AZD9291 (osimertinib) is designed for acquired T790M mutation after first- and second-generation EGFR) tyrosine kinase inhibitors have been used. Some of the resistance mechanisms that present after ...osimertinib treatment, including a newly acquired EGFR C797S mutation, have been identified. It is unclear, however, whether the bypass pathway is also a mechanism of resistance in patients after osimertinib treatment.
Cells from malignant pleural effusion were collected and cultured at the time of progression in a patient being treated with osimertinib. Tumor genotyping was done by matrix-assisted laser desorption ionization–time of flight mass spectrometry. EGFR, AKT, MEK, and ERK phosphorylation were determined. An anchorage-dependent colony formation assay was used for drug sensitivity.
An acquired mutation, BRAF V600E, was found in the patient at the time of progression while being treated with osimertinib. Cells grown from malignant pleural effusion were sensitive to BRAF V600E inhibitor and were more vulnerable to a combination treatment with osimertinib.
A potential mechanism of acquired resistance to osimertinib in patients with T790M is through the BRAF pathway. Simultaneous blockade of the BRAF and EGFR had a significant inhibitory effect.
The relationship between cholesterol level and hemorrhagic stroke is inconclusive. We hypothesized that low cholesterol levels may have association with intracerebral hemorrhage (ICH) severity at ...admission and 3-month outcomes. This study used data obtained from a multi-center stroke registry program in Taiwan. We categorized acute spontaneous ICH patients, based on their baseline levels of total cholesterol (TC) measured at admission, into 3 groups with <160, 160-200 and >200 mg/dL of TC. We evaluated risk of having initial stroke severity, with National Institutes of Health Stroke Scale (NIHSS) >15 and unfavorable outcomes (modified Rankin Scale mRS score >2, 3-month mortality) after ICH by the TC group. A total of 2444 ICH patients (mean age 62.5±14.2 years; 64.2% men) were included in this study and 854 (34.9%) of them had baseline TC <160 mg/dL. Patients with TC <160 mg/dL presented more often severe neurological deficit (NIHSS >15), with an adjusted odds ratio aOR of 1.80; 95% confidence interval CI, 1.41-2.30), and 3-month mRS >2 (aOR, 1.41; 95% CI, 1.11-1.78) using patients with TC >200 mg/dL as reference. Those with TC >160 mg/dL and body mass index (BMI) <22 kg/m2 had higher risk of 3-month mortality (aOR 3.94, 95% CI 1.76-8.80). Prior use of lipid-lowering drugs (2.8% of the ICH population) was not associated with initial severity and 3-month outcomes. A total cholesterol level lower than 160 mg/dL was common in patients with acute ICH and was associated with greater neurological severity on presentation and poor 3-month outcomes, especially with lower BMI.
Although Western theories suggest that ethical leaders should incorporate role modelling with ethical guidance to effectively promote ethical actions, we argue that, in Taiwan, a non‐Western setting ...influenced by Taoism, ‘say less, do more’ may be more appropriate. Mean comparisons, based on a latent profile analysis, indicate that, in our Taiwanese sample, leaders high in role modelling and low in ethical guidance receive at least as high a moral evaluation as that of those high in both. Findings from the United States sample, in contrast, suggest that the latter receive the highest. In a follow‐up scenario experiment, we find that, for Taiwanese respondents, leaders’ ethical guidance is negatively associated with perceived leader humility but positively associated with follower depletion and that the ‘say less, do more’ condition obtains the highest perceived leader humility and lowest expected depletion. In contrast, for US respondents, ethical guidance is unrelated to the two outcomes. Accordingly, not only the ideal content but also the ‘best’ enactment of ethical leadership varies across cultures.
The T790M mutation is the major resistance mechanism to first- and second-generation TKIs in EGFR-mutant NSCLC. This study aimed to investigate the utility of droplet digital PCR (ddPCR) for ...detection of T790M in plasma circulating tumor DNA (ctDNA), and explore its impact on prognosis.
This prospective study enrolled 80 advanced lung adenocarcinoma patients treated with gefitinib, erlotinib, or afatinib for TKI-sensitizing mutations between 2015 and 2019. Plasma samples were collected before TKI therapy and at tri-monthly intervals thereafter. Genotyping of ctDNA for T790M was performed using a ddPCR EGFR Mutation Assay. Patients were followed up until the date of death or to the end of 2021.
Seventy-five of 80 patients experienced progressive disease. Fifty-three (71%) of 75 patients underwent rebiopsy, and T790M mutation was identified in 53% (28/53) of samples. Meanwhile, plasma ddPCR detected T790M mutation in 23 (43%) of 53 patients. The concordance rate of T790M between ddPCR and rebiopsy was 76%, and ddPCR identified 4 additional T790M-positive patients. Ten (45%) of 22 patients who did not receive rebiopsy tested positive for T790M by ddPCR. Serial ddPCR analysis showed the time interval from detection of plasma T790M to objective progression was 1.1 (0-4.1) months. Compared to 28 patients with rebiopsy showing T790M, the overall survival of 14 patients with T790M detected solely by ddPCR was shorter(41.3 95% CI, 36.6-46.0 vs. 26.6 months 95% CI, 9.9-43.3, respectively).
Plasma ddPCR-based genotyping is a useful technology for detection and monitoring of the key actionable genomic alteration, namely, T790M, in patients treated with gefitinib, erlotinib, or afatinib for activating mutations, to achieve better patient care and outcome.
PurposeDuring COVID-19 restrictions, people spent more time in cyberspace and consuming health-related information. An increase was also observed in mediated caring messages or health-relevant ...information sent to one another. This study aims to explore how the information and interactions around COVID-19 can provide a good learning opportunity for public health, specifically related to eHealth literacy and eHealth promotion.Design/methodology/approachWhile mainstream literature has concentrated on experimental designs and a priming effect, this study inspects psychological distance related to a health threat under real-life circumstances. The article adopted a survey approach and utilized PLS-SEM techniques to examine the proposed hypotheses.FindingsResults indicated that whereas closer social support correlates with closer psychological distance and less usage of the social media approach, more substantial COVID-19 impacts were associated with closer psychological distance but greater use of social media. Since both closer psychological distance and social media approach contribute to eHealth literacy, social support from closer and virtual social networks should be embraced but utilized through different routes and for different purposes. The timing of messages but not psychological distance affects people's social media approach, indicating that morning messages should be employed. Moreover, eHealth literacy mediates timing preferences and leads to a preference for eHealth communication earlier in the day. Overall, morning messages create a virtuous circle during a health crisis.Originality/valueThis paper establishes a mechanism of virtuous cycles for eHealth communication during a health threat. Additionally, it bridges existing research gaps by expanding chronopsychology and CLT in the health domain using an empirical approach, a real-life case and an extension of performance regarding information-seeking and utilization.
High myopia is a sight-threatening disease that causes axial length elongation and severe complications. Data on the benefits of posterior scleral reinforcement surgery in myopia control have been ...conflicting. The purpose of this study was to explore the treatment effect and complications of posterior scleral reinforcement in the treatment of myopia.
Articles were retrieved for relevant studies from inception to July 24, 2019, by PubMed, EMBASE, and Ovid. Analyses were conducted to compare the treatment effects of controlling spherical equivalent refraction and axial length elongation. The weighted mean difference and Hedges' adjusted g were used to evaluate the treatment effects, with a random-effects model. Heterogeneity was quantified using I2 statistic and explored by subgroup analysis. Publication bias was addressed by funnel plots and Egger's test.
A total of 11 articles were included in this meta-analysis. On estimating the treatment effect, the mean differences of myopia progression and axial length changes between surgery and control groups were 0.41 diopters per year (95% CI 0.21 to 0.61; P < .001) and -0.17 mm per year (95% CI -0.22 to -0.11; P < .001). Subgroup analysis showed significant treatment effects of the single wide strip operation. Single-arm meta-analysis showed less annual axial elongation in children subgroup. These results were robust by sensitivity analysis. The incidence of some major complications in the operation group were significantly greater (5.8% vs 2.7% for myopic degeneration; 2.3% vs 1.6% for macular hemorrhage; 0.8% vs 0 for retinal detachment).
Posterior scleral reinforcement may be an effective surgery on controlling myopia progression by slowing both refraction and axial length change. However, frequent surgical complications should be considered. Further well-designed studies are needed to determine the long-term safety and efficacy.
•STFT-ranking feature is efficient for multi-channel EMG signal analysis.•STFT-ranking feature can characterize relationships between multi-channel signals.•Recognition accuracy over 90% was achieved ...applying the STFT-ranking feature.•The performance of STFT-ranking feature is superior to conventional features.•STFT-ranking feature can be applied to other multi-channel signals applications.
Electromyography (EMG) is widely applied for neural engineering. For motion pattern recognition, many features of multi-channel EMG signals were investigated, but the relationships between muscles were not considered. In this study, a novel STFT-ranking feature based on short-time Fourier transform (STFT) is proposed. The novelty of STFT-ranking features is considering and covering the relationship information between EMG signals and multiple muscles in a motion pattern. With an exoskeleton robot arm, two series of motion patterns corresponding to the shoulder and elbow in the sagittal plane were investigated. EMG signals from six muscles were acquired in arm motion patterns when participants worn the robot arm. Four types of feature combinations, including seven conventional features, were compared with the STFT-ranking feature. The principal component analysis (PCA) and support vector machine (SVM) were used to build the motion recognition model. With the STFT-ranking feature, the recognition performance (93.9%) is superior to the conventional features (33.3–90.8%). The recognition variation is smaller (SD=4.3%) than the other features tested (SD=5.9–13.8%). These achievements will contribute to the advancement of control method of exoskeleton robots or power orthoses based on multi-channel EMG signals in the future. Based on the principle of STFT-ranking feature, the method also has potential for other multi-channel signal applications, such as electroencephalography (EEG) signal processing, speech recognition, and acoustic analysis.
•This paper addresses underexplored marketing–production co-location, proposing it as a low-profile strategy to cultivate flexibility, marketing capabilities, and chances to transform into own brand ...manufacturing.•International experience breadth, local linkages to R&D and marketing as a primary knowledge source, upgrading for local demands and new product development for global supply are positively associated with marketing co-location, while international experience depth does not show a significant relationship.•Marketing innovation is an effective means during a crisis; however, there was a negative association between FDIs that had been impacted by COVID-19 and marketing co-location.
Co-location has been a relevant topic in the international business literature, yet the extant literature focuses on the co-location of research and development (R&D) and production activities and overlooks marketing value activities. Marketing innovation is an agile and effective way to respond to crises such as the COVID-19 pandemic, and many manufacturers in global value chains aim to upgrade functionally following the trajectory of the OEM-ODM-OBM. Thus, this study proposes the co-location of marketing activities as a flexible and organizational learning strategy for manufacturing upgrades, and explores the antecedents of marketing co-location in foreign direct investment (FDI) decisions. The proposed research framework was examined using survey data from 343 Taiwanese manufacturing firms in China, which were drawn from a database compiled by Taiwan’s Ministry of Economic Affairs in 2020. The results show that the breadth of international experience, linkage to R&D, marketing as a primary knowledge source in the host country, upgrading for local demands, and new product development for global supply are all positively associated with the co-location of marketing and production functions. Additionally, it was found that there was a negative association between FDIs that had been impacted by COVID-19 and marketing co-location. The findings provide valuable theoretical, practical, and strategic insights into how firms should manage their global value chains with respect to marketing co-location in case of another crisis.
Rheumatoid arthritis (RA) is a common systemic autoimmune disease in developed countries. In clinical treatment, steroids have been used as bridging and adjunctive therapy after disease-modifying ...anti-rheumatic drug administration. However, the severe side effects caused by the nonspecific targeting of organs followed by long-term administration have limited their usage in RA. In this study, poorly water-soluble triamcinolone acetonide (TA), a highly potent corticosteroid for intra-articular injection, is conjugated on hyaluronic acid (HA) for intravenous purposes with increased specific drug accumulation in inflamed parts for RA. Our results demonstrate that the designed HA/TA coupling reaction reveals >98 % conjugation efficiency in the dimethyl sulfoxide/water system, and the resulting HA-TA conjugates show lower osteoblastic apoptosis compared with that in free TA-treated osteoblast-like NIH3T3 cells. Furthermore, in a collagen-antibody-induced arthritis animal study, HA-TA conjugates enhanced the initiative targeting ability to inflame tissue and reduce the histopathological arthritic changes (score = 0). Additionally, the level of bone formation marker P1NP in HA-TA-treated ovariectomized mice (303.6 ± 40.6 pg/mL) is significantly higher than that in the free TA-treated group (143.1 ± 3.9 pg/mL), indicating the potential for osteoporotic reduction using an efficient HA conjugation strategy for the long-term administration of steroids against RA.
•Poorly water-soluble steroids triamcinolone acetonide was successfully conjugated to hyaluronic acid (HA-TA).•HA-TA showed high conjugation efficiency above 98 % using DIC/Oxyma coupling strategy.•HA-TA conjugates revealed massive targeting ability to the inflamed joint and ankle.•Bone formation marker was increased by HA-TA compared with that of glucocorticoids treatments•HA-TA significantly decreased the glucocorticoid-induced apoptosis in osteoblastic-like cells.
Background
Malignant pleural effusion (MPE)-macrophage (Mφ) of lung cancer patients within unique M1/M2 spectrum showed plasticity in M1–M2 transition. The M1/M2 features of MPE-Mφ and their ...significance to patient outcomes need to be clarified; furthermore, whether M1-repolarization could benefit treatment remains unclear.
Methods
Total 147 stage-IV lung adenocarcinoma patients undergoing MPE drainage were enrolled for profiling and validation of their M1/M2 spectrum. In addition, the MPE-Mφ signature on overall patient survival was analyzed. The impact of the M1-polarization strategy of patient-derived MPE-Mφ on anti-cancer activity was examined.
Results
We found that MPE-Mφ expressed both traditional M1 (HLA-DRA) and M2 (CD163) markers and showed a wide range of M1/M2 spectrum. Most of the MPE-Mφ displayed diverse PD-L1 expression patterns, while the low PD-L1 expression group was correlated with higher levels of IL-10. Among these markers, we identified a novel two-gene MPE-Mφ signature, IL-1β and TGF-β1, representing the M1/M2 tendency, which showed a strong predictive power in patient outcomes in our MPE-Mφ patient cohort (
N
= 60,
p
= 0.013) and The Cancer Genome Atlas Lung Adenocarcinoma dataset (
N
= 478,
p
< 0.0001). Significantly, β-glucan worked synergistically with IFN-γ to reverse the risk signature by repolarizing the MPE-Mφ toward the M1 pattern, enhancing anti-cancer activity.
Conclusions
We identified MPE-Mφ on the M1/M2 spectrum and plasticity and described a two-gene M1/M2 signature that could predict the outcome of late-stage lung cancer patients. In addition, we found that “re-education” of these MPE-Mφ toward anti-cancer M1 macrophages using clinically applicable strategies may overcome tumor immune escape and benefit anti-cancer therapies.
PDF
