Search Results (31,286)

Background/Objectives: Vedolizumab (VDZ), a monoclonal antibody targeting α4β7 integrin, is used in Crohn’s disease (CD) management, yet patients’ responses vary, underscoring the need for pharmacogenomic (PGx) markers. This study aimed to identify PGx pathways associated with suboptimal VDZ response using a rare-variant analytical framework. Methods: DNA from 63 CD patients treated with VDZ as first-line advanced therapy underwent whole-exome sequencing. Clinical response at week 14 classified patients as optimal responders (ORs) or suboptimal responders (SRs). Sequencing data were processed using GATK Best Practices, annotated with variant effect predictors, and filtered for rare damaging variants (damaging missense and high-confidence loss-of-function; minor allele frequency < 0.05). Variants were mapped to genes specific for SRs and ORs, and analyzed for pathway enrichment using the Reactome database. Rare-variant burden and composition differences were assessed with Fisher’s exact test and SKAT-O gene-set association analysis. Results: Suboptimal VDZ response was associated with pathways related to membrane transport (ABC-family proteins, ion channels), L1–ankyrin interactions, and bile acid recycling, while optimal response was associated with pathways involving MET signaling. SKAT-O identified lipid metabolism-related pathways as significantly different—SRs harbored variants in pro-inflammatory lipid signaling and immune cell trafficking genes (e.g., PIK3CG, CYP4F2, PLA2R1), whereas ORs carried variants in fatty acid oxidation and detoxification genes (e.g., ACADM, CYP1A1, ALDH3A2, DECR1, MMUT). Conclusions: This study underscores the potential of exome-based rare-variant analysis to stratify CD patients and guide precision medicine approaches. The identified genes and pathways are potential PGx markers for CD patients treated with VDZ. Full article

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage loss, extracellular matrix degradation, chondrocyte apoptosis, and elevated inflammatory mediators. Chondrocytes respond to IL-1β and other inflammatory signals by secreting cytokines and activating transcriptional pathways that perpetuate inflammation. Because current therapies do not prevent OA progression, bioactive compounds with cytoprotective and immunomodulatory activity are of considerable interest. Lonomia obliqua bristle extract (LOCBE) and its recombinant proteins rLOPAP and rLOSAC exhibit cytoprotective, proliferative, and antioxidant effects in mammalian cells, as well as the ability to influence cytoskeletal dynamics. Given the importance of Rac-1, RhoA, Rab9, and β-catenin in chondrocyte function and cartilage homeostasis, we evaluated LOCBE, rLOPAP, and rLOSAC in human chondrocytes stimulated or not with IL-1β. LOCBE and rLOPAP induced IL-6 and IL-8 secretion, although at lower levels than IL-1β. LOCBE exerts a cytoprotective effect in IL-1β-treated chondrocytes and reduces β-catenin, RhoA, and Rab9 expression without affecting NF-κB p65 translocation. rLOPAP increased mitochondrial activity, cytokine secretion, Rab9 expression, and membrane-associated β-catenin, and under inflammatory conditions, enhanced Rac-1 levels. In contrast, rLOSAC did not induce inflammatory cytokines and decreased RhoA and Rac-1 expression while increasing membrane-associated β-catenin. These findings suggest that L. obliqua extract and its derived-proteins rLOPAP and rLOSAC modulate cytoskeletal regulatory pathways and inflammatory responses in chondrocytes, supporting their potential as therapeutic leads for targeting mechanisms relevant to OA progression. Full article

Background: Acquired brain injury (ABI) affects manual dexterity (MD) and cognitive functions, limiting daily activity performance. Occupational therapy aims to improve functionality and quality of life. Objective: To examine and describe the available evidence on the impact of MD training on cognitive processes and functional performance in adults with stroke, as well as to identify the most commonly used assessment tools and intervention techniques. Methods: Scoping review. A systematic literature search was conducted in PubMed and Scopus to identify experimental studies from the last 10 years involving adults with ABI who participated in interventions targeting upper-limb, MD, and cognitive function. A three-phase screening was carried out by two authors with duplicates removed using Zotero version 7.0. Results: Ten articles published between 2016 and 2023 were included. The most frequent interventions involved robotics and virtual reality. Eight studies were conducted by occupational therapists or included occupational therapy involvement, while two were conducted by physiotherapists. Training MD and upper-limb motor skills led to improvements in attention, memory, and executive functions. Conclusions: Findings support combined motor–cognitive interventions carried out by occupational therapists or physiotherapists to optimize rehabilitation outcomes, although further research is needed to strengthen the evidence. Full article

Background: Sarcomas are rare, aggressive malignancies with limited therapeutic options in advanced stages. This is the first real-world study in the MENA region evaluating the clinical utility of Next-Generation Sequencing (NGS) in guiding sarcoma treatment and improving outcomes. Methods: We retrospectively reviewed sarcoma patients who underwent NGS at a major referral center (2021–2024), comparing clinical and molecular outcomes between those who received NGS-based treatment adjustments (NBTA) and those who did not. Results: Seventy-eight patients were included (60% male; median age 44 years). Soft tissue sarcomas accounted for 70.5% of cases (n = 55), while bone sarcomas represented 29.5% (n = 23). Prior to NGS, 64.1% of patients had received a median of one line of systemic therapy. NGS was performed late in the disease course in 73% of cases. At least one mutation was detected in 87% (median 3 mutations). Targetable alterations were identified in 33% at the time of testing, rising to 42% with updated genomic knowledge and therapeutic advances. Overall, 20.5% received NBTA. Among non-NBTA patients, 67% had no actionable targets, 17% had no detectable mutations, and 16% were ineligible due to cost, limited access, or clinical deterioration. Tumor Mutational Burden was low in 79%, intermediate in 19%, and high in 2%, and all tumors were microsatellite stable. Patients receiving NBTA had a longer median Progression-Free Survival (9 vs. 2 months; p = 0.023). Median Overall Survival was longer in the NBTA group (74 vs. 48 months), though not statistically significant (p = 0.207). Genomic alterations were subtype-specific: EWSR1 rearrangements (Ewing and Desmoplastic small round cell tumors), CDK4 and MDM2 amplifications (Liposarcoma and Osteosarcoma), TP53 and RB1 mutations (Leiomyosarcoma), CDKN2A/B deletions (Undifferentiated Pleomorphic Sarcoma and Chondrosarcoma), and SS18 rearrangements (Synovial Sarcoma). Conclusions: Genomics-guided therapy in sarcoma is feasible and impactful. Expanding timely access to molecular profiling is essential for advancing precision oncology in the MENA region. Full article

Parkinson’s disease is the second leading neurodegenerative disease of aging. For over five decades, oral levodopa has been used to manage the progressive motor deficits that are the hallmark of the disease. However, individual dose requirements are highly variable, and patients typically require increased levodopa dosage as the disease progresses, which can cause undesirable side effects. It has become increasingly apparent that the gut microbiome can have a major impact on the metabolism and efficacy of therapeutic drugs. In this Perspective, we examine recent studies highlighting the impact of metabolism by Enterococcus faecalis, a common commensal gut bacterium, on levodopa bioavailability. E. faecalis expresses a highly conserved tyrosine decarboxylase that promiscuously converts levodopa to dopamine in the gut, resulting in decreased neuronal uptake of levodopa and reduced dopamine formation in the brain. Mitochondria-targeted antioxidants conjugated to a triphenylphosphonium moiety have shown promise in transiently suppressing the growth of E. faecalis and decreasing microbial levodopa metabolism, providing an approach to modulating the microbiome that is less perturbing than conventional antibiotics. Thus, mitigating metabolism by the gut microbiota is an attractive therapeutic target to preserve and potentiate the efficacy of oral levodopa therapy in Parkinson’s disease. Full article

Liver cancer, also known as hepatocellular carcinoma (HCC), remains a major global health concern, with high mortality driven by late-stage diagnosis, limited treatment efficacy, and frequent therapeutic resistance. Matrix metalloproteinases (MMPs), a large family of zinc-dependent endopeptidases, are central to the biological processes that drive liver tumor initiation and progression. By degrading and reorganizing extracellular matrix components, MMPs facilitate tumor expansion, tissue invasion, and metastatic dissemination. In addition, these enzymes regulate the availability of growth factors, cytokines, and chemokines, thereby influencing angiogenesis, inflammation, immune cell recruitment, and the development of an immunosuppressive tumor microenvironment. Aberrant expression or activity of multiple MMP family members is consistently associated with aggressive clinicopathologic features, including vascular invasion, increased metastatic potential, and reduced patient survival, highlighting their promise as prognostic markers and actionable therapeutic targets. Past attempts to modulate MMP activity were hindered by broad inhibition profiles and dose-limiting toxicities, underscoring the need for improved specificity and delivery strategies. Recent advances in molecular design, biologics engineering, and nanotechnology have revitalized interest in MMP targeting by enabling more selective, context-dependent modulation of proteolytic activity. Preclinical studies demonstrate that carefully tuned MMP inhibition can limit tumor invasion, enhance anti-angiogenic responses, and potentially improve the efficacy of existing systemic therapies, including immuno-oncology agents. This review synthesizes current knowledge on the multifaceted roles of MMPs in HCC pathobiology and evaluates emerging therapeutic strategies that may finally unlock the clinical potential of targeting these proteases. Full article

Background and Objectives: Brain metastases frequently evolve over time in multiple waves, especially in patients with prolonged survival. Despite repeated imaging and targeted therapies, lesion-level continuity is fragmented in clinical practice, as follow-up is typically limited to pairwise MRI comparisons. The aim of the study is to assess the ability of routine narrative MRI follow-up reports to preserve longitudinal lesion identity and to reconstruct a coherent trajectory of disease evolution. Materials and Methods: We conducted a single-center, retrospective, observational study of all brain MRI examinations performed between June 2024 and June 2025 (n = 731 scans, 616 patients). All imaging reviews and longitudinal lesion tracking were performed by one board-certified neuroradiologist. Adult patients with confirmed brain metastases and at least three MRI examinations (including external studies) were included. We assessed the concordance of routine narrative MRI follow-up reports against a longitudinal review of all available MRIs and treatment timelines, which served as the reference standard. Lesion identity was considered preserved when reports explicitly recognized and linked lesions across time points, and lost when identity was omitted or ambiguous in at least one report. Results: The final cohort comprised 73 patients (477 tracked lesions). More than half of monitored lesions disappeared (42.9%) or evolved into post-treatment sequelae (9.9%), and were omitted from narrative reports, limiting retrospective recognition without prior imaging. The ability of routine reports to preserve lesion identity declined as cases became more complex. Concordance was higher in uniform evolution patterns (≈60%) but dropped to 18.2% in mixed evolution. A similar decline was seen with sequential metastatic waves, defined as new metastases appearing at distinct time points: 65.2% (1 wave), 46.7% (2 waves), 18.2% (3 waves), and complete loss of continuity when >3 waves occurred. Conclusions: Routine narrative MRI follow-up reports generally provide adequate information in simple cases with uniform lesion behavior, but tend to lose critical details as disease trajectories become more complex, particularly in heterogeneous or multi-wave disease. Even when individual lesions are identified across examinations, documentation remains fragmented and reflects only a snapshot of the disease course rather than an integrated longitudinal perspective. These findings highlight a critical vulnerability in current follow-up practices. Improving lesion-level continuity, potentially through AI-assisted tools, may enhance the accuracy, consistency, and clinical utility of MRI surveillance in patients with brain metastases. Full article

Non-alcoholic fatty liver disease (NAFLD) is a major metabolic disorder characterized by hepatic lipid accumulation, oxidative stress, and disturbance of lysosomal degradation. Central to these processes is glutathione (GSH), a key antioxidant regulating redox balance and cellular homeostasis. This study aimed to evaluate the therapeutic potential of two dietary antioxidants—astaxanthin and Garcinia indica (kokum)—in modulating hepatic redox status, lysosomal function, and metabolic gene expression in a murine model of diet-induced NAFLD. A total of 120 male Swiss Webster mice were allocated into control and steatotic groups, followed by a 90-day supplementation period with astaxanthin, kokum, or their combination. Liver tissue was collected post-supplementation for biochemical, antioxidant, and qRT-PCR analyses. Outcomes included lysosomal enzymes activities, superoxide dismutase (SOD), GSH, vitamin C, total polyphenols, DPPH radical-scavenging activity, and total antioxidant capacity (TAC). NAFLD induced marked oxidative stress, lysosomal overactivation, and alteration of antioxidant-related gene expression. Combined supplementation restored GSH, enhanced TAC, reduced lysosomal stress markers, and significantly upregulated nuclear factor erythroid 2-related factor 2 (Nfe2l2) while downregulating fatty acid synthase (FASN) and partially rescuing lipoprotein lipase (LpL). Correlation analyses revealed strong associations between antioxidant capacity, lysosomal function, and transcriptional regulation, supporting the therapeutic relevance of combined antioxidant therapy for concurrent redox and lysosomal dysregulation in NAFLD. These findings underscore the therapeutic potential of targeting redox and cellular degradation pathways with antioxidant-based interventions to re-establish hepatic metabolic balance in NAFLD and related disorders. Full article

Alzheimer’s disease (AD) is a prevalent neurodegenerative condition that progressively impairs cognitive processes, particularly learning and memory. A key pathological feature of AD involves senile plaques mainly composed of β-amyloid (Aβ) peptides, generated via the amyloidogenic pathway from amyloid precursor protein (APP) through sequential β-secretase (BACE1) and γ-secretase cleavage, positioning BACE1 inhibition as a prime therapeutic target. In this study, we applied bioassay-guided fractionation of the butanol-soluble fraction from Dryopteris crassirhizoma rhizomes, previously reported to inhibit Aβ production, to isolate and characterize Aβ-lowering constituents. Through successive chromatographic steps, nine compounds were isolated and structurally classified into flavonoids, chromones, and phloroglucinols, including epicatechin (1), β-carboxymethyl-(-)-epicatechin (2), 7-methoxy-isobiflorin (3), biflorin (4), eriodictyol (5), noreugenin (6), phloroglucinols (butyrylphloroglucinol (7), 2-propionyl-4-methylphloroglucinol (8), and 2-butyryl-4-methylphloroglucinol (9) by comprehensive spectroscopic analysis (NMR, MS, UV, IR). These compounds were assessed for effects on sAPPβ and BACE1 (β-secretase) levels by Western blot, with Aβ production quantified via ELISA in a cellular AD model (APP-CHO cells). Compounds 5–9 significantly reduced sAPPβ and BACE1 expression while potently suppressing Aβ generation. These results demonstrate that diverse constituents from D. crassirhizoma rhizomes inhibited Aβ production through BACE1 suppression, highlighting their potential as natural lead compounds for AD prevention or therapy. Full article

Ulcerative colitis (UC) is a chronic progressive inflammatory bowel disease, with evolutive potential for extension to the entire colon, development of complications and need for colectomy. Therapeutic goals in UC have moved from symptom control to more stringent outcomes such as endoscopic and histologic remission, which have been observed to correlate with improved long-term outcomes. Disease clearance, a composite endpoint simultaneously including clinical remission, endoscopic and histologic healing, has been recently proposed as the ultimate target. A treat-to-target approach, as endorsed by the STRIDE II consensus, with a tight monitoring and treatment escalation when predefined endpoints are not reached, is proposed as a strategy to achieve complete disease control. However, unlike Crohn’s disease (CD), the evidence supporting this approach for the management of UC is limited and its implementation in routine clinical practice is not widely diffused. Recent real-life data show that almost half of UC patients are not adequately controlled with current therapies according to STRIDE II criteria, due to steroid overuse, persistent signs of inflammation, active extra-intestinal manifestations and impaired quality of life. This perspective paper explores current evidence and future directions on treat-to-target strategies in UC for clinical research and practice. Full article

Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are becoming more prevalent and still lack effective disease-modifying therapies (DMTs). However, translational efficiency remains critically low. For example, a ClinicalTrials.gov analysis of AD programs (2002–2012) estimated ~99.6% attrition, while PD programs (1999–2019) achieved an overall success rate of ~14.9%. In vitro platforms are assessed, ranging from immortalized neuronal lines and primary cultures to human-induced pluripotent stem cell (iPSC)-derived neurons/glia, neuron–glia co-cultures (including neuroinflammation paradigms), 3D spheroids, organoids, and blood–brain barrier (BBB)-on-chip systems. Complementary in vivo toxin, pharmacological, and genetic models are discussed for systems-level validation and central nervous system (CNS) exposure realism. The therapeutic synthesis focuses on AD, covering symptomatic drugs, anti-amyloid immunotherapies, tau-directed approaches, and repurposed drug classes that target metabolism, neuroinflammation, and network dysfunction. This review links experimental models to translational decision-making, focusing primarily on AD and providing a brief comparative context from other NDDs. It also covers emerging targeted protein degradation (PROTACs). Key priorities include neuroimmune/neurovascular human models, biomarker-anchored adaptive trials, mechanism-guided combination DMTs, and CNS PK/PD-driven development for brain-directed degraders. Full article

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality, despite advances in pharmacological prevention and treatment. The burden of CVD necessitates implementing the treatment of risk factors including dyslipidemia. Pharmaceutical advancements and in depth understanding of pathophysiology have enabled innovative therapies targeting pathways underlying lipoprotein metabolism disorders. Angiopoietin protein-like 3 (ANGPTL3) plays a crucial role in the regulation of lipoprotein metabolism, therefore being a potential therapeutic target. Inhibition of ANGPTL3 has emerged as a new therapeutic strategy to reduce LDL-cholesterol levels independent of the LDL receptor function. Therapeutic approaches for ANGPTL3 inhibition range from monoclonal antibodies to nucleic acid therapeutics including antisense oligonucleotides and small interfering RNAs. In this review, we briefly explain the structure and mechanism of action of ANGPTL3 and discuss the therapeutic approaches for targeting ANGPTL3 in the clinical setting. We also discuss Evinacumab, a monoclonal antibody, its structure, mechanism of action, safety, tolerability, pharmacokinetics, and pharmacodynamics, as well as its clinical trial-derived results. The antisense oligonucleotides modify ANGPTL3 mRNA to inhibit protein production, and small interfering RNAs induce mRNA degradation; results from clinical trials were reviewed in detail. Finally, we discuss promising gene editing approaches including clustered regularly interspaced short palindromic repeats (CRISPR)/Cas systems. Full article

Oral infections in neutropenic patients are an underestimated but likely fatal cause of infectious complications, with clinical manifestations often diminished or absent due to immune deficiency. The evaluation and management of these infections requires a personalized multidisciplinary strategy, including prevention through pre-therapy dental assessment, individualized oral hygiene protocols, and rapid treatment of dental lesions. Antimicrobial strategies should be adapted not only to the local resistance profile and individual risk, with a priority on antibiotic stewardship and rapid de-escalation when possible, but also to individual patterns of colonization and comorbidities. Dental procedures can be performed without risk in neutropenic patients with a low complication rate, but further studies are key to stratifying risk. Future research directions include the application of artificial intelligence for infectious risk stratification, the use of salivary or microbiome biomarkers for early detection, and the development of innovative technologies for targeted antimicrobial delivery. This narrative review aims to provide an overview of the common clinical manifestations in neutropenic patients and also the potential progression of dental infections into sepsis in this category of patients. Full article

The progression of neoplastic diseases is driven by a complex interplay of biological processes, including uncontrolled proliferation, enhanced invasion, metastasis, and profound metabolic reprogramming. Among the hallmarks of cancer, as revised by Hanahan and Weinberg, the reprogramming of energy metabolism has emerged as a critical feature that enables cancer cells to meet their heightened bioenergetic and biosynthetic demands. One significant aspect of this metabolic adaptation is the accumulation of lipid droplets (LDs) dynamic, cytoplasmic organelles primarily involved in lipid storage and metabolic regulation. LDs serve as reservoirs of neutral lipids and play a multifaceted role in cancer cell physiology. Their accumulation is increasingly recognized as a marker of tumor aggressiveness and poor prognosis. By storing lipids, LDs provide a readily accessible source of energy and essential building blocks for membrane synthesis, supporting rapid cell division and growth. Moreover, LDs contribute to cellular homeostasis by modulating oxidative stress, maintaining redox balance, and regulating autophagy, particularly under nutrient-deprived or hypoxic conditions commonly found in the tumor microenvironment. Importantly, LDs have been implicated in the development of resistance to cancer therapies. They protect cancer cells from the cytotoxic effects of chemotherapeutic agents by buffering endoplasmic reticulum (ER) stress, inhibiting apoptosis, and facilitating survival pathways. The presence of LDs has been shown to correlate with increased resistance to a variety of chemotherapeutic drugs, although the precise molecular mechanisms underlying this phenomenon remain incompletely understood. Emerging evidence suggests that chemotherapy itself can induce changes in LD accumulation, further complicating treatment outcomes. Given their central role in cancer metabolism and therapy resistance, LDs represent a promising target for therapeutic intervention. Strategies aimed at disrupting lipid metabolism or inhibiting LD biogenesis have shown potential in sensitizing cancer cells to chemotherapy and overcoming drug resistance. In this review, we comprehensively examine the current understanding of LD biology in cancer, highlight studies that elucidate the link between LDs and drug resistance, and discuss emerging approaches to target lipid metabolic pathways to enhance therapeutic efficacy across diverse cancer types. Full article

Background: Behçet-like syndrome (BLS) refers to the presence of Behçet’s disease (BD) features occurring in association with distinct clinical–pathological conditions such as inborn errors of immunity, myeloproliferative disorders, infections, or drug exposure. BLS may differ clinically from BD and is increasingly recognized as a separate entity. Distinguishing BLS from primary BD is essential for appropriate management, and studying BLS may provide insights into BD pathogenesis. Objectives: To summarize clinical features, treatments, and genetic abnormalities reported in BLS, we reviewed all published cases up to January 2024. Methods: A systematic search of PubMed, Scopus, and Embase was performed using the terms “Behçet-like syndrome”, “Behçet-like disease”, and “Pseudo-Behçet disease”. We included English-language reports of patients > 12 years old with a defined underlying etiology and Behçet-like manifestations, defined by ≥2 ICBD criteria and/or gastrointestinal involvement, mucosal ulcers, thrombosis, or non-recurrent disease. Epidemiological, clinical, laboratory, histological, and treatment data were extracted and analyzed descriptively. Results: Of 679 publications, 53 met inclusion criteria, comprising 100 patients with BLS. The median age was 44 years (IQR 22–52), with a female predominance (1:2). Fifty-three percent were from non-European countries. A genetic disorder was identified in 70% of cases, while HLA-B51 was present in 10%. Frequent manifestations included skin lesions (68%), fever (56%), intestinal involvement (43%), and joint symptoms (43%). Treatments included glucocorticoids (65%), conventional DMARDs (32%), and biologics (22%), mainly anti-TNF agents. Antiviral/antibiotic therapy was used in 9% and chemotherapy in 15%. Two patients with trisomy-8 MDS underwent allogeneic stem cell transplantation. Conclusions: Diverse conditions—including monogenic diseases, immune defects, myeloproliferative disorders, infections, and drug-related reactions—can produce Behçet-like features. Our findings highlight differences in clinical expression and treatment response across BLS etiologies. Recognizing BLS is essential for appropriate management and may contribute to a deeper understanding of BD pathogenesis and future targeted therapies. Full article