BACKGROUND Noonan syndrome is a relatively common autosomal dominant genetic disorder characterized by cardiovascular defects owing to functional abnormalities in key genes such as RAF1.Mutations in RAF1 are typically...BACKGROUND Noonan syndrome is a relatively common autosomal dominant genetic disorder characterized by cardiovascular defects owing to functional abnormalities in key genes such as RAF1.Mutations in RAF1 are typically associated with hypertrophic cardiomyopathy(HCM).However,in this case,the patient exhibited atrial and ventricular septal defects(VSDs).CASE SUMMARY This case report describes an 11-year-old boy diagnosed with Noonan syndrome,in whom genetic testing revealed a c.770C>T(p.Ser257 Leu)mutation in RAF1.The patient presented with intermittent chest discomfort and shortness of breath,symptoms that significantly worsened after physical activity.Clinical evaluation revealed marked growth retardation and multiple physical abnormalities.Electrocardiographic and echocardiographic assessments revealed VSDs,atrial septal defects,and left ventricular outflow tract obstruction.Following multidisciplinary consultation,the patient underwent cardiac surgical intervention,which led to clinical improvement;however,they subsequently developed a third-degree atrioventricular block,necessitating the implantation of a permanent pacemaker.During follow-up,echocardiographic findings demonstrated near-complete resolution of the shunt across the atrial and ventricular septa,significant improvement in left ventricular outflow tract obstruction,and notable reduction in ventricular septal thickness.A genetic mutation at the c.770C>T(p.Ser257 Leu)locus of RAF1 is typically associated with HCM and pulmonary hypertension.However,this patient’s clinical phenotype manifested as HCM,atrial septal defect,and VSD,suggesting that this mutation may involve a different pathophysiological mechanism.CONCLUSION This case confirms the genotype-phenotype heterogeneity of Noonan syndrome and highlights the complex management requirements of RAF1 mutation-associated cardiac pathologies.Early surgical intervention can ameliorate structural defects,but it must be integrated with genetic counseling and lifelong monitoring to optimize patient outcomes.展开更多
Background:Glioma is the most common tumor of the central nervous system with a poor prognosis.This study aims to explore the role of calcium/calmodulin-dependent protein kinase IIβ(CAMK2B)in regulating the malignant...Background:Glioma is the most common tumor of the central nervous system with a poor prognosis.This study aims to explore the role of calcium/calmodulin-dependent protein kinase IIβ(CAMK2B)in regulating the malignant progression of glioma cells,as well as the molecular mechanisms underlying these malignant behaviors.Methods:The correlation between CAMK2B expression in gliomas and patient prognosis was analyzed using immunohistochemistry,quantitative reverse transcription polymerase chain reaction(qRT-PCR),and western blot.Furthermore,the study explored the role of CAMK2B in glioma cell proliferation,invasion,and migration using cell counting kit-8(CCK-8),5-Ethynyl-2′-deoxyuridine(EdU),wound healing,transwell,and in vivo tumor xenograft assays.Result:Patients with high CAMK2B expression exhibited significantly better prognostic outcomes compared to those with low expression levels.Furthermore,CAMK2B expression was significantly lower in glioma tissues and cells compared to both normal brain tissue and human astrocyte cell lines.Notably,overexpression of CAMK2B in glioma cells led to an approximate 40%reduction in proliferative capacity and a 60–70%decrease in invasive and migratory abilities,compared to control glioma cells.These differences were statistically significant at p<0.05.Conversely,knockdown of CAMK2B using siRNA-CAMK2B significantly enhanced the proliferative,invasive,and migratory capabilities of glioma cells in both in vitro and in vivo settings,enhancing these abilities by 1.5 to 3 times.Notably,these effects were reversed through the application of the Rat Sarcoma viral oncogene homolog(Ras)pathway inhibitor,Salirasib.Western blot analysis revealed that knockdown of CAMK2B led to activation of the Ras/Rapidly Accelerated Fibrosarcoma(Raf)/Mitogen-activated protein kinase kinase(MEK)/Extracellular signal-regulated kinase(ERK)signaling pathway in glioma cell lines,whereas overexpression of CAMK2B resulted in the suppression of this pathway.Conclusion:CAMK2B inhibits glioma proliferation,invasion,andmigration through the Ras/Raf/MEK/ERK signaling pathway.展开更多
背景与目的:细针穿刺细胞学(FNA)因所获取样本量较少等原因,其局限性包括标本无法诊断、细胞学结果不确定、假阴性及假阳性结果等,易造成患者漏诊或误诊。鼠类肉瘤滤过性毒菌致癌同源体B1(BRAF)突变作为甲状腺乳头状癌(PTC)的特异性生...背景与目的:细针穿刺细胞学(FNA)因所获取样本量较少等原因,其局限性包括标本无法诊断、细胞学结果不确定、假阴性及假阳性结果等,易造成患者漏诊或误诊。鼠类肉瘤滤过性毒菌致癌同源体B1(BRAF)突变作为甲状腺乳头状癌(PTC)的特异性生物标志,在FNA良性高风险结节中诊断价值目前研究较少。因此,本研究进一步探讨FNA良性甲状腺结节中附加BRAF^(V600E)基因突变检测的临床价值。方法:回顾性分析2019年1月—2022年9月吉林大学中日联谊医院甲状腺外科549例经668次超声提示PTC高风险、TIRADS分级为4~5类结节患者的临床资料。所有患者均接受手术治疗并于术后对切除组织进行石蜡病理学检查,根据纳入和排除标准,共84枚FNA良性结节纳入本研究,分析BRAF^(V600E)基因突变患者的临床病理特征;以术后病理结果为金标准,分析BRAF^(V600E)基因突变检测对FNA良性结节中的诊断效能。结果:84枚FNA良性甲状腺结节中,44枚(52.4%)BRAF^(V600E)基因突变检测阳性。BRAF^(V600E)基因突变阳性患者中年龄<45岁的患者占比明显高于BRAF^(V600E)基因突变阴性组患者(56.8%vs.35.0%,P=0.045)、结节中位长径明显小于BRAF^(V600E)基因突变阴性组(0.49 cm vs.0.61 cm,P=0.024)。术后病理提示,63枚甲状腺结节为PTC结节,21枚为良性结节;PTC组结节的中位长径小于良性结节(0.50 cm vs.0.70 cm,P=0.004)、结节<1 cm的占比高于良性结节组(95.2%vs.71.4%,P=0.007)、BRAF^(V600E)基因突变检出率高于良性组(68.3%vs.4.8%,P<0.001)。在甲状腺结节超声特征中,BRAF^(V600E)基因突变阳性组甲状腺结节边缘模糊/不规则发生率明显高于阴性组(86.4%vs.60.0%,P=0.006);PTC结节边缘模糊/不规则发生率高于良性结节(81.0%vs.52.4%,P=0.010)。多因素Logistic回归分析结果显示,BRAF^(V600E)基因突变阳性的甲状腺结节诊断为PTC的风险是BRAF^(V600E)基因突变阴性结节的39.184倍(P=0.001),BRAF^(V600E)基因突变阳性为甲状腺结节诊断为PTC结节的独立风险因素。BRAF^(V600E)基因突变检测诊断对PTC结节诊断的敏感度为69.3%、特异度为95.2%、阳性预测值为97.7%、阴性预测值为50.0%、准确率为75.0%。结论:BRAF^(V600E)基因突变检测具有良好的阳性预测值及准确率,可降低穿刺回报为良性结节中PTC结节的漏诊率。建议存在高度可疑超声特征的TIRADS分级为4~5类的甲状腺结节应常规进行FNA与BRAF^(V600E)基因突变联合检测。展开更多
基金Supported by the Gansu Provincial Science and Technology Plan Project,No.24JRRA886 and No.23JRRA1287Gansu Provincial People’s Hospital:Excellent Doctoral Student Cultivation Program,No.22GSSYD-14.
文摘BACKGROUND Noonan syndrome is a relatively common autosomal dominant genetic disorder characterized by cardiovascular defects owing to functional abnormalities in key genes such as RAF1.Mutations in RAF1 are typically associated with hypertrophic cardiomyopathy(HCM).However,in this case,the patient exhibited atrial and ventricular septal defects(VSDs).CASE SUMMARY This case report describes an 11-year-old boy diagnosed with Noonan syndrome,in whom genetic testing revealed a c.770C>T(p.Ser257 Leu)mutation in RAF1.The patient presented with intermittent chest discomfort and shortness of breath,symptoms that significantly worsened after physical activity.Clinical evaluation revealed marked growth retardation and multiple physical abnormalities.Electrocardiographic and echocardiographic assessments revealed VSDs,atrial septal defects,and left ventricular outflow tract obstruction.Following multidisciplinary consultation,the patient underwent cardiac surgical intervention,which led to clinical improvement;however,they subsequently developed a third-degree atrioventricular block,necessitating the implantation of a permanent pacemaker.During follow-up,echocardiographic findings demonstrated near-complete resolution of the shunt across the atrial and ventricular septa,significant improvement in left ventricular outflow tract obstruction,and notable reduction in ventricular septal thickness.A genetic mutation at the c.770C>T(p.Ser257 Leu)locus of RAF1 is typically associated with HCM and pulmonary hypertension.However,this patient’s clinical phenotype manifested as HCM,atrial septal defect,and VSD,suggesting that this mutation may involve a different pathophysiological mechanism.CONCLUSION This case confirms the genotype-phenotype heterogeneity of Noonan syndrome and highlights the complex management requirements of RAF1 mutation-associated cardiac pathologies.Early surgical intervention can ameliorate structural defects,but it must be integrated with genetic counseling and lifelong monitoring to optimize patient outcomes.
基金supported by the Natural Science Foundation of Hebei Province(H2021206037)the Government-funded Project on Training of Outstanding Clinical Medical Personnel of Hebei Province in the year 2021(303-16-20-06)the Medical Research Project of Hebei Provincial Health Commission(20230031).
文摘Background:Glioma is the most common tumor of the central nervous system with a poor prognosis.This study aims to explore the role of calcium/calmodulin-dependent protein kinase IIβ(CAMK2B)in regulating the malignant progression of glioma cells,as well as the molecular mechanisms underlying these malignant behaviors.Methods:The correlation between CAMK2B expression in gliomas and patient prognosis was analyzed using immunohistochemistry,quantitative reverse transcription polymerase chain reaction(qRT-PCR),and western blot.Furthermore,the study explored the role of CAMK2B in glioma cell proliferation,invasion,and migration using cell counting kit-8(CCK-8),5-Ethynyl-2′-deoxyuridine(EdU),wound healing,transwell,and in vivo tumor xenograft assays.Result:Patients with high CAMK2B expression exhibited significantly better prognostic outcomes compared to those with low expression levels.Furthermore,CAMK2B expression was significantly lower in glioma tissues and cells compared to both normal brain tissue and human astrocyte cell lines.Notably,overexpression of CAMK2B in glioma cells led to an approximate 40%reduction in proliferative capacity and a 60–70%decrease in invasive and migratory abilities,compared to control glioma cells.These differences were statistically significant at p<0.05.Conversely,knockdown of CAMK2B using siRNA-CAMK2B significantly enhanced the proliferative,invasive,and migratory capabilities of glioma cells in both in vitro and in vivo settings,enhancing these abilities by 1.5 to 3 times.Notably,these effects were reversed through the application of the Rat Sarcoma viral oncogene homolog(Ras)pathway inhibitor,Salirasib.Western blot analysis revealed that knockdown of CAMK2B led to activation of the Ras/Rapidly Accelerated Fibrosarcoma(Raf)/Mitogen-activated protein kinase kinase(MEK)/Extracellular signal-regulated kinase(ERK)signaling pathway in glioma cell lines,whereas overexpression of CAMK2B resulted in the suppression of this pathway.Conclusion:CAMK2B inhibits glioma proliferation,invasion,andmigration through the Ras/Raf/MEK/ERK signaling pathway.
文摘背景与目的:细针穿刺细胞学(FNA)因所获取样本量较少等原因,其局限性包括标本无法诊断、细胞学结果不确定、假阴性及假阳性结果等,易造成患者漏诊或误诊。鼠类肉瘤滤过性毒菌致癌同源体B1(BRAF)突变作为甲状腺乳头状癌(PTC)的特异性生物标志,在FNA良性高风险结节中诊断价值目前研究较少。因此,本研究进一步探讨FNA良性甲状腺结节中附加BRAF^(V600E)基因突变检测的临床价值。方法:回顾性分析2019年1月—2022年9月吉林大学中日联谊医院甲状腺外科549例经668次超声提示PTC高风险、TIRADS分级为4~5类结节患者的临床资料。所有患者均接受手术治疗并于术后对切除组织进行石蜡病理学检查,根据纳入和排除标准,共84枚FNA良性结节纳入本研究,分析BRAF^(V600E)基因突变患者的临床病理特征;以术后病理结果为金标准,分析BRAF^(V600E)基因突变检测对FNA良性结节中的诊断效能。结果:84枚FNA良性甲状腺结节中,44枚(52.4%)BRAF^(V600E)基因突变检测阳性。BRAF^(V600E)基因突变阳性患者中年龄<45岁的患者占比明显高于BRAF^(V600E)基因突变阴性组患者(56.8%vs.35.0%,P=0.045)、结节中位长径明显小于BRAF^(V600E)基因突变阴性组(0.49 cm vs.0.61 cm,P=0.024)。术后病理提示,63枚甲状腺结节为PTC结节,21枚为良性结节;PTC组结节的中位长径小于良性结节(0.50 cm vs.0.70 cm,P=0.004)、结节<1 cm的占比高于良性结节组(95.2%vs.71.4%,P=0.007)、BRAF^(V600E)基因突变检出率高于良性组(68.3%vs.4.8%,P<0.001)。在甲状腺结节超声特征中,BRAF^(V600E)基因突变阳性组甲状腺结节边缘模糊/不规则发生率明显高于阴性组(86.4%vs.60.0%,P=0.006);PTC结节边缘模糊/不规则发生率高于良性结节(81.0%vs.52.4%,P=0.010)。多因素Logistic回归分析结果显示,BRAF^(V600E)基因突变阳性的甲状腺结节诊断为PTC的风险是BRAF^(V600E)基因突变阴性结节的39.184倍(P=0.001),BRAF^(V600E)基因突变阳性为甲状腺结节诊断为PTC结节的独立风险因素。BRAF^(V600E)基因突变检测诊断对PTC结节诊断的敏感度为69.3%、特异度为95.2%、阳性预测值为97.7%、阴性预测值为50.0%、准确率为75.0%。结论:BRAF^(V600E)基因突变检测具有良好的阳性预测值及准确率,可降低穿刺回报为良性结节中PTC结节的漏诊率。建议存在高度可疑超声特征的TIRADS分级为4~5类的甲状腺结节应常规进行FNA与BRAF^(V600E)基因突变联合检测。
