Mutational separation and clinical outcomes of TP53 and CDH1 in gastric cancer

BACKGROUND Gastric cancer(GC)is a deadly tumor with the fifth highest occurrence and highest global mortality rates.Owing to its heterogeneity,the underlying mechanism of GC remains unclear,and chemotherapy offers little benefit to individuals.AIM To investigate the clinical outcomes of TP53 and CDH1 mutations in GC.METHODS In this study,202 gastric adenocarcinoma tumor tissues and their corresponding normal tissues were collected.A total of 490 genes were identified using target capture.Through t-test and Wilcoxon rank-sum test,somatic mutations,microsatellite instability,and clinical statistics,including overall survival,were detected,compared,and calculated.RESULTS The mutation rates of 32 genes,including TP53,SPEN,FAT1,and CDH1 exceeded 10%.TP53 mutations had a slightly lower overall occurrence rate(33%).The TP53 mutation rate was significantly higher in advanced stages(stage Ⅲ/Ⅳ)than that in early stages(stage Ⅰ/Ⅱ)(P<0.05).In contrast,CDH1 mutations were significantly associated with diffuse GC.TP53 is related to poor prognosis of advanced-stage tumors;nevertheless,CDH1 corresponds to a diffuse type of cancer.TP53 is exclusively mutated in CDH1 and is primarily affected by two distinct GC mechanisms.CONCLUSION Different somatic mutation patterns in TP53 and CDH1 indicate two major mechanisms of GC.

Prognostic significance of preoperative lymphocyte to monocyte ratio in patients with signet ring gastric cancer

BACKGROUND The ratio of lymphocytes to monocytes(LMR)has been shown to be an effective predictor of gastric cancer prognosis.However,its predictive accuracy for signet ring gastric cancer is currently not well understood.AIM To evaluate the prognosis predictive accuracy of preoperative LMR in signet ring gastric cancer.METHODS A total of 212 signet ring gastric cancer patients admitted at the Xiangya Hospital of Central South University,Department of Gastrointestinal Surgery,from January 2012 to December 2016 were enrolled in the study.The prognosis predictive accuracy of preoperative LMR was explored based on the area under the receiver operating characteristic.Factors that significantly affect the survival of patients were identified using single factor analysis,and those that were independently associated with signet ring gastric cancer were identified through multivariate analysis.RESULTS The results of the single factor analysis revealed a strong correlation between the survival of signet ring gastric cancer patients and several factors,including tumor invasion(χ^(2)=49.726;P<0.001),lymph node metastasis(χ^(2)=30.269;P<0.001),pTNM stage(χ^(2)=49.322;P<0.001),surgical approach(χ^(2)=8.489;P=0.004),age(t=-2.213;P<0.028),carcinoembryonic antigen(CEA)(Z=-3.265;P=0.001),platelet-to-lymphocyte ratio(Z=-2.196;P=0.028),LMR(Z=-2.226;P=0.026),ALB(t=3.284;P=0.001),prognostic nutritional index(t=-3.789;P<0.001)and FIB(Z=-3.065;P=0.002).Furthermore,the multivariate analysis further demonstrated that age(HR:0.563,95%CI:0.363-0.873),tumor invasion depth(HR:0.226,95%CI:0.098-0.520),pTNM stage(HR:0.444,95%CI:0.255-0.771),preoperative CEA level(HR:0.597,95%CI:0.386-8.790),and preoperative LMR level(HR:1.776,95%CI:1.150-2.741)were independent factors influencing the prognosis of signet ring gastric cancer.CONCLUSION In signet ring gastric cancer patients,a low preoperative LMR level predicts poor prognosis.The death risk ratio of the low LMR group compared to the high LMR group is 1.776.

TRAF6基因沉默对人视网膜母细胞瘤细胞增殖、凋亡和侵袭的影响

目的:探讨体外沉默肿瘤坏死因子受体相关因子6(TRAF6)基因对人视网膜母细胞瘤Y79细胞增殖、凋亡和侵袭的影响。方法:靶向TRAF6基因的小干扰RNA(TRAF6 siRNA)转染Y79细胞,采用qRT-PCR和Western blot法检测转染效果,MTT比色法及细胞克隆实验测定沉默TRAF6对Y79细胞增殖的影响,流式细胞术检测细胞凋亡及细胞周期,Transwell小室检测细胞迁移和侵袭能力。结果:Y79细胞经TRAF6沉默后,TRAF6 mRNA和蛋白表达水平与对照组相比均明显降低,细胞存活率、克隆形成率均明显低于对照组细胞,细胞凋亡率明显高于对照组,同时细胞周期发生明显变化,G0/G1期细胞数目增多,S和G2/M期细胞数目减少,且侵袭细胞数目、迁移细胞数目相比对照组明显减少。结论:沉默TRAF6后能显著抑制视网膜母细胞瘤Y79细胞的生长,促进肿瘤细胞的凋亡,同时抑制其侵袭和迁移能力,TRAF6可能是视网膜母细胞瘤治疗的新靶点。

BHMT对同型半胱氨酸诱导的人晶状体上皮细胞氧化损伤的保护作用

目的:观察甜菜碱高半胱氨酸甲基转移酶(BHMT)在同型半胱氨酸(Hcy)环境下对人晶状体上皮细胞(HLEC)的保护作用。方法:构建BHMT基因过表达慢病毒载体,将体外培养的HLEC随机分为3组:正常组:正常培养的HLEC;对照组:感染了空载体的HLEC-B3,BHMT过表达组(OE):感染了过表达BHMT基因载体的HLEC-B3,均培养于10%FBS(胎牛血清)培养基+5mmol/L Hcy培养液中。应用EdU(5-乙炔基-2'脱氧尿嘧啶核苷)试剂盒检测细胞的增殖能力,流式细胞仪检测活性氧(ROS)含量,可见分光光度计测算谷胱甘肽(GSH)活性,Western blotting检测内质网应激相关蛋白(GPR78,Nrf2)及凋亡相关酶Caspase-12的表达。结果:BHMT过表达组较对照组细胞增殖能力增长约30.0%(P<0.05)。ROS检测显示,正常组、对照组、过表达组荧光强度分别为(89.2043±0.3511)%、(91.4502±0.0606)%、(49.5625±0.4502)%,过表达组与正常组有差异(P<0.05);GSH活性检测显示:相比于正常组与对照组,BHMT高表达组GSH活性明显上升(P<0.05);Western blotting结果显示:GRP78的相对表达量在正常组及对照组中明显高于过表达组,Nrf2的相对表达量在正常组与对照组中明显低于过表达组。凋亡相关酶Caspase-12的相对表达量在过表达组中明显低于对照组。结论:BHMT可以抑制Hcy对HLEC的氧化损伤作用,降低ROS水平,升高GSH活性,减轻内质网应激反应,抑制细胞凋亡。BHMT对Hcy诱导的HLEC氧化损伤有重要的保护作用。

DISCOPO内镜与McCoy喉镜在困难气道清醒气管插管中的应用比较

目的观察DISCOPO内镜与McCoy喉镜在困难气道清醒气管插管中的临床应用效果。方法将符合困难气道诊断标准的择期全麻下手术患者60例随机分为DISCOPO内镜组(D组)和McCoy喉镜组(M组),每组各30例,两组患者在表面麻醉与右美托咪定镇静的基础上,M组运用McCoy喉镜进行气管插管,D组使用DISCOPO内镜进行气管插管,记录两组患者气管插管所用时间、一次性气管插管成功率,声门暴露分级、插管并发症发生情况和围插管期血流动力学[血压(BP)和心率(HR)]变化。结果 D组气管插管时间短于M组(P <0.05),一次性插管成功率及声门暴露良好率明显高于M组(P <0.05),并发症发生率明显低于M组(P <0.05),D组T_2和T_3时间点BP和HR明显低于M组(P <0.05)。结论 DISCOPO内镜用于困难气道清醒插管用时短,成功率高,并发症少,值得临床推广应用。

Comparison of lens oxidative damage induced by vitrectomy and/or hyperoxia in rabbits

● AIM: To compare of lens oxidative damage induced by vitrectomy and/or hyperoxia in rabbit.● METHODS: Sixteen New Zealand rabbits(2.4-2.5 kg) were randomly divided into two groups(Group A, n=12; Group B, n=4). In Group A, the right eyes were treated with vitrectomy and systemic hyperoxia(oxygen concentration: 80%-85%, 1 ATA, 4h/d)(Group A-right), and the left eyes were treated with hyperoxia without vitrectomy surgery(Group A-left). Four rabbits in group B(eight eyes) were untreated as the controls. Lens transparency was monitored with a slit lamp and recorded before and after vitrectomy. After hyperoxic treatment for 6mo, the eyeballs were removed and the lens cortices(containing the capsules) and nuclei were separated for further morphological and biochemical evaluation.● RESULTS: Six months after treatments, there were no significant morphological changes in the lenses in any experimental group when observed with a slit lamp. However, the levels of water-soluble proteins and ascorbate, and the activities of catalase and Na^+-K^+-ATPase were significantlyreduced, whereas the levels of malondialdehyde and transforming growth factor β2(TGF-β2) were significantly elevated, in both the cortices and nuclei of eyes treated with vitrectomy and hyperoxia. The increase in proteinglutathione mixed disulfides and the reduction in watersoluble proteins were more obvious in the lens nuclei. The levels of ascorbate in the vitreous fluid were also reduced after vitrectomy, whereas TGF-β2 increased after vitrectomy and hyperoxia. Systemic hyperoxia exposure increased these effects.● CONCLUSION: Removal of the intact vitreous gel with vitrectomy and exposing the lens to increased oxygen from the retina induce lens oxidation and aggregation. Thus, an intact vitreous gel structure may protect the lens from oxidative insult and maintain lens transparency.

Noninvasive stiffness assessment of the human lens nucleus in patients with anisometropia using an ultrasound elastography system

AIM:To investigate the significance of ultrasound elastography for evaluating stiffness of the human lens nucleus in patients with anisometropia.METHODS:A total of 14 patients(28 eyes)with anisometropia were enrolled.The difference in refractive status between two eyes≥-4.0 diopters(D)and the difference in axial length(AL)of the eyes was≥3 mm.There were 5 males and 9 females with an average age of 62±3.3 y.The test data of the long AL eye of each patient was included in group A(14 eyes),and test data of the eye with relative short AL was included in group B.Lens nuclear stiffness was measured with free-hand qualitative elastography by independent operators.Strain gray scale and color-coded elastography maps were recorded.In each case,three consecutive measurements were performed and strain ratio was used for statistical analysis.Photograph and sectional view of the lens were analyzed and archived by anterior segment image.RESULTS:In the long AL group,the strain rate in the nucleus of the lens was 0.16%±0.08%;in the short AL group,the strain rate in the nucleus of the lens was 0.54%±0.16%.Independent sample t-test analyses showed that the long AL group lens had a significantly smaller nuclear strain rate than the relatively short AL group,P<0.05.CONCLUSION:The relationship between human lens stiffness and different AL is demonstrated by ultrasound elastography.The long AL is associated with lower strain ratio and less resilience of the lens.

The role of DJ-1 in the pathogenesis of Parkinson’s disease

Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder characterized clinically by bradykinesia, rigidity, tremor, gait dysfunction, and postural instability. Several genes have been identified for monogenic disorders that variably resemble Parkinson’s disease. Here, we focus on PARK7, a gene relates to an autosomal recessive form of early-onset Parkinsonism and encodes a protein named DJ-1. Though the exact role of DJ-1 needs to be elucidated, it is generally thought to be functioned as a molecular chaperone and an oxidative sensor (or antioxidative factor). We will review the protective role of DJ-1 to prevent dopaminergic neurons in the substantia nigra pars compacta (SNpc) from degeneration and how its dysfunction would lead to neurodegeneration.

Characterization of and advanced diagnostic methods for ocular tuberculosis and tuberculosis

Tuberculosis(TB)is an airborne infection caused by Mycobacterium tuberculosis that usually affects the lungs.Timely treatment of active TB,diagnosis and prevention of latent TB are very important.However,extrapulmonary TB affects almost any tissues around the eye and orbit,and it then requires a high degree of suspicion to accurately diagnose.Diagnostic delays are common and may lead to morbidity.For ophthalmologists and infectious disease specialists,it is important to work together to accurately diagnose and treat ocular tuberculosis(OTB)to prevent vision loss.This review reports the latest advanced diagnostic methods for active TB and latent TB as well as various known manifestations of 0TB.Important elements of diagnosis and treatment are also reviewed.

Ultrasound elastography for evaluating stiffness of the human lens nucleus with aging:a feasibility study

AIM:To investigate the significance of ultrasound elastography for evaluating stiffness of the human lens nucleus in volunteers with different ages.METHODS:A total of 90 volunteers(lens transparency,uncorrected visual acuity≥0.5,intraocular pressure:14-19 mm Hg)were divided into 3 groups according to age:Group A(30 people,median age:82±3.5 y,mean axial lengths 23.7±0.5 mm);Group B(30 people,median age:46±2.1 y,mean axial lengths 23.9±0.4 mm);and Group C(30 people,median age:22±3.5 y,mean axial lengths 24.0±0.4 mm).Lens nuclear stiffness was measured by Free-hand qualitative elastography by independent operators.Strain gray scale and color-coded elastography maps were recorded.In each case,three consecutive detections were performed and strain ratio was used for statistical analysis.RESULTS:Elastography analysis showed excellent diagnostic performance for lens sclerosis.Lens strain ratio was lowest(0.03±0.01)%in Group A and highest(2.03±0.43)%in Group C.Lens strain ratio was moderate(0.64±0.10)%in Group B.There were significant differences between these three groups(P<0.05).The lens nucleus strain rate changes with age.With aging,the lens nucleus strain rate and resilience decrease,demonstrating harder texture.CONCLUSION:The relationship between human lens stiffness and age is demonstrated by ultrasound elastography.Older age is associated with lower strain ratio and less resilience of the lens.

合谷穴与面口部特异性联系的脑网络功能研究

Objective:This study was designed to observe the effect of electroacupuncture at Hégǔ(合谷L14),or Hòuxī(后溪SI3) or Wàiguān(外关TE5) acupoints on the function of the brain regions of a healthy human,and to explore the neural information mechanism of a specific connection between LI4 and the facialoral area from the point of view of the brain function connection network.A further objective was to enrich knowledge of the specific connection between the body surface and the meridian route,and the specificity of acupoint effects.Methods:A total of 30 healthy volunteers were randomly assigned to LI4,SI3,and TE5 groups.The members of each group were stimulated with electroacupuncture,and their heads were scanned using fMRI.DPARSFA 2.4 and REST 1.8 software were used for data preprocessing and statistical analysis.The paired t-test was used within group and the double sample t-test was used for two-group comparisons.Results:In healthy people,left LI4 with electroacupuncture mainly caused a decrease of the functional connection of the right orofacial motor area of the brain,which remained decreased after removing the needle.When LI4 was compared with SI3 and TE5,LI4 caused a more significant decline in the functional connection of the right side of the brain during acupuncture.Conclusions:Acupuncture at LI4 has a significant effect on the function of the face-and mouth-related areas in the brain,and there is a continuous effect.It is suggested that LI4 and the face and mouth have a specific relationship in the brain,which is most obvious during acupuncture.

The role of substantia nigra sonography in the differentiation of Parkinson’s disease and multiple system atrophy

Background:The differential diagnosis of Parkinson’s disease(PD)and multiple system atrophy(MSA)remains a challenge,especially in the early stage.Here,we assessed the value of transcranial sonography(TCS)to discriminate non-tremor dominant(non-TD)PD from MSA with predominant parkinsonism(MSA-P).Methods:Eighty-six MSA-P patients and 147 age and gender-matched non-TD PD patients who had appropriate temporal acoustic bone windows were included in this study.All the patients were followed up for at least 2 years to confirm the initial diagnosis.Patients with at least one substantia nigra(SN)echogenic size≥18 mm^(2) were classified as hyperechogenic,those with at least one SN echogenic size≥25 mm^(2) was defined as markedly hyperechogenic.Results:The frequency of SN hyperechogenicity in non-TD PD patients was significantly higher than that in MSA-P patients(74.1%vs.38.4%,p<0.001).SN hyperechogenicity discriminated non-TD PD from MSA-P with sensitivity of 74.1%,specificity of 61.6%,and positive predictive value of 76.8%.If marked SN hyperechogenicity was used as the cutoff value(≥25 mm^(2)),the sensitivity decreased to 46.3%,but the specificity and positive predictive value increased to 80.2 and 80.0%.Additionally,in those patients with SN hyperechogenicity,positive correlation between SN hyperechogenicity area and disease duration was found in non-TD PD rather than in MSA-P patients.In this context,among early-stage patients with disease duration≤3 years,the sensitivity,specificity and positive predictive value of SN hyperechogenicity further declined to 69.8%,52.2%,and 66.7%,respectively.Conclusions:TCS could help discriminate non-TD PD from MSA-P in a certain extent,but the limitation was also obvious with relatively low specificity,especially in the early stage.

考虑应力和时间作用的高厨余含量生活垃圾的持水量预测模型:基于试验现象（英文）

目的:我国城市生活垃圾厨余含量高,导致初始含水量高,从而带来填埋场渗滤液水位高、堆体稳定性低、填埋气难以收集以及焚烧厂焚烧热值低、能耗大等问题。研究降解时间和上覆应力对高厨余垃圾持水量的影响,提出快速降低高厨余垃圾的持水量的方法,大幅减小进场(厂)垃圾的含水量,避免上述问题的发生。创新点:1.获得高厨余垃圾的持水量随降解时间和上覆应力的变化规律;2.建立考虑时间和应力作用的垃圾持水量预测模型。方法:1.通过开展试验,分析高厨余垃圾的持水量随降解时间和上覆应力的变化(图3和5);2.基于试验结果,分析持水量变化机理(图7),并建立持水量预测模型(公式6);3.通过对比分析多种脱水方案的计算结果,提出高厨余垃圾堆体的快速脱水方法(图13)。结论:1.高厨余垃圾的持水量随降解时间呈复合指数形式下降,随应力的对数线性下降;2.降解作用能够降低胞内水并增大孔隙水持有量,应力作用则同时降低胞内水和孔隙水持有量;3.持水量模型计算结果与工程案例实测结果吻合较好,并进一步提出了采取加速降解和增大应力相联合的措施以实现高厨余垃圾快速脱水的目的。

Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy

Background:CSF1R-related leukoencephalopathy,also known as hereditary diffuse leukoencephalopathy with spheroids(HDLS),is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor(CSF1R)gene mutation.Few of CSF1R mutations have been functionally testified and the pathogenesis remains unknown.Methods:In order to investigate clinical and pathological characteristics of patients with CSF1R-related leukoencephalopathy and explore the potential impact of CSF1R mutations,we analyzed clinical manifestations of 15 patients from 10 unrelated families and performed brain biopsy in 2 cases.Next generation sequencing was conducted for 10 probands to confirm the diagnosis.Sanger sequencing,segregation analysis and phenotypic reevaluation were utilized to substantiate findings.Functional examination of identified mutations was further explored.Results:Clinical and neuroimaging characteristics were summarized.The average age at onset was 35.9±6.4 years(range 24–46 years old).Younger age of onset was observed in female than male(34.2 vs.39.2 years).The most common initial symptoms were speech dysfunction,cognitive decline and parkinsonian symptoms.One patient also had marked peripheral neuropathy.Brain biopsy of two cases showed typical pathological changes,including myelin loss,axonal spheroids,phosphorylated neurofilament and activated macrophages.Electron microscopy disclosed increased mitochondrial vacuolation and disorganized neurofilaments in ballooned axons.A total of 7 pathogenic variants(4 novel,3 documented)were identified with autophosphorylation deficiency,among which c.2342C>T remained partial function of autophosphorylation.Western blotting disclosed the significantly lower level of c.2026C>T(p.R676*)than wild type.The level of microtubule associated protein 1 light chain 3-II(LC3-II),a classical marker of autophagy,was significantly lower in mutants expressed cells than wild type group by western blotting and immunofluorescence staining.Conclusions:Our findings support the loss-of-function and haploinsufficiency hypothesis in pathogenesis.Autophagy abnormality may play a role in the disease.Repairing or promoting the phosphorylation level of mutant CSF1R may shed light on therapeutic targets in the future.However,whether peripheral polyneuropathy potentially belongs to CSF1R-related spectrum deserves further study with longer follow-up and more patients enrolled.