Lentiviral, α-retroviral, and γ-retroviral vector particles pseudotyped with envelope (Env) proteins of baboon endogenous retrovirus (BaEV) were shown to mediate highly efficient gene transfer into a range of primary human hematopoietic cell types in gene therapeutic strategies. However, the fusogenicity of utilized Env proteins mediated syncytia formation, hindering the establishment of stable viral packaging cell lines (VPCLs). Consequently, we used another BaEV Env variant, termed BaEV-TR—previously reported not to induce cell-to-cell fusion—and assessed its utility in stable producer cell line development. The absence of syncytia formation was reconfirmed in human 293T and HT1080 cell lines. Using HT1080 host cells, the stable VPCL HT/BaEV-TR was established. Conducting a Western blot analysis, BaEV-TR protein incorporation into vector particles was readily detected. Murine leukemia virus (MLV) pseudotype vectors efficiently transduced a variety of human target cell lines, reaching high vector titers of more than 3.0 × 106 transducing units per mL (TU/mL) in 293T target cells. In summary, this proof-of-concept study underlines the utility of the Env variant BaEV-TR for the establishment of stable pseudotype VPCLs and the utilization of HT1080 cells as an alternative to frequently used 293T host cells.
Metastatic castration-resistant prostate cancer (mCRPC) is associated with poor prognosis. Currently, treatment selection and response assessment in mCRPC still rely largely on prostate-specific antigen (PSA) and imaging tools, which may be insensitive and biologically noninformative. Liquid biopsy (LB), particularly circulating tumor DNA (ctDNA), offers a minimally invasive and reproducible approach for real-time assessment of tumor burden and tumor genomics. Across major treatment classes, ctDNA tumor fraction has shown consistent prognostic value, while selected genomic alterations may provide therapy-specific predictive information. Early on-treatment ctDNA kinetics are also emerging as dynamic markers of response, although prospective validation is required before routine clinical implementation. In this narrative review, we synthesize current evidence on ctDNA biology, detection methods, and its clinical utility across key mCRPC treatment classes, including androgen receptor pathway inhibitors (ARPIs), taxane chemotherapy, PARP inhibitors, and PSMA-targeted radioligand therapy (RLT). We critically examine ctDNA tumor fraction as a pan-therapy prognostic biomarker, genomic alterations as potential predictors of treatment sensitivity or resistance, early kinetic changes as surrogate markers of response, and the biological and technical limitations that currently restrict clinical adoption. Overall, the current evidence base for ctDNA in mCRPC remains predominantly prognostic rather than definitively predictive. Its integration into routine clinical practice will require prospective biomarker-driven trials, assay standardization, and a clear demonstration of clinical utility. At present, ctDNA is best positioned as a complementary tool for risk stratification and disease monitoring, with the potential to evolve into a clinically actionable biomarker for treatment decision-making.
Gynecological cancers account for approximately 1.4 million new cases and 680,000 deaths annually. Cervical, ovarian, endometrial, vulvar, and vaginal cancers collectively impose a major and disproportionate burden on women in low- and middle-income countries. Conventional treatments, including surgery, platinum-based chemotherapy, and radiotherapy, are limited by systemic toxicity, acquired chemoresistance, recurrence, and financial inaccessibility in resource-limited settings. Approximately 80 percent of patients with advanced ovarian cancer eventually develop platinum resistance, and cervical cancer persists as a leading cause of cancer death in regions with inadequate screening and vaccination infrastructure. Plant-derived phytochemicals have attracted substantial scientific attention as adjunct or complementary anticancer strategies. This review synthesizes preclinical, epidemiological, and emerging clinical evidence for alkaloids, flavonoids, terpenoids, polyphenols, coumarins, and organosulfur compounds in gynecological cancer prevention and management. These compounds modulate multiple oncogenic pathways relevant to gynecological malignancies: tumor cell proliferation, intrinsic and extrinsic apoptosis, angiogenesis, oxidative stress, inflammation, hormone receptor signaling, HPV E6/E7 oncoprotein expression, and epigenetic regulation. Paclitaxel, a taxane terpenoid, serves as the definitive proof of concept that plant-derived compounds can achieve gold-standard clinical status in gynecological oncology. Critical barriers limit clinical translation for most non-approved phytochemicals: oral bioavailability is poor, botanical preparations are unstandardized, randomized trial data in gynecological cancer populations are scarce, and herb-drug interaction profiles are incompletely characterized. Nanoformulation approaches, including liposomal encapsulation, PLGA nanoparticles, and phytosomes, offer practical routes to overcome these pharmacokinetic obstacles. Future work should prioritize biomarker-embedded clinical trials, molecular subtype-stratified patient selection, and rigorous evaluation of phytochemical-chemotherapy combination regimens.
IntroductionArterial hypertension and endurance training are related to left atrial (LA) remodeling and risk of atrial fibrillation (AF). Serum blood biomarkers have been explored in relation to cardiovascular risk. Our aim was to assess the influence of patient and echocardiographic characteristics on serum blood biomarkers in individuals at risk for AF.MethodsA population of 511 subjects was analyzed: 286 endurance athletes and 225 patients with arterial hypertension. Participants underwent 2D and 3D echocardiography with speckle-tracking analysis. Blood samples were obtained to evaluate biomarkers of myocardial damage (Brain Natriuretic Peptide, troponin I, Oncostatin M, heart-type Fatty Acid-Binding Protein and Placenta Growth Factor), vascular endothelial dysfunction (Endothelial cell-specific molecule 1), and fibrosis (Matrix Metalloproteinase 1, 2 and 9, C-X-C motif chemokine ligand 6 and 16, and Galectin-3 (Gal-3)). Linear regression models were fitted to discern the relationship of patient and echo characteristics and serum biomarker levels.ResultsThe results revealed the significant influence of age, gender, body mass index and renal function on biomarker levels. Parameters of myocardial damage showed a limited range of values in our cohort with no differences between groups. Biomarkers of fibrosis were uniformly elevated in hypertension, with Gal-3 levels independently associated with LA reservoir strain.ConclusionSerum levels of fibrosis biomarkers differ between populations at risk for AF. In hypertension Gal-3 levels are associated with LA reservoir function, making it a potential biomarker for LA remodeling in this setting. Clinical follow-up is needed to relate these findings with clinical outcomes.
BackgroundPsoriasis, an immune-mediated systemic inflammatory disease affecting skin, vessels, and joints, often co-occurs with depression. Routine depression screening is vital, as mood disorders link to inflammation, visible lesions, and functional limitations.MethodsThe study integrated Mendelian randomization (MR), transcriptomics, and single-cell omics via public databases to explore comorbidity mechanisms.ResultsMR identified 340 psoriasis-related and 307 depression-related eQTL-gene associations; 9 intersected. LASSO found 4 key Genes (MAP3K20, WARS2, TBXAS1, ABHD15), enriched in IL-17/NF-κB/FoxO pathways, cholesterol metabolism, and synaptic cycling. They correlated with immune infiltration, ferroptosis, and specific cell localization. Folic acid (from CTD) targeted 3 genes.ConclusionThese 4 genes mediate comorbidity via inflammation, immune metabolism, and ferroptosis. Folic acid pathways have therapeutic value, laying a foundation for precision therapy.
Relapse following anti-CD19 chimeric antigen receptor (CAR) T cell therapy remains a concern in the treatment of refractory B-cell malignancies. Although the CD19Δexon2 splice variant has been linked to treatment failure, reliable pre-treatment biomarkers for relapse risk are lacking. Here, we analyzed RNA-sequencing data from a small publicly available cohort of four anti-CD19 CAR-T-treated B-cell acute lymphoblastic leukemia patients, including one responder, one non-responder, and two who relapsed after initial response. We quantified the percent spliced in (PSI) of CD19 exon 2, as a proxy for CD19Δexon2 abundance before and after treatment. The patient with the lowest pre-treatment exon 2 PSI (i.e., highest estimated abundance of CD19Δexon2) experienced the earliest relapse, whereas the complete responder showed no detectable exon 2 skipping. In silico protein structure modeling indicated reduced structural stability of the FMC63 epitope region in the CD19Δexon2 variant, supporting a potential mechanistic link between exon 2 exclusion and antigen escape. Analysis of larger RNA-sequencing datasets from CAR-T treatment-naïve B-cell malignancies and healthy tissues revealed low-level exon 2 skipping in some individuals across both malignant and normal B cells. These findings suggest that CD19 exon 2 skipping may correlate with relapse after CAR-T therapy, and its presence in treatment-naïve individuals highlights its potential for evaluation as an RNA- or qPCR-based biomarker in future studies.
Interstitial cystitis/bladder pain syndrome (IC/BPS) with Hunner Lesions (Hunner Type Interstitial Cystitis or HIC) is characterized by lesions on the bladder wall. Previous work on these lesions identified B cells and monocytes within the lesion. However, the overall role of the adaptive immune system in the disorder remains uncertain. In this study, we performed HLA sequencing on 12 IC/BPS patients with HIC and 7 Non Hunner Type IC (NHIC) patients, and identified HLA-DQB1*02:02 and HLA-DRB1*07:01:01 have a significant association with HIC. This pilot study provides genetic evidence supporting a potential autoimmune component in HIC and may help define the pathogenesis of at least one subtype of IC/BPS, and lay the groundwork for identifying the etiology of IC/BPS as a disease complex. Identifying the mechanisms can also open new approaches to treatment. Identifying an HLA haplotype associated with HIC would indicate that it is autoimmune.
Adeno-Associated Virus (AAV) vectors are at the forefront of gene therapy, offering transformative therapeutic potential for many genetic disorders. However, the translation of this promise into accessible treatments is constrained by manufacturing challenges, including process variability, low yields, and scalability challenges. This review provides a comprehensive framework for establishing robust AAV-based gene therapy manufacturing processes by evaluating industry challenges and recent technological innovations. We studied the end-to-end AAV-based gene therapy manufacturing process, from upstream unit operations such as cell culture and transfection to downstream purification and fill-finish operations. Key upstream innovations highlighted include high-density perfusion cultures, advanced single- and dual-plasmid systems, and next-generation transfection reagents that collectively enhance the overall process quality and viral vector productivity. In the realm of downstream processing, recent advancements in serotype-agnostic affinity chromatography and ion-exchange chromatographic purifications have enhanced the critical separation of full capsids from empty capsids. The implementation of a quality-by-design framework is the heart of the AAV-based gene therapy manufacturing process. We emphasize the necessity of a rigorous process characterization, utilizing validated scale-down models and design of experiments, as a prerequisite for establishing a robust control strategy with defined proven and normal operating ranges. This data-driven approach not only mitigates process inconsistency, but it also serves as the foundation for an effective process validation and regulatory compliance. Looking ahead, the integration of artificial intelligence and continuous manufacturing methodologies will be pivotal in expediting the development of safer, more efficacious, and personalized AAV-based gene therapies.
MYC is a transcription factor crucial for a host of cellular functions from proliferation to metabolism, and MYC dysregulation contributes to disease pathogenesis. A growing body of evidence suggests that MYC signaling is regulated by the caspase activation and recruitment domain-coiled-coil (CARD-CC) proteins: a family of immunological signaling mediators that canonically drive NF-κB signaling across nearly all tissues. MYC regulation coordinated by the CARD-CC proteins occurs by multiple mechanisms, including transcription, physical binding, and subcellular localization. Herein, we highlight the hallmark studies that collectively broaden the sphere of influence of CBM complexes beyond NF-κB to include MYC, which has functional impact on cells within and likely beyond the immune system. The studies reviewed herein provide rationale for future studies that examine non-canonical CBM-MYC signaling, its relationship with canonical NF-κB signaling, and its contribution to human health and disease.
The classical cadherin (CDH), claudin (CLDN) and nectin families of transmembrane-type adhesion molecules are located at adherens or tight junctions in epithelial cells but diffuse to the nonjunctional cell surface in solid tumors with epithelial–mesenchymal plasticity. Human/humanized antibody-drug conjugates (ADCs) with chemical linkers and cytotoxic payloads have been developed for the treatment of malignancies. Here, the clinical development of ADCs that target CDH6, CDH17, CLDN6, CLDN18.2 and NECTIN4 is reviewed. Enfortumab vedotin is an NECTIN4-targeting antibody-drug conjugate that is approved for the treatment of urothelial cancer, whereas other ADCs or derivatives that target NECTIN4, such as bulumtatug fuvedotin, SHR-A2102 and zelenectide pevedotin, are being studied in randomized phase III clinical trials. In contrast, arcotatug tavatecan, garetatug rezetecan, sonesitatug vedotin and tecotabart vedotin are anti-CLDN18.2 ADCs in phase III clinical trials for the treatment of CLDN18.2-positive gastric or gastroesophageal junction adenocarcinomas, and raludotatug deruxtecan is an anti-CDH6 ADC in a phase II/III clinical trial for the treatment of platinum-resistant ovarian cancer. ADCs that target cell-cell adhesion molecules are a rapidly emerging class of cancer therapeutics, and bispecific ADCs and longitudinal companion diagnostics are emerging to further improve the clinical benefits of conventional ADCs.
One development in the growing field of Alzheimer’s Disease and related neurological disorders (ADRD) is the consideration of brain resilience, the ability to respond to and recover from adversity, which builds on a growing literature on the role of lifestyle behaviours in ADRD prevention and response. This paper reviews definitions of ‘brain health’ and integrates these with innovations in resilience system models applied to ADRD. Based on a socio-ecological framework that links physiological, behavioral, economic, and social determinants of mental health, we propose a unified model of resilience and aging in this field. We contend that applications of a resilience analytical approach to brain health require innovation in Artificial Intelligence (AI) to harness the full potential of immense interdisciplinary data mining opportunities. These include: development of digital twins, precision health analytics, AI sensors, and Multimodal Large Language Models (MLLM), knowledge graph technologies, and cognitive/decision science modeling. We apply this model to research and clinical examples to elucidate its potential value, requirements, risks, and challenges in developing new research agendas.
Coronavirus disease 2019 (COVID-19), caused by the betacoronavirus SARS-CoV-2, emerged in Wuhan, China, and rapidly evolved into a global health crisis. Recent evidence highlights the activation of the aryl hydrocarbon receptor (AHR) pathway following SARS-CoV-2 infection, implicating AHR in facilitating viral replication and impairing antiviral immunity. As a ligand-dependent transcription factor, AHR regulates immune responses, cellular differentiation, and proliferation, and is frequently exploited by viruses to evade host defences. In relation to COVID-19, AHR activation drives immune suppression, systemic inflammation, and metabolic disturbances, intensifying disease severity. Notably, in individuals with comorbidities such as obesity and diabetes, AHR overactivity exacerbates insulin resistance, oxidative stress, endothelial dysfunction, and thrombotic risk, contributing to cardiovascular complications. AHR also promotes airway remodelling and mucus hypersecretion, fostering respiratory dysfunction and fibrotic progression. This review synthesizes current insights into the mechanistic role of AHR signalling in SARS-CoV-2 pathogenesis and discusses its potential as a target for host-directed therapeutic interventions.
N6-methyladenosine (m6A) is the best-studied post-transcriptional RNA modification. It refers to the methylation in the N6 position. M6A exists universally from viruses to mammalian cells and is highly abundant in RNA polymerase II-transcribed, protein-coding transcripts and various non-coding RNAs. M6A RNA modification influences multiple physiological and pathological processes. This RNA methylation plays a role in the pathogenesis of many human diseases, including but not limited to hematopoietic, central nervous, and reproductive systems. One of the m6A-modified non-coding RNAs is the circular form of RNA. Circular RNA (circRNA) refers to a single-stranded RNA molecule with a circular structure that exists across a wide range of organisms, including eukaryotes and prokaryotes. Its unique circular structure is formed by the covalent closure between the 3'and 5'ends of the RNA molecule. This closed-loop structure prevents the circRNA from being degraded readily by the exonucleases, resulting in more stability compared to its linear RNA counterparts. CircRNAs have been reported to regulate gene expression, protein interaction, and RNA sponging. They play important roles in many human diseases. M6A modifications of the host gene mRNAs regulate the circRNA biogenesis. Furthermore, m6A modification of circRNA itself adds additional regulation of these complicated processes. This mini-review elaborates on recent advances in m6A modification on circRNA biogenesis and function, focusing on the role of circRNA m6A modification in the development of inflammatory responses.
The idea of using stem cell therapy to treat neurodegenerative diseases has undergone significant change over the years and has made significant progress recently. Neurotrophins, growth factors, and transcription factors regulate neural stem cell proliferation and differentiation. Disruption of these regulatory mechanisms, including negative feedback, can contribute to neurodegenerative diseases. Contemporary research highlights a growing global concern regarding diverse neurodegenerative disorders affecting both humans and animals. These conditions arise from neuronal cell death, axonal regeneration failure, and impairment of neuronal structure. Current pharmacological treatments primarily offer symptomatic relief without altering disease progression. Consequently, researchers are investigating innovative therapeutic strategies, with neural stem cell therapy emerging as a promising avenue. Adult neural stem cells, embryonic neural stem cells, and induced pluripotent stem cells represent potential cell sources, although challenges such as ethical considerations and technical limitations remain. The therapeutic application of neural stem cells holds significant promise for addressing neurodegenerative diseases, including Alzheimer’s disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, and multiple sclerosis. Neural stem cell therapy aims to replenish lost neurons and promote neural regeneration in these conditions. While clinical trials have demonstrated some success in improving cognitive and motor functions in individuals with neurodegenerative impairments, challenges such as immunological rejection, the identification of compatible cell sources, ethical concerns, treatment efficacy, and potential side effects necessitate thorough investigation before widespread clinical implementation. Despite these challenges, neural stem cell-based therapy offers substantial potential for revolutionizing the treatment of neurodegenerative diseases and central nervous system injuries. This paper, therefore, explores adult neurogenesis and the therapeutic potential of neural stem cells within the dynamic field of neurodegenerative disorders.
Natural human monoclonal antibodies obtained from sentinel lymph nodes of cancer patients identify cell surface vimentin. One of these vimentin-reactive antibodies, pritumumab, has been used to treat brain cancer patients. This review summarizes data on mAbs reactive with cell surface vimentin and their origin from lymph nodes of cancer patients.
Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by the progressive degeneration of motor neurons. One of the key pathogenic factors implicated in ALS is TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein encoded by the TARDBP gene. Under normal physiological conditions, TDP-43 predominantly resides in the nucleus, where it plays a critical role in regulating gene expression, alternative splicing, RNA transport, and stability. In ALS, TDP-43 undergoes pathological mislocalization from the nucleus to the cytoplasm, disrupting its normal function and contributing to disease progression. The nuclear loss of TDP-43 leads to widespread dysregulation of RNA metabolism. Moreover, mislocalized TDP-43 aggregates in the cytoplasm, acquires toxic properties that sequester essential RNA molecules and proteins. Importantly, deviations in TDP-43 levels, whether excessive or reduced, can lead to cellular dysfunction, and contribute to disease progression, highlighting the delicate balance required for neuronal health. Emerging evidence suggests that epigenetic mechanisms may play a crucial role in regulating TARDBP expression and, consequently, TDP-43 cellular levels. Epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNAs are increasingly recognized as modulators of gene expression and cellular function in neurodegenerative diseases, including ALS. Dysregulation of these processes could contribute to aberrant TARDBP expression, amplifying TDP-43-associated pathologies. This review explores and summarizes the recent findings on how specific epigenetic modifications influence TDP-43 expression and discusses their possible implications for disease progression.
