Search Results (903)

Chimeric antigen receptor (CAR) therapies are emerging as promising strategies, particularly for metastatic castration-resistant prostate cancer (PCa), as they can act independently of the androgen receptor axis. Adapter CAR-T cell platforms, such as the RevCAR system, offer precise therapeutic control and tumor targeting via small, rapidly eliminated tumor-specific adapters. To enable more convenient late-stage RevCAR-T therapy in PCa patients, allowing for discontinuous reverse target module (RevTM) infusion, we developed novel, larger IgG4-based RevTMs targeting prostate stem cell antigen (PSCA) and benchmarked them against previously described smaller adapter formats. Within the RevCAR system, PSCA-IgG4 RevTMs effectively mediated PCa killing at low effector-to-target ratios and low RevTM concentrations in a strictly antigen-dependent manner. Oncolytic activity was accompanied by a rapid and pronounced release of proinflammatory cytokines across a broad RevTM concentration range, which is particularly advantageous for immunologically cold PCa. Finally, anti-tumor activity was confirmed in a short-term mouse model. Preliminary PET studies further indicate slow blood elimination and tumor-specific accumulation of novel IgG4-RevTMs. Together, these data position PSCA-IgG4 RevTMs as promising candidates for stepwise RevCAR-T treatment in PCa, in which short-lived scFv-RevTMs are initially used to ensure a rapid safety switch, followed by larger IgG4-RevTMs once the risk profile is known. Full article

Cancer continues to be a primary cause of death globally, necessitating the constant development of effective and less toxic therapeutics. Cucurbitacins belong to the tetracyclic triterpenoids found mainly in the Cucurbitaceae family. Cucurbitaceae plants exert various biological activities such as anti-diabetic, anti-cancer and anti-inflammatory properties, which make them beneficial in addressing metabolic disorders. This review focuses on cucurbitacins namely A, B, C, D, E, I, IIa, which have been explored in cancer research. Cucurbitacins suppress tumor progression by activating cell death pathways, including apoptosis, autophagy, pyroptosis and ferroptosis. They are known to target multiple crucial biomolecular key players, such as STAT3, AKT, mTOR, ERK, EGFR and TLR4. Additionally, they disrupt cytoskeletal proteins and inhibit cell proliferation, invasion, migration, angiogenesis, and cell-cycle arrest. Cucurbitacins have been demonstrated to modulate tumor microenvironment, leading to enhanced host immune surveillance that reverses traditional therapy resistance from cisplatin, doxorubicin, and paclitaxel. In this review, we highlight the strong potential of cucurbitacins as anti-cancer agents, either as monotherapy or in combination, for the development of safer, cost-effective drugs with improved patient treatment outcomes. Full article

Melanoma is an aggressive skin cancer that has the potential to metastasize to the lymph nodes, lungs, liver, and brain. Therefore, the prevention and treatment of this condition are essential for achieving lower incidence rates and improving patient outcomes. Traditional treatment methods like surgery, radiation therapy, and chemotherapy have shown limited efficacy in the treatment of metastatic melanoma, and hence new treatment strategies have been developed. These recently developed treatment options include combining targeted therapies with immunotherapies to reduce drug resistance and improve overall effectiveness in preventing melanoma progression. Moreover, BRAF mutations are found in approximately 40–50% of cutaneous melanomas, and NRAS mutations in 15–25%, making these the two most common oncogenic drivers in the MAPK pathway. While alterations in other genes such as KRAS (~1.7%), HRAS (~1%), and MET (~2–4%) are relatively rare in melanoma, they still remain important to disease biology and are under investigation as potential therapeutic targets. These alterations may contribute to tumor progression, metastasis, and therapeutic resistance, highlighting the importance of continued investigation of targeted strategies in melanoma. This review aims to explore the role of each of these genes in melanoma, discusses their resistance mechanism, and summarizes preclinical and clinical trials involving drug combinations. By integrating current evidence on melanoma-associated genomic alterations with available targeted and immune approaches, this review aims to define molecular and clinical contexts that suggest potential treatment selections for melanoma patients. Full article

Primary liver malignancies, including hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and combined hepatocellular cholangiocarcinoma, remain major causes of cancer-related morbidity and mortality worldwide. Although systemic therapies have advanced substantially, intrahepatic tumor progression, liver failure, and portal hypertension continue to drive adverse outcomes in many patients. Interventional radiology plays a central and expanding role in the multidisciplinary management of these tumors by providing image-guided locoregional therapies for local tumor control, downstaging, bridging transplantation or resection, palliation, and potential survival benefit. This narrative review summarizes current evidence and technical considerations for major locoregional approaches, including radiofrequency ablation, microwave ablation, cryoablation, transarterial chemoembolization, transarterial radioembolization, endobiliary therapies, stereotactic body radiation therapy, irreversible electroporation, histotripsy, high-intensity focused ultrasound, hepatic arterial infusion, and brachytherapy. Interventional radiology also contributes to preoperative liver optimization through portal vein embolization, liver venous deprivation, lobar radioembolization to induce contralateral hypertrophy, and, in some patients, portal decompression before hepatic resection. For hepatocellular carcinoma, ablation and transarterial therapies are integrated into stage-based treatment algorithms and may provide curative-intent treatment in some patients. In intrahepatic cholangiocarcinoma, locoregional therapies provide meaningful disease control and may prolong survival, particularly when combined with systemic therapy. In combined hepatocellular cholangiocarcinoma, treatment remains individualized because of limited prospective data and heterogeneous tumor biology. Beyond cytoreduction, locoregional therapies can modulate the tumor immune microenvironment through immunogenic cell death, antigen release, cytokine signaling, and vascular remodeling, providing a rationale for combination strategies with immune checkpoint inhibitors, anti-angiogenic agents, and targeted therapies. As treatment paradigms evolve, the future of interventional radiology in primary liver cancer will depend on appropriate patient selection, optimized dosimetry and technique, integration with molecular and immunologic biomarkers, and coordinated multidisciplinary care. Full article

Background: Hysterectomy is one of the most frequently performed major gynecological procedures, yet its effect on sexual quality of life remains unclear. Objective: To evaluate changes in sexual quality of life following hysterectomy and to determine whether cervical preservation is associated with improved postoperative sexual function. Methods: Five databases were systematically searched from inception to February 2026. Eligible studies reported pre- and postoperative sexual quality-of-life outcomes after hysterectomy using validated or non-validated questionnaires. All surgical indications, approaches, and study designs were included. Risk of bias was assessed using RoB 2 and ROBINS-I. Mean score differences were pooled using random-effects meta-analysis and meta-regression within a frequentist framework. Heterogeneity was assessed with τ², cluster-robust standard errors were applied, and certainty of evidence was evaluated using GRADE. Results: Thirty-four studies were included in the systematic review, among them sixteen studies comprising 2341 patients were included in the statistical synthesis comprising three randomized controlled trials and thirteen observational studies. The Female Sexual Function Index (FSFI) was the most commonly reported outcome. Across all hysterectomy types, including total, abdominal, laparoscopic, and vaginal approaches, no clinically or statistically significant improvement in postoperative sexual function was observed compared with baseline. Subtotal hysterectomy did not demonstrate a meaningful advantage over total hysterectomy. FSFI total scores were consistent with sexual dysfunction at baseline and remained below the established cutoff (≤26.55) during follow-up across all surgical routes. No hysterectomy approach was associated with a clinically relevant change in sexual quality of life. Conclusions: Postoperative changes in sexual function after hysterectomy were small and non-significant overall. Cervical preservation did not provide measurable benefit. Surgical approach selection should therefore not be based on expectations of improved sexual outcomes. Full article

Background: Accurate post-treatment imaging assessment of hepatocellular carcinoma (HCC) is essential for guiding retreatment, transplantation eligibility, and prognosis. The Liver Imaging Reporting and Data System Treatment Response Algorithm (LI-RADS TRA) was updated in 2024, introducing refinements across contrast-enhanced ultrasound (CEUS), CT/MRI, and radiation-based therapies, including the TR-Nonprogressing category. We aimed to systematically review current evidence on the diagnostic performance, reproducibility, and clinical implications of LI-RADS TRA v2024 for post-treatment assessment of HCC across imaging modalities and locoregional therapies. Methods: A systematic search of PubMed, Embase, Scopus, Web of Science, and CENTRAL was conducted according to PRISMA 2020 guidelines. Original studies applying LI-RADS TRA v2024 (or comparisons with earlier versions or mRECIST) after locoregional therapies were included. Outcomes of interest comprised diagnostic accuracy metrics, inter-reader and inter-modality agreement, temporal behavior of TRA categories, and prognostic associations. Given substantial heterogeneity, results were synthesized narratively. Results: Six studies met inclusion criteria. After thermal ablation, CEUS applying the non-radiation TRA v2024 showed very high specificity (approximately 88–100%) and excellent negative predictive value (about 94–98%), with substantial-to-almost-perfect inter-reader agreement (κ up to 0.92) and excellent inter-modality agreement with CT/MRI (ICC ≈ 0.90). After transarterial chemoembolization, CEUS performance was time-dependent, with higher sensitivity at early follow-up (~15 days) and higher specificity at later assessment (~30 days). On MRI, non-radiation TRA v2024 combined with ancillary features improved sensitivity and, in some analyses, accuracy compared with v2017 and v2024 without ancillary features, while remaining more specific than mRECIST. In radiation-based therapies, the radiation TRA v2024 captured delayed-response patterns through the TR-Nonprogressing category, which demonstrated meaningful temporal evolution and prognostic separation from TR-Viable. Surgical validation confirmed preserved diagnostic performance against histology. Conclusions: Despite heterogeneous data, available evidence supports LI-RADS TRA v2024 as a clinically useful framework that improves clarity, reproducibility, and actionability of post-treatment HCC imaging. CEUS is particularly effective after ablation; timing is critical after TACE, ancillary features should be routinely applied on MRI, and TR-Nonprogressing appropriately reflects radiation biology while preserving prognostic value. Full article

Background/Objectives: To improve the potential therapeutic efficacy of albendazole (ABZ), its low solubility in alkaline environments should be addressed. Spray drying has been widely applied to increase the solubility of poorly soluble drugs. Eudragit^® E PO (EudE) has previously been used to increase the solubility of weakly basic drugs, alone and in combination with organic acids. In the present work, we aimed to demonstrate that EudE and tartaric acid (TA) significantly increase the solubility of ABZ via spray drying. Furthermore, a colon-delivery formulation was applied to deliver ABZ at pH 7.2. Methods: This study developed spray-dried formulations of ABZ-TA-EudE. The formulation with the best solubility profile was selected and loaded into the EUDRACAP^® colon to achieve colon-delivery of the ABZ formulation with enhanced solubility at basic pH. The physicochemical characteristics and in vitro drug release were evaluated and compared with those of the respective physical mixtures. Results: The addition of TA further enhanced the solubility of ABZ-EudE formulations. Both EudE and TA significantly increase ABZ solubility. The ternary ABZ-TA-EudE formulation with the best solubility, when delivered into the EUDRACAP^® colon, showed enhanced ABZ release at pH 7.2. Enhanced in vitro drug release at basic pH and physicochemical characteristics were observed for the spray-dried formulation of ABZ-TA-EudE compared with the corresponding physical mixture and the ABZ powder. Conclusions: TA and EudE significantly enhance the solubility of the weakly basic drug, ABZ, in a spray-dried formulation. Furthermore, the application of EUDRACAP^® colon is effective for colon-delivery of ABZ, as it ensures ABZ release at pH 7.2, thereby providing enhanced formulation’s solubility at its site of action. Full article

Diffuse midline glioma (DMG) is one of the most aggressive paediatric brain tumours and remains almost universally fatal despite decades of research. The defining molecular feature of approximately 80% of DMG tumours is H3K27M, which disrupts PRC2 activity and profoundly remodels chromatin architecture. Increasing evidence suggests that this epigenetic alteration not only rewires transcriptional programs but also influences tumour metabolism. Several studies indicate that H3K27M-mutant tumours exhibit altered mitochondrial metabolism, oxidative phosphorylation activity, redox regulation, and cellular stress responses, although the extent of oxidative phosphorylation dependence varies between models, tumour subtypes, and cellular states. In parallel, dopaminergic signalling has been implicated in cancer stem cell maintenance, metabolic regulation, and tumour survival across multiple malignancies, including glioma. The imipridone compound ONC201/dordaviprone, initially described as a dopamine receptor D2/3 antagonist and subsequently characterised as a mitochondrial ClpP agonist, demonstrates clinical activity in H3K27M-mutant DMG and induces mitochondrial stress responses. In this review, we examine emerging connections between epigenetic dysregulation, mitochondrial metabolism, and dopamine signalling in DMG. We propose that H3K27M-driven epigenetic reprogramming may impose metabolic constraints that increase tumour reliance on mitochondrial bioenergetics and stress-buffering pathways. Within this context, dopamine signalling may function as a metabolic rheostat that contributes to mitochondrial homeostasis; however, this remains a hypothesis requiring direct experimental validation in DMG models. Pharmacologic disruption of this axis may destabilise tumour metabolism and expose therapeutically exploitable vulnerabilities in this otherwise treatment-resistant disease. Full article

Background: Solar dermatitis (SD) is an inflammatory skin disease caused by excessive exposure to ultraviolet (UV) radiation. Gastrodia elata (GE) is a medicinal and edible plant with broad pharmacological activities; however, the polarity distribution of its active components and their specific mechanisms of action in SD remain incompletely understood. Methods: Different polarity fractions of GE-petroleum ether extract (PEE), ethyl acetate extract (EAE), and n-butanol extract (NBAE) were prepared and evaluated in a UVB-induced SD mouse model. We integrated metabolomics, network pharmacology, molecular docking, molecular dynamics simulations, and molecular biology techniques to identify key active ingredients and regulatory mechanisms. Results: The EAE group significantly ameliorated epidermal thickening and collagen damage in SD mice. Mechanistically, EAE and its active component luteolin (LUT) likely suppressed abnormal activation of the JUN pathway (binding energy: −9.1 kcal/mol), leading to downregulation of the pro-inflammatory cytokines tumour necrosis factor-alpha and inerleukin-1 beta. Conclusions: The EAE fraction alleviates SD through multi-component, multitarget synergistic effects, with LUT as a core bioactive component that inhibits the JUN pathway to mitigate skin inflammation and oxidative damage. EAE also accelerated SD recovery by modulating critical metabolic pathways, including arginine biosynthesis and terpenoid backbone biosynthesis. These findings identify EAE and LUT as promising candidate therapeutics for SD. Full article

Background: Alcohol-related liver disease (ALD) affects 4.8% of the global population. Among these patients, between 13.4% and 19.6% suffer from alcoholic hepatitis (AH), which, in its severe form, is associated with significant short- and long-term mortality. Current therapeutic options are limited, offering only modest short-term survival benefits. Recent studies suggest that microbiota-based therapies may offer a novel therapeutic opportunity for patients with ALD. Methods: Databases including Embase, Medline, and CENTRAL were searched until 4 February 2026. The pre-registered protocol on PROSPERO (CRD42023467455) was followed without deviation. Studies comparing adult patients with ALD, treated with fecal microbiota transplantation (FMT) or standard of care (SOC), were included. Outcomes investigated included overall survival, alcoholic recidivism, adverse events (AEs), and disease severity scores. Risk of bias (ROB) was assessed using the ROBINS-I and ROB 2 tools. Hazard ratios (HR) were calculated for FMT versus SOC groups. Results: Overall, 10 studies were eligible for inclusion, with 339 patients eligible for synthesis. In these patients, FMT was associated with significantly improved overall survival compared to the SOC, with an HR of 0.50 (95% confidence interval (CI): 0.35–0.72; p = 0.0002). When comparing FMT with pentoxifylline, the HR was 0.45 (95% CI: 0.21–0.96; p = 0.0345), and when FMT was compared with nutritional support alone, the HR was 0.36 (95% CI: 0.19–0.66; p = 0.0001). But FMT did not reach statistical significance when compared to glucocorticoids. ROB analysis showed a moderate to high risk of bias, and the overall certainty of evidence was low. Discussion: FMT is a promising therapeutic option for improving short- and medium-term survival in patients with severe alcoholic hepatitis (SAH), particularly in those who are ineligible or unresponsive to corticosteroid therapy. However, given the risk of bias and low certainty of evidence, clinical significance remains uncertain. Confirmation in well-designed studies is needed. Full article

Radiation-induced periodontitis represents an underrecognized and mechanistically complex toxicity of head and neck radiotherapy, arising from the interplay of oxidative stress, inflammatory dysregulation, impaired bone remodeling, and epithelial barrier disruption. Despite its clinical relevance, the molecular determinants underlying inter-individual susceptibility remain poorly defined. Heat shock protein 27 (HSP27), a stress-inducible molecular chaperone, has emerged as a candidate mediator potentially linking biological pathways relevant to radiation-induced tissue injury, including redox regulation, cytoskeletal stability, DNA repair, and apoptosis control. However, no clinical or experimental study has directly evaluated HSP27 in radiation-induced periodontitis. Therefore, the proposed involvement of HSP27 in this setting should be interpreted as a biologically plausible, hypothesis-generating framework rather than evidence of a proven causal mechanism. Convergent but indirect evidence from periodontal biology, radiation-response models, inflammatory disease, and cellular stress systems suggests that HSP27 may plausibly influence periodontal tissue resilience and injury responses after radiotherapy. Therapeutic modulation of HSP27 may represent a potential investigational strategy to mitigate radiation-induced periodontitis, but this concept requires direct validation in periodontal cell-based, animal, organoid, and prospective clinical studies. This review synthesizes current mechanistic and translational evidence to evaluate HSP27 as a candidate mediator, biomarker, and investigational therapeutic target in radiation-induced periodontitis. Full article

The TM7x strain is a genetic variant of the bacterium Nanosynbacter lyticus, which belongs to the Saccharibacteria phylum within the Candidate Phyla Radiation (CPR) or Patescibacteria group. Its biology differs significantly from that of other bacterial phyla, and its ecological role in the oral cavity remains largely undefined. Through a organyzed and comprehensive literature review, we aim to define the role this bacterium plays within the oral ecosystem. We identified relevant studies from primary sources, including scientific articles from preclinical and clinical studies obtained from three digital databases. The bacterial strain TM7x is an obligate epibiont that exhibits autonomous energy metabolism and utilizes a type IV pili system to adhere to its direct host, Schaalia odontolytica. It interacts with its host in two stages: initially as an epipatobiont and subsequently as an episymbiont. TM7x plays a complex ecological role by modulating the host’s metabolism and structure toward a less virulent phenotype resistant to phage attack, while also influencing the human host through immunomodulation and tissue protection. This organism has transitioned from being considered ‘biological dark matter’ to a key model for understanding coevolution within the human microbiome. Its ability to protect the host from phages, induce protective biofilms, and suppress destructive inflammatory responses suggests its potential role as a speculative modulator of human oral microbiome homeostasis, although direct clinical confirmation in human subjects is still lacking. Full article

Desiccation, ionizing radiation, ultraviolet exposure, and oxidative stress impose severe physicochemical stress that threatens the integrity of both DNA and RNA. Water loss promotes molecular crowding, protein and membrane destabilization, and the accumulation of reactive oxygen species (ROS), while rehydration can intensify oxidative injury and expose lesions accumulated during metabolic suppression. As a result, stress-tolerant metazoans must do more than survive water loss: they must also protect, monitor, and restore nucleic-acid integrity. Here, we review how tardigrades, bdelloid rotifers, Artemia, nematodes, and selected insect species preserve genomic and transcriptomic integrity under extreme dehydration, oxidative stress, and radiation-related insults. We compare conserved defence systems, including antioxidant enzymes, trehalose, LEA proteins, heat shock proteins, and core DNA repair pathways. These pathways include base excision repair, nucleotide excision repair, homologous recombination, and non-homologous end joining. We then examine how these conserved mechanisms contrast with lineage-specific innovations, such as the tardigrade proteins Dsup, TDR1, and TRID1, as well as the unusual genome plasticity of bdelloid rotifers. We argue that stress biology of these organisms is best understood through a framework that distinguishes damage prevention during drying from repair and recovery during rehydration. In this framework, extremotolerant metazoans provide biologically informative models for understanding oxidative nucleic-acid damage, redox defence and the molecular logic underlying radioprotection and dry-state preservation. Full article

Background/Objectives: Acral (AM) and mucosal melanomas (MM) have certain genetic similarities compared to non-acral cutaneous melanomas and share a restricted influence of UV radiation in their etiology. Yet, AM and MM arise in quite different locations from a histological perspective. This study aimed to report differences between AM and MM for the most prominently mutated genes in melanoma: BRAF, NRAS, KIT, and TERT promoter. Methods: We conducted a retrospective, single-center study including 152 patients diagnosed with AM (n = 121) or MM (n = 31) at the Fundación Instituto Valenciano de Oncología between 2000 and 2024. Clinical and histopathological data were collected, and mutational analyses of BRAF, NRAS, KIT, and the TERT promoter were performed using targeted sequencing. Results: MM presented with significantly greater Breslow thickness and higher rates of hematogenous metastasis compared to AM. While BRAF, NRAS, and TERT promoter mutations were similarly distributed between subtypes, KIT mutations were significantly more frequent in MM (33% vs. 12.3%; p = 0.043) and exhibited a broader mutational spectrum. Survival outcomes were poorer in MM, with lower 5- and 10-year survival rates compared to AM. Discussion: Despite shared UV-independent biology, AM and MM differ in clinically and molecularly meaningful ways. The higher prevalence and diversity of KIT mutations in MM suggest subtype-specific oncogenic mechanisms and potential therapeutic implications. These findings support a more refined classification of UV-independent melanomas based on anatomical and molecular distinctions. Full article

Ionizing radiation induces reactive oxygen species (ROS) and inflammatory signaling that contribute to both therapeutic efficacy and normal tissue toxicity. While the effects of high-dose radiation are well characterized, responses to low-dose-rate radiation (LDRR) remain inconsistent and are not adequately explained by conventional linear dose–response models. To address this gap, we conducted a narrative review of recent experimental studies across multiple biological systems, including body fluids, joint microenvironments, and reproductive tissues, focusing on redox and immune-related responses under LDRR conditions (dose rates: 0.39–3.49 mGy/h). Literature was identified through PubMed/MEDLINE, Web of Science, and Google Scholar, with emphasis on studies published between 2015 and 2026. These studies demonstrate that LDRR elicits nonlinear, dose-dependent effects that vary across biological compartments and involve coordinated changes in oxidative stress, immune signaling, and metabolic regulation. Based on this synthesis, we propose a unifying framework of nonlinear redox–immune coupling, in which oxidative stress functions as a threshold-dependent regulator and immune responses follow a biphasic trajectory characterized by activation at lower dose rates and attenuation or adaptation at higher levels. These responses are strongly influenced by the local microenvironment, resulting in compartment-specific variability. This integrated perspective supports a shift from dose-centric to systems-level interpretations of radiation biology and provides a basis for improving biomarker development, risk assessment, and therapeutic strategies in chronic low-dose radiation exposure settings. Future research priorities include time-resolved mechanistic studies to define compartment-specific redox thresholds, validation of candidate biomarkers under identical multi-compartment experimental conditions (e.g., GSH/GSSG ratio, 8-OHdG, circulating cytokine panels including IL-10/TNF-α ratio), and integration of subject-specific biological variables (e.g., age, sex, and baseline redox capacity) into predictive models of LDRR response. Full article