Non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (
) exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, ...an EGFR-MET bispecific antibody with immune cell-directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site.
CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with
Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum
Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5.
In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively.
Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with
Exon20ins mutations after progression on platinum-based chemotherapy.
This study aimed to challenge chemoresistance by curcumin (CUR) with drug-selected human lung cancer A549 sublines that continuously proliferate in the present of docetaxel (DOC) and vincristine ...(VCR). Their sensitivities to CUR were measured by MTT assay and the particular intracellular reactive oxygen species (ROS) was detected by fluorescence activated cell sorting (FACS) analysis. Apoptosis was analyzed by Annexin V assay of the flow cytometry. Inhibitors and RNA interference were used to examine the signaling pathway regulated by the kinases. The obtained data demonstrated that CUR induces chemoresistant cell apoptosis by generating ROS and application of N-acetylcysteine (NAC) blocks ROS production, resulting in apoptosis suppression. Phosphorylation of extracellular regulated kinase (ERK), p38 MAPK, and eIF-2α were increased but c-Jun N-terminal kinase (JNK) did not increase when chemoresistant cells were treated with CUR. Downregulation of ERK and p38 MAPK phosphorylation by their inhibitors had no effect on CUR-induced apoptosis. Interestingly, the knockdown of p38 MAPK with shRNA significantly reduced CUR-induced apoptosis on the chemoresistant sublines. Phosphorylation of the eIF-2α protein was inhibited when p38 MAPK was knocked down in DOC-resistant A549 cells, but a high level of phosphorylated eIF-2α protein remained on the VCR-resistant A549 cells when p38 MAPK was knocked down. These data confirmed that CUR-augmented ROS potently induced apoptosis via upregulated p38 MAPK phosphorylation. Therefore, activated p38 MAPK is considered a pro-apoptotic signal for CUR-induced apoptosis of chemoresistant human lung cancer cells.
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Due to the overconsumption of antimicrobials, antibiotic-resistant bacteria have become a critical health issue worldwide, especially methicillin-resistant S. aureus (MRSA) and vancomycin-resistant ...E. faecalis (VRE). Recently, many efforts have been made to load metals into bioactive glasses to enhance the multifunctionality of materials, such as antibacterial and osteoinductive functions. Zinc has been documented to stimulate the gene expression of various regulatory factors in bone cells. Meanwhile, previous studies have reported that silver and zinc could be a promising antibacterial combination with synergistic antimicrobial effects. Here, we sought to develop a biomaterial coreleasing zinc and silver, designated 80S-ZnAg, and to evaluate its antibacterial activity and biocompatibility. The textural analyses demonstrated different coreleasing patterns of zinc and silver for the materials. The chemical characterization revealed that the zinc in 80S-ZnAg could be the network modifier when its molar ratio was high, releasing more zinc; zinc could also be the network former when its molar ratio was low, showing an extremely low rate of release. However, the ICP results for 80S-Zn3Ag2 demonstrated up to 7.5 ppm of zinc and 67.6 ppm of silver. Among all the 80S-ZnAg materials, 80S-Zn3Ag2 demonstrated more marked antibacterial activity against MRSA and VRE than the others, with inhibition zones of 11.5 and 13.4 mm, respectively. The cytotoxicity assay exhibited nearly 90% cell viability at 20 mg/mL of 80-Zn3Ag2. Further clinical study is needed to develop an innovative biomaterial to address the issue of antibiotic resistance.
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For never-smokers (smoked <100 lifetime cigarettes), lung cancer (LC) has emerged as an important issue. We aimed to investigate the effects of prevalence changes in tobacco smoking and particulate ...matter (PM) 2.5 (PM2.5) levels on LC in Taiwan, in relation to contrasting PM2.5 levels, between Northern Taiwan (NT) and Southern Taiwan (ST).
We reviewed 371,084 patients with LC to assess smoking prevalence and correlations between the incidence of adenocarcinoma lung cancer (AdLC) and non-AdLC. Two subsets were selected to assess different AdLC stage trends and the effect of PM2.5 on survival of patients with AdLC.
From 1995 to 2015, the proportion of male adult ever-smokers decreased from 59.4% to 29.9% whereas the female smoking rate remained low (3.2% to 5.3%). AdLC incidence in males and females increased from 9.06 to 23.25 and 7.05 to 24.22 per 100,000 population, respectively. Since 1993, atmospheric visibility in NT improved (from 7.6 to 11.5 km), but deteriorated in ST (from 16.3 to 4.2 km). The annual percent change in AdLC stages IB to IV was 0.3% since 2009 (95% confidence interval CI: -1.9%–2.6%) in NT, and 4.6% since 2007 (95% CI: 3.3%–5.8%) in ST; 53% patients with LC had never smoked. Five-year survival rates for never-smokers, those with EGFR wild-type genes, and female patients with AdLC were 12.6% in NT and 4.5% in ST (hazard ratio: 0.79, 95% CI: 0.70–0.90).
In Taiwan, greater than 50% of patients with LC had never smoked. PM2.5 level changes can affect AdLC incidence and patient survival.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PurposeThis study aims to explore preadolescents' opinions of the social media marketing strategies hosted by libraries to promote collections.Design/methodology/approachAn experimental Facebook page ...was created with posts containing interesting animations, games and book recommendations. A questionnaire survey was administered to 262 preadolescents between 11 and 13 years old to seek their opinions about the posts, and confirmatory factor analysis was used to measure their acceptance of the marketing strategies.FindingsThe authors examined the effects of five marketing strategies: word-of-mouth marketing, buzz marketing, event marketing, viral marketing and gamification marketing. In terms of sharing, word-of-mouth marketing proved the most popular, followed by buzz marketing. Participants were least accepting of viral marketing. The authors found that gamification marketing resulted in higher engagement than did event marketing. The preadolescent participants preferred engagement marketing strategies over information sharing strategies.Originality/valueAccording to the uses and gratification theory, preadolescents seek, share and engage with information in ways that differ from other age groups. With specific reference to hedonic engagement by preadolescents, the authors built a two-fold model to describe the information-seeking behaviors of preadolescents from the perspective of marketing strategies. The study findings indicate that librarians who use Facebook to promote library collections should first employ gamification and word-of-mouth marketing to build trust with preadolescent users. Event and buzz marketing will then be more effective when applied within the context of this trust.
It is important to select appropriate targeted therapies for subgroups of patients with lung adenocarcinoma who have specific gene alterations.
This prospective study was a multicenter project ...conducted in Taiwan for assessment of lung adenocarcinoma genetic tests. Five oncogenic drivers, including EGFR, KRAS, BRAF, HER2 and EML4-ALK fusion mutations, were tested. EGFR, KRAS, BRAF and HER2 mutations were assessed by MALDI-TOF MS (Cohort 1). EML4-ALK translocation was tested by Ventana method in EGFR-wild type patients (Cohort 2).
From August 2011 to November 2013, a total of 1772 patients with lung adenocarcinoma were enrolled. In Cohort 1 analysis, EGFR, KRAS, HER2 and BRAF mutations were identified in 987 (55.7%), 93 (5.2%), 36 (2.0%) and 12 (0.7%) patients, respectively. Most of these mutations were mutually exclusive, except for co-mutations in seven patients (3 with EGFR + KRAS, 3 with EGFR + HER2 and 1 with KRAS + BRAF). In Cohort 2 analysis, 29 of 295 EGFR-wild type patients (9.8%) were positive for EML4-ALK translocation. EGFR mutations were more common in female patients and non-smokers and KRAS mutations were more common in male patients and smokers. Gender and smoking status were not correlated significantly with HER2, BRAF and EML4-ALK mutations. EML4-ALK translocation was more common in patients with younger age.
This was the first study in Taiwan to explore the incidence of five oncogenic drivers in patients with lung adenocarcinoma and the results could be valuable for physicians in consideration of targeted therapy and inclusion of clinical trials.
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Update on fosfomycin-modified genes in Enterobacteriaceae Yang, Tsung-Ying; Lu, Po-Liang; Tseng, Sung-Pin
Journal of microbiology, immunology and infection,
February 2019, 2019-Feb, 2019-02-00, 20190201, 2019-02-01, Volume:
52, Issue:
1
Journal Article
Peer reviewed
Open access
The long-used antibiotic fosfomycin has recently been re-evaluated as a potential regimen for treating extended-spectrum β-lactamases (ESBLs) and carbapenem-resistant Enterobacteriaceae (CRE). ...Fosfomycin is known for its robust bactericidal effect against ESBL-producing Enterobacteriaceae and CRE. However, fosfomycin-modified genes have been reported in transposon elements and conjugative plasmids, resulting in fosfomycin resistance in parts of East Asia. Here we review reports of fosfomycin-modified (fos) genes in Enterobacteriaceae and assess the efficacy of fosfomycin against multidrug-resistant Enterobacteriaceae infections. At least 10 kinds of fos genes have been identified in the past decade; of these, fosA (and fosA subtypes) and fosC2 are primarily found in Enterobacteriaceae. All fosA subtypes except fosA2 are found in plasmids and transposons, nearby insertion sequence elements, or integrons, indicating that mobilizing elements also play an important role in plasmid-mediated fos genes in Enterobacteriaceae. fosA3, which is prevalent in East Asia, has been transmitted (mostly by animals) within and across continents via IS26 mobile elements. The acquisition of multiple antibiotic resistance genes via plasmids and mobile elements has resulted in a need for combined treatments for Enterobacteriaceae cases. The combination of fosfomycin and carbapenem has been the focus of many in vitro studies, but there is a clear need for additional in vivo investigations involving pharmacokinetics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lung cancer is considered the number one cause of cancer-related deaths worldwide. Although current treatments initially reduce the lung cancer burden, relapse occurs in most cases; the major causes ...of mortality are drug resistance and cancer stemness. Recent investigations have provided evidence that shikonin generates various bioactivities related to the treatment of cancer. We used shikonin to treat multi-resistant non-small lung cancer cells (DOC-resistant A549/D16, VCR-resistant A549/V16 cells) and defined the anti-cancer efficacy of shikonin. Our results showed shikonin induces apoptosis in these
-dependent and independent chemoresistance cancer sublines. Furthermore, we found that low doses of shikonin inhibit the proliferation of lung cancer stem-like cells by inhibiting spheroid formation. Concomitantly, the mRNA level and protein of stemness genes (
and
) were repressed significantly on both sublines. Shikonin reduces the phosphorylated Akt and p70s6k levels, indicating that the PI3K/Akt/mTOR signaling pathway is downregulated by shikonin. We further applied several signaling pathway inhibitors that have been used in anti-cancer clinical trials to test whether shikonin is suitable as a sensitizer for various signaling pathway inhibitors. In these experiments, we found that low doses shikonin and dual PI3K-mTOR inhibitor (BEZ235) have a synergistic effect that inhibits the spheroid formation from chemoresistant lung cancer sublines. Inhibiting the proliferation of lung cancer stem cells is believed to reduce the recurrence of lung cancer; therefore, shikonin's anti-drug resistance and anti-cancer stem cell activities make it a highly interesting molecule for future combined lung cancer therapy.
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This article investigates a hybrid ferroelectric charge trap (HFCT)-based HfZrO4/HfO<inline-formula> <tex-math notation="LaTeX">_{\textit{X}}</tex-math> </inline-formula>N<inline-formula> <tex-math ...notation="LaTeX">_{\textit{Y}}</tex-math> </inline-formula>/ Al2O3/AlGaN/GaN gate-stack under constant positive gate voltage stress over time and temperature variability. The experimentally characterized breakdown (BD) analysis implies a thermally assisted tunneling (TAT) BD owing to the negative temperature coefficient of BD voltage. Moreover, the step gate stress depicts a relatively lower BD voltage of <inline-formula> <tex-math notation="LaTeX">\sim</tex-math> </inline-formula>20 V compared to the linear gate stress voltage of <inline-formula> <tex-math notation="LaTeX">\sim</tex-math> </inline-formula>21.85 V attributed to performance degradation due to stress. In addition, the Weibull distribution, which validates the intrinsic degradation of the gate-stack, is used to estimate its lifetime. An operating voltage of <inline-formula> <tex-math notation="LaTeX">\sim</tex-math> </inline-formula>7.41 V exhibits a ten-year lifetime at 150 <inline-formula> <tex-math notation="LaTeX">^{\circ}</tex-math> </inline-formula>C extrapolated over multiple stress conditions. Furthermore, the activation energy from <inline-formula> <tex-math notation="LaTeX">\sim</tex-math> </inline-formula>0.63 to <inline-formula> <tex-math notation="LaTeX">\sim</tex-math> </inline-formula>0.67 eV validates deep-level E3 traps within the GaN barrier layer and the trapping of electrons during degradation, thus, revealing the point-level defect generation leading to the time-dependent gate dielectric BD (TDDB). The robustness and superior reliability of the HFCT gate-stack are recognized, and the single degradation mechanism contributes to the final device failure in the TDDB test.
We aimed to evaluate whether different driver mutations have varying impacts on the programmed cell death-ligand 1 (PD-L1) expression of non-small cell lung cancer (NSCLC), and whether the prognostic ...roles of PD-L1 amongst our patients were divergent. This was a single-institute study that included patients with NSCLC. Six driver mutations, PD-L1 status, and the outcomes of treatment were assessed. A total of 1,001 NSCLC patients were included for analysis. Overall, the PD-L1 positive (TPS ≥ 1%) and strong positive (TPS ≥ 50%) rates were 52.2% and 17.3%, respectively. As compared with wild type lung adenocarcinoma, EGFR-mutant and HER2-mutant patients had similarly low PD-L1 and strong PD-L1 positive rates. BRAF-mutant patients had numerically higher PD-L1 and strong PD-L1 positive rates. Patients with fusion mutation (ALK and ROS1) (aOR 2.32 95% CI 1.10-4.88, P = 0.027 and 2.33 95% CI 1.11-4.89, P = 0.026), KRAS mutation (aOR 2.58 95% CI 1.16-5.75, P = 0.020 and 2.44 95% CI 1.11-5.35, P = 0.026), and non-adenocarcinoma histology (aOR 2.73 95% CI 1.72-4.34, P < 0.001 and 1.93 95% CI 1.13-3.30, P = 0.016) all had significantly higher PD-L1 and strong PD-L1 positive rates. A trend towards longer survival was noted in ROS-1 rearranged and KRAS-mutant patients with strong PD-L1 expression who had received crizotinib and chemotherapy, respectively. In conclusion, individual driver mutations had various impacts on the PD-L1 expression of NSCLC patients. The prognostic role of PD-L1 may also be divergent amongst patients harboring different driver mutations.
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