Most patients with non‐small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations, such as deletions in exon 19 or the L858R mutation in exon 21, respond ...dramatically to EGFR tyrosine kinase inhibitors (EGFR‐TKI), and their sensitivities to various EGFR‐TKI have been well characterized. Our previous article showed the in vitro sensitivities of EGFR exon 18 mutations to EGFR‐TKI, but little information regarding the sensitivities of other uncommon EGFR mutations is available. First, stable transfectant Ba/F3 cell lines harboring EGFR L858R (Ba/F3‐L858R), L861Q (Ba/F3‐L861Q) or S768I (Ba/F3‐S768I) mutations were created and their drug sensitivities to various EGFR‐TKI were examined. Both the Ba/F3‐L861Q and Ba/F3‐S768I cell lines were less sensitive to erlotinib, compared with the Ba/F3‐L858R cell line, but their sensitivities to afatinib were similar to that of the Ba/F3‐L858R cell line. The Ba/F3‐L861Q cell line was similarly sensitive and the Ba/F3‐S768I cell line was less sensitive to osimertinib, compared with the Ba/F3‐L858R cell line. The results of western blot analyses were consistent with these sensitivities. Next, similar experiments were also performed using the KYSE270 (L861Q) and KYSE 450 (S768I) cell lines, and their results were compatible with those of the transfectant Ba/F3 cell lines. Our findings suggest that NSCLC harboring the EGFR L861Q mutation might be sensitive to afatinib or osimertinib and that NSCLC harboring the EGFR S768I mutation might be sensitive to afatinib. Overall, afatinib might be the optimal EGFR‐TKI against these uncommon EGFR mutations.
In this study, we focused on the EGFR L861Q and S768I mutations and investigated the in vitro sensitivities of cells carrying these mutations to various EGFR‐tyrosine kinase inhibitors (TKIs). Non‐small cell lung cancer (NSCLC) harboring the EGFR L861Q mutation might be sensitive to afatinib or osimertinib but not to erlotinib, and NSCLC harboring the EGFR S768I mutation might be sensitive to afatinib but not to erlotinib or osimertinib. Afatinib might be the optimal EGFR‐TKI against these uncommon EGFR mutations.
Neuromuscular electrical stimulation has been used to treat cardiovascular diseases and other types of muscular dysfunction. A novel whole-body neuromuscular electrical stimulation (WB-NMES) wearable ...device may be beneficial when combined with voluntary exercises. This study aimed to investigate the safety and effects of the WB-NMES on hemodynamics, arrhythmia, and sublingual microcirculation. The study included 19 healthy Japanese volunteers, aged 22–33 years, who were not using any medication. Electrocardiogram (ECG), echocardiography, and blood sampling were conducted before a 20-min WB-NMES session and at 0 and 10 min after termination of WB-NMES. Their tolerable maximum intensity was recorded using numeric rating scale. Arrhythmia was not detected during neuromuscular electrical stimulation or during 10 min of recovery. Blood pressure, heart rate, left ventricular ejection fraction, and diastolic function remained unchanged; however, mild mitral regurgitation was transiently observed during WB-NMES in a single male participant. A decrease in blood glucose and an increase in blood lactate levels were observed, but no changes in blood fluidity, sublingual microcirculation, blood levels of noradrenaline, or oxidative stress were shown. WB-NMES is safe and effective for decreasing blood glucose and increasing blood lactate levels without changing the blood fluidity or microcirculation in healthy people.
Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little ...is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non‐small cell lung cancer. We have now applied next‐generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined in vitro, and its effects on tumor formation were examined in vivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG‐positive LSCC cell lines in association with attenuation of the FGFR1–ERK signaling pathway in vitro and in vivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy.
The angiokinase inhibitor nintedanib is a potential targeted agent for lung squamous cell carcinoma (LSCC) positive for genetic alterations affecting FGFR genes. We screened 75 LSCC specimens for FGFR alterations by next‐generation sequencing and thereby identified various such genetic changes including copy number gain, mutations, and a fusion in 15 of the 75 (20.0%) cases. Among the patients with relapse after surgery, the presence of FGFR alterations was associated with a significantly shorter overall survival.
Highlights • An in vitro model of MET exon 14 deletion using the CRISPR/Cas9 system was created. • This model has shown enhanced cellular growth and MET inhibitor sensitivity. • This CRISPR/Cas9 ...system may be useful for such experiments. • In the database, lung cancer had the highest incidence of MET exon 14 deletions. • MET inhibitors against lung cancer with MET exon 14 deletion should be developed.
Highlights • The plasma activin A level can be a prognostic factor in patents with advanced pancreatic cancer (PC). • The activin signal promotes cancer progression via non-SMAD pathways in a subset ...of PC and might be involved in cachexia. • The activin signal might be a novel target for the treatment of PC.
Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the ...MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFR-mutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.
Vigorous exercise increases blood viscosity and may pose a risk of cardiovascular events in patients with cardiovascular diseases. We recently reported that single-use of novel whole-body ...neuromuscular electrical stimulation (WB-NMES) can be safely applied in healthy subjects without adversely affecting blood fluidity. We performed a crossover study to explore the effectiveness and safety of a hybrid exercise with ergo-bicycle and WB-NMES; 15 healthy volunteers, aged 23–41 years, participated in this study. No arrhythmias were detected during the hybrid exercise and 20 min recovery, and although blood fluidity was transiently exacerbated immediately after both the exercise programs, in vivo parameters in the sublingual and nailfold microcirculation remained unchanged. There was a significant decrease in blood glucose and increase in lactic acid levels immediately after both exercise programs. Even with the same workload as the cycle ergometer exercise, the oxygen intake during the hybrid exercise remained higher than that during the cycle ergometer exercise alone (p < 0.05, r = 0.79, power = 0.81). Both the hybrid and voluntary cycle ergometer exercises transiently exacerbated blood fluidity ex vivo; however, microvascular flow was not adversely affected in vivo.
Somatic mutations in KRAS, NRAS, and BRAF genes are related to resistance to anti-EGFR antibodies in colorectal cancer. We have established an extended RAS and BRAF mutation assay using a ...next-generation sequencer to analyze these mutations. Multiplexed deep sequencing was performed to detect somatic mutations within KRAS, NRAS, and BRAF, including minor mutated components. We first validated the technical performance of the multiplexed deep sequencing using 10 normal DNA and 20 formalin-fixed, paraffin-embedded (FFPE) tumor samples. To demonstrate the potential clinical utility of our assay, we profiled 100 FFPE tumor samples and 15 plasma samples obtained from colorectal cancer patients. We used a variant calling approach based on a Poisson distribution. The distribution of the mutation-positive population was hypothesized to follow a Poisson distribution, and a mutation-positive status was defined as a value greater than the significance level of the error rate (α = 2 x 10(-5)). The cut-off value was determined to be the average error rate plus 7 standard deviations. Mutation analysis of 100 clinical FFPE tumor specimens was performed without any invalid cases. Mutations were detected at a frequency of 59% (59/100). KRAS mutation concordance between this assay and Scorpion-ARMS was 92% (92/100). DNA obtained from 15 plasma samples was also analyzed. KRAS and BRAF mutations were identified in both the plasma and tissue samples of 6 patients. The genetic screening assay using next-generation sequencer was validated for the detection of clinically relevant RAS and BRAF mutations using FFPE and liquid samples.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Type 2 diabetes mellitus (T2DM) is associated with changes in skeletal muscle quantity and quality, such as increased ectopic fat. Cardiac rehabilitation (CR) aims to improve the exercise ...capacity and muscle strength. This study aimed to determine the relationship between qualitative changes in the skeletal muscles and exercise function in patients with and without diabetes mellitus. Methods The study included patients with cardiovascular diseases who entered CR. Of 72 CR patients (68.1±9.0 years) who underwent a cardiopulmonary exercise test and skeletal muscle assessment at discharge, 15 patients with T2DM and 15 without DM were selected using propensity score matching by age and gender. Results No significant differences in the skeletal muscle echo intensity (EI) (T2DM: 58.4, Non-DM: 53.4, p=0.32), skeletal muscle index (T2DM: 7.5 kg/m
, Non-DM: 7.2 kg/m
, p=0.36), or the weight-bearing index (WBI)(T2DM: 0.44, Non-DM: 0.50, p=0.35) existed between the two groups. The phase angle (PhA) (T2DM: 3.67°, Non-DM: 4.49°, p<0.05) and peak oxygen uptake (T2DM: 12.3 mL/kg/min, Non-DM: 14.8 mL/kg/min, p<0.05) were significantly lower in the T2DM group. PhA values showed a significant correlation with the WBI, a parameter of lower limb muscle strength (r=0.50, p<0.05). Conclusion The coexistence of cardiovascular disease and T2DM resulted in a decrease in the PhA, indicating a qualitative decrease in skeletal muscle mass. The PhA is also associated with lower limb muscle strength.
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