肺浸润性黏液腺癌1例报告及文献复习

目的：探讨肺浸润性黏液腺癌（IMAs）患者的临床特征、诊断方法和治疗过程,提高临床医生对IMAs的认识。方法：收集1例IMAs患者的一般资料、影像学表现和治疗方案,并进行相关文献复习。结果：患者,女性,42岁,因咳嗽和咳痰入院,CT检查显示双肺斑片状影,因疑似双肺肺炎行抗感染治疗后症状未见好转,经支气管镜肺活检术（TBLB）及胸水脱落细胞检测结果均为炎性表现,后经皮穿刺活检病理回报为IMAs。基因检测结果为KRAS外显子2点突变。行紫杉醇加卡铂并联合应用血管靶向药物贝伐珠单抗化疗后,患者临床症状明显改善,肺部影像学表现明显改变。结论：IMAs是一种特殊病理类型的肺腺癌（ADCs）,该类患者影像学表现多样,基因表达特殊,治疗原则与其他类型ADCs不同。     

Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease

Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor (P < 0.0001), more severe postural tremor (P < 0.0001), and more severe kinetic tremor (P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration (mnd2) mice. HTRA2 p.G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.Essential tremor is one of the most frequent movement disorders in humans (1). It is characterized primarily by postural or kinetic tremor of the arms and hands, but head, legs, voice, and other regions of the body may also be affected (2). The worldwide prevalence is 0.9%, increasing to more than 4% in elderly populations (1). Familial essential tremor is genetically heterogeneous. Genetic linkage studies of multiply affected families revealed three genomic regions segregating with the condition, on chromosomes 3q13 [ETM1; Online Mendelian Inheritance in Man (OMIM) 190300], 2p22-24 (ETM2; OMIM 602134), and 6p23 (ETM3; OMIM 611456) (3–5). No clearly causal mutations have been identified in these regions, although the common variant DRD3 p.S9G in the ETM1 region has been proposed as a risk factor and HS1BP3 p.A265G in the ETM2 region appeared in two multiply affected families (6, 7). Genomewide association studies of essential tremor reported associations with common variants in an intron of LINGO1 and in an intron of SLC1A2 (8–10). Recently, DNAJC13 p.N855S, which had been identified in Parkinson disease patients, was also found in two unrelated patients with essential tremor (11). Nonsense mutation p.Q290X in the RNA-binding protein FUS was identified by whole exome sequencing in a large family with essential tremor (ETM4; OMIM 614782) (12). Screening other subjects with essential tremor for FUS revealed two rare missense variants, suggesting that mutations in FUS explain a subset of cases with the condition (13, 14).In this study, we examined a six-generation family segregating essential tremor, and in multiple relatives, essential tremor as a feature of Parkinson disease. We carried out whole exome sequencing of genomic DNA from three severely affected family members and subsequent pedigree analysis to identify the genetic basis of essential tremor and Parkinson disease in the family.     

The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: Clinical manifestations and long-term follow-up

Objective

To analyze the clinical manifestations and response to treatment in a cohort of adult patients presenting with recurrent inflammatory attacks and carrying low-penetrance TNFRSF1A variants, as well as to provide data on their long-term follow-up.

Methods

We performed a retrospective chart review of 36 patients carrying low-penetrance TNFRSF1A variants. Moreover, 60 genetically negative patients treated for recurrent inflammatory attacks and 13 patients with structural TNFRSF1A mutations were also analyzed. Detailed demographic and clinical data were collected at the time of molecular screening and at each follow-up visit. Treatments and markers of inflammation were also assessed.

Results

Individuals with low-penetrance TNFRSF1A variants have a lower family history for inflammatory attacks and present with a later disease onset compared with patients with structural mutations, but do not differ, in this respect, with genetically negative individuals. Moreover, low-penetrance variants are less frequently associated with a chronic disease course, with clinical manifestations such as abdominal pain and myalgia, and with amyloidosis. A distinctive clinical feature is a higher rate of pericarditis. Interestingly, mutation-negative patients were found to present with a significant history of recurrent pharyngitis during childhood. Patients with low-penetrance variants are mostly managed with short courses of steroids or non-steroidal anti-inflammatory drugs on attacks. Although the need for a biological treatment is significantly lower compared with patients with structural mutations, still approximately 20% of individuals with recurrent inflammatory attacks carrying low-penetrance variants ultimately require these therapies.

Conclusions

Our study confirms that low-penetrance TNFRSF1A variants can be associated with an autoinflammatory phenotype. Although a chronic disease course is rarely observed, some patients ultimately benefit from a biological treatment.     

早期反应基因在宫颈癌中表达及其与人乳头瘤病毒感染的关系

目的探讨早期反应基因(Iex-1)在宫颈癌中表达及与人乳头瘤病毒(HPV)感染的关系。方法病理科留存的宫颈病变组织石蜡包块61份,免疫组化法检测宫颈良性病变、宫颈上皮内瘤变、宫颈癌组织中Iex-1表达,分析Iex-1表达与宫颈癌临床病理特征的关系。培养3种不同HPV感染情况的宫颈癌细胞株C-33A(HPV-)、SIHA(HPV16+)、HELA(HPV18+),实时定量聚合酶链反应(RT-PCR)法和Western印迹法检测各宫颈癌细胞株中Iex-1 mRNA和蛋白表达;使用siRNA靶向沉默SIHA细胞中E6后检测Iex-1 mRNA和蛋白表达,分析其与HPV感染的关系。结果宫颈良性病变、宫颈上皮内瘤变、宫颈癌组织中Iex-1表达阳性率依次下降,差异有统计学意义(P<0.01)。分化程度为G1~G2的宫颈癌患者Iex-1阳性率明显高于分化程度为G3的患者(P<0.05);无宫旁浸润、有淋巴结转移的宫颈癌患者Iex-1阳性率明显高于宫旁浸润、无淋巴结转移的患者(P<0.05)。C-33A细胞株Iex-1 mRNA表达水平明显高于SIHA、HELA细胞株(P<0.01);C-33A细胞株Iex-1蛋白表达水平明显高于SIHA、HELA细胞株(P<0.01)。SIHA细胞株和HELA细胞株Iex-1 mRNA和蛋白表达差异无统计学意义(P>0.05)。干扰组SIHA细胞中E6 mRNA和蛋白表达水平明显低于空白对照组、阴性对照组(P<0.05);干扰组SIHA细胞中Iex-1 mRNA和蛋白表达水平明显高于空白对照组、阴性对照组(P<0.05)。空白对照组与阴性对照组E6 mRNA和蛋白、Iex-1 mRNA和蛋白表达水平差异无统计学意义(P>0.05)。结论Iex-1在宫颈癌组织中低表达,且表达水平与宫颈癌病变程度呈负相关;HPV可能经E6蛋白参与调控的信号通路下调了Iex-1表达,促进宫颈癌发展与转移;首次提出了抑制Iex-1的促凋亡作用可能为HPV诱发宫颈癌的新通路。