Search Results (30,772)

The failure of current therapeutics to elicit a durable response in metastatic ovarian cancer patients highlights the urgent need to develop more effective treatment strategies. In this study, we demonstrate that the anti-diabetic drug metformin exerts cytotoxic effects across a broad panel of ovarian cancer cell lines. Transcriptomic analyses revealed that, in addition to reducing cell viability and proliferation, metformin modulates pathways associated with metastatic progression, including cell migration, extracellular matrix remodeling, and cellular responses to chemotherapeutic agents. Consistent with these molecular changes, metformin significantly impaired ovarian cancer cell migration and invasion through Matrigel. Furthermore, metformin diminished the ability of ovarian cancer cells to form multicellular aggregates, a key property that facilitates successful metastatic dissemination within the peritoneal cavity. Although metformin produced only a modest increase in carboplatin sensitivity, systematic screening of FDA-approved drugs identified several agents whose efficacy was enhanced by metformin, including drugs not currently used to treat ovarian cancer. Collectively, these findings demonstrate that metformin suppresses metastatic phenotypes and enhances therapeutic vulnerability in ovarian cancer cells, supporting its potential repurposing as a combination therapy to improve treatment outcomes in ovarian cancer. Full article

Cutaneous melanoma is the most lethal skin cancer, and risk is strongly shaped by pigmentary phenotype. The red-hair color phenotype, marked by red hair, fair skin, freckling, and poor tanning, carries elevated melanoma risk driven largely by loss-of-function variants in the melanocortin 1 receptor gene (MC1R). This risk is not explained by reduced ultraviolet protection alone. Impaired MC1R signaling shifts melanogenesis from photoprotective eumelanin toward pheomelanin, a pigment associated with oxidative stress and partly ultraviolet-independent melanomagenesis. MC1R may also influence melanoma susceptibility through pigment-independent effects on DNA damage responses, repair signaling, and genomic stability. These mechanisms support investigation of MC1R genotype, visible phenotype, nevus burden, pigment chemistry, and imaging-derived lesion metrics as complementary tools for risk stratification. Diagnosis is also distinctive in this population. Amelanotic and hypomelanotic melanomas are associated with the red-hair color phenotype, and their low pigmentary contrast may delay recognition and contribute to diagnosis at a more advanced stage. This review integrates genetic, molecular, biomarker, diagnostic, and therapeutic literature specific to red-haired populations. We argue that elevated biological susceptibility and diagnostic difficulty compound one another, and we outline priorities for MC1R-informed surveillance, imaging adapted to pigment-poor disease, pharmacologic modulation of MC1R-related pathways, and prospective risk models integrating genotype, phenotype, nevus burden, pigment biology, and imaging. Full article

Background and Objectives: Antibody–drug conjugates (ADCs) have become a major therapeutic platform in breast cancer and other solid tumors. Trastuzumab deruxtecan (T-DXd), trastuzumab emtansine (T-DM1), and sacituzumab govitecan (SG) differ substantially in antibody target, linker, payload, drug-to-antibody ratio, and bystander effect, resulting in heterogeneous pulmonary and cardiac toxicity profiles. This narrative review critically compares interstitial lung disease (ILD)/pneumonitis and cardiotoxicity associated with these three agents, aiming to prevent inappropriate extrapolation of toxicity algorithms and to provide a practical, agent-specific framework for multidisciplinary care. Materials and Methods: A targeted narrative search of PubMed/MEDLINE, Google Scholar, ClinicalTrials.gov, regulatory product information, and oncology/cardio-oncology guidance was performed and updated on 24 August 2026. Priority was given to regulatory documents, pivotal trials, pooled safety analyses, real-world cohorts, systematic reviews, and multidisciplinary recommendations. Pharmacovigilance data and case reports were included only to characterize rare events. Results: T-DXd is associated with a clinically important ILD/pneumonitis risk (approximately 12–15% in pooled analyses), predominantly grade 1–2 but occasionally fatal, requiring proactive surveillance, immediate interruption for suspected disease, and grade-directed corticosteroid therapy. T-DM1 shows a low but established pneumonitis incidence of approximately 1%, with permanent discontinuation recommended upon diagnosis. SG-related pneumonitis is rare and incompletely defined, without a T-DXd-like surveillance mandate. Both T-DM1 and T-DXd retain trastuzumab-derived cardiac monitoring requirements; symptomatic heart failure remains uncommon, although protocol-defined LVEF declines appear more frequent with T-DXd. SG lacks an established cardiomyopathy signal. Conclusions: Cardiopulmonary toxicity of ADCs is agent-specific rather than a class effect. Monitoring intensity, diagnostic thresholds, and management pathways must be tailored to the individual drug, regimen, indication, dose, patient comorbidity, and prior therapy. Close collaboration among oncology, radiology, pulmonology, and cardio-oncology is essential to preserve both treatment efficacy and patient safety. Full article

Background: Solid tumors including glioblastoma (GBM), lung cancer (LC), and triple-negative breast cancer (TNBC) exhibit marked radioresistance driven by dysregulated cell-cycle control and genomic instability. Although CDK4/6 inhibitors suppress tumor proliferation, their radiosensitizing capacity is limited by persistent DNA repair. BUB1, a mitotic checkpoint kinase overexpressed in aggressive cancers, has emerged as a regulator of DNA damage signaling. We tested whether co-targeting BUB1 and CDK4/6 enhances radiosensitivity across solid tumors. Methods: GBM, LC, and TNBC cell lines were treated with BUB1 inhibitor BAY1816032, CDK4/6 inhibitors ribociclib and abemaciclib, and radiation. Proliferation, clonogenic survival, immunoblotting, and combination index analyses assessed cytotoxicity and synergy. CDK4/6-resistant models were generated to examine resistance. In vivo efficacy was evaluated using SUM159 xenografts. DNA damage and homologous recombination repair were measured by gH2AX, RAD51, RPA, BrdU foci and comet assay. The resection branchpoint was assessed by phospho-RPA, with ATR inhibition and BLM or EXO1 depletion testing resection dependence. Results: BUB1 inhibition increased cytotoxicity in vitro and improved therapeutic response in vivo. Combined BUB1 and CDK4/6 inhibition showed strong synergy (C.I. < 1) and enhanced radiosensitization in RB+ models. CDK4/6-resistant cells displayed increased BUB1 expression, and BUB1 inhibition partially restored sensitivity. Mechanistically, dual inhibition intensified homologous recombination defects, marked by persistent gH2AX and altered RAD51, RPA, and BrdU dynamics, consistent with sustained single stranded DNA and impaired HR repair. Persistent RPA32 Ser33 phosphorylation reflects ATR-dependent resection that requires BLM and EXO1 at later stages, supporting sustained resection and unresolved repair leading to increased cell death. Conclusions: Dual inhibition of BUB1 and CDK4/6 represents a promising therapeutic strategy for enhancing radiosensitivity in GBM, lung cancer, and TNBC, particularly in Rb-intact settings. Full article

Liquid biopsy enables minimally invasive detection and longitudinal monitoring of tumor-derived material in blood and urine. In genitourinary cancers, most applications have focused on genomic alterations in circulating tumor DNA (ctDNA), together with circulating tumor cells (CTCs), extracellular vesicles (EVs), and cell-free RNAs. These measurements are clinically informative but are often interpreted as isolated, predominantly descriptive biomarkers and therefore incompletely represent the adaptive processes that determine progression and treatment response. We propose circulating tumor function (CTF) as a systems biology framework for integrating tumor-derived and host-derived genomic, regulatory, metabolic, redox, and immune signals obtained through serial liquid biopsy. CTF is not a single analyte or assay; rather, it is an inference model intended to generate interpretable functional states, including proliferative activity, immune evasion, metastatic potential, metabolic stress, and therapeutic adaptation. We review the contributions and limitations of ctDNA, ncRNA networks, EV-mediated signaling, redox biomarkers, and tumor–host crosstalk in prostate, bladder, renal, and testicular cancers. We also outline the analytical and clinical validation required to determine whether integrated CTF models provide incremental value over established single-analyte approaches. This framework may help reposition liquid biopsy from molecular detection toward functional precision oncology. Full article

Cancer remains one of the leading causes of death globally, and breast cancer is the most frequently diagnosed cancer in women. Even though surgical excision is the main treatment of solid tumors, recurrence and metastasis to another location postoperatively provide lasting therapeutic challenges. Systemic adverse effects and a lack of sufficient drug bioavailability at the resection site can often hinder traditional adjuvant modalities, especially chemotherapy and radiotherapy. To address these drawbacks, localized drug delivery platforms have gained a lot of interest, and hydrogels have emerged as highly beneficial systems. Hydrogels are three-dimensional hydrophilic polymer networks that can be designed to be injectable and in situ-forming. They can be engineered to fit irregular surgical cavities and deliver therapeutics in a long-lasting, controlled manner. The current literature review outlines the clinical issue of tumor recurrence following surgery with a special focus on breast cancer and evaluates hydrogel-based methods of site-specific therapy. We outline the categorization, assembly, and functionalization of hydrogel systems based on natural, synthetic, and hybrid polymers, and reflect on advanced stimuli-responsive and cell-targeted formulations in the context of cancer immunotherapy. This paper presents the translational applications of hydrogel platforms to enhance postoperative management and prevent tumor recurrence by combining new advances. Full article

Pain is a complex process involving dynamic transcriptional changes in cells of the PNS and CNS following injury or inflammation. Among stress-inducible transcription factors, ATF3 has emerged as one of the most robust molecular markers of neuronal injury, particularly in sensory neurons of the DRG. Although ATF3 is widely used as an indicator of axonal damage in experimental pain models, its functional contribution to the initiation, maintenance, and resolution of pain remains poorly understood. Recent transcriptomic and functional studies suggest that ATF3 not only reflects neuronal stress but also orchestrates gene expression programs involved in axonal regeneration, neuroimmune communication, ion channel remodeling, and nociceptor plasticity. Moreover, ATF3 expression has been identified in non-neuronal cell populations, including Schwann cells and satellite glial cells, indicating broader roles in peripheral nerve repair and neuroinflammation. Despite the growing body of experimental evidence, the literature remains fragmented, and no consensus has yet been reached as to whether ATF3 primarily promotes adaptive regeneration or directly contributes to maladaptive pain signaling. This review aims to provide a comprehensive and critical overview of the current understanding of ATF3 biology in pain, building on evidence from transcriptomic and molecular analyses, experimental models of neuropathic, inflammatory, and cancer-associated pain, and emerging mechanistic insights into its role in pain-related neuronal plasticity. This review examines the regulation of ATF3 expression, its downstream transcriptional targets, its interactions with inflammatory signaling pathways, and its potential value as a therapeutic target. By consolidating current evidence and highlighting existing knowledge gaps, this review seeks to clarify the multifaceted role of ATF3 in pain pathophysiology. Full article

Cuproptosis is a novel form of metabolism-associated cell death. Cervical cancer (CC) exhibits elevated serum copper levels and mitochondrial metabolic reprogramming, making cuproptosis-related genes (CRGs) potentially critical for prognosis prediction and therapeutic targeting. However, studies on CRGs in CC remain limited. This study aimed to construct prognostic and cancer staging models for CC using machine learning (ML) algorithms. Gene expression profiles of patients with CC were obtained from the TCGA and GEO databases. Five ML algorithms were employed to identify significant factors, including random forest (RF), support vector machine (SVM), Gaussian mixture model (GMM), Bayesian, and StepCox. A prognostic model was subsequently constructed using LASSO–Cox regression based on the selected genes. Concurrently, a cancer staging model was built using ML algorithms incorporating three distinct gene categories. Finally, qRT-PCR and Western blotting were conducted to validate the expression of signature genes at both the tissue and cellular levels. Additionally, CTD-based screening and in vitro functional assays were performed to evaluate the effects of DDP on CC cells. Through integrated bioinformatics and ML approaches, a prognostic model comprising nine CRGs was successfully established (GMM = 0.72). The derived risk score served as an independent prognostic indicator for CC (p < 0.001, 95% CI: 3.681 [1.785–7.591]). Calibration curves confirmed that the nomogram accurately predicted overall survival (OS) at 1, 3, and 5 years. Additionally, a cancer staging model was effectively constructed using the GMM algorithm (AUC = 0.74). DDP dose-dependently inhibited CC proliferation/migration and down-regulated CRG expression. In this study, we developed two different models—a cuproptosis-related prognostic model and a cancer staging model—that highlight promising biomarkers for predicting patient prognosis and cancer progression in patients with CC. Full article

Although cryoablation of tumor tissue is known to induce systemic antitumor immune responses, the underlying mechanisms remain poorly understood, and therapeutic efficacy is often unpredictable. During cryoablation, the cryoprobe creates a temperature gradient, resulting in a central zone of lethal tissue destruction and a periphery characterized by sub-lethal injury. In this peripheral zone, cells undergo programmed cell death triggered by thermal shock and ischemia. A widely cited, yet debated, hypothesis suggests that these apoptotic events in the tumor periphery may suppress the antitumor immune response. The purpose of this study was to experimentally test this hypothesis. We utilized the murine breast cancer cell line (4T1-Luc) and a panel of human cell lines (MCF-7, BT-20, BT-474, MDA-MB-231, MDA-MB-453, HBL-100). Following validation via flow cytometry using Annexin V-AF488, Rhodamine 123, TMRE, PI, and 7-AAD, we established −7 °C and −80 °C as temperature conditions that predominantly induce apoptosis and necrosis, respectively. These conditions were used to prepare cryo-treated 4T1-Luc cells for the vaccination of syngeneic mice. Ten days post-immunization, the efficacy of the treatment was evaluated in subcutaneous solid tumor and lung metastasis models by monitoring tumor growth, quantifying tumor-specific antibodies, performing histological analysis of tumor and lung tissues, and quantifying lung metastases via PCR and luciferase assays. Contrary to the initial hypothesis, our findings demonstrate that tumor cells undergoing sub-lethal cryoablation do not acquire immunosuppressive characteristics. Instead, they promote systemic antitumor immunity. Although antitumor immunity induced by apoptotic and necrotic tumor cells was comparable in a subcutaneous tumor model, vaccination with necrotic tumor cells proved more effective than vaccination with apoptotic cells in controlling lung metastasis formation. Full article

Trophoblast invasion is crucial for the establishment of a functional placenta. Defects in this process can cause adverse pregnancy outcomes, such as miscarriage and preeclampsia. Aldo-keto reductase family 1 member B10 (AKR1B10), a key cytoplasmic oxidoreductase that converts retinoids, retinaldehyde isoprenoids, and lipid peroxidation-derived reactive aldehydes into their corresponding alcohols, regulates cell proliferation, inflammation, and metastasis in cancers. Here, our results demonstrated that AKR1B10 is highly expressed in the ectoplacental cone (EPC) of the mouse placenta. Deficiency of AKR1B10 leads to excessive trophoblast giant cell (TGC) invasion, impaired trophoblast cell differentiation of the junctional zone, and accelerated maternal spiral artery remodeling. Mechanistically, loss of AKR1B10 suppressed extracellular regulated protein kinase (ERK) phosphorylation in both murine placentas and human HTR8/SVneo cells, further promoting HTR8 cell migration and invasion in vitro. Our findings identify AKR1B10 as a critical regulator that restrains trophoblast invasion in the placenta, suggesting it as a new therapeutic target for placental disorders. Full article

Acquired resistance to targeted therapies is inevitable in EGFR-mutant non-small cell lung cancer (NSCLC), yet the principles governing its emergence in vivo remain incompletely understood. In particular, how lesion-level response patterns vary across distinct EGFR allele contexts during therapy has not been systematically examined at single-lesion resolution. Here, we establish a longitudinal in vivo imaging platform enabling single-lesion resolution tracking of tumor behavior during therapy in genetically engineered mouse models representing clinically relevant EGFR alleles. Using high-resolution micro-computed tomography (micro-CT) and three-dimensional reconstruction, we monitor tumor growth, therapeutic response, and resistance during osimertinib treatment. EGFR genotype is associated with distinct patterns of tumor growth, response kinetics, and resistance timing. Therapeutic response is spatially heterogeneous, with coexisting lesions undergoing complete regression, persistence, or progression within the same lung. During treatment, spatially distinct lesion-level behaviors included persistent growth during therapy and initial regression followed by regrowth. These findings demonstrate the utility of longitudinal micro-CT imaging to investigate allele-associated differences in treatment response and resistance timing at single-lesion resolution in vivo. Full article

Type 2 diabetes (T2D) is a metabolic syndrome frequently associated with obesity and endoplasmic reticulum stress-mediated inflammation, which can trigger the unfolded protein response (UPR), impair insulin signaling, and promote apoptosis. To identify potential natural therapeutic candidates, this study investigated the mechanisms of action of 14 compounds from Uncaria tomentosa (UT), a medicinal plant from the Amazon rainforest, using in silico modeling. The study focused on the UPR, TRAF2/JNK pro-inflammatory signaling pathway, and insulin signaling pathways, which play key roles in T2D. Some of the UT compounds were docked against several human proteins involved in these pathways, and molecular dynamics simulations confirmed stable interactions between the target proteins (PERK, TRAF2, JNK, TNF-α, IRS-1, PI3K, AKT, GSK3β, and PPARγ) and four of the UT compounds, 5-Carboxystrictosidine, Cinchonain, Epicatechin and Mitraphylline. Additionally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties analyses were conducted to predict the four compounds, revealing suitable pharmacokinetic properties. These findings suggest that specific UT compounds may be used in experimental tests to whether investigate their therapeutic potential in managing T2D by modulating signaling pathways related to the conditions UPR, inflammation, and insulin resistance. Full article

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive adaptive signaling plasticity and metabolic reprogramming that contribute to therapeutic resistance. While the PI3K–mTOR pathway is a central regulator of these processes, the role of the FGF19–FGFR4 axis and its interaction with PI3K-mTOR signaling remains incompletely defined in PDAC. This study investigated whether co-targeting FGFR4 and PI3K-mTOR signaling could overcome adaptive pathway reactivation and suppress tumor-promoting phenotypes. PDAC cell lines representing a spectrum of FGFR4 dependence were treated with the selective FGFR4 inhibitor fisogatinib in combination with the clinically relevant PI3K–mTOR inhibitor gedatolisib. Transcriptomic analyses of TCGA data, along with molecular and functional responses, were evaluated. Transcriptomic analysis demonstrated a positive association between FGFR4 and PI3K–mTOR signaling and linked combined pathway components with poorer overall survival. Across heterogeneous PDAC models, combined inhibition reduced viability, clonogenic survival, migration, and cell-cycle progression more consistently than monotherapy. Apoptosis induction was driven principally by fisogatinib and combination treatment, resulting in comparable apoptotic responses across cell lines. Mechanistically, combined inhibition converged on increased 4E-BP1 inhibitory activity, despite compensatory ERK-RSK pathway activation, indicating that adaptive MAPK was insufficient to restore downstream translational output. In FGFR4-dependent cells, the combined inhibition also reduced secretion of the FGFR4 ligand FGF19. The FGFR4 and PI3K–mTOR signaling comprises a partially interconnected network in PDAC that converges on 4E-BP1-dependent translational control. Dual pathway inhibition consistently and additively suppressed tumor-associated phenotypes despite compensatory MAPK activation, with the clearest added benefit over fisogatinib alone in migration, cell-cycle control, and 4E-BP1 modulation, supporting translational regulation as a shared therapeutic vulnerability. These findings provide a preliminary rationale for biomarker-guided strategies targeting FGFR4 and PI3K–mTOR signaling in pancreatic cancer. Full article

Fractional ionizing radiation (FIR) is a standard cancer therapy but often induces severe central nervous system complications, including cognitive decline and physiological dysfunction. While natural flavonoids hold therapeutic promise for radiation-induced brain injury (RIBI), optimizing their combinations and elucidating the underlying molecular pathways remain challenging. Methods: To develop a precise therapeutic strategy, we first integrated network pharmacology and UHPLC-Q-Orbitrap MS/MS analysis to identify three highly effective flavonoid monomers from a radioprotective botanical extract. Subsequently, an in vivo anti-inflammatory screening was conducted to determine the optimal combinatorial ratio, designated as the ternary formulation QLI. The neuroprotective efficacy of QLI was then systematically evaluated in a mouse model of fractional RIBI (cumulative dose of 12 Gy) through behavioral assessments, hematopoietic profiling, and neurotransmitter analyses. Transcriptomic alterations were explored via RNA-sequencing (RNA-seq) and validated by molecular docking, RT-qPCR, and Western blotting. Results: Pharmacological and mass spectrometry analyses identified Quercetin, Luteolin, and Isorhamnetin-3-O-glucoside as the core bioactive monomers. Quantitative synergistic screening established the optimal QLI formulation at a mass ratio of 2:1:1. In vivo, FIR exposure induced severe spatial memory deficits, disrupted neurotransmitter homeostasis, and caused hematopoietic decline. Administration of QLI successfully reversed these physiological and cognitive impairments. Transcriptomic profiling revealed that QLI globally reprogrammed aberrant gene expression, specifically normalizing signaling networks related to the PI3K–Akt pathway, apoptosis, and neuroactive ligand–receptor interactions. Multidimensional validation confirmed that QLI mitigated neuroinflammation, suppressed astrocyte hyperactivation (GFAP), and preserved synaptic plasticity by preventing the pathological accumulation of SynGAP and autophagic stress (Beclin-1). Conclusions: The rationally designed ternary flavonoid formulation (QLI) provides potent neuroprotection against fractional RIBI. By resolving neuroinflammation, alleviating synaptic plasticity suppression, and normalizing stress-induced transcriptomic disruptions, QLI represents a promising multi-target experimental formulation with the potential to mitigate radiotherapy-associated neurological side effects. Full article

The use of magnetotactic bacteria (MTB), proposed by the author about 25 years ago, allowed the implementation of embedded capabilities allowing the execution of specific complex tasks such as the target delivery of therapeutics in tumoral hypoxic zones that could not be implemented in artificial micro/nanorobots due to technological limitations at such a small scale. Since then, technology has evolved but the question remains about how long such superior advantage of using only certain types of live microorganisms will last before embedding such capabilities in artificial micro/nanorobots becomes feasible while being a viable alternative. Although it is difficult to answer this question, this paper aims to provide clues with a perspective view about the challenges of implementing an artificial or synthetic counterpart by providing a general description of an equivalent artificial implementation of the embedded functional units found in such magneto-aerotactic bacterial robots for cancer therapy. Full article