BACKGROUND & AIMS: BACKGROUND:The combination of inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) is recommended by treatment guidelines for the treatment of persistent asthma. Two such combination products, salmeterol/fluticasone propionate (SFC, Seretide GSK, UK) and formoterol/budesonide (FBC, Symbicort, AstraZeneca, UK) are commercially available. OBJECTIVES:The purpose of these studies was to evaluate and compare the duration of bronchodilation of both combination products up to 24 hours after a single dose. METHODS:Two randomised, double blind, placebo-controlled, crossover studies were performed. Study A was conducted in 33 asthmatic adults receiving 400-1200 mcg of budesonide or equivalent. Serial forced expiratory volume in one second (FEV1) was measured over 24 hours to determine the duration of effect of both SFC (50/100 mcg) and FBC (4.5/160 mcg). Study B was conducted in 75 asthmatic adults receiving 800-1200 mcg of budesonide or equivalent and comprised a 4 week run-in of 400 mcg bd Becotide followed by 4 weeks treatment with either SFC 50/100 mcg bd or FBC 4.5/160 mcg bd taken in a cross-over manner. Serial 24-hour FEV1 was measured after the first dose and the last dose after each 4-weeks treatment period to determine the offset of action of each treatment. RESULTS:In study A, a single inhalation of SFC and FBC produced a sustained bronchodilation at 16 hours with an adjusted mean increase in FEV1 from pre-dose of 0.22 L (95% CI 0.19, 0.35 L) for SFC and 0.25 L (95% CI 0.21, 0.37 L) for FBC, which was significantly greater than placebo for both treatments (-0.05 L; p < 0.001). In study B, the slope of decline in FEV1 from 2-24 hours post dose was -16.0 ml/hr for SFC and -14.2 ml/hr for FBC. The weighted mean AUC over 24 hours was 0.21 Lxmin and 0.22 Lxmin and mean change from pre-dose FEV1 at 12 hours was 0.21 L for SFC and 0.20 L for FBC respectively CONCLUSION:Both SFC and FBC produced a similar sustained bronchodilator effect which was prolonged beyond 12 hours post dose and was clearly measurable at 24 h.

背景与目标：

BACKGROUND & AIMS: :The National Radiological Protection Board's advisory Group on Non-ionising Radiation has recommended further study on the effects of electric charge on the deposition of 0.005-1 microm particles in the lung. Estimates have been made regarding the integrated ion exposure within the corona plume generated by a power line and by ionisers in an intensive care unit. Changes in the charge state of particles with sizes in the range 0.02-13 mum have been calculated for these exposures. The corona plume increases the charge per particle of 0.02 and 0.1 microm particles by the order of 0.1. The ionisers in the intensive care unit produced negative ions-as do power lines under most conditions. Bacteria can carry in the order of 1000 charges (of either sign) and it is shown that the repulsion between such a negatively charged bacterium and negative ions prevents further ion deposition by diffusion charging. Positively charged bacteria can, however, be discharged by the ions which are attracted to them. The data provide no support for the hypothesis that ion exposure, at the levels considered, can increase deposition in the lung.

背景与目标： : 国家放射防护委员会的非电离辐射咨询小组建议进一步研究电荷对肺中0.005-1微米颗粒沉积的影响。已经对由电力线和重症监护病房中的离子发生器产生的电晕羽流中的综合离子暴露进行了估计。对于这些暴露，已经计算了尺寸在0.02-13微米范围内的颗粒的电荷状态变化。电晕羽流使0.02和0.1微米颗粒的每个颗粒的电荷增加0.1数量级。重症监护病房中的离子发生器会产生负离子-在大多数情况下，电源线也是如此。细菌可以以1000电荷的顺序携带 (任一符号)，并且显示出这种带负电荷的细菌与负离子之间的排斥防止通过扩散电荷进一步的离子沉积。但是，带正电的细菌可以被吸引到它们的离子排出。这些数据没有支持这样的假设，即离子暴露在所考虑的水平上会增加肺中的沉积。

BACKGROUND & AIMS: :Sepsis results in a state of relative immunosuppression, rendering critically ill patients susceptible to secondary infections and increased mortality. Monocytes isolated from septic patients and experimental animals display a "deactivated" phenotype, characterized by impaired inflammatory and antimicrobial responses, including hyporesponsiveness to LPS. We investigated the role of the LPS/TLR4 axis and its inhibitor, IL-1 receptor-associated kinase-M (IRAK-M), in modulating the immunosuppression of sepsis using a murine model of peritonitis-induced sepsis followed by secondary challenge by intratracheal Pseudomonasaeruginosa. Septic mice demonstrated impaired alveolar macrophage function and increased mortality when challenged with intratracheal Pseudomonas as compared with nonseptic controls. TLR2 and TLR4 expression was unchanged in the lung following sepsis, whereas levels of IRAK-M were upregulated. Macrophages from IRAK-M-deficient septic mice produced higher levels of proinflammatory cytokines ex vivo and greater costimulatory molecule expression in vivo as compared with those of their WT counterparts. Following sepsis and secondary intrapulmonary bacterial challenge, IRAK-M(-/-) animals had higher survival rates and improved bacterial clearance from lung and blood compared with WT mice. In addition, increased pulmonary chemokine and inflammatory cytokine production was observed in IRAK-M(-/-) animals, leading to enhanced neutrophil recruitment to airspaces. Collectively, these findings indicate that IRAK-M mediates critical aspects of innate immunity that result in an immunocompromised state during sepsis.

背景与目标： 败血症导致相对免疫抑制状态，使重症患者易继发感染并增加死亡率。从败血症患者和实验动物中分离出的单核细胞显示出 “失活” 表型，其特征是炎症和抗菌反应受损，包括对LPS的低反应性。我们研究了LPS/TLR4轴及其抑制剂IL-1受体相关激酶M (IRAK-M) 在调节脓毒症免疫抑制中的作用，该模型使用腹膜炎诱导的脓毒症，然后通过气管内假单胞菌继发攻击的鼠模型。与非败血症对照组相比，败血症小鼠的肺泡巨噬细胞功能受损，死亡率增加。脓毒症后肺中TLR2和TLR4表达不变，而IRAK-M水平上调。与WT对应物相比，来自IRAK-M缺陷脓毒症小鼠的巨噬细胞在体外产生更高水平的促炎细胞因子，并在体内产生更大的共刺激分子表达。与WT小鼠相比，在败血症和继发性肺内细菌攻击后，IRAK-M(-/-) 动物具有更高的存活率，并且从肺和血液中清除细菌。此外，在IRAK-M(-/-) 动物中观察到肺趋化因子和炎性细胞因子的产生增加，导致中性粒细胞向空气空间的募集增强。总的来说，这些发现表明IRAK-M介导了先天免疫的关键方面，从而导致败血症期间的免疫功能低下状态。

BACKGROUND & AIMS: Cytogenetic and molecular genetic studies were performed on a pleomorphic sarcoma removed from the left atrium of a 15-year-old girl. Histologic analysis was consistent with a storiform-pleomorphic malignant fibrous histiocytoma (MFH). Although MFH is the most common soft-tissue sarcoma of late adulthood. It is extremely rare in childhood and its existence in the pediatric population remains controversial. Cytogenetic analysis revealed several alterations previously associated with adult MFH, including abnormalities of chromosomal bands 11p11 and 19p13. Moreover, the tumor demonstrated homogeneously staining regions (HSR) and double minute chromosomes (dmin) suggestive of gene amplification. We therefore screened the case for amplification of genes localized to chromosomal bands 12q13-14, including the putative protooncogenes MDM2, CDK4, SAS, CHOP, and CLI, which are frequently amplified and overexpressed in adult MFH. Southern and Northern blot analysis confirmed the coamplification of MDM2, CDK4, SAS, and CHOP. To our knowledge, such coamplification studies of the 12q13-14 amplicon have not been previously detected in pediatric MFH. Our results provide cytogenetic and molecular genetic evidence that pediatric and adult MFH are histogenetically related entities.

背景与目标： 对一名15岁女孩左心房切除的多形性肉瘤进行了细胞遗传学和分子遗传学研究。组织学分析与多形性恶性纤维组织细胞瘤 (MFH) 一致。尽管MFH是成年后期最常见的软组织肉瘤。在儿童时期极为罕见，其在儿科人群中的存在仍然存在争议。细胞遗传学分析显示了先前与成人MFH相关的几种改变，包括染色体带11p11和19p13的异常。此外，肿瘤显示出均匀染色区域 (HSR) 和双分钟染色体 (dmin)，提示基因扩增。因此，我们筛选了扩增定位于染色体带12q13-14的基因的案例，包括假定的原癌基因MDM2，CDK4，SAS，CHOP和CLI，它们在成年MFH中经常被扩增和过表达。Southern和Northern印迹分析证实了MDM2，CDK4，SAS和CHOP的共扩增。据我们所知，这种12q13-14扩增子的共扩增研究以前尚未在小儿MFH中检测到。我们的结果提供了细胞遗传学和分子遗传学证据，表明儿科和成年MFH是与组织遗传学相关的实体。

BACKGROUND & AIMS: :The distinction between ectopic hamartomatous thymoma and sarcoma is difficult, and preoperative biopsy and intraoperative histopathological examination fail to give a definitive diagnosis. It is important to recognise ectopic hamartomatous thymoma as one of the differential diagnoses of a cervical tumour.

背景与目标： : 异位错构瘤性胸腺瘤和肉瘤之间的区别很困难，术前活检和术中组织病理学检查未能给出明确的诊断。重要的是要认识到异位错构瘤性胸腺瘤是宫颈肿瘤的鉴别诊断之一。

BACKGROUND & AIMS: BACKGROUND:Brain metastasis (BM) is associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). Recent studies demonstrated that microRNA-330-3p (miR-330-3p) was involved in NSCLC brain metastasis (BM). However, the exact parts played by miR-330-3p in BM of NSCLC remain unknown. Discovery and development of biomarkers and elucidation of the mechanism underlying BM in NSCLC is critical for effective prophylactic interventions. Here, we evaluated the expression and biological effects of miR-330-3p in NSCLC cells and explored the underlying mechanism of miR-330-3p in promoting cell migration and invasion in NSCLC. METHODS:Stable over-expression and knockdown of miR-330-3p in NSCLC cells was constructed with lentivirus. Expression levels of miR-330-3p in NSCLC cells were quantified by quantitive real-time PCR (qRT-PCR). The effects of miR-330-3p on NSCLC cells were investigated using assays of cell viability, migration, invasion, cell cycle, apoptosis, western blotting, immunohistochemical, and immunofluorescence staining. A xenograft nude mouse model and in situ brain metastasis model were used to observe tumor growth and brain metastasis. The potential target of miR-330-3p in NSCLC cells was explored using the luciferase reporter assay, qRT-PCR, and western blotting. The miR-330-3p targets were identified using bioinformatics analysis and verified by luciferase reporter assay. The correlation between GRIA3 and DNA methyltransferase (DNMT) 1 and DNMT3A was tested by RT-PCR, western blotting, and co-immunoprecipitation (IP). RESULTS:miR-330-3p was significantly up-regulated in NSCLC cell lines. MTT assay, transwell migration, and invasion assays showed that miR-330-3p promoted the growth, migration, and invasion of NSCLC cells in vitro and induced tumor growth and metastasis in vivo. Luciferase reporter assays showed that GRIA3 was a target of miR-330-3p. qRT-PCR and western blotting exhibited that miR-330-3p promoted the growth, invasion, and migration of NSCLC cells by activating mitogen-activated protein kinase (MAPK)/extracellular-regulated protein kinases (ERK) signaling pathway. Furthermore, miR-330-3p up-regulated the total DNA methylation in NSCLC cells, and co-IP-demonstrated GRIA3 was directly related with DNMT1 and DNMT3A. CONCLUSIONS:miR-330-3p promoted the progression of NSCLC and might be a potential target for the further research of NSCLC brain metastasis.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:To examine the analytic role of arsenic exposure on cancer mortality among the low-dose (well water arsenic level <150 μg/L) villages in the Blackfoot-disease (BFD) endemic area of southwest Taiwan and with respect to the southwest regional data. METHOD:Poisson analyses of the bladder and lung cancer deaths with respect to arsenic exposure (μg/kg/day) for the low-dose (<150 μg/L) villages with exposure defined by the village median, mean, or maximum and with or without regional data. RESULTS:Use of the village median well water arsenic level as the exposure metric introduced misclassification bias by including villages with levels >500 μg/L, but use of the village mean or the maximum did not. Poisson analyses using mean or maximum arsenic levels showed significant negative cancer slope factors for models of bladder cancers and of bladder and lung cancers combined. Inclusion of the southwest Taiwan regional data did not change the findings when the model contained an explanatory variable for non-arsenic differences. A positive slope could only be generated by including the comparison population as a separate data point with the assumption of zero arsenic exposure from drinking water and eliminating the variable for non-arsenic risk factors. CONCLUSION:The cancer rates are higher among the low-dose (<150 μg/L) villages in the BFD area than in the southwest Taiwan region. However, among the low-dose villages in the BFD area, cancer risks suggest a negative association with well water arsenic levels. Positive differences from regional data seem attributable to non-arsenic ecological factors.

背景与目标：

BACKGROUND & AIMS: :Abstract Type III interferon (IFN-λ) is a novel member of the interferon family, which preferentially promotes antiviral responses from epithelial cells and cooperates with type I IFNs in the clearance of viral infections. However, the effect of mIFN-λ2 to the LA795 lung adenocarcinoma cell is largely unknown. In this study, we transfected Ad-mIFN-λ2 vector into LA795 tumor-bearing mice to explore the effect of mIFN-λ2 on the proliferation of LA795 lung adenocarcinoma cell and on the immune response of the mice. Transfected by Ad-mIFN-λ2 vector, a significant decrease in the tumor growth, the subcutaneous tumor necrosis, cystic degeneration, and tumor apoptosis were more evident; at the same time, mIFN-λ2 protein and gene were significantly more expressed. And, flow cytometry analysis suggested that CD3(+)CD4(+), CD3(+)CD8(+), and NK (CD3(-)CD49(+)) cells were all significantly increased after transfected by Ad-mIFN-λ2. The study demonstrated that recombinant Ad-mIFN-λ2 transfection effectively inhibited the growth of LA795 lung adenocarcinoma cell, which may work through inducing apoptosis of tumor cell and regulating cell immune response.

背景与目标： : 摘要III型干扰素 (IFN-λ) 是干扰素家族的新成员，它优先促进上皮细胞的抗病毒反应，并与I型IFN协同清除病毒感染。然而，mIFN-λ2对LA795肺腺癌细胞的作用在很大程度上是未知的。在这项研究中，我们将Ad-mIFN-λ2载体转染到LA795荷瘤小鼠中，以探讨mIFN-λ2对LA795肺腺癌细胞增殖和小鼠免疫反应的影响。转染Ad-mIFN-λ2载体后，肿瘤生长明显减少，皮下肿瘤坏死、囊性变性和肿瘤凋亡更明显; 同时，mIFN-λ2蛋白和基因表达明显更多。流式细胞术分析表明，Ad-mIFN-λ2转染后，CD3(+)CD4(+) 、CD3(+)CD8(+) 和NK (CD3(-)CD49(+) 细胞均显著增加。研究表明，重组Ad-mIFN-λ2转染可有效抑制LA795肺腺癌细胞的生长，可能通过诱导肿瘤细胞凋亡和调节细胞免疫反应而起作用。

BACKGROUND & AIMS: :We recently showed that non-small cell lung carcinomas (NSCLCs) are of dismal prognosis when encompassing accelerated autophagic activity. The regulation of this abnormally functioning degradation system and its association with hypoxia and apoptosis in lung carcinoma patients is unexplored. In this study we used 115 NSCLC tissues to examine the immunohistochemical expression of four distinct molecules - the major regulator of autophagy Beclin 1, the anti-apoptotic and anti-autophagic protein Bcl-2, the pro-apoptotic and pro-autophagic protein BNIP3, and a marker of hypoxia and glucolysis, the glucose transporter Glut 1. Most cases showed reduced reactivity for Beclin 1 (62%) and Bcl-2 (82%) proteins, almost half of our sample revealed strong BNIP3 expression (57%), whereas most of the carcinomas strongly expressed Glut 1 antigen (71%). Beclin 1 expression showed no association with survival. Bcl-2 positivity was a marker of good prognosis (p = 0.04), whereas BNIP3 (p = 0.0004) and Glut 1 (p = 0.03) expression correlated with poor outcome in Stage I disease. Autophagic status was negatively associated with Bcl-2 (p = 0.0006), but positively with Glut 1 expression (p = 0.001). In conclusion, the accelerated autophagic status in NSCLC is unrelated to Beclin 1 and BNIP3 expression, but does show significant association with Bcl-2 reactivity. Furthermore, we showed important correlations between glucolysis and autophagy, guiding new pathways in future lung carcinoma research.

背景与目标： : 我们最近发现，当包括加速的自噬活性时，非小细胞肺癌 (nsclc) 的预后很差。尚未探索这种功能异常的降解系统的调节及其与肺癌患者缺氧和凋亡的关系。在这项研究中，我们使用了115个NSCLC组织来检查四个不同分子的免疫组织化学表达-自噬的主要调节剂Beclin 1，抗凋亡和抗自噬蛋白Bcl-2，促凋亡和自噬蛋白BNIP3，以及缺氧和葡萄糖溶解的标志物，葡萄糖转运蛋白Glut 1。大多数病例显示对Beclin 1 (62%) 和Bcl-2 (82%) 蛋白的反应性降低，几乎一半的样本显示BNIP3强表达 (57%)，而大多数癌强烈表达Glut 1抗原 (71%)。Beclin 1表达与生存率无关。Bcl-2阳性是预后良好的标志 (p = 0.04)，而BNIP3 (p = 0.0004) 和Glut 1 (p = 0.03) 表达与I期疾病不良预后相关。自噬状态与Bcl-2呈负相关 (p = 0.0006)，但与Glut 1表达呈正相关 (p = 0.001)。总之，NSCLC的加速自噬状态与Beclin 1和BNIP3表达无关，但确实显示出与Bcl-2反应性的显着关联。此外，我们还显示了葡萄糖溶解与自噬之间的重要相关性，为未来肺癌研究提供了新的途径。

BACKGROUND & AIMS: :Sensitizing mutations in the epidermal growth factor receptor (EGFR) predict response to EGFR tyrosine kinase inhibitors (TKIs) and both first- and second-generation TKIs are available as first-line treatment options in patients with advanced EGFR-mutant non-small cell lung cancer. Eventual resistance develops with multiple mechanisms identifiable both upon repeat biopsy and in plasma circulating tumor DNA. The T790M gatekeeper mutation is responsible for almost 60% of cases. A number of third-generation TKIs are in clinical development, and osimertinib has been approved by the US Food and Drug Administration for the treatment of patients with EGFR T790M mutant lung cancer after failure of initial EGFR kinase therapy. Resistance mechanisms are being identified to these novel agents, and the treatment landscape of EGFR-mutant lung cancer continues to evolve. The sequence of EGFR TKIs may change in the future and combination therapies targeting resistance appear highly promising.

背景与目标： : 表皮生长因子受体 (EGFR) 的致敏突变可预测对EGFR酪氨酸激酶抑制剂 (TKIs) 的反应，并且第一代和第二代TKIs均可作为晚期EGFR突变型非小细胞肺癌患者的一线治疗选择。在重复活检和血浆循环肿瘤DNA中，最终的耐药性可通过多种机制识别。T790M网守突变负责几乎60% 的病例。许多第三代TKIs正在临床开发中，奥希替尼已获得美国食品药品监督管理局的批准，可用于治疗EGFR T790M突变型肺癌患者的初始EGFR激酶治疗失败。这些新药物的耐药机制正在被确定，并且EGFR突变型肺癌的治疗前景继续发展。EGFR TKIs的序列可能会在未来发生变化，针对耐药性的联合疗法似乎很有希望。

BACKGROUND & AIMS: BACKGROUND:Interstitial lung disease (ILD) frequently complicates systemic autoimmune disorders resulting in considerable morbidity and mortality. The connective tissue diseases (CTDs) most frequently resulting in ILD include: systemic sclerosis, idiopathic inflammatory myositis (including dermatomyositis, polymyositis and anti-synthetase syndrome) and mixed connective tissue disease. Despite the development, over the last two decades, of a range of biological therapies which have resulted in significant improvements in the treatment of the systemic manifestations of CTD, the management of CTD-associated ILD has changed little. At present there are no approved therapies for CTD-ILD. Following trials in scleroderma-ILD, cyclophosphamide is the accepted standard of care for individuals with severe or progressive CTD-related ILD. Observational studies have suggested that the anti-CD20 monoclonal antibody, rituximab, is an effective rescue therapy in the treatment of refractory CTD-ILD. However, before now, there have been no randomised controlled trials assessing the efficacy of rituximab in this treatment population. METHODS/DESIGN:RECITAL is a UK, multicentre, prospective, randomised, double-blind, double-dummy, controlled trial funded by the Efficacy and Mechanism Evaluation Programme of the Medical Research Council and National Institute for Health Research. The trial will compare rituximab 1 g given intravenously, twice at an interval of 2 weeks, with intravenously administered cyclophosphamide given monthly at a dose of 600 mg/m2 body surface area in individuals with ILD due to systemic sclerosis, idiopathic inflammatory myositis (including anti-synthetase syndrome) or mixed connective tissue disease. A total of 116 individuals will be randomised 1:1 to each of the two treatment arms, with stratification based on underlying CTD, and will be followed for a total of 48 weeks from first dose. The primary endpoint for the study will be change in forced vital capacity (FVC) at 24 weeks. Key secondary endpoints include: safety, change in FVC at 48 weeks as well as survival, change in oxygen requirements, total 48-week corticosteroid exposure and utilisation of health care resources. DISCUSSION:This is the first randomised control trial to study the efficacy of rituximab as first-line treatment in CTD-associated ILD. The results generated should provide important information on the treatment of a life-threatening complication affecting a rare group of CTDs. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01862926. Registered on 22 May 2013.

背景与目标：

BACKGROUND & AIMS: :Inversin, encoded by NPHP2, is one of the 10 NPHP proteins known to be involved in nephronophthisis (an autosomal recessive cystic kidney). Although the previous reports showed that inversin played an important role in embryonic development and renal diseases, its function in cancer was not revealed clearly so far. As measured by immunohistochemical staining, inversin was highly expressed in the cytoplasm of lung cancer samples (63.4%, 161/254) compared with adjacent normal lung tissues (22.0%, 11/50, p < 0.01). Moreover, its expression was positively correlated with differentiation ( p = 0.014), tumor node metastasis staging ( p = 0.007), and lymph node metastasis ( p = 0.020). The overall survival of non-small cell lung cancer patients with inversin positive expression (45.41 ± 1.800 months) was significantly reduced compared with those with inversin negative expression (51.046 ± 2.238 months, p = 0.042). Consistently, we found that the invasion capacity of A549 cells transfected with inversin was significantly stronger than that of control cells ( p < 0.05), while inversin siRNA-treatment significantly reduced cell invasion in H1299 cells ( p < 0.05). Additionally, we demonstrated that inversin could upregulate the expression of N-cadherin, Vimentin, matrix metalloproteinase-2, and matrix metalloproteinase-9. Collectively, these results indicated that inversin might promote the tumorigenicity of lung cancer cells and serve as a novel therapeutic target of non-small cell lung cancer.

背景与目标： : 由NPHP2编码的Inversin是已知参与肾炎 (常染色体隐性遗传性囊性肾脏) 的10种NPHP蛋白之一。尽管先前的报道表明，invers素在胚胎发育和肾脏疾病中起着重要作用，但到目前为止，其在癌症中的功能尚不清楚。免疫组织化学染色显示，与癌旁正常肺组织 (22.0% 、11/50、p  <  0.01) 相比，肺癌标本 (63.4% 、161/254) 胞浆中inversin高表达。其表达与分化程度 (p   =   0.014) 、淋巴结转移分期 (p   =   0.007) 、淋巴结转移 (p   =   0.020) 呈正相关。非小细胞肺癌患者中，inversin阳性表达 (45.41   ±   1.800  个月) 的总生存期明显低于inversin阴性表达 (51.046   ±   2.238  个月，p   =   0.042)。一致地，我们发现用逆转录蛋白转染的A549细胞的侵袭能力明显强于对照细胞 (p  <  0.05)，而逆转录蛋白siRNA处理显著降低H1299细胞的细胞侵袭能力 (p  <  0.05)。此外，我们证明了inversin可以上调N-钙粘蛋白，波形蛋白，基质metalloproteinase-2和基质metalloproteinase-9的表达。总之，这些结果表明，inversin可能促进肺癌细胞的致瘤性，并可作为非小细胞肺癌的新治疗靶标。

BACKGROUND & AIMS: :The objective of this study was to evaluate the effects of ultrasound-mediated analyte diffusion on permeability of normal, benign, and cancerous human lung tissue in vitro and to find more effective sonophoretic (SP) delivery in combination with the optical clearing agents (OCAs) method to distinguish normal and diseased lung tissues. The permeability coefficients of SP in combination with OCAs diffusion in lung tissue were measured with Fourier-domain optical coherence tomography (FD-OCT). 30% glucose and SP with a frequency of 1 MHz and an intensity of 0.80  W/cm2 over a 3 cm probe was simultaneously applied for 15 min. Experimental results show that the mean permeability coefficients of 30% glucose/SP were found to be (2.01±0.21)×10(-5)  cm/s from normal lung (NL) tissue, (2.75±0.28)×10(-5)  cm/s from lung benign granulomatosis (LBG) tissue, (4.53±0.49)×10(-5)  cm/s from lung adenocarcinoma tumor (LAT) tissue, and (5.81±0.62)×10(-5)  cm/s from lung squamous cell carcinoma (LSCC) tissue, respectively. The permeability coefficients of 30% glucose/SP increase approximately 36.8%, 125.4%, and 189.1% for the LBG, LAT, and LSCC tissue compared with that for the NL tissue, respectively. There were statistically significant differences in permeability coefficients of 30% glucose/SP between LBG and NL tissue (p<0.05), between LAT and NL tissue (p<0.05), and between LSCC and NL tissue (p<0.05). The results suggest that the OCT functional imaging technique to combine an ultrasound-OCAs combination method could become a powerful tool in early diagnosis and monitoring of changed microstructure of pathologic human lung tissue.

背景与目标： : 这项研究的目的是评估超声介导的分析物扩散对体外正常，良性和癌性人肺组织通透性的影响，并找到与光学清除剂 (OCAs) 结合更有效的超声电泳 (SP) 递送方法，以区分正常和患病的肺组织。用傅里叶域光学相干断层扫描 (fd-oct) 测量SP与OCAs扩散在肺组织中的渗透系数。在3厘米探针上同时施加频率为1 MHz且强度为0.80   W w/cm2的30% 葡萄糖和SP 15分钟。实验结果表明，30% 葡萄糖/SP对正常肺 (NL) 组织的平均渗透系数为 (2.01 ± 0.21)× 10(-5)  cm cm/s，肺良性肉芽肿 (LBG) 组织 (2.75 ± 0.28)× 10(-5)  cm/s，肺腺癌肿瘤 (LAT) 组织 (4.53 ± 0.49)× 10(-5)  cm/s，和 (5.81 ± 0.62)× 10(-5)  cm cm/s分别来自肺鳞状细胞癌 (LSCC) 组织。与NL组织相比，LBG、LAT和LSCC组织的30% 葡萄糖/SP的渗透系数分别增加约36.8% 、125.4% 和189.1%。LBG与NL组织之间 (p<0.05)，LAT与NL组织之间 (p<0.05) 以及LSCC与NL组织之间 (p<0.05) 的30% 葡萄糖/SP的渗透系数差异有统计学意义。结果表明，OCT功能成像技术结合超声-OCAs组合方法可以成为早期诊断和监测病理性人肺组织微观结构变化的有力工具。

BACKGROUND & AIMS: :Lung cancer is the leading cause of cancer-related mortality in both men and women throughout the world. This disease is strongly associated with tobacco smoking. The aim of this manuscript was to establish an in vitro model that mimics the chronic exposures of alveolar epithelial type II cells to the tobacco-specific nitrosamine carcinogen, NNK. Immortalized non-neoplastic alveolar epithelial cells type II, (E10 cells), from BALB/c mice were exposed to low concentration of NNK (100 pM) during 5, 10, 15, and 20 cycles of 48 h. NNK-transformed cells showed an increase of proliferation rate and motility. Moreover, these cells underwent epithelial-to-mesenchymal transition (EMT). Increased migratory capacity and EMT were correlated to the time of exposure to NNK. NNK-transformed cells were tested for their growth and metastatic capacity in vivo. Subcutaneous injection of cells exposed to NNK for 20 cycles (E10-NNK20 clone) into BALB/c mice led to the formation of subcutaneous tumors that arose after 40 ± 17 d in all animals, which died 95 ± 18 d after cell inoculation, with lymph nodes and lung metastasis. The morphological characteristics of tumors were compatible with metastatic undifferentiated carcinoma. Cells exposed to NNK for 5-10 cycles did not display metastatic capacity, while those exposed for 15 cycles displayed low capacity. Our results show that prolonged exposures to NNK led the cells to increasingly acquire malignant properties. The cellular model presented in this study is suitable for studying the molecular events involved in the different stages of malignant transformation.

背景与目标： : 肺癌是全世界男性和女性癌症相关死亡率的主要原因。这种疾病与吸烟密切相关。本手稿的目的是建立一个体外模型，该模型模拟肺泡上皮II型细胞对烟草特异性亚硝胺致癌物NNK的慢性暴露。来自BALB/c小鼠的永生化的非肿瘤性II型肺泡上皮细胞 (E10细胞) 在48  h的5、10、15和20个周期中暴露于低浓度的NNK (100  pM)。NNK转化的细胞显示出增殖速率和运动能力的增加。此外，这些细胞经历了上皮-间质转化 (EMT)。迁移能力和EMT的增加与NNK暴露时间相关。测试NNK转化的细胞在体内的生长和转移能力。在BALB/c小鼠中皮下注射暴露于NNK 20个周期的细胞 (E10-NNK20克隆) 导致所有动物皮下肿瘤的形成，该肿瘤在40  ±   17 d后出现，在细胞接种后95  ±   18 d死亡，并伴有淋巴结和肺转移。肿瘤的形态特征与转移性未分化癌相容。暴露于NNK 5-10个周期的细胞未显示转移能力，而暴露于15个周期的细胞显示低容量。我们的结果表明，长时间暴露于NNK导致细胞越来越多地获得恶性特性。本研究中提出的细胞模型适用于研究恶性转化不同阶段涉及的分子事件。

BACKGROUND & AIMS: PURPOSE:In the regulation of chromatin-structure and histone function, histone deacetylases (HDACs) are key enzymes and thus modulators of epigenetic regulation and gene expression. Accesses of the HDAC inhibitor vorinostat to intracellular compartments are essential to exert epigenetic effects. METHODS:In ten sarcoma patients receiving oral Zolinza (400 mg qd) vorinostat concentrations in plasma and peripheral blood mononuclear cells (PBMCs) were quantified using validated LC/MS/MS assays to determine intracellular and extracellular pharmacokinetic data. Cellular HDAC activity was evaluated using a fluorogenic assay. Concentration-response relationships were established between intracellular and extracellular vorinostat concentrations and HDAC inhibition in PBMCs. RESULTS:Pharmacokinetics of vorinostat and its two main inactive metabolites were determined over 8 h in plasma and PBMCs. Steady state AUCs (±SD) and T1/2 (±SD) were calculated to 4.61 ± 0.87 h µM and 1.73 ± 0.69 h (plasma) and 15.2 ± 9.03 h µM and 5.30 ± 4.27 h (PBMCs). Intracellular accumulation of vorinostat was determined together with prolonged vorinostat elimination in PBMCs. Cellular HDAC inhibition increased parallel with vorinostat concentrations in plasma and PBMCs. For effective inhibition of cellular HDACs (IC50) vorinostat concentrations of 0.05 µM in plasma and 0.17 µM in PBMCs were necessary. CONCLUSION:HDAC inhibition closely followed intracellular vorinostat concentrations and was short-lasting, which may contribute to the limited efficacy seen with vorinostat in solid tumors so far.

背景与目标：