Osimertinib is the only Food and Drug Administration‐approved third‐generation epidermal growth factor receptor (EGFR) tyrosine‐kinase inhibitor (TKI). A meta‐analysis was performed to aggregate the ...mixed results of published clinical trials to assess the efficacy and safety of osimertinib. A systematic search of the PubMed, Web of Science, and Cochrane Library electronic databases was performed to identify eligible literature. The primary endpoints were overall response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), and adverse events (AEs). A total of 3,086 advanced nonsmall cell lung cancer (NSCLC) patients from 11 studies have been identified. The aggregate efficacy parameters for treatment‐naïve patients with EGFR‐TKI‐sensitizing mutations are as follows: ORR 79% (95% CI 75–84%), DCR 97% (95% CI 95–99%), 6‐month PFS 83% (95% CI 80–87%), and 12‐month PFS 64% (95% CI 59–69%). The aggregate efficacy parameters for advanced NSCLC harboring T790M mutations after earlier‐generation EGFR‐TKI therapy are as follows: ORR 58% (95% CI 46–71%), DCR 80% (95% CI 63–98%), 6‐month PFS 63% (95% CI 58–69%), and 12‐month PFS 32% (95% CI 17–47%). EGFR‐TKI‐naïve patients with EGFR‐positive mutations tend to have longer median PFS than EGFR‐TKI‐pretreated counterparts (19.17 vs. 10.58 months). The most common AEs were diarrhea and rash, of which the pooled incidences were 44 and 42%, respectively. Generally, osimertinib is a favorable treatment option for previously treated T790M mutation‐positive advanced NSCLC as well as a preferable therapy for untreated EGFR mutation‐positive advanced NSCLC. Additionally, osimertinib is well tolerated by most patients.
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Epidermal growth factor receptor (EGFR) tyrosine‐kinase inhibitors (TKIs) have shown significant promise in treating advanced non‐small‐cell lung cancer (NSCLC). In this meta‐analysis, the authors found that osimertinib, a third‐generation EGFR‐TKI, is an especially favorable treatment option. Outcomes were encouraging for previously‐treated, advanced NSCLCs that carried T790M mutations. In addition, treatment‐naïve patients whose advanced NSCLC had EGFR‐TKI‐sensitizing mutations tended to have a better response with osimertinib than did previous patients treated with earlier‐generation EGFR‐TKIs. These results indicate that further clinical trials are warranted for optimizing the use of osimertinib in advanced NSCLC.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Several studies were carried out to explore the prognostic role of neutrophil-to-lymphocyte ratio (NLR) in pancreatic cancer, however, with contradictory results. The objectives of this study were to ...summarize the prognostic value of NLR in pancreatic cancer. Embase, PubMed and Cochrane Library were comprehensively retrieved. All the cohort studies focusing on the prognostic value of NLR in pancreatic cancer were eligible. 37 papers containing 43 cohort studies with pancreatic cancer were finally included into this study. The results presented that patients with low NLR might have longer OS when compared to the patients with high NLR (HR = 1.81, 95%CI = 1.59–2.05, P < 0.00001; I2 = 82%). Similar results were detected in the subgroup analyses of OS, which was based on the analysis model, ethnicity, treatment, sample size and cut-off value. In additions, low NLR was significantly associated with longer DFS when compared to high NLR in pancreatic cancer (HR = 1.66, 95%CI = 1.17–2.35, P = 0.005; I2 = 67%). Moreover, patients with low NLR had significantly smaller tumor size (P = 0.0007), better differentiation (P = 0.003), earlier stage (P = 0.02) and low CA-199 level (P = 0.007). In conclusion, it was revealed that low NLR was a favorable predictor of OS and DFS in patients with pancreatic cancer, and NLR is a promising prognostic biomarker for pancreatic cancer.
•Low NLR was obviously associated with longer OS and DFS compared to high NLR in pancreatic cancer.•The association between NLR and clinical parameters was explored.•The relatively large sample size strengthened the convincing of the results.•NLR might be a promising prognostic biomarker for pancreatic cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
In the era of artificial intelligence, the conservation and restoration of museum artifacts encounter both new possibilities and hurdles. The limitations of conventional conservation techniques, in ...terms of efficiency and accuracy, are becoming increasingly apparent. This study explores the potential of 3D reconstruction technologies, SIFT algorithms, and Poisson’s equation to revolutionize the digital restoration of cultural relics. These advanced approaches allow for precise, efficient restorations and the ability to undertake complex projects without risking harm to the original items. Our approach integrates cutting-edge algorithms to tailor 3D reconstruction strategies for museum artifacts, culminating in creating a comprehensive digital artifact database. Through the innovative use of feature point detection and texture synthesis, we have achieved notable successes, including a 12% improvement in 3D model accuracy and a significant enhancement in the automation of the restoration process. With an SSIM value of 0.9964 for restored images, our method demonstrates superiority over traditional restoration techniques, marking a significant stride towards the efficient digital preservation of cultural heritage.
Therapeutic options for treating
infections are extremely limited; quinolones are important. The
anti-
activities of nine quinolones, emphasizing sitafloxacin, were investigated. Antimicrobial ...susceptibility testing was performed on 10 non-tuberculous mycobacterium reference strains and 194 clinical,
isolates. The activity of sitafloxacin against intracellular
residing within macrophages was also evaluated. A checkerboard assay was conducted to determine synergy between sitafloxacin and 10 clinically important antibiotics. Among the nine quinolones tested, sitafloxacin exhibited the greatest anti-
activity with MIC
and MIC
of 1 and 2 mg/L, respectively. Sitafloxacin exerted a bacteriostatic effect on
and inhibited the intracellular growth of
at concentrations equivalent to clarithromycin. No antagonism between sitafloxacin and 10 clinically important anti-
antibiotics was evident. In summary, sitafloxacin exhibited a significant advantage relative to other quinolones in inhibiting the growth of
, suggesting the potential inclusion of sitafloxacin in new strategies to treat
infections.
Abstract Lithium sulfide (Li 2 S) is a promising electrode material with high specific capacity and can be paired with commercial anode materials such as graphite. However, bulk Li 2 S requires a ...high activation energy during the initial charge due to its inert electrochemical activity, resulting in high charge overpotential. Here, lithium phenyl selenide (PhSeLi) is proposed as a mediator that can effectively activate Li 2 S by altering the oxidation pathway in the initial charge process. It enables Li 2 S to release normal capacity over the general voltage range (1.5–3 V). The composite cathode with the Li 2 S:PhSeLi molar ratio of 4:1 exhibits a high reversible capacity of 615.9 mAh g −1 at 0.2 A g −1 after 400 cycles in all‐solid‐state batteries with Li 7 P 3 S 11 sulfide electrolyte and In–Li anode (the corresponding capacity based on Li 2 S is 1016.6 mAh g −1 ). In a full cell with a partially pre‐lithiated silicon anode, it can still provide an average discharge capacity of 524 mAh g −1 at 0.1 A g −1 (the capacity based on Li 2 S is 844.2 mAh g −1 ). This work will contribute to the further development of Li 2 S‐based all‐solid‐state Li–S batteries.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
During infection, Mycobacterium abscessus encounters numerous environmental changes and adapts to them using a variety of complex mechanisms. Non‐coding small RNAs (sRNAs) have been shown ...in other bacteria to be involved in post‐transcriptional regulatory pathways, including environmental stress adaptation. However, the potential role of sRNAs in the resistance to oxidative stress in M. abscessus was not clearly described.
Methods
In the present study, we analyzed putative sRNAs identified by RNA‐sequencing (RNA‐seq) experiments in M. abscessus ATCC_19977 under oxidative stress, and the transcription profiles of sRNAs with differential expression were verified by quantitative reverse transcription‐PCR (qRT‐PCR). Six sRNA overexpression strains were constructed, and the differences in growth curves between these strains and the control strain were verified. An upregulated sRNA under oxidative stress was selected and named sRNA21. The survival ability of the sRNA21 overexpression strain was assessed, and computer‐based approaches were used to predict the targets and pathways regulated by sRNA21. The total ATP production and NAD+/NADH ratio of the sRNA21 overexpression strain were measured. The expression level of antioxidase‐related genes and the activity of antioxidase were tested to confirm the interaction of sRNA21 with the predicted target genes in silico.
Results
In total, 14 putative sRNAs were identified under oxidative stress, and the qRT‐PCR analysis of six sRNAs showed comparable results to RNA‐seq assays. Overexpression of sRNA21 in M. abscessus increased cell growth rate and intracellular ATP level before and after peroxide exposure. The expression of genes encoding alkyl hydroperoxidase and superoxide dismutase was significantly increased, and superoxide dismutase activity was enhanced in the sRNA21 overexpression strain. Meanwhile, after sRNA21 overexpression, the intracellular NAD+/NADH ratio decreased, indicating changes in redox homeostasis.
Conclusions
Our findings show that sRNA21 is an oxidative stress‐induced sRNA that increases M. abscessus survival and promotes the expression of antioxidant enzymes under oxidative stress. These findings may provide new insights into the adaptive transcriptional response of M. abscessus to oxidative stress.
In the present study, we analyzed putative small RNAs (sRNAs) identified by RNA‐seq experiments in oxidative stress condition in Mycobacterium abscessus ATCC_19977. An upregulated sRNA under oxidative stress was selected and named sRNA21. Our results showed that sRNA21 is an oxidative stress induced sRNA, which increased the survival ability of M. abscessus and promoted the expression of antioxidant enzymes under oxidative stress.
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Biofilm formation is an important factor for Mycobacterium abscessus to resist harsh environment and produce drug resistance. The anti-biofilm activity of a newly designed antibacterial peptide, ...RP557, was investigated. The effect of RP557 alone or in combination with several clinically effective antibiotics, including clarithromycin, amikacin, cefoxitin and imipenem, on M. abscessus growth in biofilms was determined. Microstructural changes in biofilms after RP557 treatment were observed by scanning electron microscope. The effect of RP557 on the viability of bacteria was determined by Syto9/PI staining and fluorescence microscopy. Finally, the potential mechanism of RP557 action on biofilm development was explored by transcriptome analysis. M. abscessus growing in biofilms showed increased resistance to antimicrobial drugs. RP557 alone exhibited only moderate anti-M. abscessus activity in vitro, but significantly increased the antibiotic sensitivity of M. abscessus in biofilms. The inhibitory effect of RP557 on biofilm formation was visualized by the scanning electron microscope; fluorescence staining demonstrated increased bacterial death in response to RP557 treatment. Furthermore, comparative analysis of transcriptomic data suggested RP557 may inhibit biofilm formation by down-regulating nitrogen and fatty acid metabolism, as well as peptidoglycan biosynthesis. As such, RP557 is a potential candidate to include in novel strategies to treat M. abscessus infections.
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•Mature M. abscessus biofilm formed after 7 days growth in Sauton’s medium•M. abscessus growing in biofilms showed increased resistance to antimicrobial drugs.•Antimicrobial peptides RP557 significantly increased the antibiotic sensitivity of M. abscessus in biofilms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Macrolide resistance is always a concern when treating Mycobacterium abscessus infections. MAB_2355c was identified previously as a possible new factor that confers the intrinsic resistance of 194 ...clinical M. abscessus isolates to clarithromycin. Herein, the potential mechanism by which MAB_2355c exerts macrolide resistance was explored by bioinformatics analysis,
cloning and protein purification, ATP hydrolysis assay, gene knockout and complementation, antibiotic sensitivity, and transcription-translation assays. MAB_2355c is a putative ATP-binding cassette F (ABC-F) family protein. Purified MAB_2355c protein exhibits ATP hydrolysis activity, which can be inhibited by ribosome-targeting antibiotics.
mRNA expression is upregulated more significantly after exposure to macrolides than after exposure to other ribosome-targeting antibiotics.
deleted strains showed increased sensitivity to macrolides, which was reduced by
complementation. Finally, MAB_2355c rescued the transcription and translation activities affected by macrolides
. These findings suggest that MAB_2355c confers the resistance of M. abscessus to macrolides by ribosome protection, thus complementing other known resistance mechanisms.
An evaluation of the anti-Mycobacterium abscessus activity expressed by a novel oxazolidinone, contezolid (MRX-I), toward 12 reference strains and 194 clinical isolates was conducted. Contezolid was ...active against M. abscessus in vitro, with effects comparable to the anti-M. abscessus effects of linezolid both extracellularly and intracellularly. Contezolid did not antagonize the most frequently used anti-M. abscessus drugs, and preexposure to contezolid did not induce drug resistance. These results provide a novel approach to treating M. abscessus infections.
Nitrogen is indispensable for the synthesis of biomacromolecules. The correlation between nitrogen metabolism and Mycobacterium abscessus (M. abscessus) biofilm formation is unclear. This study ...constructed global nitrogen regulator gene GlnR (Mab_0744) knockout (ΔglnR) and complementation (ΔglnR::glnR) M. abscessus strains.
Global nitrogen regulator gene glnR (Mab_0744) knockout (ΔglnR) and complementation (ΔglnR::glnR) M. abscessus strains were constructed. Sauton's medium was used to culture M. abscessus pellicle biofilm. To test the antibiotic susceptibility of pellicle biofilm, clarithromycin, amikacin, cefoxitin or imipenem was added to the medium under biofilms after 14 days of incubation. RT-qPCR and ChIP-qPCR were performed to analyse the transcriptional regulatory function of GlnR.
GlnR knockout decreased the growth rate of planktonic cells, reduced biofilm mass and wrinkle formation, and diminished the resistance of biofilms to antibiotics. However, the susceptibility of planktonic cells to antibiotics was not changed by glnR knockout. The growth rate of planktonic ΔglnR cells was accelerated by adding nitrogen sources to the medium; the addition of glutamine or sodium glutamate rescued ΔglnR biofilm morphology and resistance to amikacin, cefoxitin, clarithromycin and imipenem. GlnR bound the promoter region and activated the transcription of eight nitrogen metabolic pathway genes (i.e. glnA, amt, ansP, nirB, nirD, glnD, glnK and narK3), which are closely related to glutamine/glutamate biosynthesis and, thus, regulate biofilm formation.
This study provides insights into the mechanisms of M. abscessus biofilm formation and its resistance to antibiotics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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