Search Results (16,316)

Triple-negative breast cancer is defined by the absence of druggable receptor targets and by a biologically dynamic phenotype that renders static, single-timepoint biomarker strategies fundamentally inadequate. Current predictive markers, including PD-L1 expression, tumor mutational burden, and genomic profiling, fail to capture the therapy-induced transcriptional reprogramming, spatial heterogeneity, and drug-tolerant persister states that drive resistance and relapse. In this review, we argue that RNA, particularly non-coding RNA (ncRNA), represents a complementary and state-aware platform for biomarker development in TNBC, capable of capturing transcriptional adaptation, regulatory threshold dynamics, and cell state transitions that static genomic markers cannot fully detect. Unlike messenger RNAs, which reflect active transcriptional programs, long non-coding RNAs and circular RNAs modulate the stability of state transitions and are specifically induced under conditions of therapeutic stress, immune exclusion, and drug tolerance, which are properties that make them suitable as potential early and sensitive indicators of adaptive reprogramming. We review the biological rationale for RNA as a state-aware readout across five dimensions: tumor plasticity, immune context, stress response, therapy adaptation, and microenvironment composition. An examination is conducted regarding how spatial transcriptomics can map RNA-defined resistant niches within TNBC, how serial liquid biopsy RNA measurements, including extracellular vesicle RNA and circulating tumor RNA, enable temporal monitoring of transcriptional state shifts before radiologic progression, and what analytical and clinical standards deployable RNA assays must meet. Finally, a state-guided adaptive management framework is proposed in which RNA signatures function as iteratively updated measurement layers informing therapy selection, on-treatment monitoring, and early resistance detection. This review outlines trial design models and defines the validation standards required before RNA-guided adaptation can enter clinical practice. Full article

Background: Diffuse Large B-cell Lymphoma (DLBCL) is a biologically heterogeneous subtype of non-Hodgkin’s lymphoma (NHL), accounting for 30–40% of cases worldwide. Despite the incorporation of rituximab into standard chemo-immunotherapy regimen, approximately one-third of patients present with relapsed or refractory disease, implicating the need for improved prognostic markers and therapeutic targets. Gene expression profiling successfully classified DLBCL into Germinal Center B-cell-like (GCB) and non-GCB subtypes, which differ in genetic alterations, response to therapy, and clinical outcome. While intrinsic tumor biology has been extensively studied, the contribution of the tumor microenvironment (TME) to disease progression and therapeutic resistance still remains incompletely understood. Methods: In this study, we investigated the mutational landscape of stromal-related genes in DLBCL and evaluated their impact on gene expression, downstream signaling pathways, and tumor progression. Results: A total of 176 DLBCL patients were screened, of which 113 were enrolled based on availability of complete clinical data. The cohort demonstrated male predominance (male:female ratio: 2.1:1), advanced disease stage in 72.6% of patients, and elevated serum lactate dehydrogenase levels in 57.5%. Based on immunohistochemistry, 43.4% cases were classified as GCB-DLBCL and 56.6% as non-GCB DLBCL. Although the International Prognostic Index (IPI) retained prognostic significance for event-free survival (EFS) and overall survival (OS), considerable heterogeneity was observed within similar risk groups. Whole-exome sequencing (WES) uncovered recurrent somatic mutations in key oncogenic and epigenetic regulators, including TNFAIP3, NFIB, NOTCH1, TSC2, EZH2, EP300, KMT2D, and B2M, with subtype-specific distribution. Pathway enrichment analysis implicated role of Notch, Wnt, mTOR, JAK-STAT, TGF-β, and antigen-presentation pathways. Comprehensive WES analysis identified multiple novel mutations in genes associated with the stromal/extracellular matrix with distinct patterns in GCB and non-GCB DLBCL, accompanied by concordant alterations in gene expression profiles, suggesting functional relevance within the TME. Functional validation through primary cell culture demonstrated significantly elevated Th2 (IL-4, IL-6, IL-10) and Th17 (IL-17) cytokines in co-cultures containing both neoplastic cells and stromal components, underscoring the role of TME in DLBCL progression. Conclusions: Taken together, this study provides novel insights into stromal mutational signatures and cytokine-mediated tumor–stroma interactions, offering potential prognostic biomarkers and therapeutic targets for the improved management of DLBCL. Full article

Resistance to 5-fluorouracil (5-FU) and oxaliplatin (OXA) remains an obstacle in colorectal cancer (CRC) therapy, but the upstream mechanisms enabling adaptive survival remain unclear. Angiomotin (AMOT), a Hippo-YAP regulator, is expressed as two major isoforms, p130 and p80, but the contribution of isoform-specific AMOT regulation to chemoresistance is unknown. RNA-seq of OXA-resistant cells identified AMOT as a candidate determinant, and its isoform-specific regulation and functional relevance were then examined in OXA- and 5-FU-resistant CRC sublines. AMOT-p80 was preferentially upregulated, whereas AMOT-p130 remained largely unchanged. Common AMOT pre-mRNA was elevated, whereas p130-specific pre-mRNA was unchanged, consistent with preferential transcriptional activation favoring the p80 isoform. Functionally, AMOT depletion minimally affected basal viability but significantly sensitized resistant cells to 5-FU or OXA, with increased apoptotic responses. AMOT silencing reduced nuclear YAP and lowered c-Myc and Cyclin D1 protein levels, whereas AMOT-p80 re-expression restored nuclear YAP, with recovery of c-Myc/Cyclin D1 levels and drug tolerance. YAP knockdown attenuated these outputs and blunted the additional effect of AMOT depletion. AMOT-p80 overexpression in parental cells increased c-Myc/Cyclin D1 protein levels and enhanced tolerance to 5-FU and OXA. These findings suggest that preferential AMOT-p80 upregulation is linked to YAP-associated chemoresistant phenotypes in CRC cells. Full article

Background and Clinical Significance: Cutaneous paraneoplastic phenomena are infrequently characterised in colorectal cancer (CRC), and chronic pruriginous inflammatory eruptions in particular have received limited attention. In older adults, persistent treatment-resistant dermatoses of unclear aetiology may represent overlooked extraintestinal diagnostic clues to occult malignancy, including potentially curable CRC. Faecal immunochemical testing (FIT) for occult bleeding is a low-cost, non-invasive tool whose role outside conventional alarm-symptom triage remains underexplored. Case presentation: A 72-year-old woman presented for outpatient evaluation with several months of pruriginous, pustular, and crusted symmetric eruption involving the dorsal aspects of the limbs, refractory to standard dermatologic treatment, and without gastrointestinal symptoms. A non-invasive systemic stool-based work-up demonstrated detectable faecal haemoglobin (iFOBT), mildly elevated faecal calprotectin (51.6 mg/kg, ULN 50 mg/kg), markedly elevated faecal alpha-1-antitrypsin (631 µg/mL; 2.3× ULN), and predominance of Escherichia coli on stool culture. Colonoscopy revealed a locally advanced rectal adenocarcinoma; staging classified the lesion as cT3N1M0. The patient received long-course neoadjuvant chemoradiotherapy (50 Gy, concurrent capecitabine) followed by low anterior resection with total mesorectal excision and pathological complete response (ypT0N0, R0), and adjuvant capecitabine. The cutaneous eruption resolved progressively in parallel with antineoplastic therapy without specific dermatologic intervention. The patient remains in remission at over 36 months. Conclusions: Persistent, unexplained, treatment-resistant pruriginous/pustular cutaneous eruptions may, in selected patients, coincide with an underlying malignancy, including colorectal cancer, and should prompt careful individualised clinical assessment, including review of age-appropriate colorectal cancer screening status. This single case raises the hypothesis that quantitative faecal immunochemical testing (FIT) may be prospectively evaluated as a low-cost, non-invasive triage tool in carefully selected patients aged ≥50 years with persistent dermatoses of unclear aetiology, even in the absence of gastrointestinal symptoms. Positive FIT results should be managed according to established local colorectal referral pathways. NICE diagnostics guidance DG56 supports FIT use in symptomatic adults with suspected lower gastrointestinal pathology; however, any extension of FIT to extraintestinal presentations remains investigational and requires formal validation through prospective studies assessing diagnostic yield, cost-effectiveness, and stage distribution. Full article

Background/Objectives: Psoriasis is a chronic immune-mediated skin disease, with plaque psoriasis being its most prevalent form. Although biologic therapies have significantly improved outcomes for patients with moderate to severe disease, certain anatomical regions often remain resistant to treatment. Given the observed variability in treatment response depending on lesion location, we aimed to explore anatomical site-specific differences in the skin transcriptome. Methods: Using a non-invasive tape-stripping technique, we collected and analyzed 44 psoriatic plaque samples from the scalp, trunk, upper extremities, and lower extremities, followed by differential gene expression and gene ontology analysis. Moreover, we included 80 samples obtained from healthy skin biopsies (GSE54456) to conduct an inflammation-controlled approach. We used two different approaches, an intra-disease approach, in which anatomically different sites were compared, and an inflammation-controlled approach, in which the inflammation bias was reduced. Results: Our findings indicate distinct molecular signatures and biological pathways across different anatomical sites, including differential expression of SERPINB7 and miRNAs such as miR-205 and miR-203a, along with different pathways. Furthermore, our results emphasized the heterogeneity of psoriasis and suggested that site-specific molecular mechanisms may contribute to variations in disease manifestation and treatment response. Conclusions: This study highlights the need for more personalized, site-specific therapeutic strategies. It should be considered an exploratory pilot study, and larger studies with paired samples from multiple anatomical sites within the same patients are needed to validate the identified transcriptomic signatures. Full article

Recurrent intrauterine adhesions (IUA) and refractory thin endometrium are associated with impaired endometrial regeneration, reduced implantation, and poor live birth outcomes. Regenerative therapy using mesenchymal stromal cells (MSCs) has shown promising results; however, factors associated with reproductive success remain unclear. In this prospective, single-centre, single-arm uncontrolled observational study, 35 women with recurrent IUA and thin endometrium (<7 mm) unresponsive to standard surgical and hormonal therapy received combined subendometrial and systemic administration of placenta-derived MSCs. The primary endpoint was live birth. Secondary endpoints included clinical pregnancy rate, time to pregnancy, endometrial thickness changes, uterine blood flow (resistance index, RI), and anti-Müllerian hormone (AMH) levels. Univariable logistic regression was performed to identify factors associated with live birth. Clinical pregnancy occurred in 13/35 patients (37.1%), and live birth was achieved in 11/35 (31.4%). Median time to pregnancy was 7 (5–8) months. Shorter duration of infertility or prior pregnancy loss (OR 1.55 per year; 95% CI 1.10–2.57), AFS stage I adhesions (OR 6.8; 95% CI 1.1–42; p = 0.04), lower baseline RI in uterine, arcuate and radial arteries, and higher baseline AMH (OR 2.59 per doubling; 95% CI 1.15–6.89) were significantly associated with live birth. Endometrial thickness increased after therapy but was not significantly associated with live birth. No severe adverse events were observed. Placenta-derived MSC therapy was followed by live birth in 31.4% of women with recurrent IUA and refractory thin endometrium. A shorter duration of reproductive disorders, less severe adhesions, lower baseline RI in uterine, arcuate and radial arteries, and higher AMH levels were associated with live birth after treatment and may help identify patients with a more favourable reproductive prognosis in future controlled studies. Full article

Mesothelin (MSLN) is a cell surface glycoprotein with limited expression in normal tissues but frequent overexpression in solid tumors, including gynecological malignancies. This review summarizes the state of the art on the biological role, diagnostic value, prognostic significance, and therapeutic potential of MSLN in ovarian, endometrial, and cervical cancers. Evidence from clinical and experimental studies indicates that MSLN contributes to tumor progression through interactions with CA125, promotion of cell adhesion and peritoneal metastasis, activation of oncogenic signaling pathways, modulation of immune responses, and development of chemoresistance. Elevated MSLN expression has been associated with advanced clinical stage of the disease, platinum resistance, and poorer survival outcomes, particularly in ovarian cancer patients, although prognostic findings remain inconsistent. Circulating soluble MSLN may serve as a minimally invasive biomarker and may improve diagnostic accuracy when combined with established markers. Therapeutic MSLN strategies—antibody-drug conjugates, CAR-T and NK cell therapies, monoclonal antibodies, immunotoxins, vaccines, and checkpoint blockade—provide promising pre-clinical and early clinical results, particularly in resistant or recurrent forms of the disease. Overall, MSLN constitutes a promising target for precision oncology in gynecological cancers, although further clinical studies are required to validate its diagnostic utility and optimize targeted therapeutic approaches. Full article

Ovarian cancer (OC) remains one of the most lethal gynaecological malignancies, which is mainly due to late diagnosis, high frequency of metastasis, and the risk of developing resistance to systemic therapy. In recent years, exosomes—small extracellular vesicles (EVs) secreted by cancer cells and components of the tumour microenvironment (TME)—have been identified as potential mediators of OC progression. Exosomes participate in intercellular communication and enable the transfer of RNA, proteins, and lipids. These vesicles may modulate the immune response, promote angiogenesis, remodel the extracellular matrix, and drive epithelial–mesenchymal transitions. Exosomes also appear to play a role in the development of drug resistance via direct transfer of resistance factors or indirect modification of TME. In this review article, we summarise current knowledge on the biological role of exosomes in OC pathogenesis. We also discuss their possible diagnostic, prognostic, and therapeutic relevance. The properties and composition of exosomes make them promising noninvasive liquid biomarkers and convenient carriers for anticancer drugs. However, to fully exploit their potential, further large-scale preclinical and clinical studies are required, which should focus primarily on standardising research methods and assessing the safety and efficacy of exosome-based diagnostic and therapeutic methods. Full article

Background/Objectives: Skin and soft tissue infections (SSTIs) represent a significant clinical challenge, largely due to the high prevalence of antibiotic-resistant Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA). Treatment is further complicated by biofilm formation, which reduces antibiotic efficacy. The limitations of conventional therapies highlight the need for alternative approaches. Phage therapy has emerged as a promising biological strategy; however, its effectiveness may be constrained by factors such as phage instability and biofilm regrowth. This study aimed to enhance phage-based treatment by combining a newly isolated phage, vB_Sau-E, with lactoferrin (Lf), a multifunctional protein of the innate immune system. Methods: Phage vB_Sau-E was characterized in terms of its infection dynamics and lytic activity. Biocompatibility was further examined using human skin cell lines. The potential effect of Lf was assessed by evaluating its impact on phage infectivity and stability under a range of environmental conditions and by checkerboard assay. Results: Phage vB_Sau-E belongs to the Silviavirus genus in the Herelleviridae family. It was shown to infect 12 out of 22 tested clinical MRSA isolates, with 10 strains identified as good hosts. The phage has a ~30 min life cycle, and ~50 progeny virions are released after bacterial cell lysis. We have also observed that Lf increased plating efficiency and enhanced phage stability at a pH of 5.5 and at −20° C. It also proved to have an additive antibacterial effect, though this was observed to be strain-dependent. Conclusions: Lactoferrin functions as a stabilizing adjuvant for phage vB_Sau-E. Its additive effect supports the development of more effective, biofilm-targeting therapies for staphylococcal SSTIs. Full article

Cellular senescence and polyploidy are fundamental stress responses that shape cancer progression and therapeutic outcomes. While senescence initially suppresses tumor growth, senescent cells accumulate in aging and therapy-exposed tissues and actively remodel the tumor microenvironment through the senescence-associated secretory phenotype (SASP) and extracellular matrix (ECM) reorganization. Senescent stromal cells increase collagen deposition and generate disordered matrix architectures, as evidenced by enhanced second harmonic generation (SHG) signal and increased anisotropic variation across in vitro systems, 3D co-culture models, and fibrotic lung tissues. These biochemical and mechanical alterations promote cancer cell plasticity and create conditions permissive for disease progression. Polyploid giant cancer cells (PGCCs) are a rare but highly resilient cancer cell population enriched under genotoxic stress. PGCCs arise through mitotic failure, including mitotic slippage and cytokinesis defects, and can survive chemotherapy and radiation due to their altered cell-cycle regulation. Emerging evidence indicates that senescence-driven microenvironments promote the formation of PGCCs and multinucleated cells, linking ECM remodeling and mechanical stress to polyploidization. Functionally, PGCCs exhibit abnormal cytoskeletal and nuclear mechanics that support migratory persistence and enable survival within hostile tumor environments. In addition, PGCCs can promote the survival of neighboring cancer cells during treatment, suggesting a stromal-like role in establishing therapy-resistant niches. These cells can persist in a dormant state and later generate proliferative progeny, contributing to tumor recurrence and metastasis. Together, these findings support a model in which senescent niches may promote PGCC formation, persistence, and tumor repopulation. Targeting both senescence-associated microenvironments and PGCC-specific survival mechanisms may improve long-term therapeutic outcomes. Full article

This review summarizes mechanisms regulating mRNA translation under cellular stress and highlights design strategies to improve translation efficiency and stability in the gene therapy of human diseases. mRNA-based therapeutics are emerging as a versatile gene therapy platform enabling transient and controllable expression of therapeutic proteins for the treatment of cancer, genetic disorders, and inflammatory diseases. The efficacy of mRNA-based gene therapy is strongly influenced by sequence design, chemical modifications, and structural features. Evidence shows that rational mRNA engineering can significantly enhance translation efficiency even under stress conditions that impair canonical protein synthesis, as observed in many pathological states. Cellular stress activates regulatory pathways that suppress global translation; however, optimized mRNA constructs can partially bypass these inhibitory mechanisms, enabling sustained protein expression. By improving mRNA stability and resistance to stress-responsive translational control, robust therapeutic protein production can be achieved even in challenging cellular environments. This article was prepared as a narrative review focused on translational regulation mechanisms relevant to therapeutic mRNA design under cellular stress conditions. Literature was collected from PubMed, Google Scholar, and Web of Science using keywords including “mRNA therapeutics,” “cellular stress,” “translation regulation,” “UTR engineering,” and “cap-independent translation.” Studies published mainly between 2010 and 2025 were considered. Original articles and reviews related to stress-responsive translation and therapeutic mRNA optimization were included, while studies outside the scope of translational control and mRNA engineering were excluded. Priority was given to recent and mechanistically relevant publications. Full article

Antibiotic resistance is a growing global health threat. However, its evolution cannot be fully understood without considering antibiotic tolerance and persistence. Persister cells are phenotypic variants that survive lethal antibiotic exposure without heritable resistance, primarily through growth arrest, metabolic slowdown, and stress-adaptive states. Although persistence has been viewed as a transient survival phenomenon, increasing evidence suggests that it may also have a genetic basis by preserving populations during antibiotic-induced bottlenecks and enabling regrowth, mutation, and selection under certain conditions. This review examines the molecular mechanisms underlying persister formation, including toxin–antitoxin systems, stringent-response signaling, ATP depletion, translational arrest, and stress-response networks. We discuss how persistence contributes to antibiotic tolerance in biofilms, host environments, and recurrent infections, and how repeated antibiotic exposure may promote stepwise evolution from phenotypic survival to stable resistance in specific contexts. Evidence from experimental evolution, clinical observations, and system-level analyses supports a potential but context-dependent link between persistence and resistance. We also highlight therapeutic strategies targeting persister cells, including antipersister compounds, metabolic activation, combination therapies, bacteriophages, and alternative approaches. Finally, we outline future research directions, emphasizing single-cell technologies, systems biology, longitudinal clinical studies, and evolution-informed treatment design. A comprehensive understanding of persistence and its evolutionary implications is essential for improving treatment efficacy and limiting the emergence of long-term antibiotic resistance. Full article

The term bacterial biofilm refers to a complex community of microorganisms embedded within a self-produced matrix of extracellular polymeric substances. This structural organization creates an environment that, when present in an infectious context within a living organism, limits the effectiveness of conventional antibiotic therapy. Consequently, such conditions substantially promote the development of antibiotic resistance. The decline in the discovery of novel antibiotic agents, coupled with a concurrent increase in the prevalence of multidrug-resistant microorganisms, has intensified the search for alternative strategies to combat such infections. At the same time, advances in nanoscience have stimulated substantial research into the use of micro/nanorobots for the eradication of bacterial biofilms. These devices, engineered at the micro- to nanoscale, are capable of targeted intervention in otherwise inaccessible sites. However, the development of such “microscopic therapeutic agents” is still at an early stage. To date, the vast majority of available data has been derived from in vitro studies, while evidence regarding their feasibility, safety, and therapeutic effects in living organisms remains limited. This review discusses their antimicrobial mechanisms and critically evaluates the current evidence concerning their in vivo applications. Full article

GLP-1 receptor agonists and dual GLP-1/GIP agonists have significantly transformed the treatment of obesity, enabling clinically meaningful weight reduction and improvements in cardiometabolic parameters. However, clinical trial data indicate that cessation of therapy is associated with biologically driven weight regain and a partial loss of metabolic benefits. This phenomenon underscores the chronic nature of obesity and the limited durability of effects achieved through pharmacotherapy alone. Nevertheless, structured clinical frameworks describing how to maintain satiety and metabolic stability after GLP-1/GIP dose reduction or discontinuation remain limited. The aim of this narrative review is to discuss the mechanisms underlying weight regain following dose reduction or discontinuation of GLP-1/GIP pharmacotherapy and to present strategies supporting long-term metabolic stabilisation. Weight regain is driven in part by persistent metabolic adaptations, including a reduction in resting energy expenditure (adaptive thermogenesis), alterations in the hunger–satiety axis (increased ghrelin, reduced leptin signalling), and potentially incomplete restoration of adipose tissue and liver-related metabolic function, although direct evidence in this specific setting remains limited. Weight loss is often accompanied by a reduction in fat-free mass, which further lowers energy expenditure and increases susceptibility to a positive energy balance after treatment cessation. It remains unclear whether pharmacological suppression of appetite results in sustained normalisation of endogenous satiety regulation after treatment cessation, and its effects on gut microbiota function remain uncertain. In clinical practice, key priorities include preserving muscle mass (adequate protein intake, resistance training), maintaining dietary nutrient density, stabilising postprandial glycaemia, and ensuring sufficient intake of fermentable fibre to support short-chain fatty acid production and gut–brain signalling. GLP-1/GIP pharmacotherapy should be viewed as a component of an integrated model of obesity treatment. We propose that long-term weight stabilisation may require a transition from pharmacologically induced satiety to satiety supported by diet quality, preserved fat-free mass, and metabolic stability. Further research is needed to define optimal post-treatment strategies and to identify patients in whom therapy can be safely reduced or discontinued. This transition should be regarded as a conceptual framework and forward-looking hypothesis requiring validation in prospective studies. Full article