Mechanisms Of Resistance Research Articles

Interplay between Amino Acid Substitution in GyrA and QnrB19: Elevating Fluoroquinolone Resistance in Salmonella Typhimurium.

Globally, there have been increasing reports of antimicrobial resistance in nontyphoidal Salmonella (NTS), which can develop into severe and potentially life-threatening diarrhea. This study focuses on the synergistic effects of DNA gyrase mutations and plasmid-mediated quinolone resistance (PMQR) genes, specifically qnrB19, on fluoroquinolone (FQ) resistance in Salmonella Typhimurium. By utilizing recombinant mutants, GyrAS83F and GyrAD87N, and QnrB19's, we discovered a significant increase in fluoroquinolones resistance when QnrB19 is present. Specifically, ciprofloxacin and moxifloxacin's inhibitory concentrations rose 10- and 8-fold, respectively. QnrB19 was found to enhance the resistance capacity of mutant DNA gyrases, leading to high-level FQ resistance. Additionally, we observed that the ratio of QnrB19 to DNA gyrase played a critical role in determining whether QnrB19 could protect DNA gyrase against FQ inhibition. Our findings underscore the critical need to understand these resistance mechanisms, as their coexistence enables bacteria to withstand therapeutic FQ levels, posing a significant challenge to treatment efficacy.

Complete response in a lung adenocarcinoma with pleural metastases initially treated with gefitinib and switched to osimertinib after cerebral oligo-progression with unknown T790M mutation: a case report and review of literature

BackgroundFirst- and second-generation anti-epithelial growth factor receptor tyrosine kinase inhibitors have shown great efficacy in the treatment of advanced adenocarcinoma with epithelial growth factor receptor mutations, but this efficacy is limited by certain resistance mechanisms, in particular the T790M mutation, which must be screened before second-line treatment with osimertinib is indicated. The search for this mutation is sometimes difficult, especially in cases of intracranial relapse, through this case report we attempt to discuss the possibility of initiating treatment with osimertinib despite an unknown T790M mutation in such situation.Case reportWe present the case of a 70-year-old Moroccan male patient diagnosed with non-small cell lung carcinoma initially metastatic to the pleura with an epithelial growth factor receptor mutation who received gefitinib in first line with a complete response, he subsequently presented with cerebral oligo-progression with extra cranial stability. The patient was started on osimertinib with unknown T790M status, as it was impossible to perform a cerebral biopsy, the evolution was characterized by a partial response followed by stereotactic radiotherapy then a complete response for 2 years.ConclusionWe can discuss osimertinib as an option for patients with stage IV non-small cell lung cancer with brain oligo-progression on prior tyrosine kinase inhibitors and unknown T790M status, further studies are needed in this area.

Targeting the FGFR Pathway in Patients with Advanced Solid Tumors.

In the phase II FUZE trial targeting the FGFR pathway, Debio 1347 showed limited antitumor activity and manageable toxicity in patients with advanced solid tumors. Results from transcriptomic-based analysis enhanced our understanding of the genomic landscape of FGFR fusion-driven tumors, informing clinical trial design and generating hypotheses for resistance mechanisms.

Soybean transcription factor GmNF-YB20 confers resistance to stripe rust in transgenic wheat by regulating nonspecific lipid transfer protein genes.

Worldwide food security is severely threatened by the devastating wheat stripe rust disease. The utilization of resistant wheat cultivars represents the most cost-effective and efficient strategy for combating this disease. However, the lack of resistant resources has been a major bottleneck in breeding for wheat disease resistance. Therefore, revealing novel gene resources for combating stripe rust and elucidating the underlying resistance mechanism is of utmost urgency. In this study, we identified that the soybean NF-YB transcription factor GmNF-YB20 in wheat provides resistance to the stripe rust fungus (Puccinia striiformis f. sp. tritici, Pst). Wheat lines with stable overexpression of the GmNF-YB20 enhanced resistance against multiple Pst races. Transcriptome profiling of GmNF-YB20 transgenic wheat under Pst infection unveiled its involvement in the lipid signaling pathway. RT-qPCR assays suggested that GmNF-YB20 increased transcript levels of multiple nonspecific lipid transfer protein (LTP) genes during wheat-Pst interaction, luciferase reporter analysis illustrates that it activates the transcription of TaLTP1.50 in wheat protoplast, and GmNF-YB20 overexpressed wheat plants had higher total LTP content in vivo during Pst infection. Overexpression of TaLTP1.50 in wheat significantly increased resistance to Pst, whereas knockdown of TaLTP1.50 exhibited the opposite trends, indicating that TaLTP1.50 plays a positive role in wheat resistance. Taken together, our findings provide perspective regarding the molecular mechanism of GmNF-YB20 in wheat and highlight the potential use for wheat breeding.

Osimertinib-induced DNA resistance mutations in cerebrospinal fluid of EGFR mutated NSCLC patients developing leptomeningeal metastases: ORA-LM study.

Diagnosis and treatment of leptomeningeal metastases (LM) in epidermal growth factor receptor mutation positive (EGFRm+) NSCLC is challenging. We aimed to identify resistance mechanisms (RM) to osimertinib in cerebrospinal fluid (CSF) and plasma. EGFRm+ patients with new or progressive LM during osimertinib were enrolled. NGS Ampliseq was performed on DNA isolated from CSF. Patients were prescribed osimertinib dose escalation (DE, 160mg QD) following lumbar puncture. Clinical and radiological response was evaluated four weeks after osimertinib DE. Twenty-eight patients were included. The driver mutation was identified in 93% of CSF samples (n=26). Seven (27%) harbored ≥1 RM. Twenty-five patients (89%) were prescribed osimertinib DE. Four weeks afterwards, symptoms improved in five patients, stabilized in nine and worsened in eleven patients. Twenty-one (84%) patients underwent MR imaging. Four showed radiological improvement, fourteen stabilization, and three worsening. In 27% of patients an RM was found in CSF ctDNA, none of which are targetable at time of writing, and clinical efficacy of osimertinib DE seems limited. There is much to gain in diagnostic as well as therapeutic strategies in EGFRm+ NSCLC LM.

An update on tinea capitis in children.

Tinea capitis presents a significant public health care challenge due to its contagious nature, and potential long-term consequences if unrecognized and untreated. This review explores the prevalence, risk factors, diagnostic methods, prevention strategies, impact on quality of life, and treatment options for pediatric tinea capitis. Epidemiological analysis spanning from 1990 to 1993 and 2020 to 2023 reveals prevalence patterns of pediatric tinea capitis influenced by geographic, demographic, and environmental factors. Notably, Trichophyton species is most prevalent in North America; however, Microsporum species remain the primary causative agent globally, with regional variations. Risk factors include close contact and environmental conditions, emphasizing the importance of preventive measures. Accurate diagnosis relies on clinical evaluation, microscopic examination, and fungal culture. Various treatment modalities including systemic antifungals show efficacy, with terbinafine demonstrating superior mycological cure rates particularly for Trichophyton species. Recurrent infections and the potential development of resistance can pose challenges. Therefore, confirming the diagnosis, appropriately educating the patient/caregiver, accurate drug and dose utilization, and compliance are important components of clinical cure. Untreated or poorly treated tinea capitis can lead to chronic infection, social stigma, and psychological distress in affected children. Prevention strategies focus on early detection and healthy lifestyle habits. Collaborative efforts between healthcare providers and public health agencies are important in treating pediatric tinea capitis and improving patient outcomes. Education and awareness initiatives play a vital role in prevention and community-level intervention to minimize spread of infection. Future research should explore diagnostic advances, novel treatments, and resistance mechanisms in order to mitigate the disease burden effectively.

Concomitant targeting of FLT3 and SPHK1 exerts synergistic cytotoxicity in FLT3-ITD+ acute myeloid leukemia by inhibiting β-catenin activity via the PP2A-GSK3β axis

BackgroundApproximately 25–30% of patients with acute myeloid leukemia (AML) have FMS-like receptor tyrosine kinase-3 (FLT3) mutations that contribute to disease progression and poor prognosis. Prolonged exposure to FLT3 tyrosine kinase inhibitors (TKIs) often results in limited clinical responses due to diverse compensatory survival signals. Therefore, there is an urgent need to elucidate the mechanisms underlying FLT3 TKI resistance. Dysregulated sphingolipid metabolism frequently contributes to cancer progression and a poor therapeutic response. However, its relationship with TKI sensitivity in FLT3-mutated AML remains unknown. Thus, we aimed to assess mechanisms of FLT3 TKI resistance in AML.MethodsWe performed lipidomics profiling, RNA-seq, qRT-PCR, and enzyme-linked immunosorbent assays to determine potential drivers of sorafenib resistance. FLT3 signaling was inhibited by sorafenib or quizartinib, and SPHK1 was inhibited by using an antagonist or via knockdown. Cell growth and apoptosis were assessed in FLT3-mutated and wild-type AML cell lines via Cell counting kit-8, PI staining, and Annexin-V/7AAD assays. Western blotting and immunofluorescence assays were employed to explore the underlying molecular mechanisms through rescue experiments using SPHK1 overexpression and exogenous S1P, as well as inhibitors of S1P2, β-catenin, PP2A, and GSK3β. Xenograft murine model, patient samples, and publicly available data were analyzed to corroborate our in vitro results.ResultsWe demonstrate that long-term sorafenib treatment upregulates SPHK1/sphingosine-1-phosphate (S1P) signaling, which in turn positively modulates β-catenin signaling to counteract TKI-mediated suppression of FLT3-mutated AML cells via the S1P2 receptor. Genetic or pharmacological inhibition of SPHK1 potently enhanced the TKI-mediated inhibition of proliferation and apoptosis induction in FLT3-mutated AML cells in vitro. SPHK1 knockdown enhanced sorafenib efficacy and improved survival of AML-xenografted mice. Mechanistically, targeting the SPHK1/S1P/S1P2 signaling synergizes with FLT3 TKIs to inhibit β-catenin activity by activating the protein phosphatase 2 A (PP2A)-glycogen synthase kinase 3β (GSK3β) pathway.ConclusionsThese findings establish the sphingolipid metabolic enzyme SPHK1 as a regulator of TKI sensitivity and suggest that combining SPHK1 inhibition with TKIs could be an effective approach for treating FLT3-mutated AML.

Advances on MXene-Based Memristors for Neuromorphic Computing: A Review on Synthesis, Mechanisms, and Future Directions.

Neuromorphic computing seeks to replicate the capabilities of parallel processing, progressive learning, and inference while retaining low power consumption by drawing inspiration from the human brain. By further overcoming the constraints imposed by the traditional von Neumann architecture, this innovative approach has the potential to revolutionize modern computing systems. Memristors have emerged as a solution to implement neuromorphic computing in hardware, with research based on developing functional materials for resistive switching performance enhancement. Recently, two-dimensional MXenes, a family of transition metal carbides, nitrides, and carbonitrides, have begun to be integrated into these devices to achieve synaptic emulation. MXene-based memristors have already demonstrated diverse neuromorphic characteristics while enhancing the stability and reducing power consumption. The possibility of changing the physicochemical properties through modifications of the surface terminations, bandgap, interlayer spacing, and oxidation for each existing MXene makes them very promising. Here, recent advancements in MXene synthesis, device fabrication, and characterization of MXene-based neuromorphic artificial synapses are discussed. Then, we focus on understanding the resistive switching mechanisms and how they connect with theoretical and experimental data, along with the innovations made during the fabrication process. Additionally, we provide an in-depth review of the neuromorphic performance, making a connection with the resistive switching mechanism, along with a compendium of each relevant performance factor for nonvolatile and volatile applications. Finally, we state the remaining challenges in MXene-based devices for artificial synapses and the next steps that could be taken for future development.

Metabolic changes associated with polysaccharide utilization reduce susceptibility to some β-lactams in Bacteroides thetaiotaomicron.

Antibiotic therapy alters bacterial abundance and metabolism in the gut microbiome, leading to dysbiosis and opportunistic infections. Bacteroides thetaiotaomicron (Bth) is both a commensal in the gut and an opportunistic pathogen in other body sites. Past work has shown that Bth responds to β-lactam treatment differently depending on the metabolic environment both in vitro and in vivo. Studies of other bacteria show that an increase in respiratory metabolism independent of growth rate promotes susceptibility to bactericidal antibiotics. We propose that Bth enters a protected state linked to an increase in polysaccharide utilization and a decrease in the use of simple sugars. Here, we apply antibiotic susceptibility testing, transcriptomic analysis, and genetic manipulation to characterize this polysaccharide-mediated tolerance (PM tolerance) phenotype. We found that a variety of mono- and disaccharides increased the susceptibility of Bth to several different β-lactams compared to polysaccharides. Transcriptomics indicated a metabolic shift from reductive to oxidative branches of the tricarboxylic acid cycle on polysaccharides. Accordingly, supplementation with intermediates of central carbon metabolism had varying effects on PM tolerance. Transcriptional analysis also showed a decrease in the expression of the electron transport chain (ETC) protein NQR and an increase in the ETC protein NUO, when given fiber versus glucose. Deletion of NQR increased Bth susceptibility while deletion of NUO and a third ETC protein NDH2 had no effect. This work confirms that carbon source utilization modulates antibiotic susceptibility in Bth and that anaerobic respiratory metabolism and the ETC play an essential role.IMPORTANCEAntibiotics are indispensable medications that revolutionized modern medicine. However, their effectiveness is challenged by a large array of resistance and tolerance mechanisms. Treatment with antibiotics also disrupts the gut microbiome which can adversely affect health. Bacteroides are prevalent in the gut microbiome and yet are frequently involved in anaerobic infections. Thus, understanding how antibiotics affect these bacteria is necessary to implement proper treatment. Recent work has investigated the role of metabolism in antibiotic susceptibility in distantly related bacteria such as Escherichia coli. Using antibiotic susceptibility testing, transcriptomics, and genetic manipulation, we demonstrate that polysaccharides reduce β-lactam susceptibility when compared to monosaccharides. This finding underscores the profound impact of metabolic adaptation on the therapeutic efficacy of antibiotics. In the long term, this work indicates that modulation of metabolism could make Bacteroides more susceptible during infections or protect them in the context of the microbiome.

Genome-wide CRISPR-Cas9 knockout screens identify DNMT1 as a druggable dependency in sonic hedgehog medulloblastoma

Sonic hedgehog subgroup of medulloblastoma (SHH-MB) is characterized by aberrant activation of the SHH signaling pathway. An inhibition of the positive SHH regulator Smoothened (SMO) has demonstrated promising clinical efficacy. Yet, primary and acquired resistance to SMO inhibitors limit their efficacy. An understanding of underlying molecular mechanisms of resistance to therapy is warranted to bridge this unmet need. Here, we make use of genome-wide CRISPR-Cas9 knockout screens in murine SMB21 and human DAOY cells, in order to unravel genetic dependencies and drug-related genetic interactors that could serve as alternative therapeutic targets for SHH-MB. Our screens reinforce SMB21 cells as a faithful model system for SHH-MB, as opposed to DAOY cells, and identify members of the epigenetic machinery including DNA methyltransferase 1 (DNMT1) as druggable targets in SHH-dependent tumors. We show that Dnmt1 plays a crucial role in normal murine cerebellar development and is required for SHH-MB growth in vivo. Additionally, DNMT1 pharmacological inhibition alone and in combination with SMO inhibition effectively inhibits tumor growth in murine and human SHH-MB cell models and prolongs survival of SHH-MB mouse models by inhibiting SHH signaling output downstream of SMO. In conclusion, our data highlight the potential of inhibiting epigenetic regulators as a novel therapeutic avenue in SMO-inhibitor sensitive as well as resistant SHH-MBs.

How Tea Plant Defends Against Blister Blight Disease: Facts Revealed and Unexplored Horizons.

Tea (Camellia sinensis [L.] O. Kuntze) is cultivated as a beverage crop. Despite being a hardy perennial, the tea plant is susceptible to various biotic stresses. Among them, the foliar disease blister blight (BB) is considered the most serious threat to the tea industry, particularly in Asia. BB caused by Exobasidium vexans (Basidiomycetes) was first reported from Northern India in 1868 and gradually established in other tea-growing countries. The fungus E. vexans attacks young harvestable shoots and causes 20 to 50% crop loss. Over the past 150 years, scientific research has delved into various aspects of BB disease, including pathogen biology, disease cycle, epidemiology, disease forecasting, crop loss assessment, and disease management strategies. In a recent shift in research focus, scientists have begun to investigate the resistance mechanisms of tea plants against BB and apply this knowledge to commercial tea cultivation. Although progress has been significant in understanding the fundamental aspects of BB resistance, the detailed molecular mechanisms driving this resistance remain under investigation. This paper focuses on the current understanding of defense mechanisms employed by tea plants against E. vexans and, conversely, how E. vexans overcomes these defenses. Furthermore, we discuss the application of plant resistance strategies in commercial tea cultivation. Lastly, we identify existing research gaps and propose future research directions in the field.

Trends in the Prevalence of Antimicrobial Resistance in Escherichia coli Isolated from Outpatient Urine Cultures in French Amazonia.

Antimicrobial resistance (AMR) in the community is increasing worldwide. We aimed to assess AMR trends in Escherichia coli from the community urine isolates in French Amazonia. We conducted a retrospective study from January 2016 to December 2022 in the Cayenne General Hospital microbiology laboratory (French Guiana). It included all urine samples positive for E. coli collected from adult outpatients. During the study period, 3,443 urinalyses positive for E. coli were studied. In 46% of cases, patients were women. In 64.4% of cases, E. coli were β-lactamase producers. The most frequently diagnosed resistance mechanisms were penicillinase production and sparing third-generation cephalosporins. Isolated E. coli were extended-spectrum β-lactamase (ESBL) producers in 6.1% of cases. Overall, E. coli was susceptible to amoxicillin in 35.9% [95% CI: 34.3-37.5], to amoxicillin/clavulanic acid in 62.2% [95% CI: 60.6-63.9], to cefotaxime in 94% [95% CI: 93.1-94.7], to gentamicin in 92.1% [95% CI: 89.1-92.6], to ofloxacin in 76.8% [95% CI: 75.3-78.2], to trimethoprim/sulfamethoxazole (SXT) in 58.8% [95% CI: 57.1-60.5], to fosfomycin in 99.1% [95% CI: 98.6-99.4], and to nitrofurantoin in 99% of cases [95% CI: 98.6-99.3]. We have observed a gradual decline in the susceptibility profile of E. coli for amoxicillin/clavulanic acid (P <0.001), piperacillin/tazobactam (P = 0.003), and temocillin (P = 0.006). However, susceptibility to ciprofloxacin was increasing (P = 0.001). In contrast, the susceptibility trends for amoxicillin, third-generation cephalosporins, gentamicin, SXT, nitrofurantoin, and fosfomycin remained stable over the 28 quarters of the study. In conclusion, isolated E. coli from outpatient urinalyses showed increased resistance profiles involving penicillinase and ESBL production. Close monitoring and strategies to decrease antibiotic consumption in the community are needed.

Honey bee populations surviving Varroa destructor parasitism in Latin America and their mechanisms of resistance

The honey bee (Apis mellifera) parasitic mite, Varroa destructor, is considered one of the main causes of colony losses in European honey bee (EHB) populations around the world. However, some EHB and Africanized honey bee (AHB) populations (derived from the African subspecies A. m. scutellata) that inhabit tropical and subtropical regions of the Americas, have survived varroa mite infestations in the absence of acaricide treatments. It is conceivable to expect that these honey bee populations, which have been subjected to natural selection over decades, would have developed resistance against V. destructor or possess pre-existing adaptations that allow them to survive mite parasitism. Here, we present a comprehensive literature review describing the spread of V. destructor and the honey bee populations occurring in Latin America (LA), and summarize the evidence of resistance of those populations to V. destructor. We also analyze reports describing the potential mechanisms of mite resistance and how they operate in those honey bee populations. Studies of a few EHB, as well as of numerous AHB populations exhibiting resistance to V. destructor in LA, unveil the existence of evolutionary adaptations that restrain V. destructor population growth and provide insight into the current host-parasite relationship. This review supports the notion that selective breeding of local honey bee populations from LA could be a viable strategy to manage varroa mite infestations in colonies.

Resistance to ceftazidime-avibactam and other new β-lactams in Pseudomonas aeruginosa clinical isolates: a multi-center surveillance study.

Multidrug-resistant Pseudomonas aeruginosa infections are a growing threat due to the limited therapeutic options available. Ceftazidime-avibactam (CZA) is among the last-resort antibiotics for the treatment of difficult-to-treat P. aeruginosa infections, although resistance due to the acquisition of transferable β-lactamase genes is increasing. With this work, we report that CZA represents a highly active antipseudomonal β-lactam compound (after cefiderocol), and that metallo-β-lactamases (VIM-type) and extended-spectrum β-lactamases (GES and PER-type) production is the major factor underlying CZA resistance in isolates from Southern Italian hospitals. In addition, we reported that such resistance mechanisms were mainly carried by the international high-risk clones ST111 and ST235.

Distribution and community structure of antibiotic resistance genes in the Three Gorges Reservoir Area.

Antibiotic resistance genes (ARG) are widespread across various regions. While several studies have investigated the distribution of antibiotic resistance in natural environments, the occurrence and diversity of ARGs in the Three Gorges Reservoir have not been fully elucidated. In this study, we employed metagenomic sequencing techniques to investigate the abundance, diversity, and influencing factors of ARGs in the ecosystem of the Three Gorges Reservoir. A total of 874 ARGs, 20 antibiotic classes, and 6 resistance mechanisms were detected. The dominant ARG is the macB, the dominant antibiotic class is multidrug resistance (MDR), and the dominant resistance mechanism is antibiotic efflux. The microorganisms with the highest contribution to ARGs are Betaproteobacteria and Gammaproteobacteria. In this region, pH and NH4+ concentration were significantly negatively correlated with the relative abundance of most ARGs, while NO3- concentration and TN were significantly positively correlated with the relative abundance of most ARGs. The results indicate that the Three Gorges Reservoir constitutes a significant reservoir of ARGs. By studying the distribution of ARGs in the sediments of the Three Gorges Reservoir Area and the relationship between environmental factors and ARGs, we can more comprehensively understand the pollution status of ARGs in this area, and provide theoretical support for subsequent treatment.

Underlying mechanism of Dendrobium huoshanense resistance to lead stress using the quantitative proteomics method

Lead affects photosynthesis and growth and has serious toxic effects on plants. Here, the differential expressed proteins (DEPs) in D. huoshanense were investigated under different applications of lead acetate solutions. Using label-free quantitative proteomics methods, more than 12,000 peptides and 2,449 proteins were identified. GO and KEGG functional annotations show that these differential proteins mainly participate in carbohydrate metabolism, energy metabolism, amino acid metabolism, translation, protein folding, sorting, and degradation, as well as oxidation and reduction processes. A total of 636 DEPs were identified, and lead could induce the expression of most proteins. KEGG enrichment analysis suggested that proteins involved in processes such as homologous recombination, vitamin B6 metabolism, flavonoid biosynthesis, cellular component organisation or biogenesis, and biological regulation were significantly enriched. Nearly 40 proteins are involved in DNA replication and repair, RNA synthesis, transport, and splicing. The effect of lead stress on D. huoshanense may be achieved through photosynthesis, oxidative phosphorylation, and the production of excess antioxidant substances. The expression of 9 photosynthesis-related proteins and 12 oxidative phosphorylation-related proteins was up-regulated after lead stress. Furthermore, a total of 3 SOD, 12 POD, 3 CAT, and 7 ascorbate-related metabolic enzymes were identified. Under lead stress, almost all key enzymes involved in the synthesis of antioxidant substances are up-regulated, which may facilitate the scavenging of oxygen-free radical scavenging. The expression levels of some key enzymes involved in sugar and glycoside synthesis, the phenylpropanoid synthesis pathway, and the terpene synthesis pathway also increased. More than 30 proteins involved in heavy metal transport were also identified. Expression profiling revealed a significant rise in the expression of the ABC-type multidrug resistance transporter, copper chaperone, and P-type ATPase with exposure to lead stress. Our findings lay the basis for research on the response and resistance of D. huoshanense to heavy metal stress.

Identification of Key Genes and Signaling Pathways in Entrectinibresistant Non-small Cell Lung Cancer Using Bioinformatic Analysis and Experimental Verification.

Entrectinib, a ROS1 inhibitor, is effective in patients with ROS1-positive non-small-cell lung cancer (NSCLC). However, entrectinib resistance remains a challenge worldwide. The biomarkers of entrectinib resistance and molecular mechanisms have not been clarified based on the Gene Expression Omnibus (GEO) database. The aim of this study is to identify key genes and signaling pathways involved in the development of entrectinib-resistant NSCLC through bioinformatics analysis and experimental validation. Differentially expressed genes (DEGs) were screened between entrectinib resistant and parental human NSCLC cell lines of the GSE214715 dataset, lung adenocarcinoma (LUAD) and non-tumor adjacent tissues of the GSE75037 dataset, and NSCLC and non-tumor adjacent tissues of the GSE18842 dataset. Functional enrichment analyses were performed, including Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Overlapped DEGs among those three datasets were identified using the Venn diagram package. The transcriptional levels of key genes were investigated using the University of ALabama at Birmingham CANcer data analysis Portal (UALCAN). The association between transcriptional levels of key genes and survival was analyzed using Kaplan-Meier Plotter (https://www.kmplot.com/analysis/). The correlations between hub genes and immune cell infiltration were investigated using the Tumor Immune Estimation Resource (TIMER) database. Specific signaling pathway enrichment analysis was performed using Gene Set Enrichment Analysis (GSEA) of LinkedOmics. Competitive endogenous RNA (ceRNA) networks, genome-wide association studies (GWAS), and drug sensitivity analyses of key genes were further investigated. The expression of ZEB2 was subsequently confirmed in both parental HCC78 cells and entrectinib-resistant HCC78 cells using real-time quantitative polymerase chain reaction (qRT-PCR). 708 DEGs were identified between entrectinib-resistant CUTO28 (CUTO28-ER) and parental CUTO28 cell lines in the GSE214715 dataset. One thousand three hundred and ninety-five DEGs were identified between entrectinib resistant (CUTO37-ER) and parental CUTO37 cell lines in the GSE214715 dataset. Eight hundred and forty-nine DEGs were identified between LUAD and non-tumor adjacent tissues in the GSE75037 dataset. Seven hundred and sevety-three DEGs were identified between NSCLC and non-tumor adjacent tissues in the GSE18842 dataset. Among these three datasets, seven overlapped DEGs were identified, including ZBED2, CHI3L2, CELF2, SEMA5A, ZEB2, S100A12, and PDK4. Among these seven overlapped DEGs, the expression levels of CHI3L2, ZEB2, and S100A12 were downregulated in those three datasets. The results of analysis using the UALCAN database showed that these three genes were significantly downregulated in LUAD and LUSC patients compared with the normal population. However, only the lower transcriptional level of ZEB2 was linked to worse survival in patients with lung cancer. GSEA analysis revealed that ZEB2 was significantly negatively correlated with nucleotide excision repair (NER) in LUAD, and homologous recombination (HR) and NER in LUSC, which were linked to drug resistance. A ceRNA network of THRB-AS1/ has-miR-1293/ ZEB2 in LUAD was established. We have identified core genes associated with non-small cell resistance to entrectinib, including CHI3L2, ZEB2, and S100A12. ZEB2 is a core gene associated with acquired resistance to entetinib in NSCLC.

Optimization of Fused Filament Fabrication for High-Performance Polylactic Acid Parts under Wear Conditions

This paper investigates the impact of various manufacturing parameters on the mechanical and tribological properties of high-performance PLA (polylactic acid) parts produced using Fused Filament Fabrication (FFF). It addresses the challenges associated with optimizing additive manufacturing processes, particularly for polymer-based materials, and emphasizes the importance of understanding how factors such as build orientation, layer thickness, and infill density influence the final properties of the printed parts. This study highlights the improvements that can be achieved by incorporating reinforcements such as carbon fibers and graphene nanoplatelets into PLA, enhancing its mechanical strength and wear resistance. Experimental results show that optimizing printing parameters can significantly reduce the coefficient of friction and wear, leading to better performance in applications involving movement and mechanical stress. Key findings include the observation that higher infill densities and specific build orientations improve the fatigue life and tensile strength of PLA parts. Additionally, post-printing thermal treatments can alleviate internal stresses and enhance interlayer adhesion, further improving mechanical properties. The article concludes that with proper optimization, high-performance PLA can be a viable material for industrial applications, offering both environmental benefits and enhanced performance.

An Update on Colistin in Clinical Healthcare Unit in the Kingdom of Saudi Arabia: A Narrative Review.

Globally, gram-negative bacteria are a significant cause of morbidity. Multi-drug resistance bacteria are responsible for an increasing surge in infections that place a high cost on healthcare systems around the world. Recently, colistin, an antibiotic belonging to the polymyxin family, was reintroduced to combat multidrug- resistant gram-negative bacteria. Excessive and persistent use of colistin has led to the development and spread of colistin-resistant gram-negative bacteria throughout the globe. Healthcare units in various countries, including Saudi Arabia, are currently battling colistin-resistant gram-negative bacteria. Recently, colistin-resistant gram-negative bacteria have become a major health concern in Saudi Arabia. Hence, extensive epidemiological surveys and studies are required to understand the current status of the colistin antibiotic. Examining the knowledge currently available to the medical community on the molecular mechanism, clinical effectiveness, molecular epidemiology, and bacterial resistance to colistin in Saudi Arabia is the aim of this review.

Impact of waste rockwool on the performance of LC3-based lightweight mortar: A promising solution for greener construction

The objective of this study is to explore the influence of waste rockwool (RW) on the mechanical strength and fire resistance performance of high-volume expanded vermiculite (EVM) lightweight mortar made with limestone-calcined clay cement (LC3). LC3 binder was prepared by blending ordinary Portland cement (OPC), metakaolin (MK), and limestone (LS) powder at weight percentages of 40, 40, and 20 wt%, respectively. LC3-based lightweight mortar with a binder-to-aggregate ratio of 1:3 was prepared by replacing 50 vol% of the sand with EVM aggregate. The waste RW was added to the EVM-blended LC3 mortar with different percentages of 1, 3, and 5 % by weight of binder. The compressive strength, flexural strength, drying shrinkage, bulk density, thermal conductivity, fire resistance, and microstructural properties of the hardened LC3-lightweight mortars were determined in accordance with ASTM standards after 28 days of water curing. The results revealed remarkable enhancements in both mechanical and fire resistance performances with RW addition. The addition of 3 wt% RW into the EVM-blended LC3 mortar provided the appropriate enhancement ratios of 56.55 % and 52.83 % in compressive and flexural strengths respectively and increased the fire resistance rating by 25 %. A residual compressive strength of 76.19 % has been maintained after exposure to standard fire for an hour (1 h). The doping of RW into the EVM-blended LC3 mortars led to significant reduction in drying shrinkage rate. A slight, insignificant variation in the thermal conductivity of EVM-blended LC3 lightweight mortar incorporated with RW has been obtained. RW addition resulted in improved microstructure in terms of compactness.