Mechanisms Of Resistance Research Articles

The essential genome of Plasmodium knowlesi reveals determinants of antimalarial susceptibility

Measures to combat the parasites that cause malaria have become compromised because of reliance on a small arsenal of drugs and emerging drug resistance. We conducted a transposon mutagenesis screen in the primate malaria parasite Plasmodium knowlesi , producing the most complete classification of gene essentiality in any Plasmodium spp. to date, with the resolution to define truncatable genes. We found conservation in the druggable genome between Plasmodium spp. and divergences in mitochondrial metabolism. Perturbation analyses with the frontline antimalarial artemisinin revealed modulators that both increase and decrease drug susceptibility. Our findings aid prioritization of drug and vaccine targets for the Plasmodium vivax clade and reveal mechanisms of resistance that can inform therapeutic development.

Pharmacogenomics influence on MDR1-associated cancer resistance and innovative drug delivery approaches: advancing precision oncology.

Currently, there is a growing concern surrounding the treatment of cancer, a formidable disease. Pharmacogenomics and personalized medicine have emerged as significant areas of interest in cancer management. The efficacy of many cancer drugs is hindered by resistance mechanisms, particularly P-glycoprotein (P-gp) efflux, leading to reduced therapeutic outcomes. Efforts have intensified to inhibit P-gp efflux, thereby enhancing the effectiveness of resistant drugs. P-gp, a member of the ATP-binding cassette (ABC) superfamily, specifically the multidrug resistance (MDR)/transporter associated with antigen processing (TAP) sub-family B, member 1, utilizes energy derived from ATP hydrolysis to drive efflux. This review focuses on genetic polymorphisms associated with P-gp efflux and explores various novel pharmaceutical strategies to address this challenge. These strategies encompass SEDDS/SNEDDS, liposomes, immunoliposomes, solid lipid nanoparticles, lipid core nanocapsules, microemulsions, dendrimers, hydrogels, polymer-drug conjugates, and polymeric nanoparticles. The article aims to elucidate the interplay between pharmacogenomics, P-gp-mediated drug resistance in cancer, and formulation strategies to improve cancer therapy by tailoring formulations to genetically susceptible patients.

C10-Benzoate Esters of Anhydrotetracycline Inhibit Tetracycline Destructases and Recover Tetracycline Antibacterial Activity.

Tetracyclines (TCs) are an important class of antibiotics threatened by enzymatic inactivation. These tetracycline-inactivating enzymes, also known as tetracycline destructases (TDases), are a subfamily of class A flavin monooxygenases (FMOs) that catalyze hydroxyl group transfer and oxygen insertion (Baeyer-Villiger type) reactions on TC substrate scaffolds. Semisynthetic modification of TCs (e.g., tigecycline, omadacycline, eravacycline, and sarecycline) has proven effective in evading certain resistance mechanisms, such as ribosomal protection and efflux, but does not protect against TDase-mediated resistance. Here, we report the design, synthesis, and evaluation of a new series of 22 semisynthetic TDase inhibitors that explore D-ring substitution of anhydrotetracycline (aTC) including 14 C10-benzoate ester and eight C9-benzamides. Overall, the C10-benzoate esters displayed enhanced bioactivity and water solubility compared to the corresponding C9-benzamides featuring the same heterocyclic aryl side chains. The C10-benzoate ester derivatives of aTC were prepared in a high-yield one-step synthesis without the need for protecting groups. The C10-esters are water-soluble, stable toward hydrolysis, and display dose-dependent rescue of tetracycline antibiotic activity in E. coli expressing two types of tetracycline destructases, represented by TetX7 (Type 1) and Tet50 (Type 2). The best inhibitors recovered tetracycline antibiotic activity at concentrations as low as 2 μM, producing synergistic scores <0.5 in the fractional inhibitory concentration index (FICI) against TDase-expressing strains of E. coli and clinical P. aeruginosa. The C10-benzoate ester derivatives of aTC reported here are promising new leads for the development of tetracycline drug combination therapies to overcome TDase-mediated antibiotic resistance.

Biofilm Resilience: Molecular Mechanisms Driving Antibiotic Resistance in Clinical Contexts

Healthcare-associated infections pose a significant global health challenge, negatively impacting patient outcomes and burdening healthcare systems. A major contributing factor to healthcare-associated infections is the formation of biofilms, structured microbial communities encased in a self-produced extracellular polymeric substance matrix. Biofilms are critical in disease etiology and antibiotic resistance, complicating treatment and infection control efforts. Their inherent resistance mechanisms enable them to withstand antibiotic therapies, leading to recurrent infections and increased morbidity. This review explores the development of biofilms and their dual roles in health and disease. It highlights the structural and protective functions of the EPS matrix, which shields microbial populations from immune responses and antimicrobial agents. Key molecular mechanisms of biofilm resistance, including restricted antibiotic penetration, persister cell dormancy, and genetic adaptations, are identified as significant barriers to effective management. Biofilms are implicated in various clinical contexts, including chronic wounds, medical device-associated infections, oral health complications, and surgical site infections. Their prevalence in hospital environments exacerbates infection control challenges and underscores the urgent need for innovative preventive and therapeutic strategies. This review evaluates cutting-edge approaches such as DNase-mediated biofilm disruption, RNAIII-inhibiting peptides, DNABII proteins, bacteriophage therapies, antimicrobial peptides, nanoparticle-based solutions, antimicrobial coatings, and antimicrobial lock therapies. It also examines critical challenges associated with biofilm-related healthcare-associated infections, including diagnostic difficulties, disinfectant resistance, and economic implications. This review emphasizes the need for a multidisciplinary approach and underscores the importance of understanding biofilm dynamics, their role in disease pathogenesis, and the advancements in therapeutic strategies to combat biofilm-associated infections effectively in clinical settings. These insights aim to enhance treatment outcomes and reduce the burden of biofilm-related diseases.

First case of glyphosate resistance in Polypogon fugax: possible involvement of P450-based mechanisms.

Polypogon fugax has evolved resistance to multiple herbicides in China, yet there has been no documented case of glyphosate resistance. A putative glyphosate-resistant P. fugax (HN-R) population was collected from canola fields in Hunan Province, China, surviving glyphosate treatment at the field-recommended rate [540 g acid equivalent (a.e.) ha-1]. The aims of this study were to elucidate the resistance level and mechanism of HN-R population. Dose-response and shikimic acid assays indicated that the HN-R population has developed a low-level resistance (up to 4.6-fold) to glyphosate, compared to two glyphosate-susceptible populations (HN-S and SC-S). No evidence of EPSPS gene mutations and differential EPSPS gene expression were found in association with the resistance. However, pre-treatment with the known cytochrome P450 monooxygenases (P450s) inhibitor, malathion, reversed glyphosate resistance in the HN-R population. Transcriptomic and reverse transcription quantitative polymerase chain reaction (RT-qPCR) analyses showed up-regulation of the PfCYP51 and PfABCG25 genes in the HN-R population. Expression of PfCYP51 in yeast cells significantly enhanced glyphosate tolerance, whereas expression of PfABCG25 did not. Molecular docking experiments suggest that PfCYP51 may catalyze glyphosate metabolism. This is the first report of glyphosate resistance in P. fugax, with evidence suggesting P450 involvement in this resistance. This study enhances our understanding of herbicide-resistant weeds and provides valuable insights into the management of glyphosate-resistant weeds in agriculture. © 2025 Society of Chemical Industry.

Mechanical Properties and High-Temperature Steam Oxidation of Cr/CrN Multi-Layers Produced by High-Power Impulse Magnetron Sputtering

In this study, Cr coatings, CrN coatings, and CrN/Cr multi-layer coatings were deposited on the surface of Zr-4 alloy by high-power impulse magnetron sputtering (HiPIMS). We have investigated the effect of coating structure on the microstructure, mechanical properties, and high-temperature steam oxidation properties of coatings. The results show that the single-layer CrN coating has higher hardness but performs poorly in high-temperature steam oxidation compared to the Cr coating due to its greater brittleness, which makes it prone to cracking and spalling in high-temperature steam environments and provides a channel for Zr diffusion. In multi-layer coatings, however, they form a fine columnar crystal structure and a smoother surface, and the more layers there are, the better the mechanical properties and resistance to high-temperature steam oxidation of the coating. In a high-temperature steam environment, the CrN layer decomposes to form Cr2N and N2, and the N atoms diffuse inwards and react with Zr to form an α-Zr(N) layer, which restricts interdiffusion between Cr and Zr and blocks the diffusion of O into the substrate. Therefore, (CrN/Cr)n coatings with a multi-layer structure have excellent high-temperature steam corrosion resistance.

Pore-Forming Protein LIN-24 Enhances Starvation Resilience in Caenorhabditis elegans by Modulating Lipid Metabolism and Mitochondrial Dynamics

The ability to survive starvation is a critical evolutionary adaptation, yet the molecular mechanisms underlying this capability remain incompletely understood. Pore-forming proteins (PFPs) are typically associated with immune defense, where they disturb the membranes of target cells. However, the role of PFPs in non-immune functions, particularly in metabolic and structural adaptations to starvation, is less explored. Here, we investigate the aerolysin-like PFP LIN-24 in Caenorhabditis elegans and uncover its novel function in enhancing starvation resistance. We found that LIN-24 expression is upregulated during starvation, leading to increased expression of the lipase-encoding gene lipl-3. This upregulation accelerates the mobilization and degradation of lipid stores, thereby sustaining energy levels. Additionally, LIN-24 overexpression significantly preserves muscle integrity, as evidenced by the maintenance of muscle structure compared to wild-type worms. Furthermore, we demonstrate that LIN-24 induces the formation of donut-shaped mitochondria, a structural change likely aimed at reducing ATP production to conserve energy during prolonged nutrient deprivation. This mitochondrial remodeling depends on genes involved in mitochondrial dynamics, including mff-1, mff-2, drp-1, and clk-1. Collectively, these findings expand our understanding of PFPs, demonstrating their multifaceted role in stress resistance beyond immune defense. LIN-24’s involvement in regulating metabolism, preserving muscle structure, and remodeling mitochondria highlights its crucial role in the adaptive response to starvation, offering novel insights into the evolution of stress resistance mechanisms and potential therapeutic targets for conditions related to muscle preservation and metabolic regulation.

New bispecific antibodies in diffuse large B-cell lymphoma.

The CD20xCD3 T-cell-engaging bispecific antibodies are a highly active new treatment option for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Epcoritamab and glofitamab have both been approved in over thirty countries as monotherapy for DLBCL after two prior treatment lines; odronextamab has recent European approval, and mosunetuzumab is active and is being developed as a combination partner. These agents can be safely combined with other immunotherapies and chemotherapy, and single-arm and randomised trial outcomes promise an expanding role for this class of drugs in earlier treatment lines. This review examines the clinical development of the CD20xCD3 bispecific antibodies in DLBCL, how the phase I and II trials inform their current use, and the key distinctions between the agents. We focus on the efficacy and safety of those bispecific antibodies most advanced in development. We also consider emerging understandings of resistance mechanisms. Finally, we review key ongoing trials and combinations and consider the potential future of bispecific antibodies within the sequence of available treatments for DLBCL.

Cyclin-dependent kinase 4/6 inhibitor resistance mechanisms and strategies for subsequent treatment in breast cancer: A comprehensive review

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed the therapeutic landscape for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, demonstrating significant efficacy in both early and advanced stages of the disease. Combined with endocrine therapy, these inhibitors have dramatically improved survival outcomes. However, resistance to CDK4/6 inhibitors inevitably develops, posing a significant challenge in clinical management. Resistance to CDK4/6 inhibitors can develop through inherent and acquired fashions, and their mechanisms are explored in this comprehensive review. Inherent resistance arises from pre-existing genetic or signaling pathway alterations that diminish cancer cell sensitivity to CDK4/6 inhibitors. Acquired resistance, on the other hand, develops over time through mechanisms, such as the activation of alternative signaling pathways or changes in the tumor microenvironment. The review also examines potential biomarkers for predicting resistance, especially circulating tumor DNA markers, and discusses strategies to overcome resistance. These include combination therapies targeting multiple pathways simultaneously, sequential approaches to delay the onset of resistance, and the development of next-generation CDK4/6 inhibitors with improved efficacy and reduced resistance potential. Understanding resistance mechanisms and developing effective countermeasures are crucial for optimizing patient outcomes and extending the clinical benefits of CDK4/6 inhibitors in cancer therapy. Leveraging these insights will enable clinicians to personalize treatment strategies, ultimately enhancing the long-term effectiveness of CDK4/6 inhibitors in managing breast cancer.

Advancements in cellular immunotherapy: overcoming resistance in lung and colorectal cancer

Immunotherapy has revolutionized cancer treatment, offering hope for patients with otherwise treatment-resistant tumors. Among the most promising approaches are cellular therapies, particularly chimeric antigen receptor T-cell (CAR-T) therapy, which has shown remarkable success in hematologic malignancies. However, the application of these therapies to solid tumors, such as lung and colorectal cancers, has faced significant challenges. Tumor resistance mechanisms—ranging from immune evasion, antigen loss, and immune checkpoint upregulation, to tumor microenvironment immunosuppression—remain major obstacles. This mini-review highlights the latest advancements in tumor immunotherapy, with a focus on cellular therapies, and addresses the resistance mechanisms that hinder their effectiveness in lung and colorectal cancers. We examine the evolution of CAR-T cell therapy, as well as the potential of engineered natural killer (NK) cells and macrophages in solid tumor treatment. The review also explores cutting-edge strategies aimed at overcoming resistance, including combination therapies, gene editing technologies, and nanotechnology for targeted drug delivery. By discussing the molecular, cellular, and microenvironmental factors contributing to resistance, we aim to provide a comprehensive overview of how these challenges can be overcome, paving the way for more effective, personalized immunotherapies in lung and colorectal cancer treatment.

S-Adenosylmethionine: A Multifaceted Regulator in Cancer Pathogenesis and Therapy

S-adenosylmethionine (SAMe) is a key methyl donor that plays a critical role in a variety of cellular processes, such as DNA, RNA and protein methylation, essential for maintaining genomic stability, regulating gene expression and maintaining cellular homeostasis. The involvement of SAMe in cancer pathogenesis is multifaceted, as through its multiple cellular functions, it can influence tumor initiation, progression and therapeutic resistance. In addition, the connection of SAMe with polyamine synthesis and oxidative stress management further underscores its importance in cancer biology. Recent studies have highlighted the potential of SAMe as a biomarker for cancer diagnosis and prognosis. Furthermore, the therapeutic implications of SAMe are promising, with evidence suggesting that SAMe supplementation or modulation could improve the efficacy of existing cancer treatments by restoring proper methylation patterns and mitigating oxidative damage and protect against damage induced by chemotherapeutic drugs. Moreover, targeting methionine cycle enzymes to both regulate SAMe availability and SAMe-independent regulatory effects, particularly in methionine-dependent cancers such as colorectal and lung cancer, presents a promising therapeutic approach. Additionally, exploring epitranscriptomic regulations, such as m6A modifications, and their interaction with non-coding RNAs could enhance our understanding of tumor progression and resistance mechanisms. Precision medicine approaches integrating patient subtyping and combination therapies with chemotherapeutics, such as decitabine or doxorubicin, together with SAMe, can enhance chemosensitivity and modulate epigenomics, showing promising results that may improve treatment outcomes. This review comprehensively examines the various roles of SAMe in cancer pathogenesis, its potential as a diagnostic and prognostic marker, and its emerging therapeutic applications. While SAMe modulation holds significant promise, challenges such as bioavailability, patient stratification and context-dependent effects must be addressed before clinical implementation. In addition, better validation of the obtained results into specific cancer animal models would also help to bridge the gap between research and clinical practice.

Class B scavenger receptor resists WSSV replication by recognizing the viral lipid molecule and promoting phagocytosis.

Class B scavenger receptors (SRBs) have been well-studied in bacteria-induced immune responses in invertebrates. However, the status of SRB-defending viruses remains unclear. In this study, we identified a scavenger receptor in Procambarus clarkii (crayfish), which is homologous to mammalian SRBs, and designated it as PcSRB. The expression of PcSRB was upregulated after the WSSV challenge. The survival rate of crayfish was decreased, but the WSSV copy number increased after PcSRB knockdown during virus invasion. In addition, PcSRB bound to WSSV. Furthermore, we detected how PcSRB interacted with WSSV, and we found that PcSRB could bind to cholesta-3,5-diene, (CD3,5), a novel WSSV lipid ligand, rather than dibutyl phthalate (DBP). Besides, PcSRB could bind to VP19, VP26, and VP28, rather than VP24. Mutant-binding experiments demonstrated that the hydrophobic domain (130-180 aa) of PcSRB is important for recognizing WSSV. Furthermore, PcSRB might promote lysosomal eliminating function to degrade WSSV. Altogether, we identified a new mechanism for scavenger receptor recognition and resistance to WSSV.IMPORTANCEPcSRB could bind to WSSV directly. PcSRB could interact with WSSV via binding to lipid molecule CD3,5 and viral envelope proteins. PcSRB could influence lysosomal activation.

Integrative analysis of anoikis-related prognostic signature to evaluate the immune landscape and predict therapeutic response in stomach adenocarcinoma

Stomach adenocarcinoma (STAD) is the most prevalent gastrointestinal malignancy and seriously threatens the life of the global population. Anoikis, a process of programmed cell death that occurs when cells detach from the extracellular matrix, is closely associated with tumor invasion and metastasis. In this study, we used the TCGA-STAD database to identify the expression patterns and prognostic relevance of anoikis-related genes (ARGs) in STAD. Functional enrichment analysis was used to explore the potential pathway. LASSO and Cox regression were used to construct anoikis-related prognostic signature. The anoikis risk score (ARS) incorporated 7 genes and stratified patients into highand low-risk subgroups by median value splitting. In addition, external validation was performed based on GSE66229, GSE15459, and GSE84437 cohorts. Nomograms were created based on risk characteristics in combination with clinical variants and the performance of the model was validated with time-dependent AUC, calibration curves, and decision curve analysis (DCA). The prognostic signature indicated that the low-risk subgroup had better outcomes and significant correlations with tumor microenvironment, immune landscape, immunotherapy response, and drug sensitivity. In addition, single-cell analysis displayed the cell types, the subcellular localization of prognostic genes, and the cellular interaction to reveal the potential molecular communication mechanism of anoikis resistance. Finally, in vitro experiments confirmed the critical role of CRABP2 in STAD. The results indicated that CRABP2 knockdown inhibited gastric cancer cell proliferation, migration and invasion, and promoted apoptosis. In summary, ARS can serve as a biomarker for predicting survival outcomes in STAD patients, providing new tools for personalized treatment decisions for STAD patients.

Circadian rhythm related genes signature in glioma for drug resistance prediction: a comprehensive analysis integrating transcriptomics and machine learning

BackgroundGliomas, 24% of all primary brain tumors, have diverse histology and poor survival rates, with about 70% recurring due to acquired or de novo resistance. Insomnia in patients is correlated strongly with circadian rhythm disruptions. The correlation between circadian rhythm disorders and drug resistance of some tumors has been proved. However, the precise mechanism underlying the relationship between glioma and circadian rhythm disorders has not been elucidated.MethodsCircadian rhythm-related genes (CRRGs) were identified using the least absolute shrinkage and selection operator (LASSO) regression, and stochastic gradient descent (SGD) was performed to form a circadian rhythm-related score (CRRS) model. The studies of immune cell infiltration, genetic variations, differential gene expression pattern, and single cell analysis were performed for exploring the mechanisms of chemotherapy resistance in glioma. The relationship between CRRGs and chemosensitivity was also confirmed by IC 50 (half maximal inhibitory concentration) analysis.ResultSignatures of 16 CRRGs were screened out and identified. Based on the CRRS model, an optimal comprehensive nomogram was created, exhibiting a favorable potential for predicting drug resistance in samples. Immune infiltration, cell–cell communication, and single cell analysis all indicated that high CRRS group was closely related to innate immune cells. IC50 analysis showed that CRRG knockdown enhanced the chemosensitivity of glioma.ConclusionA significant correlation between CRRGs, drug resistance of glioma, and innate immune cells was found, which might hold a significant role in the drug resistance of glioma.

Genome-wide identification and characterization of transcription factors involved in defense responses against Sclerotinia sclerotiorum in Brassica juncea

Sclerotinia sclerotiorum could cause significant yield losses of up to 70% in rapeseed cultivation. Nevertheless, the availability of immune or highly resistant germplasm and mechanisms to combat S. sclerotiorum, particularly in B. juncea, remains insufficient. Transcription factors (TFs) are recognized for their critical role in plant defense against S. sclerotiorum. In the present study, a total of 4807 TFs from 48 families were expressed and identified at 12, 24, and 36 h after inoculation (HAI) in two B. juncea lines: G21-912, exhibiting higher S. sclerotiorum resistance (HR), and G21-853, displaying lower S. sclerotiorum resistance (LR). The number of differentially expressed TFs (DETs) between the HR and the LR lines peaked at 24 HAI, with 202 upregulated and 105 downregulated TFs. Through expression and subcellular localization analyses, three candidate DETs, namely BjuA037408 (ETHYLENE RESPONSIVE FACTOR 59, ERF59), BjuB028842 (RELATED TO ABI3/VP1 1, RAV1), and BjuA016484 (WRKY25), were identified as the primary TFs in defense against S. sclerotiorum inoculation. The expression of these three genes was validated in the double haploid lines of BC3 (the third backcrossing generation) derived from the HR×LR cross. This study serves as a valuable case study for the characterization of TFs associated with defense mechanisms against S. sclerotiorum in B. juncea. The confirmed resistant B. juncea line of HR, along with the three key DETs, is expected to significantly contribute to future breeding efforts aimed at developing Sclerotinia-resistant varieties.

Cancer stem cell populations are resistant to 5-aminolevulinic acid-photodynamic therapy (5-ALA-PDT)

Photodynamic therapy (PDT) is a minimally invasive treatment approved for many types of cancers. PDT involves the administration of photoactive substances called photosensitizers (PS) that selectively accumulate in cancer cells and are subsequently excited/activated by irradiation with light at wavelengths of optimal absorbance. Activated PS leads to the generation of singlet oxygen and other reactive oxygen species (ROS), promoting cancer cell death. 5-aminolevulinic acid (5-ALA) is a naturally occurring PS precursor, which is metabolically converted to the PS, protoporphyrin IX (PPIX). Although 5-ALA-PDT is effective at killing cancer cells, in prior studies conducted by our group we normally observed in in vitro experiments that approximately 5–10% of cells survive 5-ALA-PDT, which served as an impetus for further investigation. Identifying the mechanisms of resistance to 5-ALA-PDT-mediated cell death is important to prevent tumor recurrence following 5-ALA-PDT. Previously, we reported that oncogenic activation of Ras/MEK promotes PPIX efflux and reduces cellular sensitivity to 5-ALA-PDT through increased expression of ABCB1 transporter. As cancer stem cells (CSCs) are known to drive resistance to other cancer treatments and have high efflux of chemotherapeutic agents via ABC-family transporters, we hypothesize that CSCs underlie 5-ALA-PDT resistance. In this study, we determined (1) if CSCs are resistant to 5-ALA-PDT and (2) if CSCs play roles in establishing resistant populations of 5-ALA-PDT. When we compared CSC populations before and after 5-ALA-PDT, we found that CSCs were less susceptible to 5-ALA-PDT. Moreover, we found that the CSC population was enriched in 5-ALA-PDT-resistant cell lines compared to the parental cell line. Our results indicate that CSCs are not sensitive to 5-ALA-PDT, which may contribute to establishment of 5-ALA-PDT resistance.

Nanocarrier-mediated modulation of cGAS-STING signaling pathway to disrupt tumor microenvironment.

The cGAS-STING signaling plays an important role in the immune response in a tumor microenvironment (TME) of triple-negative breast cancer (TNBC). The acute and controlled activation of cGAS-STING signaling results in tumor suppression, while chronic activation of cGAS-STING signaling results in immune-suppressive TME that could result in tumor survival. There is a need, therefore, to develop therapeutic strategies for harnessing tumor suppressive effects of cGAS-STING signaling while minimizing the risks associated with chronic activation. Combination therapies and nanocarriers-based delivery of cGAS-STING agonists have emerged as promising strategies in immunotherapy for controlled modulation of cGAS-STING signaling in cancer. These approaches aim to optimize the tumor suppressive effects of the cGAS-STING pathway while minimizing the challenges associated with modulators of cGAS-STING signaling. In the present review, we discuss recent advancements and strategies in combination therapies and nanocarrier-based delivery systems for effectively controlling cGAS-STING signaling in cancer immunotherapy. Further, we emphasized the significance of nanocarrier-based approaches for effective targeting of the cGAS-STING signaling, tackling resistance mechanisms, and overcoming key challenges like immune suppression, tumor heterogeneity, and off-target effects.

EPSPS target site mechanisms confer glyphosate resistance in Arctotheca calendula.

The first case of glyphosate resistance was reported in a capeweed population from Western Australia in our previous study. This current study investigates the resistance mechanisms in the population. Target-site EPSPS gene sequencing revealed two partial sequences of the EPSPS transcripts (1001 bp and 998 bp), and the full-length sequence (1551 bp) containing the 1001-bp transcript was cloned as it was found in the resistant plants. A known resistance-endowing target-site mutation in the 1551-bp transcript was identified in the resistant plants, resulting in the Pro-106-Ser substitution. The subpopulation derived from these mutant plants exhibited >10-fold resistance to glyphosate compared to the susceptible population. Additionally, the EPSPS gene (1551 bp) was constitutively expressed at a higher level (4.3-fold) in the resistant than in the susceptible populations. However, 14C-glyphosate foliar uptake was similar with no visual difference in 14C-glyphosate translocation from leaves to other parts of a plant, between the resistant and susceptible population. Glyphosate resistance in the studied population is associated with both a target-site mutation (Pro-106-Ser) and increased EPSPS gene expression. © 2025 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Colorectal Cancer: Current and Future Therapeutic Approaches and Related Technologies Addressing Multidrug Strategies Against Multiple Level Resistance Mechanisms

Colorectal cancer (CRC) is the third most common cancer and is associated with a poor prognosis. The mutation profile and related involved pathways of CRC have been, in broad terms, analyzed. The main current therapeutic approaches have been comprehensively reviewed here, and future possible therapeu-tic options and related technologies have been perspectively presented. The complex scenario represented by the multiple-level resistance mechanism in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAF V600E, is discussed. Examples of engineered therapeutic approaches from the literature along with a drug combination tested in clinical trials are discussed. The encouraging results observed with the latter combination (the BEACON clinical trial), totally free from chemotherapy, prompted the authors to imagine a future possible nanotechnology-assisted therapeutic approach for bypassing multiple-level resistance mechanisms, hopefully allowing, in principle, a complete biological cancer remission.

Pathogens of Medical Importance Identified in Hospital-Collected Cockroaches: A Systematic Review

Cockroaches serve as mechanical vectors for medically important pathogens, and their presence in hospitals is a common occurrence. This review summarizes the pathogens carried by cockroaches collected in hospitals around the world during the period 2000–2024 and focuses on their antibiotic resistance mechanisms and potential impact on the public health system. The conventional techniques are most used to identify microorganisms and determine antibiotic resistance, but there are few studies that use molecular techniques for bacterial identification and resistance mechanism detection. The species that appear most frequently in the selected articles were Escherichia coli (22 articles) and Pseudomonas aeruginosa (11 articles). Regarding antibiotic resistance, this review describes 79.0% (34/43) of the studies analyzed. E. coli and P. aeruginosa bacteria were found to be resistant to antibiotics in 51.2% and 25.6% of articles, respectively. The identification of pathogens carried by cockroaches collected in hospitals suggests a potential risk of these insects in the transmission of healthcare-associated infections, mainly in developing countries, where this issue is most alarming. The collected data suggest that integrated approaches to cockroach control and infestation management should be put in place based on scientific evidence.