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The mitochondrial genome of plants contains an open reading frame, orfx, which encodes a protein classified as very rare and which has so far escaped mass spectrometric detection. The protein resembles the c-subunit of bacterial twin-arginine-motif-dependent protein translocases (TatC). Using native prefractionation of mitochondrial protein complexes from Arabidopsis and trapped-ion mobility spectrometry (TIMS) time-of-flight mass spectrometry, we report the identification of three peptides of the orfx protein. Our experimental approach was used to trace the native forms of the protein and show that it is present in protein complexes in the size range of 450-530 kDa, which also contain TatB. We suggest that mitochondrial TatBC complexes in plants may bind to late assembly intermediates of respiratory chain complex III.
Leishmania tarentolae, a reptile-associated parasite, is poorly documented in France. This study provides the first molecular survey of L. tarentolae in sand flies across mainland France and Corsica (2023-2024), combining morphological and molecular vector identification with PCR-based parasite detection. A total of 2,731 female sand flies were collected, and 412 unfed pools and 132 blood-fed females were analysed. Sergentomyia minuta was the main carrier, with higher infection rates than Phlebotomus perniciosus. Among unfed females, L. tarentolae was detected in 56 pools, mainly from Corsica, whereas only two positive pools were found in mainland France. One pool from Montpellier in mainland France was positive for L. infantum. Of the 132 blood-fed females analysed, 24 tested positive for L. tarentolae. Blood-meal analyses revealed multi-host feeding, humans, livestock, hares and first evidence of goat feeding in Se. minuta, indicating flexible feeding behaviour. Co-circulation of L. tarentolae and L. infantum complicates diagnostics and epidemiology. These findings expand the known range of Sauroleishmania in Western Europe and provide a framework for entomological and eco-epidemiological surveillance. Integrated monitoring of vectors, reptiles, and domestic animals is essential for assessing transmission risks amid environmental and climatic changes.
Cancer is one of the leading causes of global morbidity and mortality and is characterized by its high heterogeneity, genomic instability and adaptive plasticity. Applying Darwin's theory of evolution, the concept of tumor evolution has improved our understanding of the biological behavior of advanced cancer, while technological limitations have long left how to dynamically characterize the evolutionary process unsolved. In recent years, the development of high-throughput sequencing, single-cell and spatial omics, lineage tracing, computational modeling, and noninvasive biopsy technology has helped explain tumor heterogeneity and track the evolutionary trajectory of tumors, which has attracted widespread attention in tumor evolution. Here, we discuss the models and drivers of tumor evolution, focusing on how cancer cells adapt and evolve under multidimensional selective pressure, including the intracellular, extracellular, and exogenous levels. We further summarize key signaling pathways and molecular mechanisms involved in genomic instability, epigenetic regulation, metabolic reprogramming, tumor microenvironment remodeling, immune escape and therapy-induced selection. In addition, emerging therapeutic strategies guided by tumor evolution are also discussed, emphasizing that the identification of key genetic and epigenetic targets, together with dynamic monitoring of clonal changes, is crucial for overcoming treatment resistance and improving patient outcomes. By systematically summarizing the signaling pathways and molecular mechanisms underlying tumor evolution, this review aims to provide new targets and conceptual frameworks for promoting precision treatment strategies in oncology in the future.
Anti-bacteriophage systems such as restriction-modification and CRISPR-Cas have DNA substrate specificity mechanisms that enable the identification of invaders. How Gabija, a highly prevalent nuclease-helicase antiphage system, limits phage replication while executing self- vs. non-self-discrimination remains unknown. Here, we show that phage-encoded DNA end-binding proteins that antagonize host RecBCD sensitize phages to Gabija. When targeting a temperate lambda-like phage in Pseudomonas aeruginosa, Gabija prevents phage genome circularization and subsequent replication. DNA end-binding complexes, including a phage exonuclease and a single-stranded DNA (ssDNA)-annealing protein or GamMu dimers that prevent loading of the host repair complex RecBCD, are necessary and sufficient to license phage and plasmid sensitivity to Gabija. Mutant escape phages lacking these DNA end-binding proteins become protected from Gabija by RecBCD translocation activities. RecBCD activity on the bacterial genome, presumably whenever it is linearized, also prevents Gabija from targeting self-DNA. Therefore, we propose that Gabija antagonizes the circularization and replication of linear DNA devoid of RecBCD as a mechanism to identify and antagonize foreign invaders.
Multidrug resistance and invasive metastasis constitute pivotal clinical bottlenecks that severely compromise curative outcomes of malignant tumors. Conventional chemotherapy and immunotherapy frequently fail to achieve satisfactory efficacy due to drug resistance barriers and tumor immune escape. Herein, a hyaluronic acid‑cinnamaldehyde Schiff base micelle nanoplatform loading quaternary ammonium‑modified carbon dots (HACA@QASCDs) is rationally constructed, which achieves targeted killing of drug‑resistant tumor cells, remodeling of immunosuppressive microenvironments, and inhibition of distant metastasis via a sequential cascade of irreversible membrane perforation, mitochondria‑dependent apoptosis, and immunogenic cell death (ICD). HACA@QASCDs actively accumulate in drug‑resistant CT26 (DR‑CT26) cells through HA‑CD44 recognition and enable pH‑triggered QASCDs release in acidic tumor microenvironments. The liberated QASCDs elicit irreversible membrane perforation, leading to lactate dehydrogenase leakage, disrupted calcium homeostasis, mitochondrial depolarization, and subsequent intrinsic apoptosis. Such membrane damage simultaneously ignites ICD, and the released damage‑associated molecular patterns effectively drive dendritic cell maturation and M2‑to‑M1 macrophage polarization. In vivo evaluations in bilateral syngeneic tumor models reveal that HACA@QASCDs alone yields 54.2% primary tumor inhibition and 28.6% distant tumor inhibition. Upon combination with αPD‑L1, the distant tumor inhibition rate is markedly elevated to 68.7%. By integrating membrane perforation‑mediated direct cytotoxicity and ICD‑evoked immune activation, HACA@QASCDs offers a highly potent and clinically translatable synergistic strategy to surmount tumor multidrug resistance and block invasive metastasis.
Hydrogen─chlorine (H2─Cl2) batteries are attractive high-power energy storage systems but remain fundamentally limited by inefficient Cl2 confinement and sluggish interfacial Cl2/Cl- redox kinetics. Here, we report a hydrogen-bonded porphyrin framework with atomically dispersed Cu sites (SACu-GTUB5) that enables efficient Cl2 storage and accelerates Cl2/Cl- conversion. The intrinsic porosity of the framework combined with chemically active Cu─N4 centers enables synergistic physical confinement and chemical adsorption of Cl2, effectively suppressing Cl2 escape and improving Coulombic efficiency. As a result, the SACu-GTUB5-based H2─Cl2 battery exhibits stable operation across a wide temperature range (-40°C to 60°C) and achieves a high areal discharge capacity of 2.55 mAh cm-2 over 300 cycles. Spectroscopic analyses combined with density functional theory calculations reveal that Cu─N4 sites govern Cl2 adsorption, electron redistribution, and reaction pathways, substantially lowering the energy barriers for Cl2 reduction. This work establishes an atomic-level interfacial regulation strategy for controlling halogen redox chemistry in electrochemical energy storage.
Hepatocellular carcinoma (HCC) is a malignant tumor with high heterogeneity and immunotherapeutic resistance worldwide, presenting a severe challenge in clinical prevention and treatment. N6-methyladenosine (m6A) is the most common reversible post-transcriptional modification on eukaryotic mRNA, whose dynamic balance is precisely regulated by "demethylases" (Erasers). Recent studies have confirmed that the two core m6A Erasers (FTO and ALKBH5) exhibit significant expression imbalance in HCC, which strongly drives malignant tumor progression. Erasers enhance the ferroptosis resistance of HCC cells by regulating the stability of lipid metabolism-related RNAs such as GPNMB and FLAD1, helping them adapt to adverse metabolic microenvironments such as hypoxia and nutrient deprivation. Meanwhile, FTO can promote exosome release, inhibit the antigen-presenting function of dendritic cells (DCs), and further induce CD8⁺ T cells into an exhausted state. These processes synergistically construct an immunosuppressive tumor microenvironment (TIME), facilitating HCC to escape immune attack. Small-molecule inhibitors targeting core targets such as FTO and the emerging PROTAC technology have shown potential in preclinical models for reversing immunosuppression and enhancing the efficacy of systemic therapy. This review systematically synthesizes the regulatory mechanisms of Erasers in the HCC "metabolism-immunity" axis, comprehensively summarizes Eraser intervention strategies based on different etiological backgrounds for the first time, and concludes the clinical translation progress of related targeted drugs, providing new ideas and targets at the epitranscriptomic level for overcoming HCC immunotherapeutic resistance.
Pancreatic ductal adenocarcinoma (PDAC) is driven by oncogenic KRAS in roughly 90% of cases, and KRAS-pathway inhibition has finally become clinically active. Durable benefit, however, will require identifying the adaptive and baseline vulnerabilities that shape response to KRAS inhibition. Two resistance mechanisms have been proposed separately in the literature - receptor-tyrosine-kinase bypass of KRAS, and dependence on the adhesion kinase FAK - but whether they are one target class or two, and which should partner a KRAS inhibitor, is unresolved. We integrate public perturbation, dependency, and survival data to nominate them as mechanistically separable candidate combination partners. Two findings define the separation. First, KRAS loss increases ERBB2/3 receptor expression. This appeared in both an inducible genetic KRAS-extinction model and, independently, in five PDAC lines treated with pharmacological KRAS-G12C/D inhibitors, while MAPK output collapsed as expected. The signal was clearest for ERBB2 and in the genetic model; in the small pharmacological cohort the effect was modest and its confidence intervals crossed zero, so we treat ERBB2/3 up-regulation as a candidate adaptive response - ERBB2-dominant and ERBB3-compatible - not a proven resistance mechanism. Second, focal adhesion kinase (FAK/PTK2) is the top-ranked standing druggable dependency within the KRAS/Src/RTK/adhesion network we examined (essential in 58% of pancreatic lines), yet it is not induced by KRAS shutdown. FAK dependency is present at baseline and, in DepMap, is statistically independent of a line's KRAS dependency (Spearman ρ = +0.05, n.s.) - a genuinely standing vulnerability rather than a KRAS-rebound effect. The candidate adaptive response and the standing dependency are not positively co-regulated across the perturbed lines (pooled Spearman ρ = -0.43, but n = 8 and n.s., so this cannot by itself establish independence); we therefore treat them as separable on mechanistic grounds - each nominated by different data and engaged by a different drug - rather than as statistically demonstrated independent programs. A Src-centered signaling-landscape analysis associates patient prognosis with the coordinated invasion-and-RTK program these nodes organize, rather than with any single transcript; this program remains prognostic after adjustment for a conventional EMT/stromal signature, which does not (Src-neighborhood per-standard-deviation OS hazard ratio 1.9, p ≈ 3 × 10⁻⁵; EMT signature null on adjustment). Together these results motivate a concrete, testable hypothesis: that FAK inhibition (a standing dependency) and ERBB inhibition (a candidate induced adaptive response) are separable candidate partners for a KRAS inhibitor, best evaluated as distinct arms of a biomarker-stratified platform. They also clarify why single-agent Src inhibition - a non-oncogene dependency tested as monotherapy, without a KRAS backbone, in advanced rather than micro-metastatic disease - was not positioned to surface either mechanism. No protein-level, phospho-signaling, or combination-response validation is performed here; all findings are computational nominations that require experimental validation before any clinical inference. KRAS inhibition is associated with an induced ERBB2/3 up-regulation - ERBB2-dominant, ERBB3-compatible - directionally reproduced across genetic KRAS extinction and pharmacological KRAS-G12C/D inhibition; the pharmacological effect is modest and underpoweredGenome-wide dependency nominates FAK - essential in 58% of pancreatic lines - as the top-ranked standing candidate co-target within the KRAS network; FAK dependency is present at baseline, statistically independent of KRAS dependency, and not co-regulated with the induced ERBB response Patient prognosis associates with a Src-organized invasion-and-RTK program, not with SRC , KRAS , or any single-gene transcript, and this program stays prognostic after adjustment for a conventional EMT/stromal signature The two mechanisms are separable on mechanistic grounds - nominated by different data and not positively co-regulated (though the direct correlation is underpowered, n = 8, n.s.) - motivating a multi-arm platform that could test FAK and ERBB partner arms as distinct hypotheses rather than one bundled combination. Blocking KRAS in pancreatic cancer is now clinically feasible, but resistance is the obstacle. Using only public data, Chen and colleagues nominate two mechanistically separable candidate combination partners for KRAS inhibitors: a candidate ERBB2-dominant adaptive (putative escape) response that is induced when KRAS is blocked, and FAK, the top-ranked standing dependency in the KRAS network - present at baseline and independent of a tumor's KRAS dependency. Because the two are nominated by different data and are not positively co-regulated, they argue for a multi-arm KRAS-combination trial that tests each as a separate hypothesis - and they explain why the earlier single-agent Src trials, run without a KRAS backbone and in the wrong disease setting, were not positioned to detect either. The findings are computational nominations that require experimental validation.
The evolutionary trajectory of SARS-CoV-2 is shaped by competing pressures for angiotensin-converting enzyme 2 (ACE2) binding, viability, and escape from neutralizing antibodies targeting its receptor-binding domain (RBD). Here, we present EscapeMap, a modular framework that enables the prediction and design of variants escaping antibodies. EscapeMap integrates deep mutational scanning data for ACE2 and 31 monoclonal antibodies with a generative sequence model trained on pre-pandemic Coronaviridae. To experimentally probe escape potential, we designed RBD variants under pressure from four clinically relevant antibodies (SA55, S2E12, S309, and VIR-7229). Among these designs, bearing up to 21 mutations from wild type, 50% expressed as stable proteins. Binding assays confirm that S309 and VIR-7229 retain recognition across diverse mutation combinations. EscapeMap accurately forecasts which antibodies are vulnerable to escape by our designed sequences. Finally, by identifying correlated escape routes, we predict and experimentally verify antibody combinations less prone to simultaneous escape, offering a quantitative basis for guiding therapeutic strategies.
Piezocatalytic water splitting offers a sustainable route for hydrogen evolution, yet is challenged by weak polarity and slow charge separation kinetics under stress. Herein, we report strong polar hydroxylated Bi2O2CO3 (BOC) synthesized scalably, characterized by noncentrosymmetric (NCS) planar triangular [CO3] groups and surface hydroxyls, which applies as a robust piezocatalyst for hydrogen evolution. The aligned NCS planar [CO3] triangulars in BOC enable oriented accumulation of dipole moments to produce strong spontaneous polarization, and the intrinsic delocalized π-electrons within these structural units construct a conjugation freeway that minimizes charge migration resistance. Further external mechanical stress triggers a highly anisotropic lattice response; specifically, compression along the b-axis induces extreme geometric and electronic asymmetries that amplify the interlayer internal electric field (IEF) for charge separation. When synergistically coupled with surface hydroxylation, this stress-induced structural distortion significantly lowers the work function and interfacial kinetic barrier for electron escape. Consequently, the hydroxylated BOC catalyst achieves an ultrahigh piezocatalytic H2 evolution rate of 3055 µmol·g-1·h-1 and a record mechanical-to-hydrogen (MTH) energy conversion efficiency of 0.31% in pure water. It also maintains robust H2 evolution from real-world aquatic matrices, including rainwater, seawater, and antibiotic wastewater. This work establishes a polar group design-oriented paradigm for exploiting advanced piezocatalysts.
Lipid nanoparticles (LNPs) are highly modular drug nanocarriers that have significantly progressed in the development and application of novel RNA therapeutics. While instrumental in current vaccine and hepatic gene therapy applications, extrahepatic LNP delivery remains a challenging hurdle, severely limiting clinical applications for individualized therapies that require cellular- and tissue-specific enrichment. Novel platform development remains needed to generate targeted LNPs capable of modeling targeted uptake in vitro prior to in vivo applications. Herein, we developed and utilized an antibody-based targeting bispecific-LNP (TbsAb-LNP) platform simultaneously binding LNP polyethylene glycol motifs and desired cell surface markers. By colocalizing TbsAb-LNP complexes with desired cell surface markers, we enable mRNA-LNP accumulation in the desired cell types. We additionally assessed the endosomal efficiency kinetics of TbsAb-LNP complexes generated at various bispecific loading ratios in a Galectin-9 in vitro expression model. Leveraging this facile and modular platform that eliminates the need for complex chemical conjugation approaches, we successfully achieved targeted LNP delivery to xhuCD3-expressing lymphoblasts and xmTfR1-expressing cell lines in vitro as well as xmTfR1-expressing cells in vivo. Enrichment of TbsAb-LNPs to splenic cells demonstrates the potential utility of this platform for clinical vaccine and T-cell delivery applications.
Assessing the effects of the release of biologically contained microorganisms into the environment represents a challenging task as it requires both the tracking of escape events as well as the changes that result in the indigenous microbes, which cannot be effectively determined based on conventional culture-based methodologies. Toward closing this gap, we set up closed, laboratory mesocosms with water from a nearby recreational-use freshwater reservoir that were subsequently spiked with the Escherichia coli strain DEP to simulate an accidental spill of a synthetic organism into the environment. Strain DEP is a chloramphenicol-resistant synthetic auxotroph harboring three redesigned genes encoding nonstandard amino acid (nsAA)-dependent gene products for l-4,4'-biphenylalanine (BipA) dependence. Shotgun metagenome sequencing of the mesocosms revealed a sharp decline in the relative abundance of strain DEP over time, with minimal impact on the indigenous freshwater microbial communities as evidenced by the recovery of these communities to the preperturbation state after 2 days of incubation. Further, there were no observations of transfer of the nsAA-dependent genes to the indigenous populations at the limit of detection of our metagenome sequencing effort or based on culturing on BipA-supplemented media. Collectively, our results show that this particular strain DEP may not pose a serious environmental threat if accidentally released into the environment due to low competitiveness against the indigenous freshwater microbes and the lack of escape mutants. Notably, this work establishes a holistic approach to assess biocontainment efficacy that should be applicable to additional genetically modified organisms.
Glioblastoma (GBM) remains one of the most lethal primary brain tumors, with limited therapeutic improvement despite maximal surgical resection, radiotherapy, and temozolomide. A major barrier to durable treatment response is the profoundly immunosuppressive tumor microenvironment, which is characterized by immune exclusion, defective antigen presentation, myeloid dominance, and severe T-cell dysfunction. Tumor-associated macrophages, resident microglia, myeloid-derived suppressor cells, neutrophils, regulatory T cells, and glioma-derived extracellular vesicles collectively establish a suppressive niche through cytokine signaling, metabolic restriction, checkpoint ligand expression, impaired phagocytosis, and extracellular matrix remodeling. Key pathways, including TGF-β/SMAD, IL-10/STAT3, IDO-kynurenine metabolism, arginase-1-mediated amino acid depletion, adenosine signaling, hypoxia-HIF-1α activation, and VEGF-driven vascular dysfunction, converge to prevent effective antitumor immunity. This review summarizes the cellular and molecular mechanisms underlying immune suppression in GBM and discusses emerging therapeutic strategies, including myeloid reprogramming, phagocytosis checkpoint blockade, neutrophil and NET targeting, cellular immunotherapy, checkpoint blockade combinations, and metabolic intervention. Understanding these interconnected barriers may guide rational multimodal strategies to convert immune-excluded GBM into immune-responsive disease.
Programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule important in tumor immune evasion acting primarily by inhibiting T cell activation. In breast cancer, PD-L1 is frequently abnormally expressed and associated with tumor progression, metastasis, and poor prognosis. Recent studies have revealed that non-coding RNAs (ncRNAs) including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are important post-transcriptional regulators of PD-L1. ncRNAs regulate PD-L1 expression through multiple mechanisms, including direct binding to PD-L1 mRNA 3' UTR, acting as competing endogenous RNAs (ceRNAs), altering transcription factor activity, and altering epigenetic modifications. Dysregulation of ncRNAs not only impact PD-L1-mediated immune escape (i.e., cancer immune evasion), but can also remodel the tumor microenvironment (TME) through impact on immune cell infiltration and activity, and alterations to cytokine production. This review provides an overview of current understanding of ncRNAs regulating PD-L1 in breast cancer, specifically their molecular mechanisms, therapeutic potential, and clinical relevance as biomarkers and/or therapeutic targets. The broad ncRNA-PD-L1 regulatory network is complex, and discoveries in this field may create novel avenues for precision immunotherapy and combination strategies in treating breast cancer.
EMILIN-1 is an extracellular matrix glycoprotein with tumor-suppressive functions. While its loss is implicated in cancer progression, its specific role in the gastric tumor microenvironment and its clinical relevance remain poorly defined. Using in vitro cellular systems and genetically modified mouse models we investigated the consequences of impaired EMILIN-1 function on gastric epithelial transformation, stromal remodeling, and fibroblast reprogramming. Histopathological analysis, gene expression profiling, and functional assays were employed to assess phenotypic changes in epithelial, fibroblastic, and endothelial compartments. We found that gastric cancer (GC) cells downregulate EMILIN-1 in stromal fibroblasts and lymphatic endothelial cells via paracrine signaling, leading to reduced EMILIN-1 deposition and disrupted lymphatic organization. Mechanistically, the interaction between EMILIN-1 and α4β1 integrin, which is absent in GC cells, modulates tumor cell proliferation; loss of this axis allows tumor cells to escape ECM-mediated growth control. Furthermore, EMILIN-1 downregulation reprograms fibroblasts into a pro-tumorigenic phenotype, which enhances GC cell migration and clonogenic potential. EMILIN-1 loss-of-function (E955A) mice showed increased susceptibility to pre-neoplastic lesions, a finding mirrored in human dysplastic tissues where EMILIN-1 was markedly reduced. Our findings establish EMILIN-1 as a master regulator of gastric tissue integrity. Its loss creates a tumor-permissive microenvironment by disrupting epithelial homeostasis, impairing lymphatic structure, and promoting fibroblast activation. The consistent reduction of EMILIN-1 in early human dysplasia highlights its potential as a novel stromal biomarker for early GC risk stratification. Moreover, restoring the EMILIN-1/integrin axis represents a promising therapeutic strategy to re-establish growth control and suppress tumor progression.
The 3-min all-out test is considered a time-efficient alternative for estimating critical power (CP) and curvature constant (W'), by means of endtest power (EP) and work done above endtest power (WEP), respectively. This review aims to assess its reliability and validity with respect to methodology. Following the PRISMA 2020 guidelines, a systematic literature search was conducted on June 20th 2025, using a specified search term in PubMed and Web of Science. Included studies were English-language, peer-reviewed original articles, that provided empirical data on the 3-min all-out test in cycling and used appropriate protocols for assessing reliability/validity. Quality of studies was assessed using a modified critical appraisal tool. Meta-analysis for validity was done using pooled Hedge's gz with random effects synthesis and 95%prediction intervals. Twenty studies comprising N = 284 participants met all inclusion criteria. Thereof, 15 studies examined validity, 8 reliability and 3 both. Included studies demonstrated methodological heterogeneity and small sample sizes (n = 6-21). Test-retest reliability demonstrated 'good' to 'excellent' agreement for EP (ICC = 0.89-0.99) and WEP (ICC = 0.76-0.98). EP systematically overestimates CP (gz= 0.408 [0.024, 0.792]) while WEP underestimates W' (gz= -0.389 [-0.954, 0.176]). Whereas the 3-min all-out test provides reliable results for EP and WEP if tests are conducted within three weeks, its validity seems to largely depend on the methodological approach. Certain power profiles and/or isokinetic 3-min tests lead to better estimates of CP, while the variability of WEP does not allow to accurately estimate W'. Familiarisation trials and proper verbal encouragement during the 3-min test are mandatory.
Large language models (LLMs) for biological sequences are transforming computational biology, enabling a nuanced understanding of protein and nucleotide sequence data. Recent models, including ESM2, ESM3, AlphaGenome, Evo-1, and Evo-2, adapt natural language processing principles to the biological domain by learning high-dimensional hidden representations that capture evolutionary constraints, structural patterns, and functional motifs. This mini-review summarizes recent developments in devising and applying such models, emphasizing viral protein analysis. We highlight studies that have leveraged sequence-based LLMs in the protein domain (i.e. protein language models, or PLMs) for important application tasks such as viral protein annotation, variant effect prediction, and immune escape characterization. Additionally, we present a benchmark evaluation of these state-of-the-art protein language models to evaluate their core ability to capture evolutionary relationships between viral protein sequences. By discussing the opportunities and challenges of PLMs, the review outlines a road map for the potential application of LLMs in empowering virology research and pathogen surveillance.
Doxorubicin (DOX) resistance is a major factor limiting the efficacy of chemotherapy in breast cancer. Its development is associated not only with conventional mechanisms, such as enhanced drug efflux, increased DNA damage repair capacity, and evasion of apoptosis, but also with the adaptive escape of tumor cells from ferroptotic stress. Ferroptosis is a form of regulated cell death driven by the accumulation of iron-dependent lipid peroxidation and is coordinately regulated by multiple mechanisms, including the system Xc⁻-GSH-GPX4 axis, the FSP1-CoQ10 pathway, NRF2-mediated antioxidant responses, remodeling of iron metabolism, and regulation of lipid peroxidation. Non-coding RNA (ncRNAs), including miRNAs, lncRNAs, and circRNAs, can act on these ferroptosis defense modules through post-transcriptional regulation, competing endogenous RNA (ceRNA) networks, epigenetic modulation, and extracellular vesicle-mediated intercellular communication, thereby reshaping the sensitivity of breast cancer cells to DOX. This review systematically summarizes the major mechanisms by which ncRNAs regulate ferroptosis and contribute to DOX resistance in breast cancer, and further discusses subtype-specific differences in ncRNA-ferroptosis regulatory circuits among triple-negative, ER-positive, and HER2-positive breast cancers. In addition, this review highlights the potential value of circulating ncRNAs as resistance-associated biomarkers, as well as the translational prospects of miRNA mimics, siRNAs, antisense oligonucleotides (ASOs), and nanodelivery systems targeting the ncRNA-ferroptosis axis. Overall, ncRNA-mediated ferroptosis reprogramming provides a new mechanistic framework and potential therapeutic strategies for understanding and overcoming DOX resistance in breast cancer; however, its clinical application still requires further resolution of key challenges, including validation of causal evidence, insufficient delivery efficiency, off-target effects, and immunological safety.
Multiple myeloma (MM), a hematological malignancy, remains an incurable disease due to the development of resistance to the treatment; thus, there is an urgent need for new and effective therapeutic strategies, particularly for patients who do not respond to standard therapies. High levels of Cluster of Differentiation 47 (CD47) expression have been reported in MM and are associated with disease progression. CD47 acts as a cancer immune escape mechanism by binding to SIRPα protein, resulting in inhibiting phagocytosis of macrophages and NK cell activity. Therefore, blocking the CD47 signaling pathway has emerged as a promising strategy for cancer immunotherapy. In this study, we confirmed that MM cells have high CD47 expression. We generated and characterized a tri-specific killer engager targeting CD47, namely TriKE-CD47, that targets both CD47 on MM cells and CD16 on NK cells. Additionally, it incorporates an IL-15 moiety to enhance NK cell proliferation. TriKE-CD47 treatment promoted a remarkable proliferation of NK cells overexpressing CD16 (N6 cells). Co-culturing MM cells with N6 cells, primary NK cells, and monocyte-derived macrophages in the presence of 200 ng of TriKE-CD47 significantly improved NK cytotoxicity and macrophage phagocyte activities against MM cells. Notably, the efficacy of TriKE-CD47 was directly correlated with CD47 expression levels on the target cells reflecting the specificity of TriKE-CD47 to target antigen. Furthermore, TriKE-CD47 effectively suppressed tumor growth in MM xenograft mice models. Taken together, these findings strongly supported that TriKE-CD47 could be a potential therapeutic for MM patients.
For patients who are suffering, the bedside presence of a family member can provide comfort, and many people hold that there is moral value in being present with a conscious, suffering patient. Yet what is the moral significance of the absence of family members when a patient is minimally conscious or unconscious and not aware of their absence? Clinicians are often troubled when family members and surrogate decision-makers who are able to spend a significant amount of time at an unconscious, seriously ill patient's bedside do not do so. Clinicians feel frustrated that they must bear the burden of witnessing the patient's actual or perceived suffering while the family escapes this burden and therefore appears to fail to uphold a duty to the patient. What are we to make of this point of view? What is the source of this frustration? What is the nature of the perceived duty? Is it morally defensible to request or require family members to be present with an unresponsive patient to bear witness to their actual or perceived suffering? If so, on what grounds?