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Renal cell carcinoma (RCC) is the prevalent form of kidney cancer in adults, with clear cell renal carcinoma (ccRCC) being the predominant subtype. While surgical resection remains the primary curative approach for localized RCC, a significant number of patients encounter disease relapse. The advent of targeted therapies, including tyrosine kinase inhibitors (TKI), mammalian target of rapamycin (mTOR) inhibitors, and immune checkpoint inhibitors, has revolutionized the treatment of metastatic RCC. However, despite therapeutic advancements, the emergence of resistance poses a significant challenge. Resistance mechanisms in RCC involve the disruption of hypoxia pathways, activation of the PI3K/AKT/mTOR pathway, and increased expression of alternate proangiogenic factors. Furthermore, the sequestration of TKI within lysosomes contributes to reduced drug effectiveness and development of resistance. Current research is focused on overcoming resistance by identifying predictive biomarkers for treatment efficacy, developing novel variations of existing therapies that target alternative signalling pathways, and exploring combination therapy approaches. The objective of this review article was to provide a comprehensive assessment of resistance mechanisms to systemic therapies and explore emerging treatment strategies for RCC.

Tomato cultivars containing the Tm‐22 resistance gene have been widely known to resist tobacco mosaic virus (TMV) and tomato mosaic virus. Tomato brown rugose fruit virus (ToBRFV), a new emerging tobamovirus, can infect tomato plants carrying the Tm‐22 gene. However, the virulence determinant of ToBRFV that overcomes the resistance conferred by the Tm‐22 gene remains unclear. In this study, we substituted the movement protein (MP) encoding sequences between ToBRFV and TMV infectious clones and conducted infectivity assays. The results showed that MP was the virulence determinant for ToBRFV to infect Tm‐22 transgenic Nicotiana benthamiana plants and Tm‐22‐carrying tomato plants. A TMV MP chimera with amino acid residues 60–186 of ToBRFV MP failed to induce hypersensitive cell death in the leaves of Tm‐22 transgenic N. benthamiana plants. Chimeric TMV containing residues 60–186 of ToBRFV MP could, but chimeric ToBRFV containing 61–187 residues of TMV MP failed to infect Tm‐22 transgenic N. benthamiana plants, indicating that 60–186 residues of MP were important for ToBRFV to overcome Tm‐22 gene‐mediated resistance. Further analysis showed that six amino acid residues, H67, N125, K129, A134, I147, and I168 of ToBRFV MP, were critical in overcoming Tm‐22‐mediated resistance in transgenic N. benthamiana plants and tomato plants. These results increase our understanding of the mechanism by which ToBRFV overcomes Tm‐22‐mediated resistance. Six amino acid residues, H67, N125, K129, A134, I147, and I168, located in the central region of the movement protein are involved in tomato brown rugose fruit virus to evade Tm‐22‐mediated resistance.

Antimicrobial resistance (AMR) emerges when antimicrobial agents are unable to kill microbes, and it is a major global concern. Therapeutic antimicrobial agents, such as antibiotics, are not so effective nowadays due to the development of antibiotic resistance in bacteria. This created an urgent need for alternative antimicrobials that can solve such intricate global issues. With the advancement in nanotechnology, antibiotics and drugs can be delivered directly to bacterial infection sites in higher doses using nanoparticles as carriers/conjugates. Nanoparticle-based approaches to antimicrobial delivery have the potential to overcome existing drug resistance mechanisms due to their unique targeting characteristics, multiple antimicrobial mechanisms, controlled release, and ability to penetrate barriers like biofilms and reach intracellular bacteria. Thus, the conjugation of nanomaterials with antimicrobials may offer a solution to the global problem of resistance. This permits specific, localized treatment that lessens the likelihood of adverse effects of drugs and promotes less widespread resistance. This review highlights the recent developments in the application of nanotechnology to fight against AMR. The development of nanoparticle-based vaccinations and novel antimicrobial medicines, as well as the use of artificial intelligence and machine learning–based tools to predict and detect bacteria and their resistance mechanisms, is spotlighted which is normally not reviewed utterly. However, toxicity, regulatory difficulties, and cost-effectiveness must be addressed for nanotechnology to be implemented in clinical practice. More study into nanotechnology is necessary to create efficient tactics to address worldwide health concerns of AMR, and it can potentially play a significant role as a therapeutic tool towards diminishing resistance with effective and improved characteristics.

FLT3 ITD and TKD mutations occur in 20% and 10% of Acute Myeloid Leukemia (AML), respectively, and they represent the target of the first approved anti-leukemic therapies in the 2000s. Type I and type II FLT3 inhibitors (FLT3i) are active against FLT3 TKD/ITD and FLT3 ITD mutations alone respectively, but they still fail remissions in 30–40% of patients due to primary and secondary mechanisms of resistance, with variable relapse rate of 30–50%, influenced by NPM status and FLT3 allelic ratio. Mechanisms of resistance to FLT3i have recently been analyzed through NGS and single cell assays that have identified and elucidated the polyclonal nature of relapse in clinical and preclinical studies, summarized here. Knowledge of tumor escape pathways has helped in the identification of new targeted drugs to overcome resistance. Immunotherapy and combination or sequential use of BCL2 inhibitors and experimental drugs including aurora kinases, menin and JAK2 inhibitors will be the goal of present and future clinical trials, especially in patients with FLT3-mutated (FLT3mut) AML who are not eligible for allogeneic transplantation.

ABSTRACT Purpose To develop a nanostructured lipid carrier (NLC) co-loaded with doxorubicin and docosahexaenoic acid (DHA) and to evaluate its potential to overcome drug resistance and to increase antitumoral effect in MCF-7/Adr cancer cell line. Methods The NLC was prepared by a hot homogenization method and characterized for size, zeta potential, entrapment efficiency (EE) and drug loading (DL). Drug release was evaluated by dialysis in complete DMEM, and NLC aggregation was assayed in the presence of serum. The cytotoxicity of formulations, doxorubicin uptake or penetration were evaluated in MCF-7 and MCF-7/Adr as monolayer or spheroid models. Results The formulation had a size of about 80 nm, negative zeta potential, EE of 99%, DL of 31 mg/g, a controlled drug release in DMEM and no particles aggregation in presence of serum. The NLC loaded with doxorubicin and DHA showed the same activity as free drugs against MCF-7 but a stronger activity against MCF-7/Adr cells. In monolayer model, the doxorubicin uptake as free and encapsulated form was similar in MCF-7 but higher for the encapsulated drug in MCF-7/Adr, suggesting a bypassing of P-glycoprotein bomb efflux. For spheroids, the NLC loaded with doxorubicin and DHA showed a prominent cytotoxicity and a greater penetration of doxorubicin. Conclusions These findings suggest that the co-encapsulation of doxorubicin and DHA in NLC enhances the cytotoxicity and overcomes the doxorubicin resistance in MCF-7/Adr. Figure ᅟ

Fusarium wilt, caused by Fusarium oxysporum f. sp. lycopersici (Fol), causes losses in tomato production worldwide, with major impacts on Californian tomato processing. Single-gene resistance is the primary management tool, but its efficacy has been compromised following the emergence of two successive resistance-breaking races, which, in California, emerged within 12 years of resistance deployment. Fol race 3-resistant (F3) processing tomato cultivars (containing the I3 resistance gene) were deployed in the state starting in approximately 2009. The emergence of a new resistance-breaking race (which would be called race 4) is imminent, and early detection will be critical to delay the spread while new resistance is sought. The detection of Fol race 4 is challenged by the lack of validated, rapid, and accurate diagnostic tools. In evaluating in planta phenotyping methods, this study found that rapid seedling phenotyping is not reliable and generates false positives for nonpathogens. Longer (10 weeks) mature plant assays are the most reliable, but may not be sufficiently timely. As an additional challenge, based on field and greenhouse studies, Fol race 3 can cause symptoms in resistant F3 cultivars at frequencies greater (30%) than expected for off-types (<2%). We developed a three-F3 cultivar in planta assay to overcome the challenges this posed to differentiating Fol race 3 and Fol race 4. Using the assay, we determined that all putative resistance-breaking cases were Fol race 3; Fol race 4 was not detected in these early survey efforts. These results highlight the need for developing rapid Fol race 4 detection tools and a better understanding of the factors underlying inconsistent I3 gene expression in Fol race 3.

Despite clinical intervention, glioblastoma (GBM) remains the deadliest brain tumor in adults. Its incurability is partly related to the establishment of drug resistance, both to standard and novel treatments. In fact, even though small kinase inhibitors have changed the standard clinical practice for several solid cancers, in GBM, they did not fulfill this promise. Drug resistance is thought to arise from the heterogeneity of GBM, which leads the development of several different mechanisms. A better understanding of the evolution and characteristics of drug resistance is of utmost importance to improve the current clinical practice. Therefore, the development of clinically relevant preclinical in vitro models which allow careful dissection of these processes is crucial to gain insights that can be translated to improved therapeutic approaches. In this review, we first discuss the heterogeneity of GBM, which is reflected in the development of several resistance mechanisms. In particular, we address the potential role of drug resistance mechanisms in the failure of small kinase inhibitors in clinical trials. Finally, we discuss strategies to overcome therapy resistance, particularly focusing on the importance of developing in vitro models, and the possible approaches that could be applied to the clinic to manage drug resistance.

This article analyses non-trivial forms of resistance encountered in the implementation of zero-emission neighbourhoods in Norway, based on eight years of living lab experiments and interviews with key stakeholders. Drawing on a socio-material approach to infrastructuring, it identifies three distinct categories of resistance: tensions between professional groups—particularly between energy and construction sectors; resistance ‘from above’ through lack of political and regulatory support; and resistance ‘from below’ by local stakeholders and future users. The analysis reveals that these forms of resistance go beyond simple opposition to change, instead reflecting deep-seated professional practices, shifting political priorities and local social contexts that compete with or contradict zero-emission planning goals. Practice relevance For practitioners and policymakers, this study demonstrates that successful implementation of zero-emission neighbourhoods requires more than technical solutions and regulatory frameworks. The findings suggest that—at least in the Norwegian context—future zero-emission planning must better integrate diverse professional expertise, particularly from energy and building experts, but also from local planners and user groups, while developing strategies that can succeed with minimal state support. These insights can help practitioners design more inclusive and effective approaches to neighbourhood-scale decarbonisation efforts.

Ovarian cancer is the most lethal gynecologic malignancy. Platinum-based chemotherapy is the backbone of treatment for ovarian cancer, and although the majority of patients initially have a platinum-sensitive disease, through multiple recurrences, they will acquire resistance. Platinum-resistant recurrent ovarian cancer has a poor prognosis and few treatment options with limited efficacy. Resistance to platinum compounds is a complex process involving multiple mechanisms pertaining not only to the tumoral cell but also to the tumoral microenvironment. In this review, we discuss the molecular mechanism involved in ovarian cancer cells’ resistance to platinum-based chemotherapy, focusing on the alteration of drug influx and efflux pathways, DNA repair, the dysregulation of epigenetic modulation, and the involvement of the tumoral microenvironment in the acquisition of the platinum-resistant phenotype. Furthermore, we review promising alternative treatment approaches that may improve these patients’ poor prognosis, discussing current strategies, novel combinations, and therapeutic agents.

This review introduces a paradigm-shifting concept of Dual Distinct Immunotherapy (DDI), which strategically integrates two distinct immunotherapeutic modalities to overcome the limitations of current monotherapies and dual immune checkpoint inhibitor (ICI) combinations. The concept of DDI extends beyond traditional ICI combinations to encompass various innovative pairings: ICIs with oncolytic viruses (OVs), adoptive cell therapies (CAR-T/TIL), cancer vaccines, or cytokine therapies. These combinations demonstrate unique synergistic mechanisms and enhanced therapeutic potential through multi-faceted immune activation. Significantly, this work advances the field by analyzing potential third-agent sensitizers to complement DDI strategies. We systematically evaluate emerging candidates including PCNA inhibitors, HDAC inhibitors, and carbonic anhydrase inhibitors, focusing on their ability to modulate the tumor microenvironment and enhance immunotherapy responses. This \"DDI + 1\" approach targets alternative pathways to overcome resistance mechanisms and expand treatment efficacy to traditionally immunotherapy-resistant cancers. Through comprehensive analysis of preclinical evidence and ongoing clinical trials, we address critical challenges in immunotherapy, including primary and acquired resistance, cold tumor conversion, and pathway exhaustion. The review synthesizes current findings while proposing innovative solutions and future research directions. Our framework demonstrates how strategic integration of multiple immune-based approaches can significantly improve therapeutic outcomes across diverse cancer types, potentially revolutionizing cancer treatment paradigms. This concept of DDI, enhanced by rational third-agent selection, represents a promising direction for addressing urgent clinical needs in oncology. By establishing a theoretical foundation for this approach, we aim to guide future research and clinical applications in cancer immunotherapy.