cholangiocarcinoma admitted to Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine from February 2016 to July 2018 were retrospectively analyzed. All patients received 192Ir brachytherapy combined with external beam radiation. First, percutaneous hepatobiliary stent implantation was given, followed by external beam radiotherapy (radiotherapy dose 45 Gy, 25 times), and then 192Ir brachytherapy (radiotherapy dose 20 Gy, 4 times), a total of 4 to 6 cycles of chemotherapy. The short-term and long-term efficacy were evaluated, and the Karnofsky performance status (KPS) score, CA19-9, total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST) level changes and percutaneous transhepatic biliary drainage (PTCD) tube indwelling time were analyzed. Adverse reactions were recorded according to the Radiation Therapy Oncology Group (RTOG) injury classification standard. Results:Three months after the end of treatment, 4 cases (15.4%) were completely remitted, 20 cases (76.9%) were partially remitted, 2 cases (7.7%) were stable, and there was no disease progression. The objective remission rate was 92.3% (24/26). The 1-year and 2-year local control rates were 75.0% and 62.5% respectively, and the 1-year and 2-year overall survival rates were 57.7% and 26.9% respectively. The KPS score was 70.39±10.76 one month after the treatment, which was significantly higher than the 60.00±10.58 before treatment ( t=-27.00, P<0.001). The levels of CA19-9 before treatment and 1 month, 2 months and 3 months after treatment were (390.88±202.62) U/ml, (322.45±204.06) U/ml, (254.00±160.49) U/ml, (182.85±124.05) U/ml, which showed a gradual decrease trend, and there was a statistically significant difference ( F=126.94, P<0.001). TBIL [(250.88±80.83) μmol/L, (153.98±61.74) μmol/L, (93.45±38.12) μmol/L, (53.82±26.75) μmol/L], DBIL [(205.82±66.68) μmol/L, (133.23±58.53) μmol/L, (64.31±36.25) μmol/L, (40.55±26.16) μmol/L], ALT [(163.92±54.12) U/L, (68.23±28.86) U/L, (45.73±21.94) U/L, (32.66±12.88) U/L], AST [(177.69±58.68) U/L, (79.23±32.87) U/L, (49.77±25.45) U/L, (35.54±16.10) U/L] showed progressive decline, with statistically significant differences ( F=315.60, P<0.001; F=385.30, P<0.001; F=284.24, P<0.001; F=311.80, P<0.001), and liver function was improved. The PTCD tube was removed after treatment in all patients, with a median time of 54 days (49-96 days). During the treatment, bone marrow suppression, nausea and vomiting, abdominal pain and biliary tract infection occurred. All of them improved after symptomatic treatment. No serious complications such as bile leakage and biliary hemorrhage occurred. Conclusion:192Ir brachytherapy combined with external beam radiation has a reliable curative effect in the treatment of unresectable hilar cholangiocarcinoma. It can improve the quality of life of patients, and the adverse reactions can be tolerated. It provides a feasible and safe treatment method for the clinic.

The substitution of SERCA2 redox cysteine 674 promotes pulmonary vascular remodeling by activating IRE1α/XBP1s pathway

Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling, in which hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) plays an important role. The cysteine 674 (C674) in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) is the critical redox regulatory cysteine to regulate SERCA2 activity. Heterozygous SERCA2 C674S knock-in mice (SKI), where one copy of C674 was substituted by serine to represent partial C674 oxidative inactivation, developed significant pulmonary vascular remodeling resembling human PH, and their right ventricular systolic pressure modestly increased with age. In PASMCs, substitution of C674 activated inositol requiring enzyme 1 alpha (IRE1α) and spliced X-box binding protein 1 (XBP1s) pathway, accelerated cell cycle and cell proliferation, which reversed by IRE1α/XBP1s pathway inhibitor 4μ8C. In addition, suppressing the IRE1α/XBP1s pathway prevented pulmonary vascular remodeling caused by substitution of C674. Similar to SERCA2a, SERCA2b is also important to restrict the proliferation of PASMCs. Our study articulates the causal effect of C674 oxidative inactivation on the development of pulmonary vascular remodeling and PH, emphasizing the importance of C674 in restricting PASMC proliferation to maintain pulmonary vascular homeostasis. Moreover, the IRE1α/XBP1s pathway and SERCA2 might be potential targets for PH therapy.

Status quo and insights in building national regional medical centers from the perspective of resources integration / 中华医院管理杂志

The constrution of national regional medical centers has been included in the 14th Five-Year Plan. As a major project to build a high-quality and efficient medical health service system in China, it is imperative to expand such high quality medical resources and balance their regional distribution. The authors analyzed the dual resources integration attributes of regional medical centers—horizontal expansion and vertical extension—from the perspective of medical resources integration, and by means of literature methodology and content analysis methods. With both two work paths and progresses led by the National Development and Reform Commission and the National Health Care Commission, the authors identified setbacks in the construction of such medical centers in terms of building a synergy system, optimizing the cooperation modes, and enhancing the awareness of the entity bodies. On such basis, the authors suggested that government departments should hold on to the leadership in general, while in the construction process, output hospitals and input hospitals should respectively take their entity responsibilities in both operation management and cooperation.

Post-marketing immunogenicity and safety of domestic 23-valent pneumococcal polysaccharide vaccine: a multicenter study / 中华微生物学和免疫学杂志

Objective:To evaluate the post-marketing safety and immunogenicity of a 23-valent pneumococcal polysaccharide vaccine (PPV23).Methods:From September 2020 to June 2021, a clinical trial of single-dose PPV23 was conducted in people ≥3 years old in Centers for Disease Control and Prevention of Guizhou, Hunan and Fujian provinces. Blood samples were collects from the subjects before and 30 d after vaccination. ELISA was used to quantitatively detect IgG antibodies against capsular polysaccharides of 23 Streptococcus pneumoniae serotypes in serum samples. The adverse events (AEs) were monitored within 7 d after vaccination. Results:A total of 409 subjects were enrolled and included in safety analysis. Except for one with antibody level inversion, the other 408 participants were included in immunogenicity analysis. The levels of antibodies against the 23 Streptococcus pneumoniae serotypes were all increased after vaccination by an average of 4.24 folds. The two-fold growth rates of the antibodies ranged from 51.72% to 96.81% with a total two-fold growth rate of 78.59%. The overall rate of AEs was 27.14% (111/409). Local AEs were mainly pain, induration, redness and swollen. No serious adverse events related to vaccination occurred. Conclusions:This study preliminarily demonstrated the good immunogenicity and safety of PPV23 vaccine.

Age-related changes in pancreatic histology and ultrastructure in rats / 中华老年医学杂志

Objective:To investigate age-related histological and ultrastructural changes of the pancreas in Sprague-Dawley(SD)rats, and to provide a theoretical basis for the high incidence of pancreatic diseases in the elderly.Methods:Thirty 6-month-old specific pathogen-free male SD rats were fed until 6, 12, 18 and 25 months of age.Five rats of each age group were randomly selected, killed and then sampled to make histological(HE staining)and electron microscopic sections to observe age-related changes in pancreatic histology and ultrastructure.Results:The pancreatic tissue of rats showed increasing fibrosis with age, especially around the duct.Fat infiltration of the pancreatic tissue also increased with age( H=15.88, P=0.001). With the increase of age, the number(density)of pancreatic islets decreased gradually( F=3.55, P=0.039), but the average cross-sectional area of islets increased significantly( F=7.76, P=0.002), and the round and oval islets became irregular.Nuclear pyknosis, mitochondrial dehydration, mitochondrial swelling, and dilatation and loose organization of rough endoplasmic reticula were observed in the cytoplasm of pancreatic acinar cells and islet beat cells in aged rats.With the increase of age, the number of zymogen granules at the apical pole of pancreatic acinar cells of rats decreased( F=9.73, P<0.001), and the average area and total area of granules were significantly decreased( F=6.51, P=0.001; F=22.18, P<0.001); The number of non-senescent mitochondria and senescent mitochondria in the cytoplasm of acinar cells increased significantly( H=8.22, P=0.045; H=32.95, P<0.001); The amount of proinsulin in islet beta cells was significantly decreased( F=16.20, P<0.001). Conclusions:With aging, the rat pancreas exhibits a series of degenerative manifestations(stromal hyperplasia, adipose tissue infiltration, decreased numbers of zymogen granules in acinar cells, increases in the number of senescent mitochondria, reduced islets and reduced proinsulin in islet beta cells), while there are some compensatory phenomena(increasing numbers of islets and non-senescent mitochondria).