Search Results (2,970)

Introduction: Stroke remains one of the leading causes of long-term disability worldwide. Post-stroke motor recovery depends on neuroplasticity, which is stimulated by intensive, repetitive, and task-specific training. Modern technologies such as robotic rehabilitation (RR), virtual reality (VR), functional electrical stimulation (FES), brain–computer interfaces (BCIs), and non-invasive brain stimulation (NIBS) offer novel opportunities to enhance rehabilitation. They operate through sensory feedback, neuromodulation, and robotic assistance which promote neural reorganization and motor relearning. Neurobiological Basis of Motor Recovery: Mechanisms such as long-term potentiation, mirror neuron activation, and cerebellar modulation underpin functional reorganization after stroke. Literature Review Methodology: A narrative review was conducted of studies published between 2005 and 2025 using PubMed, Scopus, Web of Science, Cochrane Library, and Google Scholar. Randomized controlled trials, cohort studies, and systematic reviews assessing the efficacy of these modern technologies were analyzed. Literature Review: Evidence indicates that RR, VR, FES, BCIs, and NIBS improve upper and lower limb motor function and strength, and enhance activities of daily living, particularly when combined with conventional physiotherapy (CP). Furthermore, integrated rehabilitation technologies (IRT) demonstrate synergistic neuroplastic effects. Discussion: Modern technologies enhance therapy precision, intensity, and motivation but face challenges related to cost, standardization, and methodological heterogeneity. Conclusions: RR, VR, FES, BCIs, NIBS, and IRT are effective complements to CP. Early, individualized, and standardized implementation can optimize neuroplasticity and functional recovery. Full article

Ritonavir (RTV), an effective aspartyl protease inhibitor, was originally developed to counter the replication of human immune deficiency virus and then employed as a pharmacokinetic enhancer in antiretroviral therapy. Yet unexpectedly, RTV exerted antitumor effects that added to its antiviral action, as it impacted the migration, invasion, oxidative stress, and proteasome function of human tumor cells. More recently, RTV was shown to directly inhibit DNA repair enzymes, thereby enhancing radiosensitivity and synergizing with chemotherapeutics across multiple cancer models. However, RTV induced oxidative stress and DNA damage also in non-tumor cells, including the reproductive ones. This duality highlights both the possibility of RTV anticancer use and the concern for its safety. In this Perspective, we propose the repurposing of RTV as a novel tool to potentiate DNA-damage-based antitumor therapies such as radiotherapy and/or chemotherapy. At the same time, we underscore the need for a careful assessment of RTV side effects. Full article

Non-muscle invasive bladder cancer (NMIBC) accounts for the majority of bladder cancer diagnoses and remains a clinical challenge due to its high recurrence and progression rates despite intravesical Bacillus Calmette–Guérin (BCG) therapy. In recent years, tumor-infiltrating lymphocytes (TILs) have emerged as promising biomarkers, reflecting the interplay between the tumor and host immune system. However, the evidence regarding their prognostic and predictive role is still conflicting, largely due to methodological heterogeneity, lack of standardized evaluation criteria, and limited prospective validation. This narrative review summarizes the current knowledge on TILs in NMIBC, focusing on their compartmental distribution (stromal, intraepithelial, and tumor–stroma interface), compositional diversity (CD4⁺, CD8⁺, Treg, B cells), and spatial dynamics. Special attention is given to their role in predicting response to BCG immunotherapy, the contribution of tumor-associated macrophages and tertiary lymphoid structures, and the emergence of immune escape pathways, including Programmed Death-Ligand 1 (PD-L1) and the HLA-E/NKG2A axis. Advances in digital pathology, spatial transcriptomics, and integrated immunoscore models provide more accurate metrics compared to simple cell counts, highlighting the importance of functional and spatial signatures. Despite encouraging progress, TILs are not yet ready for routine incorporation into histopathological reporting. Future directions include standardized assessment, integration with molecular biomarkers, and prospective multicenter validation to enable their translation into risk stratification and personalized therapeutic decision-making. Full article

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality globally, driven by marked molecular and cellular heterogeneity that complicates diagnosis and treatment. Despite advances in targeted therapies and immunotherapies, treatment resistance frequently emerges, and clinical benefits remain limited to specific molecular subtypes. To improve early detection and dynamic monitoring, novel diagnostic strategies—including liquid biopsy, low-dose computed tomography scans (CT) with radiomic analysis, and AI-integrated multi-modal platforms—are under active investigation. Non-invasive sampling of exhaled breath, saliva, and sputum, and high-throughput profiling of peripheral T-cell receptors and immune signatures offer promising, patient-friendly biomarker sources. In parallel, multi-omic technologies such as single-cell sequencing, spatial transcriptomics, and proteomics are providing granular insights into tumor evolution and immune interactions. The integration of these data with real-world clinical evidence and machine learning is refining predictive models and enabling more adaptive treatment strategies. Emerging therapeutic modalities—including antibody–drug conjugates, bispecific antibodies, and cancer vaccines—further expand the therapeutic landscape. This review synthesizes recent advances in NSCLC diagnostics and treatment, outlines key challenges, and highlights future directions to improve long-term outcomes. These advancements collectively improve personalized and effective management of NSCLC, offering hope for better-quality survival. Continued research and integration of cutting-edge technologies will be crucial to overcoming current challenges and achieving long-term clinical success. Full article

Background: Stroke leads to lasting disability by disrupting the connectivity of functional brain networks. Although several rehabilitation methods are promising, our full understanding of how these strategies restore network function is still limited. Here, we map how non-invasive brain stimulation (NIBS), brain–computer interface (BCI)/neurofeedback, virtual reality (VR), and robot-assisted therapy restore connectivity within the sensorimotor network (SMN), default mode network (DMN), and salience network, and we contextualize these effects within the known temporal evolution of post-stroke motor network reorganization. Methods: This scoping review adhered to PRISMA guidelines and searched PubMed, Cochrane, and Medline from January 2015 to January 2025 for clinical trials focused on stroke rehabilitation with functional connectivity outcomes. Included studies used conventional therapy, neuromodulation, or feedback-based interventions. Results: Twenty-three studies fulfilled the inclusion criteria, covering interventions like robotic training, transcranial stimulation (tDCS/TMS), brain–computer interfaces, virtual reality, and cognitive training. Motor impairments were linked to disrupted interhemispheric sensorimotor connectivity, while cognitive issues reflected changes in frontoparietal and default mode networks. Combining neuromodulation with feedback-based methods showed better network recovery than standard therapy alone, with clinical improvements closely associated with connectivity alterations. Conclusions: Effective stroke rehabilitation depends on targeting specific disrupted networks through various modalities. Robotic interventions focus on restoring structural motor pathways, feedback-enhanced methods improve temporal synchronization, and cognitive training aims to enhance higher-order network integration. Future research should work toward standardizing connectivity assessment protocols and conducting multicenter trials. This will help develop evidence-based, network-focused rehabilitation guidelines that effectively translate mechanistic insights into personalized clinical treatments. Full article

Background: Neurological disorders are the leading cause of disability, affecting over three billion people worldwide. Amyotrophic lateral sclerosis (ALS) is among the most feared and uniformly fatal neurodegenerative diseases, with no therapy capable of restoring lost function. Methods: We report the first application of therapeutic fever to ALS using Computerized Brain-Guided Intelligent Thermofebrile Therapy (CBIT²). This fully noninvasive treatment, delivered through an FDA-approved computerized platform, digitally reengineers the 1927 Nobel Prize-recognized malarial fever therapy into a modern treatment guided by the Brain–Eyelid Thermoregulatory Tunnel. CBIT² induces therapeutic fever through synchronized hypothalamic feedback, activating heat shock proteins, which are known to restore proteostasis and neuronal function. Case presentation: A 56-year-old woman was diagnosed with progressive ALS at the Mayo Clinic, with electromyography (EMG) demonstrating fibrillation and fasciculation indicative of denervation corroborated by neurological and MRI findings; the patient was informed that she had an expected survival of three to five years. A neurologist from Northwestern University confirmed the diagnosis and thus maintained the patient on FDA-approved ALS drugs (riluzole and edaravone). Her condition rapidly worsened despite pharmacological treatment, and she underwent CBIT², resulting in (i) electrophysiological reversal with complete disappearance of denervation; (ii) biomarker correction, including reductions in neurofilament and homocysteine, IL-10 normalization (previously linked to mortality), and robust HSP70 induction; (iii) restoration of gait, swallowing, respiration, speech, and cognition; (iv) reconstitution of tongue structure; and (v) return to complex motor tasks, including golf, pickleball, and swimming. Discussion: This case provides the first documented evidence that ALS can be reversed through digitally reengineered fever therapy aligned with thermoregulation, which induces heat shock response and upregulates heat shock proteins, resulting in the patient no longer meeting diagnostic criteria for ALS and discontinuation of ALS-specific medications. Beyond ALS, shared protein-misfolding pathology suggests that CBIT² may extend to Alzheimer’s, Parkinson’s, and related disorders. By modernizing this Nobel Prize-recognized therapeutic principle with computerized precision, CBIT² establishes a framework for large-scale clinical trials. A century after fever therapy restored lost brain function and so decisively reversed dementia paralytica such that it earned the 1927 Nobel Prize in Medicine, CBIT² now safely harnesses the therapeutic power of fever through noninvasive, intelligent, brain-guided thermal modulation. Amid a global brain health crisis, fever-based therapies may offer a path to preserve thought, memory, movement, and independence for the more than one-third of humanity currently affected by neurological disorders. Full article

The escalating threat of antibiotic resistance has prompted the search for alternative antibacterial therapies. Antibacterial photodynamic therapy (aPDT), which utilizes light-activated photosensitizers to generate reactive oxygen species (ROS), offers a promising, non-invasive approach. The aim of this review is to analyze recent advances in nanoparticle-mediated aPDT and synthesize crucial design principles necessary to overcome the current translational barriers, thereby establishing a roadmap for future clinically applicable antimicrobial treatments. Emerging nanoparticle platforms, including upconverting nanoparticles (UCNPs), carbon dots (CDs), mesoporous silica nanoparticles (MSNs), liposomes, and metal–organic frameworks (MOFs), have demonstrated improved photosensitizer delivery, enhanced ROS generation, biofilm disruption, and targeted bacterial eradication. Synergistic effects are observed when aPDT is integrated with photothermal, chemodynamic, or immunotherapeutic approaches. The review further examines the mechanisms of action, biocompatibility, and antibacterial performance of these nanoparticle systems, particularly against drug-resistant strains and in challenging environments such as chronic wounds. Overall, nanomaterial-mediated aPDT presents a highly promising and versatile solution to antimicrobial resistance. Future perspectives include the integration of artificial intelligence to personalize aPDT by predicting optimal light dosage and nanoplatform design based on patient-specific data, rigorous clinical validation through trials, and the development of safer, more efficient nanoparticle platforms. Full article

Background: Bladder cancer is the ninth most prevalent cancer globally. Most cases are urothelial carcinoma, classified as non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC); approximately 70% are diagnosed as NMIBC. Current standard of care for high-risk NMIBC includes transurethral tumour resection, followed by intravesical therapy with Bacillus Calmette-Guérin (BCG). However, significant unmet needs persist due to disease recurrence, BCG unresponsiveness, or progression to MIBC. Radical cystectomy is recommended after BCG unresponsiveness but may not be viable due to its invasiveness and morbidity. The paucity of treatment options for BCG-unresponsive NMIBC has driven research into alternatives such as gene therapy. The bladder’s anatomy allows direct vector–tumour contact, while urine and tissue samples allow for easy monitoring of therapeutic effects. Methods: This narrative review integrates findings from recent clinical and preclinical studies identified through comprehensive searches of peer-reviewed literature to provide an overview of the current landscape of gene therapy for BCG-unresponsive NMIBC. Results: Nadofaragene firadenovec, a recombinant adenovirus delivering interferon alpha-2b (IFNα2b), is the first FDA-approved gene therapy for BCG-unresponsive NMIBC with carcinoma in situ (CIS). A phase III nadofaragene firadenovec study (NCT02773849) demonstrated a 53% complete response (CR) rate at 3 months; and 43% of patients with CIS had bladder preservation at 60 months. Cretostimogene grenadenorepvec (CG0070), an oncolytic vector, demonstrated a 47% 6-month CR rate in a phase II study (NCT02365818). Detalimogene voraplasmid (EG-70), a nonviral gene therapy, demonstrated a 47% 6-month CR in a phase I/II study (NCT04752722). Future advances are likely to focus on patient selection, novel vectors, and combination strategies to improve treatment outcomes. Conclusions: Gene therapy represents a significant addition to the bladder cancer treatment landscape by offering bladder-sparing alternatives where conventional therapies are limited. Full article

Metabolic immune evasion is a major factor limiting the long-term efficacy of intravesical Bacillus Calmette–Guérin (BCG) therapy in non-muscle-invasive bladder cancer (NMIBC). TIA1 is a stress granule RNA-binding protein with liquid–liquid phase separation (LLPS) capacity. Its role in tumor metabolism and immunotherapy response has been unclear. Here, we demonstrated that high TIA1 expression was independently associated with favorable survival across multiple cohorts. Full-length TIA1 formed cytoplasmic condensates, repressed LDHA/PKM2/HK2, reduced lactate, and lowered extracellular acidification. A condensate-defective ΔLCD (deletion of the low-complexity domain) mutant was inactive. TIA1 showed physical association with these glycolytic mRNAs in human cells, consistent with mRNA-linked control. Condensate-competent TIA1 promoted CD8⁺ T-cell proliferation, increased CD69 and Granzyme-B, and reduced PD-1 in co-culture. TIMER (Tumor Immune Estimation Resource) and spatial-omics supported co-localization with tumoral CD8A. BCG induced this metabolic–immune signature in cell lines, murine models, and patient explants, but the effects were abolished by TIA1 knock-down. Conversely, TIA1 over-expression alone limited tumor growth and recapitulated BCG-mediated glycolytic restraint and T-cell activation. Together, these results support an LLPS-linked, mRNA-associated regulation of tumor glycolysis. BCG-driven glycolytic suppression and CD8⁺ T cell activation track with the condensate-forming capacity of TIA1. TIA1 emerges as a prognostic biomarker and a potential therapeutic axis to improve intravesical immunotherapy in NMIBC. Full article

Background: Cerebral echinococcosis is a rare, potentially serious parasitic disease in children, that can lead to intracranial hypertension, focal neurological deficits, seizures, and severe complications. We conducted a systematic review and meta-analysis on diagnostic, therapeutic approaches, and outcomes in pediatric cerebral echinococcosis. Methods: A systematic search was performed on PubMed, Scopus, and Web of Science, selecting English studies on children (0–18 years). Studies describing clinical, imaging, surgical, pharmacological, and outcome data were eligible. Statistical analyses (Fisher’s exact and chi-square tests) were performed in R. Results: A total of 100 studies with 462 pediatric patients met the inclusion criteria. High-resolution imaging has largely replaced invasive diagnostics; MRI-based diagnosis correlated with better outcomes. Headaches, vomiting, papilledema, seizures, and hemiparesis were common. Surgical cysts’ removal remained the main therapy. Additional treatment with albendazole was associated with a higher probability of good outcome (p < 0.001). A greater number of cyst localizations was significantly associated with a worse prognosis (p < 0.001). Overall mortality was 8.9%, while approximately 2/3 of patients achieved a good outcome. Conclusions: Advances in non-invasive imaging, refinement of surgical technique, and targeted antiparasitic therapy improved outcomes. Nevertheless, heterogeneous reporting and the prevailing paucity of evidence limit definitive recommendations. Prospective multicenter studies are needed to refine treatment and develop pediatric-specific guidelines. Full article

Background: Assessing the efficacy of combination therapies in hepatocellular carcinoma (HCC) requires both accurate tumor delineation and biologically validated prediction of therapeutic response. Conventional MRI-based criteria, which rely primarily on tumor size, often fail to capture treatment efficacy due to tumor heterogeneity and pseudo-progression. This study aimed to develop and biologically validate a multi-task deep learning model that simultaneously segments HCC tumors and predicts treatment outcomes using clinically relevant multi-parametric MRI in a preclinical rat model. Methods: Orthotopic HCC tumors were induced in rats assigned to Control, Sorafenib, NK cell immunotherapy, and combination treatment groups. Multi-parametric MRI (T1w, T2w, and contrast enhanced MRI) scans were performed weekly. We developed a U-Net++ architecture incorporating a pre-trained EfficientNet-B0 encoder, enabling simultaneous segmentation and classification tasks. Model performance was evaluated through Dice coefficients and area under the receiver operator characteristic curve (AUROC) scores, and histological validation (H&E for viability, TUNEL for apoptosis) assessed biological correlations using linear regression analysis. Results: The multi-task model achieved precise tumor segmentation (Dice coefficient = 0.92, intersection over union (IoU) = 0.86) and reliably predicted therapeutic outcomes (AUROC = 0.97, accuracy = 85.0%). MRI-derived deep learning biomarkers correlated strongly with histological markers of tumor viability and apoptosis (root mean squared error (RMSE): viability = 0.1069, apoptosis = 0.013), demonstrating that the model captures biologically relevant imaging features associated with treatment-induced histological changes. Conclusions: This multi-task deep learning framework, validated against histology, demonstrates the feasibility of leveraging widely available clinical MRI sequences for non-invasive monitoring of therapeutic response in HCC. By linking imaging features with underlying tumor biology, the model highlights a translational pathway toward more clinically applicable strategies for evaluating treatment efficacy. Full article

Oral squamous cell carcinoma (OSCC) remains one of the most prevalent and aggressive malignancies worldwide, with late diagnosis contributing to poor survival rates. Recent evidence suggests that periodontitis may act as a co-factor in development of OSCC through persistent inflammation, microbial dysbiosis, and subsequent tissue remodeling. Identifying molecular signatures that link periodontitis with early oral cancerization is therefore of paramount importance for risk assessment, prevention, and timely intervention. This narrative review aims to provide an integrative overview of the current knowledge on molecular, genetic, and epigenetic biomarkers associated with oral cancer risk in patients with periodontitis. Specifically, periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum promote oral cancerization by modulating molecular, genetic, and epigenetic pathways, including p53, Cyclin D1, Ki-67, p16^INK4A, DNA methylation, histone modifications, and microRNA regulation. Therefore, this review provides a discussion about the role of inflammatory mediators, oxidative stress-related molecules, microbial-derived products, genetic markers and epigenetic mechanisms as early molecular signals of malignant transformation. The study of these salivary biomarkers (salivaomics) has emerged as a promising non-invasive diagnostic tool, although variability in sampling, biomarker stability, and confounding factors such as coexisting periodontal disease remain significant limitations. By synthesizing the available evidence, this review summarizes recent evidence linking periodontitis to oral cancerization, highlights potential salivary, proteomic, and inflammatory biomarkers, and considers the role of periodontal therapy in improving inflammatory profiles and modulating tumor-related biomarkers. Finally, it explores future perspectives, including the integration of Artificial Intelligence (AI) to enhance biomarker-based diagnosis and risk stratification in OSCC patients. Full article

Ischemic stroke remains a major cause of mortality and long-term disability, yet current therapeutic strategies are largely limited to reperfusion approaches such as intravenous thrombolysis and thrombectomy, which are constrained by narrow treatment windows and the risk of complications. Moreover, the blood–brain barrier (BBB) severely restricts drug penetration into the injured brain, limiting the translation of promising neuroprotective agents into clinical success. Intranasal (IN) delivery has emerged as a compelling alternative route that bypasses the BBB and enables rapid access to the central nervous system through olfactory, trigeminal, and perivascular pathways. This narrative review highlights recent advances in preclinical research on IN therapeutics for ischemic stroke, ranging from small molecules and biologics to nucleic acids and cell-based therapies. Particular emphasis is placed on the application of nanotechnology, including extracellular vesicles, liposomes, and inorganic nanoparticles, which enhance drug stability, targeting, and bioavailability. Studies demonstrate that IN delivery of growth factors, cytokines, and engineered stem cells can promote neurogenesis, angiogenesis, white matter repair, and functional recovery, while nanocarriers further expand the therapeutic potential. Overall, intranasal delivery represents a promising and non-invasive strategy to overcome the limitations of conventional stroke therapies, offering new avenues for neuroprotection and regeneration that warrant further investigation toward clinical translation. Full article

Background: Migraine is a complex neurological condition characterized by a range of symptoms, such as intense to severe headaches, sensitivity to light and sound, and feelings of nausea and vomiting. The most common complaints regarding acute treatment are that medication causes adverse effects, that pain returns, or that pain relief is either too slow or inconsistent. Certain non-pharmacological methods, such as non-invasive neuromodulators, might be beneficial for alleviating migraines and require evidence for clinical judgment. Objective: The objective of the study was to determine the effects and compare the effects of green light and transcranial direct current stimulation on migraine frequency, intensity, impact, and quality of life. Methods: A randomized controlled trial was conducted with 69 migraine patients of both genders aged over 18 years, experiencing headache attacks lasting more than 4 h, characterized by pulsating and unilateral pain with an intensity of 5 or higher on the numeric pain scale. Active tDCS, sham tDCS, and green light, along with prescribed medications, were applied to Groups A, B, and C, respectively, for four weeks. The outcomes were measured at baseline, week 2, and week 4 for primary outcomes, including a structured headache diary, numeric pain scale, multidimensional pain inventory, and migraine-specific quality of life version 2.1 as a secondary variable. Results: Significant results were found for the NPS and MSQ with a p-value < 0.05 between and within the groups. There was a substantial reduction in pain intensity and improved quality of life in all three groups. Group A and Group C had p-values < 0.05 for most of the subscales of MPI, showing decreased pain interference, enhanced support, improved emotional function, and increased participation in everyday activities. Medication dependency in Group A was reduced to four weeks with 22 (95.7%) with ‘no medication’ use. The number of migraine attacks in Group A at four weeks reduced to ‘no attack’ for 7 (30.4%) participants, showing a reduction in both the number of attacks and their duration to 1–5 h in 12 (52.2%) participants. Conclusions: Both tDCS and green light therapy were found to be effective non-pharmacological therapies for reducing pain intensity, frequency, impact, and drug usage and for improving the quality of life of migraine patients. However, tDCS showed an advantage in terms of reducing pain intensity and its impact on daily living, while green light therapy showed a slightly greater improvement in quality of life. Full article

Therapeutic peptides have gained significant attention due to their high specificity, potency, and safety profiles in treating various diseases. However, their clinical application via the oral route remains challenging. Peptides are inherently unstable in the gastrointestinal environment, where they are rapidly degraded by proteolytic enzymes and acidic pH, leading to poor bioavailability. Additionally, their large molecular size and hydrophilicity restrict passive diffusion across the epithelial barriers of the gastrointestinal tract. These limitations have traditionally necessitated parenteral administration, which reduces patient compliance and convenience. The oral cavity, comprising the buccal and sublingual mucosa, offers a promising alternative for peptide delivery. Its rich vascularization allows for rapid systemic absorption while bypassing hepatic first-pass metabolism. Furthermore, the mucosal surface provides a relatively permeable and accessible site for drug administration. However, the oral cavities also present significant barriers: the mucosal epithelium limits permeability, the presence of saliva causes rapid clearance, and enzymes in saliva contribute to peptide degradation. Therefore, innovative strategies are essential to enhance peptide stability, retention, and permeation in this environment. Nanoparticle-based delivery systems, including lipid-based carriers such as liposomes and niosomes, as well as polymeric nanoparticles like chitosan and PLGA, offer promising solutions. These nanocarriers protect peptides from enzymatic degradation, enhance mucoadhesion to prolong residence time, and facilitate controlled release. Their size and surface properties can be engineered to improve mucosal penetration, including through receptor-mediated endocytosis or by transiently opening tight junctions. Among these, niosomes have shown high encapsulation efficiency and sustained release potential, making them particularly suitable for oral peptide delivery. Despite advances, challenges remain in translating these technologies clinically, including ensuring biocompatibility, scalable manufacturing, and patient acceptance. Nevertheless, the oral cavity’s accessibility, combined with nanotechnological innovations, offers a compelling platform for personalized, non-invasive peptide therapies that could significantly improve treatment outcomes and patient quality of life. Full article