Further delineation of the KBG syndrome caused by ANKRD11 aberrations

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.     

LOXL2 induces aberrant acinar morphogenesis via ErbB2 signaling

Introduction

Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has been shown to play a key role in invasion and metastasis of breast carcinoma cells. However, very little is known about its role in normal tissue homeostasis. Here, we investigated the effects of LOXL2 expression in normal mammary epithelial cells to gain insight into how LOXL2 mediates cancer progression.

Methods

LOXL2 was expressed in MCF10A normal human mammary epithelial cells. The 3D acinar morphogenesis of these cells was assessed, as well as the ability of the cells to form branching structures on extracellular matrix (ECM)-coated surfaces. Transwell-invasion assays were used to assess the invasive properties of the cells. Clinically relevant inhibitors of ErbB2, lapatinib and Herceptin (traztuzumab), were used to investigate the role of ErbB2 signaling in this model. A retrospective study on a previously published breast cancer patient dataset was carried out by using Disease Specific Genomic Analysis (DSGA) to investigate the correlation of LOXL2 mRNA expression level with metastasis and survival of ErbB2-positive breast cancer patients.

Results

Fluorescence staining of the acini revealed increased proliferation, decreased apoptosis, and disrupted polarity, leading to abnormal lumen formation in response to LOXL2 expression in MCF10A cells. When plated onto ECM, the LOXL2-expressing cells formed branching structures and displayed increased invasion. We noted that LOXL2 induced ErbB2 activation through reactive oxygen species (ROS) production, and ErbB2 inhibition by using Herceptin or lapatinib abrogated the effects of LOXL2 on MCF10A cells. Finally, we found LOXL2 expression to be correlated with decreased overall survival and metastasis-free survival in breast cancer patients with ErbB2-positive tumors.

Conclusions

These findings suggest that LOXL2 expression in normal epithelial cells can induce abnormal changes that resemble oncogenic transformation and cancer progression, and that these effects are driven by LOXL2-mediated activation of ErbB2. LOXL2 may also be a beneficial marker for breast cancer patients that could benefit most from anti-ErbB2 therapy.     

中西医结合医院单病种的质量管理及其作用

针对中西医结合医院单病种质量评定没有现成的、规范的标准的现状,就中西医结合单病种的质量管理方法及其在中西医结合医院建设中的作用进行了论述。     

Early stage nasopharyngeal carcinoma: radiotherapy dose and time factors in tumor control

OBJECTIVE: To evaluate radiotherapy dose and length of treatment in the control of early stage nasopharyngeal carcinoma (NPC) treated with a combination of external radiotherapy and brachytherapy, MATERIALS & METHODS: We reviewed the records of 133 patients with early stage nasopharyngeal carcinoma (stage I or II, AJC/UICC staging system) who received definitive radiotherapy in Chang Gung Memorial Hospital from 1979 to 1991. The median follow-up time was 7.1 years with a minimum of 2 years. All patients were treated with megavoltage external radiotherapy to the nasopharynx area (63-72 Gy) followed by high dose rate intracavitary brachytherapy (5-16.5 Gy in one to three fractions, spaced 1-2 weeks apart). The median total dose and time of irradiation was 75 Gy (69.8-81.4 Gy) and 11.6 weeks (7.8-20 weeks) respectively. Survival analysis was used to examine the effect of several variables on prognosis. RESULTS: The 5-year rates were 86.4% for local control, 84.7% for disease free survival, 88.5% for actuarial survival and 84.2% for overall survival. The treatment group (combination of time and dose of irradiation) was the most important prognostic factor according to Cox's proportional hazard model. Patients receiving radiation at a total dose of < or = 75 Gy completed in < 12 weeks showed the best prognosis. CONCLUSION: Treatment time and total treatment dose are both important factors in treating early stage NPC. Decreasing the total radiation time to < 12 weeks and not exceeding a radiation dose of 75 Gy gave the best results.      

高速逆流色谱在天然产物分离中的应用——紫杉烷类二萜及二萜生物碱的制备分离

高速逆流色谱是一种新发展起来的无载体的液液分配色谱技术。它利用聚四氟乙烯(PTFE)螺旋管的方向性与高速行星式运动相结合,产生一种独特的流体动力学现象,使互不相溶的两相溶液在螺旋管中充分混合,顺序传递,导致样品中各个组分由于分配系数的差别而有效的分离。本文介绍了国产的高速逆流色谱仪及应用该仪器制备分离云南红豆杉中结构相近的三种紫杉烷类二萜及二萜生物碱。     

雷公藤红素对IL-1和IL-2活性及PGE2释放的抑制作用

雷公藤红素0.1～1.0μg/ml在试管内能降低LPS诱导的小鼠腹腔巨噬细胞外和细胞内白细胞介素-1(IL-1)的活性,也能抑制ConA诱导的小鼠脾细胞产生白细胞介素-2(IL-2).动态观察表明,雷公藤红素经预处理8h和3h后已能分别抑制IL-1和IL-2的产生。此外,雷公藤红素能降低A23187刺激家兔滑膜细胞释放前列腺素E₂(PGE₂)。     

巫山淫羊藿的化学研究

从小檗科Berberidaceae淫羊藿属Epimedium植物巫山淫羊藿Epimedium wushanense T.S.Ying的地上部分中分得两种黄酮甙单体,经理化性质鉴定及紫外、红外、质谱、氢谱、碳谱等光谱分析,确定甙Ⅰ是新化合物,命名为巫山淫羊藿甙(wushanicariin)。甙Ⅱ是已知化合物淫羊藿甙(icariin),系首次从该种植物中分离。     

保元强肾Ⅱ号胶囊对慢性肾功能衰竭肾小管间质损伤的临床研究

目的:探讨中药保元强肾Ⅱ号胶囊对慢性肾功能衰竭(CRF)的疗效及机理。方法:60例CRF患者随机分为保元强肾Ⅱ号胶囊加洛汀新组(治疗组,30例)及必需氨基酸加洛汀新组(对照组,30例),观察肾功能及肾小管标志蛋白的改变。结果:治疗组显效率及总有效率分别为633%及933%;对照组分别为300%及567%,治疗组疗效明显优于对照组(P<001);治疗组治疗后BUN、SCr及CCr均较治前明显改善,尿视黄醇结合蛋白、尿β2微球蛋白及尿N乙酰氨基葡萄糖苷酶均比治疗前显著降低,TammHorfau蛋白比治疗前显著增高(P<001或P<005)。结论:保元强肾Ⅱ号胶囊对肾小管间质损伤有明显的改善作用,从而改善肾功能,提高疗效。     

Pathway analysis of gene signatures predicting metastasis of node-negative primary breast cancer

Background  

Published prognostic gene signatures in breast cancer have few genes in common. Here we provide a rationale for this observation by studying the prognostic power and the underlying biological pathways of different gene signatures.