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1.
As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.  相似文献   
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Opioids are widely used for the pain management of acute pancreatitis (AP), but their impact on disease progression is unclear. Therefore, our aim was to study the effects of clinically relevant opioids on the severity of experimental AP. Various doses of fentanyl, morphine, or buprenorphine were administered as pre- and/or post-treatments in rats. Necrotizing AP was induced by the intraperitoneal injection of L-ornithine-HCl or intra-ductal injection of Na-taurocholate, while intraperitoneal caerulein administration caused edematous AP. Disease severity was determined by laboratory and histological measurements. Mu opioid receptor (MOR) expression and function was assessed in control and AP animals. MOR was expressed in both the pancreas and brain. The pancreatic expression and function of MOR were reduced in AP. Fentanyl post-treatment reduced necrotizing AP severity, whereas pre-treatment exacerbated it. Fentanyl did not affect the outcome of edematous AP. Morphine decreased vacuolization in edematous AP, while buprenorphine pre-treatment increased pancreatic edema during AP. The overall effects of morphine on disease severity were negligible. In conclusion, the type, dosing, administration route, and timing of opioid treatment can influence the effects of opioids on AP severity. Fentanyl post-treatment proved to be beneficial in AP. Clinical studies are needed to determine which opioids are best in AP.  相似文献   
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We investigated the influences of odor exposure on performance and on breathing measures. The task was composed of tracking, short-term memory, and peripheral reaction parts. During rest or while performing the task, 12 participants were exposed to 4 different odors in 2 intensities. The higher intensity of the malodors induced a short-term decrement in mean inspiration flow (Vi/Ti) after stimulus onset and impaired performance in the short-term memory task, as compared with control trials; no effect was found for the positively judged odors. The study suggests that a distractor as simple as a bad smell may pull a person off task, however briefly, and may result in a detriment to performance. Actual or potential applications of this research involve designing or securing tasks in such a way that a brief withdrawal of attention does not have fatal consequences.  相似文献   
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西九文化区     
正OMA发展西九文化区,必须面对一项挑战:将一个盛载政府极大抱负,以及持分者多元利益的超大型多用途项目,转化成一个既有趣又严肃、既有规划又允许即兴、既中国化又国际化的文化区。这个文化区规模庞大,但不失亲密融洽的感觉;富地标性,但十分谦和;容易理解,却能带来惊喜。为避免造成过分冲击,OMA采纳了一种每个香港市民都熟悉的建筑类型作为方案的发展  相似文献   
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Within this study, a novel gastrointestinal patch system was developed and investigated regarding water-absorbing capacity, adhesive properties, in vitro release, unidirectional release and permeation enhancing effect. Water uptake studies revealed that the weight of patch systems with Ch-GSH increased about 44.5 ± 2.3 mg (127%) after 90 min. This patch system remained even after 180 h on the mucosa and released 49.7 ± 0.7% of FD4 within 8 h. A 2.5-fold higher transport of FD4 can be obtained in contrast to control. In conclusion this patch system could be an interesting possibility for the transport through the intestinal mucosa of macromolecules which will normally be degraded in the intestinal tract.  相似文献   
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Inappropriate nutrition and a sedentary lifestyle can lead to obesity, one of the most common risk factors for several chronic diseases. Although regular physical exercise is an efficient approach to improve cardiometabolic health, the exact cellular processes are still not fully understood. We aimed to analyze the morphological, gene expression, and lipidomic patterns in the liver and adipose tissues in response to regular exercise. Healthy (wild type on a normal diet) and hyperlipidemic, high-fat diet-fed (HFD-fed) apolipoprotein B-100 (APOB-100)-overexpressing mice were trained by treadmill running for 7 months. The serum concentrations of triglyceride and tumor necrosis factor α (TNFα), as well as the level of lipid accumulation in the liver, were significantly higher in HFD-fed APOB-100 males compared to females. However, regular exercise almost completely abolished lipid accumulation in the liver of hyperlipidemic animals. The expression level of the thermogenesis marker, uncoupling protein-1 (Ucp1), was significantly higher in the subcutaneous white adipose tissue of healthy females, as well as in the brown adipose tissue of HFD-fed APOB-100 females, compared to males. Lipidomic analyses revealed that hyperlipidemia essentially remodeled the lipidome of brown adipose tissue, affecting both the membrane and storage lipid fractions, which was partially restored by exercise in both sexes. Our results revealed more severe metabolic disturbances in HFD-fed APOB-100 males compared to females. However, exercise efficiently reduced the body weight, serum triglyceride levels, expression of pro-inflammatory factors, and hepatic lipid accumulation in our model.  相似文献   
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This paper proposes an efficient combination of algorithms for the automated localization of the optic disc and macula in retinal fundus images. There is in fact no reason to assume that a single algorithm would be optimal. An ensemble of algorithms based on different principles can be more accurate than any of its individual members if the individual algorithms are doing better than random guessing. We aim to obtain an improved optic disc and macula detector by combining the prediction of multiple algorithms, benefiting from their strength and compensating their weaknesses. The location with maximum number of detectors’ outputs is formally the hotspot and is used to find the optic disc or macula center. An assessment of the performance of integrated system and detectors working separately is also presented. Our proposed combination of detectors achieved overall highest performance in detecting optic disc and fovea closest to the manually center chosen by the retinal specialist.  相似文献   
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