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Oncogenic mutations in BRAF genes are found in approximately 5–10% of colorectal cancers. The majority of BRAF mutations are located within exons 11–15 of the catalytic kinase domains, with BRAF V600E accounting for more than 80% of the observed BRAF mutations. Sensitivity to BRAF- and mitogen-activated protein kinase (MEK) inhibitors varies depending on BRAF mutations and tumor cell types. Previously, we newly identified, BRAF L525R-mutation, in the activation segment of the kinase in colorectal cancer patient. Here, we characterized the function of the BRAF L525R mutation.
MethodsHEK293 cells harboring a BRAF mutation (V600E or L525R) were first characterized and then treated with cetuximab, dabrafenib, and selumetinib. Cell viability was measured using WST-1 assay and the expression of proteins involved in the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signaling pathways was evaluated using western blot analysis.
ResultsThe MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in BRAF L525R cells but not in BRAF V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in BRAF L525R cells but not in BRAF V600E cells or selumetinib-resistant BRAF L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance.
ConclusionsWe established a model system harboring BRAF L525R using HEK293 cells. BRAF L525R constitutively activated ERK. AKT phosphorylation caused sensitivity and resistance to selumetinib. Our results suggest that a comprehensive network analysis may provide insights to identify effective therapies.
相似文献Objectives
Initial gait speed is a good predictor of dementia in later life. This prospective study used repeated measures analysis to identify potential gait performance trajectory patterns and to determine whether gait performance trajectory patterns were associated with incident disabling dementia among community-dwelling older Japanese.Design
A prospective, observational, population-based follow-up study.Setting
Japan, 2002 to 2014.Participants
A total of 1686 adults without dementia (mean [SD] age, 71.2 [5.6] years; women, 56.3%) aged 65 to 90 years participated in annual geriatric health assessments during the period from June 2002 through July 2014. The average number of follow-up assessments was 3.9, and the total number of observations was 6509.Measurements
Gait performance was assessed by measuring gait speed and step length at usual and maximum paces. A review of municipal databases in the Japanese public long-term care insurance system revealed that 196 (11.6%) participants developed disabling dementia through December 2014.Results
We identified 3 distinct trajectory patterns (high, middle, and low) in gait speed and step length at usual and maximum paces in adults aged 65 to 90 years; these trajectory patterns showed parallel declines among men and women. After adjusting for important confounders, participants in the low trajectory groups for gait speed and step length at usual pace were 3.46 (95% confidence interval 1.88–6.40) and 2.12 (1.29–3.49) times as likely to develop incident disabling dementia, respectively, as those in the high trajectory group. The respective values for low trajectories of gait speed and step length at maximum pace were 2.05 (1.02–4.14) and 2.80 (1.48–5.28), respectively.Conclusions
Regardless of baseline level, the 3 major trajectory patterns for gait speed and step length tended to show similar age-related changes in men and women in later life. Individuals with low trajectories for gait speed and step length had a higher dementia risk, which highlights the importance of interventions for improvements in gait performance, even among older adults with low gait performance. 相似文献Study Design
Multicenter retrospective study.Background
Postoperative surgical site infection is one of the most serious complications following spine surgery. Previous studies do not appear to have investigated pyogenic discitis following lumbar laminectomy without discectomy. This study aimed to identify risk factors for postoperative pyogenic discitis following lumbar decompression surgery.Methods
We examined data from 2721 patients undergoing lumbar laminectomy without discectomy in five hospitals from April 2007 to March 2012. Patients who developed postoperative discitis following laminectomy (Group D) and a 4:1 matched cohort (Group C) were included. Fisher's exact test was used to determine risk factors, with values of p < 0.05 considered statistically significant.Results
The cumulative incidence of postoperative discitis was 0.29% (8/2721 patients). All patients in Group D were male, with a mean age of 71.6 ± 7.2 years. Postoperative discitis was at L1/2 in 1 patient, at L3/4 in 3 patients, and at L4/5 in 4 patients. Except for 1 patient with discitis at L1/2, every patient developed discitis at the level of decompression. The associated pathogens were methicillin-resistant Staphylococcus aureus (n = 3, 37.5%), methicillin-susceptible Staphylococcus epidermidis (n = 1, 12.5%), methicillin-sensitive S. aureus (n = 1, 12.5%), and unknown (n = 3, 37.5%). In the analysis of risk factors for postoperative discitis, Group D showed a significantly lower ratio of patients who underwent surgery in the winter and a significantly higher ratio of patients who had Modic type 1 in the lumbar vertebrae compared to Group C.Conclusions
Although further prospective studies, in which other preoperative modalities are used for the evaluation, is needed, our data suggest the presence of Modic type 1 as a risk factor for discitis following laminectomy. Latent pyogenic discitis should be carefully ruled out in patients with Modic type 1. If lumbar laminectomy is performed for such patients, more careful observation is necessary to prevent the development of postoperative discitis. 相似文献Purpose
The aim of this retrospective study was to evaluate inflammation-based scoring as a prognostic factor for operable non-small-cell lung cancer (NSCLC) in elderly patients.Methods
We collected preoperative data from 108 patients aged above 80 years with NSCLC. Inflammation-based scoring systems, including the C-reactive protein to albumin ratio (CAR) and the Glasgow prognostic score (GPS), as well as other clinicopathological factors, were evaluated as potential prognostic factors.Results
The median patient age was 82 (range 80–93) years and the 5-year overall and disease-specific survival rates were 49.7 and 73.9%, respectively. The cut-off value for CAR was calculated using a receiver operator characteristics analysis and patients were dichotomized accordingly. Patients with a low CAR had significantly higher overall survival than those with a high CAR (<0.028; 65.2% vs. ≥0.028; 31.0%, respectively; p < 0.01). In univariate analysis, female gender, a low Charlson comorbidity index of 0 or 1 and a low CAR were significantly identified in overall survival. On multivariate analysis, a low CAR (p = 0.03, hazard ratio: 2.13, 95% confidence interval 1.074–4.295) was identified as a significant prognostic factor.Conclusions
The preoperative CAR is a useful predictor of overall survival and could be a simple prognostic tool to help identify resectable NSCLC in elderly patients.Purpose
The aim of this study is to investigate the surgical outcomes of surgery for non-small cell lung cancer (NSCLC) in patients with coronary artery disease (CAD).Methods
Among 805 patients who underwent surgery for NSCLC at our hospital within a recent 10-year period, 43 (5.3 %) had a history of CAD. We analyzed the surgical outcomes and risk factors for postoperative complications in these 43 patients.Results
The postoperative mortality and morbidity rates were 2 and 42 %, respectively. The morbidity rate was significantly higher in the patients with CAD than in those without CAD (P < 0.01). Postoperative cerebrovascular or cardiovascular events occurred in four patients (9 %). Having two of the following was significantly associated with the development of postoperative complications: decreased cardiac function, respiratory dysfunction, or deteriorated renal function (p = 0.04). The 5-year overall and disease-free survival rates of the patients with CAD were 75.6 and 64.5 %, respectively; comparable with those of the patients without CAD; at 77.9 % and 72.5 %, respectively (p = 0.46 and 0.69).Conclusions
Patients with NSCLC and a history of CAD are at higher risk of complications after pulmonary resection. Combined decreased organ function is a risk factor for postoperative complications. CAD did not influence the long-term outcomes of patients after pulmonary resection for NSCLC.![点击此处可从《Pediatric blood & cancer》网站下载免费的PDF全文](/ch/ext_images/free.gif)