NOTCH3基因C260S位点突变导致CADASIL的临床和影像学特征分析

目的探讨NOTCH3基因第5外显子C260S位点突变导致的伴有皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病(cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy,CADASIL)家系的临床和影像学特征。方法选取2021年12月首都医科大学附属北京同仁医院来自同一家庭的CADASIL患者,对所有患者进行NOTCH3基因测序,回顾性分析患者的临床表现和头颅影像学特征。复习既往文献报道的导致同一位置氨基酸改变的其他突变类型的临床及影像学特征。结果4名家庭成员中,包括先证者(46岁,女)及其两个姐姐(分别为48岁和50岁)和女儿(18岁)。先证者及其父亲、两个姐姐都有偏头痛病史,其中大姐有记忆力减退;先证者患有脑梗死及伴有视觉先兆的偏头痛;先证者女儿体健;先证者父亲因脑梗死去世。4名家庭成员均存在C260S位点的NOTCH3基因突变。既往文献无此位点突变的报道,先证者头颅MRI示右侧脑桥亚急性梗死,颞叶、脑室周围及脑干异常高信号改变,其大姐脑桥可见腔隙性梗死灶。结论NOTCH3基因第5外显子c.778T>A(p.C260S)的罕见突变导致的CADASIL发病时间早,早期会出现认知障碍。合并偏头痛的脑干梗死患者,需警惕CADASIL的可能。

Prognostic significance and relationship of SMAD3 phosphoisoforms and VEGFR-1 in gastric cancer:A clinicopathological study

BACKGROUND The TGF-β/SMAD3 and VEGFR-1 signaling pathways play important roles in gastric cancer metastasis.SMAD3 phosphorylation is a crucial prognostic marker in gastric cancer.AIM To determine the prognostic value and relationship of SMAD3 phospho-isoforms and VEGFR-1 in gastric cancer.METHODS This was a single-center observational study which enrolled 98 gastric cancer patients and 82 adjacent normal gastric tissues from patients aged 32-84 years(median age 65)between July 2006 and April 2007.Patients were followed up until death or the study ended(median follow-up duration of 28.5 mo).The samples were used to generate tissue microarrays(TMAs)for immunohistochemical(IHC)staining.The expressions of TGF-β1,pSMAD3C(S423/425),pSMAD3L(S204),and VEGFR-1 in gastric cancer(GC)tumor tissue and normal tissue were measured by IHC staining using TMAs obtained from 98 GC patients.Prognosis and survival information of the patients was recorded by Outdo Biotech from May 2007 to July 2015.The relationship between TGF-β1,pSMAD3C(S423/425),pSMAD3L(S204),and VEGFR-1 protein expression levels was analyzed using Pearson's correlation coefficient.The relationship between protein expression levels and clinicopathological parameters was analyzed using the Chi-squared test.A survival curve was generated using the Kaplan-Meier survival analysis.RESULTS TGFβ-1 and VEGFR-1 expression was significantly upregulated in gastric cancer tissue compared to adjacent noncancerous tissue.The positive expression of phosphorylated isoforms of Smad3 varied depending on the phosphorylation site[pSMAD3C(S423/425):51.0%and pSMAD3L(S204):31.6%].High expression of pSMAD-3L(S204)was significantly correlated with larger tumors(P=0.038)and later N stages(P=0.035).Additionally,high expression of VEGFR-1 was closely correlated with tumor size(P=0.015)and pathological grading(P=0.013).High expression of both pSMAD3L(S204)and VEGFR-1 was associated with unfavorable outcomes in terms of overall survival(OS).Multivariate analysis indicated that high expression of pSMAD3L(S204)and VEGFR-1 were independent risk factors for prognosis in GC patients.VEGFR-1 protein expression was correlated with TGF-β1(r=0.220,P=0.029),pSMAD3C(S423/425)(r=0.302,P=0.002),and pSMAD3L(S204)(r=0.201,P=0.047),respectively.Simultaneous overexpression of pSMAD3L(S204)and VEGFR-1 was associated with poor OS in gastric cancer patients.CONCLUSION Co-upregulation of pSMAD3L(S204)and VEGFR-1 can serve as a predictive marker for poor gastric cancer prognosis,and pSMAD3L(204)may be involved in enhanced gastric cancer metastasis in a VEGFR-1-dependent manner.

双子星——MSI S260C/S425

作为12.1英寸超轻薄笔记本，微星260C的“身子板”可不脆弱，镁铝合金底壳将轻便与防震融为一体，同时外观还相当讨巧，仅重1.78kg的它可以轻松放置在商务白领，女士的手提包里，让商务旅行，移动办公都变得轻松自如。

Smad3 and its phosphoisoforms are prognostic predictors of hepatocellular carcinoma after curative hepatectomy

BACKGROUND:Progression of hepatocellular carcinoma (HCC) often leads to vascular invasion and intrahepatic metastasis,which correlate with recurrence after surgical treatment and poor prognosis.HCC may be an unusual cancer affected by continuous inflammation that can lead to consistent upregulation of transforming growth factor-β (TGF-β).Chronic inflammation shifts hepatocytic TGF-β signaling from the tumor-suppressive pSmad3C pathway to the oncogenic pSmad3L pathway.In this study,we investigated the functional roles of Smad3 and its phosphoisoforms in the progression of HCC.METHODS:Tumor tissue microarrays of samples from 272 HCC patients who underwent curative surgical resection were used to detect the expression of Smad3,Smad4,pSmad3C (S423/425),pSmad3L (T179),pSmad3L (S204),and pSmad3L (S213).Disease-specific death was defined as 1) tumor occupying more than 80% of the liver,2) portal venous tumor thrombus (PVTT) proximal to the second bifurcation,3) obstructive jaundice due to tumor,4) distant metastases,or 5) variceal hemorrhage with PVTT proximal to the first bifurcation.At the time of analysis,tumor recurrence was detected in 184 (67.6%) patients,and 96 (35.3%) had died of HCC.RESULTS:Nuclear and cytoplasmic localization of Smad3,and nuclear localization of Smad4 were observed in 18.0%,9.9%,and 9.2% of HCCs,respectively.The rates of Smad3 phosphoisoform-immunoreactive HCC varied according to the location of phosphorylation:pSmad3C (S423/425) 8.1%,pSmad3L (T179) 2.6%,pSmad3L (S204) 2.2%,and pSmad3L (S213) 10.3%.Multivariate analyses revealed that pSmad3C (S423/425) (P=0.022) was an independent predictor of longer recurrence-free survival.pSmad3L (S213) (P=0.006),intrahepatic metastasis,multicentric occurrence,and liver cirrhosis were independent predictors of shorter recurrence- free survival.Cytoplasmic Smad3 (P=0.006),larger tumor size,and intrahepatic metastasis were independent predictors of shorter disease-specific survival.Only pSmad3L (S213) did not show an unfavorable influence on recurrence-free survival (P=0.331) on univariate analysis.CONCLUSIONS:pSmad3C (S423/425),pSmad3L (S213),and Smad3 may be predictors of prognosis in HCC patients after curative hepatectomy.pSmad3C (S423/425) and pSmad3L (S213) may be used as immunohistochemical biomarkers to identify patients with a high risk of recurrence.