فایل ورد کامل جلوگیری مهار کننده مسیر نانوذرات پلیمری کپسوله شده HPI-1 از متاستاز سیستمی در مدل ارتوتوپیک کارسینومای هپاتوسلولی

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تعداد صفحات این فایل: ۳۵ صفحه

 با این حال آنها اثرات معنا دار سورافنیب را بر روی متاستازیس تومور نشان دادند اختلاف کلیدی بین این مطالعه ها با استفتده از کالبد شکافی جزئی برای خارج کردن تومور قبل از تزریق سورافنیب است. این درمان ها دارای مسیر های متناوبی می باشند. ترکیب درمانی سورافنیب و نانو HHI تقریبا نتایج مشابهی را در اختیار گذاشته است. مکانیسم های احتمالی کارایی آنتی متا استاتیک نانو HHI شامل مهار مسیر تولید سیگنال – کاهش جمعیت سلول های سرطانی کبد می باشد که خود موسوم به سلول های بنیانی کبد و منبع متاستازیس می باشد. مطالعه ی اخیر رابطه بین فعالیت HHIو CD133 را نشان می دهد و بی برد که تومور های متمایز شده موجب حفظ جمعیت های بیان کننده ی CD133شدند.که خود یک تومور زا است و نیازمند سلول های مثبت برای از بین بردن آن می باشد. این جمعیت HCC منبعی از سلول ها را دارد که دارای تقسیم غیر متقارن بوده و عامل برگشت بیماری بعد از جراحی می باشند.بعلاوه جمعیت مثبت CD133 سلول ها ارتباط تنگاتنگ مقاومت و شیوع بیماری را تحت شیمی رادیو در مانی نشان داد.

عنوان انگلیسی:Polymeric Nanoparticle-Encapsulated Hedgehog Pathway Inhibitor HPI-1 (NanoHHI) Inhibits Systemic Metastases in an Orthotopic Model of Human Hepatocellular Carcinoma~~en~~

function to control tissue development of many tissue types (7–۹). For example, in the fetus, this signaling pathway functions early in the endoderm to establish hepatic progenitor cells (10). However, Hh signaling appears to have a far more significant role in maintaining hepatic progenitors in the adult liver (11–۱۳). The Hh pathway is activated during liver regeneration (13) and in response to chronic liver injury (11, 12, 14, 15). Inappropriate activation of Hh pathway has been implicated in several gastrointestinal tumor types (16). Several studies have shown aberrant Hh signaling in human HCC tissues and cell lines. Hh signaling appears to be particularly active in the setting of chronic liver disease and might partially account for the common occurrence of HCC in the setting of chronic liver disease and cirrhosis (17, 18). Blockade of Hh signaling results in decreased proliferation and migration and an increase in apoptosis of human HCC cell lines (19–۲۶). Other groups have implicated Hh transcriptional targets as critical to tumor progression and metastasis (21, 23). Of the multiple small-molecule Hh inhibitors currently undergoing evaluation in clinical trials, all are Smo antagonists (27). However, there are 2 potential shortcomings for targeting Smo in human cancers. First is the recently described ability of tumors to secondarily acquire Smo mutations that can abrogate the ability of antagonists to bind to the heptahelical bundle of Smo protein (28–۳۱). Second, Smo-independent pathways leading to Gli activation have been shown recently by Hanahan and colleagues (32). For these reasons, and evidence showing that RNAmediated interference of Gli1 causes apoptosis in human HCC cell lines but not in normal hepatocytes (20), we evaluated a direct inhibitor of Gli which might provide improved therapeutic advantage in HCC. Recently, 4 Hh pathway inhibitors (HPI 1–۴) have been identified that block Hh signaling downstream of Smo (33). In particular, HPI-1 is a potent antagonist of Gli proteins (Gli1 and 2) and also blocks Hh signaling in the setting of exogenous Gli expression. However, it might be difficult to translate these in vitro findings to in vivo studies as this inhibitor has poor systemic bioavailability. Its lipophilic nature and poor aqueous solubility make it difficult to deliver in vivo. We developed and characterized (34) a novel polymeric nanoparticle encapsulating HPI-1 (NanoHHI). In this study, we first established the clinical significance of Ptch1 expression in HCC, as a marker of downstream Hh activity. We show that Ptch1 expression in patients undergoing curative HCC resection correlated with early recurrence and was a poor prognostic feature. Furthermore, we show that NanoHHI is effective at inhibiting the proliferation and motility of 2 human HCC cell lines in vitro and significantly inhibits subcutaneous tumor growth at least as effectively as the current standard-of-care chemotherapeutic agent, sorafenib. Notably, however, NanoHHI is remarkably more effectively than sorafenib at inhibiting metastasis in a lethal orthotopic model of human HCC. The ability to potently suppress systemic metastasis is likely attributed to the ability of NanoHHI to significantly downregulate CD133-expressing cells, which are implicated as tumorinitiating cells in HCCs. These studies provide early evidence of a nanoparticle-encapsulated agent that might be useful for chemotherapy in patients at high risk of HCC recurrence after curative surgical resection. Materials and Methods Patients and specimens Tumor specimens used in tissue microarrays (TMA) were obtained from 396 patients with HCC who underwent surgical resection at the Liver Cancer Institute, Zhong Shan Hospital, Fudan University (Shanghai, PR China) from February 1, 2000, to December 1, 2002. Tumor specimens were taken from viable areas of the tumors and necrotic tissues were avoided. The inclusion criteria of all the patients in this study were as follows: (i) confirmed histopathologic diagnosis of HCC based on the WHO criteria (35); (ii) without any prior therapy; (iii) with an “intent-tocure” surgical resection, which is defined as the complete resection of all tumor nodules and the margins being free of cancer by histologic examination (36); (iv) with suitable formalin-fixed, paraffin-embedded tissues; and (v) patients with demographic and clinicopathologic follow-up data. Tumor differentiation was defined according to the Edmondson grading system (37). Liver function was assessed by the Child–Pugh classification. Tumor staging was defined according to the sixth edition of tumor-nodemetastasis (TNM) classification of Unio Internationale Contra Cancrum (UICC). The clinicopathologic characteristics of all the patients are summarized in Table 1. Ethical approval for human subjects was obtained from the research ethics committee of Zhong Shan Hospital and the Johns Hopkins University (Baltimore, MD) Institutional Review Board. Follow-up and tumor recurrences Patients were followed up every 2 months during the first postoperative year and at least every 3 to 4 months afterward. Follow-up was obtained until March 30, 2010. All patients were prospectively monitored by serum a-fetoprotein (AFP), abdominal ultrasonography, and radiography every 1 to 6 months in the postoperative period. A computed tomographic (CT) scan of the abdomen was conducted every 6 months. Bone scan or MRI was done if localized bone pain was reported. If recurrence was suspected, CT scan or MRI was conducted immediately. Most patients died from recurrence or metastasis or complicated liver cirrhosis. Patients with confirmed recurrence received further treatment, which followed the same protocol on the basis of the size, site, number of tumor nodules, and liver function. Briefly, if the recurrent tumor was localized, a second liver resection, radiofrequency ablation (RFA), or percutaneous ethanol injection (PEI) was conducted; if the recurrent tumor was multiple or diffuse, then transcatheter arterial chemoembolization (TACE) was the choice. External radiotherapy was given if lymph node or bone metastasis was found. Otherwise, symptomatic treatment was provided. OS was defined as the interval between surgery and death or the last observation taken. The data were censored at the last follow-up for living patients. Time to recurrence (TTR) was measured from the date of resection until the detection of recurrent tumor and data were censored for patients without signs of recurrence.

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