11^C-蛋氨酸的体内生物学分布和初步临床应用

目的研究新型脑肿瘤显像剂：11^C-蛋氨酸（11^C-MET）的体内生物学分布，探讨11^C—MET的临床显像方法及其在脑肿瘤显像中的应用．方法测定11^C—MET在小鼠体内的分布，对健康志愿者和病理证实胶质瘤患者进行PET脑显像．结果小鼠体内分布实验和脑PET显像发现，11^C—MET在血液中清除较慢，在肿瘤内有较长的滞留时问，平台期位于30—45min之间，延迟相对有利于脑瘤的显像，其余放射性主要集中在消化系统．结论11^C—MDT有较高的肿瘤／脑比值，是理想的脑肿瘤显像剂．     

Macrofollicular Variant of Follicular Thyroid Carcinoma (MV-FTC) with a Somatic DICER1 Gene Mutation: Case Report and Review of the Literature

Benign thyroid lesions such as multinodular goiter and adenomatoid nodules are well-circumscribed lesions displaying a macrofollicular growth pattern and lack of nuclear atypia. The highly unusual macrofollicular variant of follicular thyroid carcinoma (MV-FTC) mirrors these attributes and is thereby misclassified by cytological examination of fine-needle aspiration biopsies. The MV-FTC diagnosis is instead suggested following histological investigation, in which malignant attributes, most commonly capsular invasion, are noted. The bulk of MV-FTCs described in the literature arise in younger female patients and carry an excellent prognosis. A recent coupling to mutations in the DICER1 tumor suppressor gene has been proposed, possibly indicating aberrancies in micro-RNA (miRNA) patterns as responsible of the tumorigenic process. We describe the cytological, histological and molecular phenotype of a 35 mm large MV-FTC arising in the right thyroid lobe of a 33-year-old female with a family history of multinodular goiter. The tumor was encapsulated and strikingly inconspicuous in terms of cellularity and atypia, but nevertheless displayed multiple foci with capsular invasion. A next-generation molecular screening of tumor DNA revealed missense variants in DICER1 (p. D1709N) and MET (p. T1010I), but no established fusion gene events. After sequencing of germline DNA, the DICER1 mutation was confirmed as somatic, while the MET variant was constitutional. The patient is alive and well, currently awaiting radioiodine treatment. This MV-FTC mirrors previous publications, suggesting that these tumors carry a favorable prognosis and predominantly arise in younger females. Moreover, DICER1 mutations should be considered a common driver event in the development of MV-FTCs.     

Overview: Cellular plasticity,cancer stem cells and metastasis

Recently, a number of hypotheses have converged into a unified theoretical framework which addresses the most vexing aspects of cancer: metastasis, relapse and therapeutic resistance. The central component of this framework is the new paradigm of cellular differentiation, once viewed as a unidirectional process, but now recognized as a plastic process in which cancer cells can dedifferentiate into more primitive, stem-like phenotypes. This plasticity is controlled by both intrinsic biochemical processes and bi-directional environmental cues involving cancer-associated non-cancerous cells. Such plastic phenotypic shifts may influence the discontinuous behavior of cancers, in which some cancers remain dormant for months or years after therapy, only to relapse and wreak havoc. This Special Issue of Cancer Letters assembles a collection of mini-reviews describing the current knowledge of cellular plasticity and its relationship to cancer “stemness” and progression, illuminating how progress in this field may yield major benefits in overcoming resistance and thwarting metastasis.     

抗ENO1抗体联合二甲双胍通过靶向肿瘤干细胞逆转人非小细胞肺癌A549细胞对西妥昔单抗的抵抗

目的:探究抗烯醇化酶1 (enolase 1,ENO1)抗体、二甲双胍(metformin,MET)通过靶向肿瘤干细胞对西妥昔单抗(cetuximab,CTX)耐药型非小细胞肺癌A549细胞增殖、迁移、侵袭和干性的影响及其可能的作用机制.方法:10 mmol/L MET联合40μg/ml抗ENO1抗体处理CTX(35 ...     

新药物辅助排石疗法在输尿管下段结石的临床研究

目的探讨新药物辅助排石疗法（α1-RB＋NSAIDs）在治疗输尿管下段结石的作用。方法输尿管下段结石患者120例,随机平分为3组。每组患者皆应用左氧氟沙星0.2g,2次/d;吲哚美辛栓1枚,塞肛2次/d;对照组患者加用中成药结石通1.0g,3次/d;组2在对照组基础上加服硝苯地平10mg,3次/d;组3在对照组基础上加服萘哌地尔25mg,2次/d。以结石排出输尿管或治疗随访期满2周为疗效观察终点。结果3组均无因发生药物不良反应而退出研究者。3组患者的平均年龄、性别比例、结石大小比较差异均无统计学意义（P〉0.05）。2周内排出结石者组：组1为15例（37.5%）,组2为28例（70%）,组3为37例（92.5%）。组2、组3与组1的排石率比较有统计学意义（P〈0.05）,而组2与组3间排石率亦有统计学意义（P〈0.05）。组1-组3平均排石时间分别为9d,8d和4d：组1与组3比较差异有统计学意义（P〈0.05）,组2与组1、组3比较差异无统计学意义（P〉0.05）。2周内肾绞痛再次发作：组1有8例（20%）,组2有5例（12.5%）,组3为0例,经肌注酮络酸氨丁三醇30mg或哌替啶50mg后缓解。3组间比较差异有统计学意义（P〈0.05）。结论新药物辅助排石疗法可明显提高输尿管下段结石的排出率,缩短结石排出时间,减少肾绞痛发作概率,可作为输尿管下段结石药物治疗的一线选择。     

Contribution of Cardiorespiratory Fitness to the Obesity Paradox

Until recently, cardiorespiratory fitness (CRF) has been overlooked as a potential modifier of the inverse association between obesity and mortality (the so-called obesity paradox), observed in patients with known or suspected cardiovascular (CV) disease. Evidence from five observational cohort studies of 30,104 patients (87% male) with CV disease indicates that CRF significantly alters the obesity paradox. There is general agreement across studies that the obesity paradox persists among patients with low CRF, regardless of whether adiposity is assessed by body mass index, waist circumference, or percentage body fat. However, among patients with high CRF, risk of all-cause mortality is lowest for the overweight category in some, but not all, studies, suggesting that higher levels of fitness may modify the relationship between body fatness and survival in patients manifesting an obesity paradox. Further study is needed to better characterize the joint contribution of CRF and obesity on mortality in diverse populations.     

MET receptor is a potential therapeutic target in high grade cervical cancer

Cervical cancer is one of the leading causes of death among women suffering from tumors. Current treatment options are insufficient. Here, we investigated the MET receptor as a potential molecular target in advanced cervical cancer. Downregulation of MET receptor expression via RNA interference in different cervical carcinoma cell lines dramatically decreased tumor growth and forced tumor differentiation in vivo. MET receptor silencing also led to a dramatic decrease in cell size and a decrease in proliferation rate under normal and stress conditions. MET receptor downregulation also resulted in decreased cyclin D1 and c-myc levels but did not increase apoptosis. Subsequent experiments showed that downregulation of the MET receptor decreased the expression of a key regulator of the epithelial-to-mesenchymal transition, SLUG. and increased the expression of E-cadherin, a hallmark of the epithelial phenotype. Moreover, MET downregulation impairs expression and signaling of CXCR4 receptor, responsible for invasive phenotype.Taken together, our results strongly suggest that the MET receptor influences the oncogenic properties of cervical carcinoma cells in vitro and in vivo. These findings highlight a unique role of the MET receptor in cervical carcinoma cells and indicate the MET receptor as a potential therapeutic target for advanced cervical carcinoma.     

Acquired MET D1228N Mutations Mediate Crizotinib Resistance in Lung Adenocarcinoma with ROS1 Fusion: A Case Report

Patients with non‐small cell lung cancer (NSCLC) containing ROS1 fusions can have a marked response to the ROS1‐targeted tyrosine kinase inhibitors (TKIs), such as crizotinib. Common resistance mechanisms of ROS1‐fusion targeted therapy are acquired mutations in ROS1. Along with the use of next‐generation sequencing in the clinical management of patients with NSCLC during sequential targeted therapy, many mechanisms of acquired resistance have been discovered in patients with activated tyrosine kinase receptors. Besides acquired resistance mutations, bypass mechanisms of resistance to epidermal growth factor receptor (EGFR)‐TKI treatment are common in patients with EGFR mutations. Here we describe a patient with metastatic lung adenocarcinoma with CD74‐ROS1 fusion who initially responded to crizotinib and then developed resistance by the acquired mutation of D1228N in the MET kinase domain, which showed short‐term disease control for cabozantinib.Key Points

• The D1228N point mutation of MET is an acquired mutation for crizotinib resistance.
• The patient obtained short‐term clinical benefit from cabozantinib therapy after resistance to crizotinib.
• The clinical use of next‐generation sequencing could maximize the benefits of precision medicine in patients with cancer.

     

Wound healing potential of a dimeric InlB variant analyzed by in vitro experiments on re-epithelialization of human skin models

A constitutively dimeric truncated variant of internalin B (InlB₃₂₁-CD), acting as stimulator of the receptor tyrosine kinase MET, was tested for dermal wound-healing potential. Due to a lack of the endogenous MET agonist HGF/SF in chronic wounds, HGF/SF substitution by an InlB₃₂₁-CD-loaded hydrogel might be beneficial in chronic wound therapy.In this study, InlB₃₂₁-CD in solution and incorporated in a hydrogel was tested for mitogenic effects on immortalized human dermal keratinocytes (HaCaT) with an MTT assay. Cell migration was investigated with a scratch assay on primary keratinocytes (PHK) and on HaCaT. For the latter, scratching needed to be mitomycin C-controlled. InlB₃₂₁-CD effects on a model of human skin were analyzed histologically with respect to viability.InlB₃₂₁-CD led to dose-dependent proliferative effects on HaCaT cells whereas the equimolar dose of monomeric InlB₃₂₁ did not. Upon hydrogel incorporation of InlB₃₂₁-CD its mitogenic activity for HaCaT cells was maintained thus confirming the hydrogel as a promising drug delivery system. Motogenic effects were shown on both HaCaT and PHK cells. InlB₃₂₁-CD neither possesses cytotoxic effects on the viability of a human skin model nor alters its organotypic cell morphology.