Biallelic variants in RBM42 cause a multisystem disorder with neurological, facial, cardiac, and musculoskeletal involvement

Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout ΔFgRbp1 in Fusarium while it was rescued by the wild-type (WT) human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing (AS). Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.

Ginkgolide B inhibits the malignant biological behaviors of gastric cancer HGC-27 cells by blocking the PI3K/Akt/mTOR signaling pathway / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探讨银杏内酯B（GKB）是否通过阻抑PI3K/Akt/mTOR信号通路抑制胃癌HGC-27细胞的增殖、凋亡、迁移及侵袭。方法：将HGC-27细胞分为对照、GKB低剂量（100 mg/L）、GKB高剂量（200 mg/L）、GKB高剂量（200 mg/L）+740Y-P（PI3K激活剂）、Ly294002（PI3K抑制剂）组。采用MTT、Edu、FCM、Transwell实验分别检测各组细胞的增殖、凋亡、迁移和侵袭能力，qPCR和WB法分别检测各组细胞中PI3K mRNA、Akt mRNA、mTOR mRNA和Ki-67、caspase-3、p-PI3K/PI3K、p-Akt/Akt、p-mTOR/mTOR蛋白的表达。构建胃癌HGC-27细胞裸鼠移植瘤模型，观察GKB对移植瘤生长的影响，WB法检测移植瘤组织中Ki-67、caspase-3、p-PI3K/PI3K、p-Akt/Akt、p-mTOR/mTOR蛋白的表达。结果：体外实验结果表明，与对照组相比，GKB低剂量组、GKB高剂量组、Ly294002组HGC-27细胞的增殖活力及细胞增殖率、迁移和侵袭细胞数，PI3K、Akt、mTOR mRNA表达，以及Ki-67、p-PI3K/PI3K、p-Akt/Akt、p-mTOR/mTOR蛋白表达均显著降低（均P<0.05）；细胞凋亡率、caspase-3蛋白表达均显著升高（均P<0.05）；740Y-P可部分逆转GKB对HGC-27细胞的抑制作用（均P<0.05）。荷瘤裸鼠实验结果显示，GKB可显著抑制HGC-27细胞裸鼠移植瘤的生长（P<0.05），且可下调PI3K/Akt/mTOR通路相关蛋白的表达。结论：GKB可通过阻抑PI3K/Akt/mTOR信号通路而抑制胃癌HGC-27细胞增殖、迁移与侵袭并促进其凋亡。

Advances in cGAS-STING pathway and its inhibitors in immune and inflammatory diseases / 中国药理学通报

The cGAS-STING signaling pathway is one of the main pathways of immune defense against many types of pathogens. cGAS catalyzes the production of the second messenger cGAMP (cyclic GMP-tVMP) by recognizing plasma DNA and cGAMP subsequently binds to the interferon gene stimulating factor (STING). The pathway induces the production of type I interferon (IFN-I) and activates the innate immune system. The activation of the cGAS-STI]NG pathway could facilitate self-protection,thus STI]NG agonists for tumor immunotherapy have attracted much attention in recent years,and several drug candidates have been in clinical trials. Meanwhile,aberrant activation of cGAS-STI]NG could lead to autoimmune diseases and has attracted extensive interest in developing its inhibitors. This paper summarizes the mechanism and regulatory sites of the cGAS-STI]NG pathway,and outlines the research progress of cGAS-STING pathway-related immune and inflammatory diseases and its inhibitors.

Significance of preventing developmental origins of diseases in improving population quality / 中华预防医学杂志

More studies show that various diseases, especially chronic non-infectious diseases, have developmental origin. Developmental origins of diseases are mainly due to gametes and early life development stage being exposed to adverse environment, resulting in abnormal modification of epigenetic and stable inheritance to the adult stage, which could make the risk of various long-term diseases of individuals high. The theory of developmental origin provides a new perspective for the occurrence and development of diseases, and also provides a theoretical basis for disease prevention. Attaching importance to maternal and child health care and life-cycle management is conducive to the prevention of developmental diseases and is of great significance to the improvement of population quality.

A study on the biological effects of electromagnetic pulse with different high⁃intensity on condylar cartilage in rats / 口腔疾病防治

Objective@#To explore the biological effects of electromagnetic pulse (EMP) with different high intensities on condylar cartilage in rats. @*Methods@#SD rats were randomly divided into a sham group (Sham) and an irradiation group (EMP1: 500 kV/m, 10 Hz; EMP2: 270 kV/m, 10 Hz). Then, they were sacrificed at 1 h, 3 h, 12 h, 24 h and 3 d after irradiation. The degree of cartilage degeneration was evaluated by HE, safranine O-fast green, type Ⅱ collagen immunohistochemistry and TUNEL staining. Immunohistochemistry and western blot were performed to detect the expression of the matrix degradation factors: matrix metalloproteinase-13 (MMP-13), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-5) and the apoptosis key factor cleaved-cysteinyl aspartate specific proteinase (cleaved-Caspase3) in condylar cartilage. @*Results @#HE staining showed that, compared with the Sham group, a small amount of exfoliation was found on the fibrous surface layer of the cartilage after irradiation in the EMP1 and EMP2 groups. Compared with the Sham group, the percentage of safranine O-fast green-positive area decreased significantly at 12 h and 24 h (both P<0.01) in the EMP1 group and 12 h and 24 h in the EMP2 group (both P<0.05); the percentage of type Ⅱ collagen-positive area decreased significantly at 3 h and 12 h (P<0.05, P<0.001) in the EMP1 group. In addition, the number of TUNEL-positive apoptotic cells increased significantly at 1 h, 3 h, 12 h, and 24 h in the EMP1 group and 1 h, 3 h, and 12 h in the EMP2 group (P<0.05). Moreover, at different timepoints (except at 3 d) in the EMP1 group and EMP2 group, the percentage of MMP-13, ADAMTS-5- and cleaved Caspase3-positive chondrocytes and their protein levels in condylar cartilage increased significantly after irradiation (P<0.05). @* Conclusion@# EMP with a certain degree of high-intensity can induce early transient damage to condylar cartilage. This effect is dose-and time-dependent.

Male reproductive system and simulated high-altitude environment: preliminary results in rats / 亚洲男科学杂志(英文版)

This study assessed the effects of a simulated high-altitude environment on the reproductive system of prepubertal male rats and the reversibility of these effects upon return to a normal environment. Three-week-old male Wistar rats were randomly allocated to 4 groups that were exposed to different conditions: a normal environment for 6 weeks and 12 weeks, respectively, hypobaric hypoxia for 6 weeks, and hypobaric hypoxia for 6 weeks followed by a normal environment for 6 weeks. Multiple pathophysiological parameters were evaluated at the histological, endocrine, and molecular levels. Hypobaric hypoxia exposure for 6 weeks during the prepubertal phase significantly altered physiological parameters, body functions, blood indices, and reproductive potential. Six weeks after returning to a normal environment, the damaged reproductive functions partially recovered due to compensatory mechanisms. However, several changes were not reversed after returning to a normal environment for 6 weeks, including disorders of body development and metabolism, increased red blood cells, increased fasting blood glucose, abnormal blood lipid metabolism, decreased testicular and epididymis weights, abnormal reproductive hormone levels, excessive apoptosis of reproductive cells, and decreased sperm concentration. In summary, a hypobaric hypoxic environment significantly impaired the reproductive function of prepubertal male rats, and a return to normal conditions during the postpubertal phase did not fully recover these impairments.

24-hour sodium and potassium excretion in the Americas: a systematic review and meta-analysis / Excreción de sodio y potasio en 24 horas en la Región de las Américas: revisión sistemática y metanálisis / Excreção de sódio e potássio em 24 horas na Região das Américas: revisão sistemática e meta-análise

ABSTRACT Objective. To determine the 24-hour urinary sodium and potassium excretions in the Americas. Methods. A systematic review and meta-analysis were performed seeking for studies conducted between 1990 and 2021 in adults living in any sovereign state of the Americas in Medline, Embase, Scopus, SciELO, and Lilacs. The search was first run on October 26th, 2020 and was updated on December 15th, 2021. Of 3 941 abstracts reviewed, 74 studies were included from 14 countries, 72 studies reporting urinary sodium (27 387 adults), and 42 studies reporting urinary potassium (19 610 adults) carried out between 1990 and 2020. Data were pooled using a random-effects meta-analysis model. Results. Mean excretion was 157.29 mmol/24h (95% CI, 151.42-163.16) for sodium and 57.69 mmol/24h (95% CI, 53.35-62.03) for potassium. When only women were considered, mean excretion was 135.81 mmol/24h (95% CI, 130.37-141.25) for sodium and 51.73 mmol/24h (95% CI, 48.77-54.70) for potassium. In men, mean excretion was 169.39 mmol/24h (95% CI, 162.14-176.64) for sodium and 62.67 mmol/24h (95% CI, 55.41-69.93) for potassium. Mean sodium excretion was 150.09 mmol/24h (95% CI, 137.87-162.30) in the 1990s and 159.79 mmol/24h (95% CI, 151.63-167.95) in the 2010s. Mean potassium excretion was 58.64 mmol/24h (95% CI, 52.73-64.55) in the 1990s and 56.33 mmol/24/h (95% CI, 48.65-64.00) in the 2010s. Conclusions. These findings suggest that sodium excretions are almost double the maximum level recommended by the World Health Organization and potassium excretions are 35% lower than the minimum requirement; therefore, major efforts to reduce sodium and to increase potassium intakes should be implemented.

RESUMEN Objetivo. Determinar la excreción urinaria de sodio y potasio en 24 horas en la Región de las Américas. Métodos. Se realizaron una revisión sistemática y un metanálisis en busca de estudios realizados entre los años 1990 y 2021 con adultos residentes en cualquier Estado soberano de la Región publicados en Medline, Embase, Scopus, SciELO y Lilacs. La búsqueda se llevó a cabo por primera vez el 26 de octubre del 2020 y se actualizó el 15 de diciembre del 2021. De los 3941 resúmenes revisados, se incluyeron 74 estudios de 14 países, 72 estudios sobre excreción urinaria de sodio (27 387 adultos) y 42 estudios sobre excreción urinaria de potasio (19 610 adultos) realizados entre el 1990 y el 2020. Se agruparon los datos mediante un modelo de metanálisis de efectos aleatorios. Resultados. La excreción media de sodio fue de 157,29 mmol/24h (IC de 95%, 151,42-163,16); la de potasio, de 57,69 mmol/24 h (IC de 95%, 53,35-62,03). En los casos en que se consideraron únicamente mujeres, la excreción media de sodio fue de 135,81 mmol/24h (IC de 95%, 130,37-141,25); la de potasio, de 51,73 mmol/24h (IC de 95%, 48,77-54,70). En varones, la excreción media de sodio fue de 169,39 mmol/24h (IC de 95%, 162,14-176,64); la de potasio, de 62,67 mmol/24h (IC de 95%, 55,41-69,93). La excreción media de sodio fue de 150,09 mmol/24h (IC de 95%, 137,87-162,30) en la década de 1990 y de 159,79 mmol/24 h (IC de 95%, 151,63-167,95) en la década del 2010. La excreción media de potasio fue de 58,64 mmol/24h (IC de 95%, 52,73-64,55) en la década de 1990 y de 56,33 mmol/24h (IC de 95%, 48,65-64,00) en la década del 2010. Conclusiones. Estos resultados sugieren que la excreción de sodio casi duplica el nivel máximo recomendado por la Organización Mundial de la Salud y las excreción de potasio es 35% más baja que el requisito mínimo, por lo que se deben invertir grandes esfuerzos para reducir el consumo de sodio y aumentar la ingesta de potasio.

RESUMO Objetivo. Determinar as excreções urinárias de sódio e potássio em 24 horas na Região das Américas. Métodos. Revisão sistemática e metanálise de estudos realizados entre 1990 e 2021, em adultos vivendo em qualquer estado soberano da região, indexados nos bancos de dados MEDLINE, Embase, Scopus, SciELO e LILACS. A pesquisa foi realizada pela primeira vez em 26 de outubro de 2020 e foi atualizada em 15 de dezembro de 2021. Dos 3.941 resumos revisados, foram incluídos 74 estudos de 14 países, 72 estudos relatando sódio urinário (27.387 adultos) e 42 estudos relatando potássio urinário (19.610 adultos), realizados entre 1990 e 2020. Os dados foram reunidos utilizando um modelo de metanálise de efeitos aleatórios. Resultados. A excreção média foi de 157,29 mmol/24h (IC95% 151,42-163,16) para o sódio e 57,69 mmol/24h (IC95% 53,35-62,03) para o potássio. Quando somente mulheres foram consideradas, a excreção média foi de 135,81 mmol/24h (IC95% 130,37-141,25) para o sódio e 51,73 mmol/24h (IC95% 48,77-54,70) para o potássio. Nos homens, a excreção média foi de 169,39 mmol/24h (IC95% 162,14-176,64) para o sódio e 62,67 mmol/24h (IC95% 55,41-69,93) para o potássio. A excreção média de sódio foi de 150,09 mmol/24h (IC95% 137,87-162,30) na década de 1990 e 159,79 mmol/24h (IC95% 151,63-167,95) na década de 2010. A excreção média de potássio foi de 58,64 mmol/24h (IC95% 52,73-64,55) na década de 1990 e 56,33 mmol/24/h (IC95% 48,65-64,00) na década de 2010. Conclusões. Estes achados sugerem que as excreções de sódio são quase o dobro do nível máximo recomendado pela Organização Mundial da Saúde e as excreções de potássio são 35% menores do que o mínimo exigido; portanto, será necessário envidar esforços importantes para reduzir a ingestão de sódio e aumentar a de potássio.

Timing of surgery for esophageal cancer patients after neoadjuvant chemoradiotherapy: A systematic review and meta-analysis / 中国胸心血管外科临床杂志

@#To investigate the effect of the interval between neoadjuvant chemoradiotherapy (nCRT) and surgery on the clinical outcome of esophageal cancer. Methods    PubMed and EMbase databases from inception to March 2018 were retrieved by computer. A random-effect model was used for all meta-analyses irrespective of heterogeneity. The meta-analysis was performed by RevMan5.3 software. The primary outcomes were operative mortality, incidence of anastomotic leakage, and overall survival; secondary outcomes were pathologic complete remission rate, R0 resection rate, and positive resection margin rate. Results    A total of 17 studies with 18 173 patients were included. Among them, 13 were original studies with 2 950 patients, and 4 were database-based studies with a total of 15 223 patients. The results showed a significant positive correlation between the interval and operative mortality (Spearman coefficient=0.360, P=0.027). Dose-response meta-analysis revealed that there was a relatively better time window for  surgery after nCRT. Further analysis for primary outcomes at different time cut-offs found the following results: (1) when the time cut-off point within 30-70 days, the shorter interval was associated with a reduced operative mortality (7-8 weeks: RR=0.67, 95% CI 0.55-0.81, P<0.05; 30-46 days: RR=0.63, 95%CI 0.47-0.85, P<0.05; 60-70 days: RR=0.64, 95%CI 0.48-0.85, P<0.05); (2) when the time cut-off point within 30-46 days, the shorter interval correlated with a reduced incidence of anastomotic leakage (RR=0.39, 95%CI 0.21-0.72, P<0.05); when the time cut-off point within 7-8 weeks, the shorter interval could achieve a critical-level effect of reducing the incidence of anastomotic leakage (RR=0.73, 95%CI 0.52-1.03, P>0.05); (3) when the time cut-off point within 7-8 weeks, increased interval significantly was associated with the poor overall survival (HR=1.17, 95% CI 1.00-1.36, P<0.05). Secondary outcomes found that the shorter interval could significantly reduce the positive resection margin rate (RR=0.53, 95% CI 0.38-0.75, P<0.05) when time cut-off point within 56-60 days. Conclusion    Shortening the interval between nCRT and surgery can reduce the operative mortality, the incidence of anastomotic leakage, long-term mortality risk, and positive resection margin rate. It is recommended that surgery should be performed as soon as possible after the patient's physical recovery, preferably no more than 7-8 weeks, which supports the current study recommendation (within 3-8 weeks after nCRT).

Effect of automatic angle measuring instrument on long-term outcome and prognosis of patients with total hip arthroplasty / 局解手术学杂志

Objective To analyze the long-term effect and prognosis of automatic angle measuring instrument in measuring anteversion angle of patients with total hip arthroplasty(THA).Methods A total of 120 patients with THA from June 2012 to January 2017 were divided into two groups by random number table,with 60 cases in each group.The anteversion angle of THA in control group was measured by CT, while the anteversion angle of THA in observation group was measured by automatic angle measuring instrument.The recovery of hip joint, score of living quality,incidence of complications before and after surgery were compared between the two groups. Results After surgery,the score of hip joint recovery in control group was lower than that in observation group,the difference was significant(P<0.05).After surgery, the scores of living quality in two groups increased compared with those before surgery,and the increased range of observation group was lar-ger,the difference was significant(P<0.05).The incidence of complications in control group was 13.33% ,which was higher than 1.67% of observation group,the difference was significant(P<0.05). Conclusion Automatic angle measuring instrument in measuring anteversion angle of THA can increase measuring accuracy,decrease the incidence of complications,increase living quality and promote prognosis,which is worthy of promotion in clinical application.

Preparation of egg yolk antibodies against human isomaltase and determination of their biological activities / 医学研究生学报

Objective Antibody drugs are one of the hot topics in biomedical research.This study aims to develop egg yolk antibodies (IgYs) against human isomaltase and determine their biological activities.Methods The purified recombinant isomaltase protein was used as an antigen to immunize egg-laying hens in combination with complete Freund adjuvant (CFA).Anti-isomahase IgYs were extracted by water dilution-sodium sulfate extraction assay and further analyzed for their purity,specificity,titer and stability by SDS-PAGE,Western blot and ELISA respectively,and their inhibitory effect on human alpha-glycosidase enzymes was evaluated by the PNPG method.Results Anti-isomaltase IgYs were obtained,with a titer of 1 ∶ 12800,capable of specifically binding human isomaltase,and with a good thermal stability,acid/alkali stability and pepsin resistance.Conclusion Anti-human isomaltase IgYs were successfully prepared,which may provide an experimental ground for further investigation of oral antihyperglycemic agents for type Ⅱ diabetes mellitus.

Risk factors for gestational diabetes mellitus among multiparae / 上海交通大学学报（医学版）

Objective·To investigate the risk factors for gestational diabetes mellitus (GDM) among multiparae. Methods?·?Women who had two consecutive pregnancies records in the International Peace Maternity and Child Health Hospital from January 2012 to January 2017 were included into this study. The case group (116 cases) and control group (464 cases) were matched at the ratio of 1:4 according to the pre-pregnancy age in index pregnancy. Clinical characteristics, biochemical parameters including oral glucose tolerance test (OGTT) and lipid profiles were took into consideration by virtue of their medical records. Multivariate Logistic regression analysis was used to compute the adjusted odds ratio (aOR) and 95%CI so as to identify the risk factors. Results?·?Compared with the control group, the case group was associated with greater body mass index (BMI) change between pregnancies (aOR=1.35, 95%?CI=1.07-1.69), greater postprandial 1 h glucose load (aOR=1.99, 95%?CI=1.55-2.55) and 2 h glucose load (aOR=2.02, 95%?CI=1.51-2.70) at OGTT in index pregnancy, and greater first-trimester fasting plasma glucose (aOR=1.96, 95%?CI=1.16-3.32), total cholesterol (aOR=1.37, 95%?CI=1.06-1.77) and triacylglycerol (aOR=1.53, 95%?CI=1.10-2.14) in subsequent pregnancy. Conclusion?·?The elevated BMI change between pregnancies, the abnormal glucose and lipid profiles persisting from index to subsequent pregnancy lead to the occurrence of GDM.

Roles of gut microbiota in the occurrence and development of polycystic ovary syndrome / 上海交通大学学报（医学版）

Polycystic ovary syndrome (PCOS) is a gynecologic endocrine disorder with complex etiology and pathogenesis.Many women of reproductive age are influenced by this disease due to infertility.The pathogenesis of PCOS remains unclear despite increasing studies in recent years.It is generally accepted that insulin resistance,hyperandrogenism and abnormal follicle development play a pivotal role in PCOS.Gut microbiota becomes a research hotspot in the aspect of infectious,immune and metabolic diseases recently.Previous studies have found that gut microbiota could modulate the synthesis and secretion of insulin,and affect metabolism of androgen and follicle development,providing us a new idea for unravelling the pathogenesis of PCOS.Based on these researches,fecal microbiota transplantation may be a promising treatment in rectifying intestinal microecology imbalance and improving metabolism.This paper reviewed recent research advances in the roles of gut microbiota in the occurrence and development of PCOS.

Research advances in the role of inflammatory factors in polycystic ovary syndrome / 上海交通大学学报（医学版）

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of childbearing age, which features oligo- or anovulation, polycystic ovaries, hyperandrogenism and the related clinical signs, such as acne and hirsutism. At present, PCOS patients are considered to be in a long-time condition of chronic inflammation. It is reported that increased expression of inflammatory factors and/or increased levels of inflammation exist in peripheral blood, granulosa cells, follicular fluid, ovarian stroma, adipocytes and endometrial cells in patients with PCOS. Studies on the role of inflammatory factors in the pathogenesis of PCOS suggest that inflammatory factors may have an influence on the clinical outcome through affecting follicular development, androgen levels and so on.

Paeoniflorin Promotes Angiogenesis in A Vascular Insufficiency Model of Zebrafish in vivo and in Human Umbilical Vein Endothelial Cells in vitro / 中国结合医学杂志

<p><b>OBJECTIVE</b>To investigate the pro-angiogenic effects of paeoniflorin (PF) in a vascular insufficiency model of zebrafish and in human umbilical vein endothelial cells (HUVECs).</p><p><b>METHODS</b>In vivo, the pro-angiogenic effects of PF were tested in a vascular insufficiency model in the Tg(fli-1:EGFP)y1 transgenic zebrafish. The 24 h post fertilization (hpf) embryos were pretreated with vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor II (VRI) for 3 h to establish the vascular insufficiency model and then post-treated with PF for 24 h. The formation of intersegmental vessels (ISVs) was observed with a fluorescence microscope. The mRNA expression of fms-like tyrosine kinase-1 (flt-1), kinase insert domain receptor (kdr), kinase insert domain receptor like (kdrl) and von Willebrand factor (vWF) were analyzed by real-time polymerase chain reaction (PCR). In vitro, the pro-angiogenic effects of PF were observed in HUVECs in which cell proliferation, migration and tube formation were assessed.</p><p><b>RESULTS</b>PF (6.25-100 μmol/L) could rescue VRI-induced blood vessel loss in zebrafish and PF (25-100 μmol/L), thereby restoring the mRNA expressions of flt-1, kdr, kdrl and vWF, which were down-regulated by VRI treatment. In addition, PF (0.001-0.03 μmol/L) could promote the proliferation of HUVECs while PF stimulated HUVECs migration at 1.0-10 μmol/L and tube formation at 0.3 μmol/L.</p><p><b>CONCLUSION</b>PF could promote angiogenesis in a vascular insufficiency model of zebrafish in vivo and in HUVECs in vitro.</p>

The effect of time delay on tumor-immune system in tumor growth / 医用生物力学

Objective To study the effect of time delay on tumor-immune system in tumor growth through theoretical approaches. Methods A mathematical model of the tumor-immune system interactions was established, and a time delay in the logistic growth term was introduced to investigate the processes of the interaction between immune system and tumor cells through qualitative analysis and numerical simulations. The relationship between the states of tumor and time delay was analyzed and the results were compared with the stages of the cancer immunoediting. Results Qualitative analysis and numerical simulations indicated that the tumor-immune system was a stable equilibrium state if the time delay was small. With the time delay increasing, the tumor-immune system entered equilibrium and escape stages of the cancer immunoediting, which described the alteration from dormant state to malignant state. Conclusions The time delay plays a key role in the interaction between immune system and tumor cells. The different time delays can result in different behaviors of tumor. The results will help to deepen clinical understanding of the tumor-immune system and provide references for the analysis and treatment of tumor.

Mechanism of microRNA-138-5p inhibiting proliferation, migration and invasion of lung cancer cells / 中国病理生理杂志

AIM:To investigate the mechanism of microRNA-138-5p (miR-138-5p) inhibiting the proliferation,migration and invasion abilities of lung cancer cells.METHODS:The lung cancer A549 and H460 cells were transfected with miR-NC (control group) or miR-138-5p (experimental group).The bioinformatic analysis was performed to predict the target genes of miR-138-5p.The expression levels of miR-138-5p,forkhead box protein C1 (FOXC1) mRNA and vimentin mRNA were detected by RT-qPCR.The protein expression of FOXC1,vimentin,E-cadhcrin,N-cadherin and β-catenin was determined by Western blot.MTS method and colony formation assay were used to detect cell viability and proliferation ability.Wound healing assay and Transwell assay were used to detect cell migration and invasion ability.RESULTS:Over-expression of miR-138-5p significantly reduced the expression of FOXC1 and vimentin at mRNA and protein levels (P ＜ 0.05).The expression of E-cadherin and β-catenin were up-regulated and the expression of N-cadherin was down-regulated.The proliferation,migration and invasion abilities of the lung cancer cells were inhibited by the over-expression of miR-138-5p.CONCLUSION:miR-138-5p inhibits the proliferation,migration and invasion abilities of lung cancer cells by targeting FOXC1 and vimentin.It may be a potential target for lung cancer gene therapy.

Mechanism of microRNA-138-5p inhibiting proliferation, migration and invasion of lung cancer cells / 中国病理生理杂志

AIM:To investigate the mechanism of microRNA-138-5p (miR-138-5p) inhibiting the proliferation,migration and invasion abilities of lung cancer cells.METHODS:The lung cancer A549 and H460 cells were transfected with miR-NC (control group) or miR-138-5p (experimental group).The bioinformatic analysis was performed to predict the target genes of miR-138-5p.The expression levels of miR-138-5p,forkhead box protein C1 (FOXC1) mRNA and vimentin mRNA were detected by RT-qPCR.The protein expression of FOXC1,vimentin,E-cadhcrin,N-cadherin and β-catenin was determined by Western blot.MTS method and colony formation assay were used to detect cell viability and proliferation ability.Wound healing assay and Transwell assay were used to detect cell migration and invasion ability.RESULTS:Over-expression of miR-138-5p significantly reduced the expression of FOXC1 and vimentin at mRNA and protein levels (P ＜ 0.05).The expression of E-cadherin and β-catenin were up-regulated and the expression of N-cadherin was down-regulated.The proliferation,migration and invasion abilities of the lung cancer cells were inhibited by the over-expression of miR-138-5p.CONCLUSION:miR-138-5p inhibits the proliferation,migration and invasion abilities of lung cancer cells by targeting FOXC1 and vimentin.It may be a potential target for lung cancer gene therapy.

RNAi-mediated Human Nestin Silence Inhibits Proliferation and Migration of Malignant Melanoma Cells by G1/S Arrest via Akt-GSK3β-Rb Pathway / 华中科技大学学报（医学）（英德文版）

Human Nestin (hNestin) has been found to express in melanoma,and its expression is positively correlated with the advanced stage of melanoma.However,the precise role of hNestin in the development of melanoma has not been fully understood.The present study aimed to explore the role of hNestin in the proliferation and invasion of melanoma cells.The lentivirus vector carrying a short hairpin RNAs (shRNAs) targeting hNestin (hNestin-shRNA-LV) was stably infected into human melanoma cells UACC903,which expressed high levels of hNestin.The effects of hNestin knockdown on the proliferation,apoptosis,migration of melanoma cells and the related signaling pathways were investigated by immunofluorence,Western blotting and reverse transcription polymerase chain reaction (RT-PCR),respectively.The results showed that hNestin was expressed in most melanoma specimens and the melanoma cells studied.Knockdown of hNestin expression significantly inhibited the proliferation of melanoma cells,blocked the formation of cell colony,arrested cell cycle at G1/S stage and suppressed the activation of Akt and GSK3β.hNestin-silent cells also showed a sheet-like appearance with tight cell-cell adhesion,decreased membrane expression of N-cadherin and β-catenin,and attenuated migration.Furthermore,hNestin silence resulted in the inhibition of tumor growth in vivo.Our study indicates that hNestin knockdown suppresses the proliferation of melanoma cells,which might be through affecting Akt-GSK3β-Rb pathway-mediated G1/S arrest,and hNestin silence inhibits the migration by selectively modulating the expression of cell adhesion molecules in the process of epithelial-mesenchymal transition.

Comparison of the Reference Intervals Used for the Evaluation of Maternal Thyroid Function During Pregnancy Using Sequential and Nonsequential Methods / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Maternal thyroid dysfunction is common during pregnancy, and physiological changes during pregnancy can lead to the overdiagnosis of hyperthyroidism and misdiagnosis of hypothyroidism with nongestation-specific reference intervals. Our aim was to compare sequential with nonsequential methods for the evaluation of thyroid function in pregnant women.</p><p><b>METHODS</b>We tested pregnant women who underwent their trimester prenatal screening at our hospital from February 2011 to September 2012 for serum thyroid stimulating hormone (TSH) and free thyroxine (FT4) using the Abbott and Roche kits. There were 447 and 200 patients enrolled in the nonsequential and sequential groups, respectively. The central 95% range between the 2.5th and the 97.5th percentiles was used as the reference interval for the thyroid function parameter.</p><p><b>RESULTS</b>The nonsequential group exhibited a significantly larger degree of dispersion in the TSH reference interval during the 2nd and 3rd trimesters as measured using both the Abbott and Roche kits (all P < 0.05). The TSH reference intervals were significantly larger in the nonsequential group than in the sequential group during the 3rd trimester as measured with both the Abbott (4.95 vs. 3.77 mU/L, P < 0.001) and Roche kits (6.62 vs. 5.01 mU/L, P = 0.004). The nonsequential group had a significantly larger FT4 reference interval as measured with the Abbott kit during all trimesters (12.64 vs. 5.82 pmol/L; 7.96 vs. 4.77 pmol/L; 8.10 vs. 4.77 pmol/L, respectively, all P < 0.05), whereas a significantly larger FT4 reference interval was only observed during the 2nd trimester with the Roche kit (7.76 vs. 5.52 pmol/L, P = 0.002).</p><p><b>CONCLUSIONS</b>It was more reasonable to establish reference intervals for the evaluation of maternal thyroid function using the sequential method during each trimester of pregnancy. Moreover, the exclusion of pregnancy-related complications should be considered in the inclusion criteria for thyroid function tests.</p>

Effects of cell-mediated immunity induced by intramuscular chitosan-pJME/ GM-CSF nano-DNA vaccine in BAlb/c mice / 病毒学报

This study aimed to investigate the immune adjuvant effect and mechanism induced by chitosan nanoparticles carrying pJME/GM-CSF. In this study, plasmid DNA (pJME/GM-CSF) was encapsulated in chitosan to prepare chitosan-pJME/GM-CSF nanoparticles using a complex coacervation process. Immunohistochemistry was used to detect the type of infiltrating cells at the site of intramuscular injection. The phenotype and functional changes of splenic DCs were measured by flow cytometry after different immunogens were injected intramuscularly. The killing activity of CTLs was assessed using the lactate dehydrogenase (LDH) release assay. The preparation of chitosan-pJME/GM-CSF nanoparticles matched the expected theoretical results. Our results also found that, after pJME/GM-CSF injection, the incoming cells were a mixture of macrophages, neutrophils, and immature DCs. Meanwhile, pJME/GM-CSF increased the expression of MHC class II molecules on splenic DCs, and enhanced their Ag capture and presentation functions. Cell-mediated immunity was induced by the vaccine. Furthermore, chitosan-pJME/GM-CSF nanoparticles outperformed the administration of standard pJME/GM-CSF in terms of DC recruitment, antigen processing and presentation, and vaccine enhancement. These findings reveal that chitosan could be used as delivery vector for DNA vaccine intramuscular immunizations, and enhance pJME/GM-CSF-induced cellular immune responses.