Search Results (185)

Ribosome biogenesis is a highly coordinated, multi-step process that assembles the ribosomal machinery responsible for translating mRNAs into proteins. It begins with the rate-limiting step of RNA polymerase I (Pol I) transcription of the 47S ribosomal RNA (rRNA) genes within a specialised nucleolar region in the nucleus, followed by rRNA processing, modification, and assembly with ribosomal proteins and the 5S rRNA produced by Pol III. The ribosomal subunits are then exported to the cytoplasm to form functional ribosomes. This process is tightly regulated by the PI3K/RAS/MYC oncogenic network, which is frequently deregulated in many cancers. As a result, ribosome synthesis, mRNA translation, and protein synthesis rates are increased. Growing evidence supports the notion that dysregulation of ribosome biogenesis and mRNA translation plays a pivotal role in the pathogenesis of cancer, positioning the ribosome as a promising therapeutic target. In this review, we summarise current understanding of dysregulated ribosome biogenesis and function in cancer, evaluate the clinical development of ribosome targeting therapies, and explore emerging targets for therapeutic intervention in this rapidly evolving field. Full article

Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10⁻⁵). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD), a recently proposed term to replace non-alcoholic fatty liver disease (NAFLD), emphasizes the critical role of metabolic dysfunction and applies broader diagnostic criteria. Diagnosis of MAFLD requires evidence of hepatic steatosis combined with obesity, type 2 diabetes mellitus, or other metabolic dysregulation conditions, all of which significantly elevate the risk of chronic kidney disease (CKD). This review discusses the pathological mechanisms of lipid accumulation and insulin resistance in MAFLD and CKD, highlighting their mechanistic connections. Specifically, ectopic fat accumulation triggered by metabolic reprogramming, oxidative stress and inflammation induced by energy overload, modified lipids, uremic toxins, and senescence, as well as insulin resistance pathways activated by pro-inflammatory factors and lipotoxic products, collectively exacerbate simultaneous hepatic and renal injury. Moreover, interactions among hyperinsulinemia, the sympathetic nervous system, the renin–angiotensin system (RAS), and altered adipokine and hepatokine profiles further amplify insulin resistance, ectopic lipid deposition, and systemic damage. Finally, the review explores potential therapeutic strategies targeting lipid metabolism, insulin sensitivity, and RAS activity, which offer promise for dual-organ protection and improved outcomes in both hepatic and renal systems. Full article

Background/Objectives: Neurofibromatosis type 1 (NF1) and Noonan syndrome spectrum disorders (NSSD) are the most common RASopathies, resulting from germline mutations that affect the RAS-MAPK signaling pathway. Both are associated with increased risk for neurodevelopmental and psychiatric conditions, yet few studies have used structured diagnostic interviews to compare their psychiatric comorbidities. Methods: We conducted clinician-administered DSM-5 diagnostic assessments (KSADS) in 123 children with RASopathies (NF1 = 29, NSSD = 94; ages 5–15). Diagnosis prevalence was compared within each group and to population-based estimates. Results: Psychiatric diagnoses were highly prevalent, at 79.3% in NF1 and 76.6% in NSSD, with ADHD (NF1 = 72.4%, NSSD = 51.1%) and anxiety disorders (NF1 = 37.9% and NSSD = 43.6%) being the most common, rates substantially higher than those reported in general population estimates. Behavioral and sleep disorders were identified in approximately 25% of both groups. Notably, social anxiety disorder was identified in 14.9% of NSSD but not in NF1. Full-scale IQ did not significantly differ by diagnosis status. Specific anxiety disorders, elimination disorders, obsessive–compulsive disorder, and post-traumatic stress disorder were characterized, expanding the known psychiatric phenotype of RASopathies. Conclusions: Children with NF1 and NSSD demonstrate similarly high rates of ADHD, anxiety, and behavioral disorders compared to the general population; in addition, we report sleep disorders in NSSD and characterize psychiatric disorders not previously described in RASopathies. The shared psychiatric profiles may reflect the common effect of RAS-MAPK pathway dysregulation on psychiatric outcomes. These findings highlight the need for early, syndrome-informed mental health screening and intervention in the clinical care of individuals with RASopathies. Full article

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder that predominantly affects synovial joints, leading to inflammation, pain, and progressive joint damage. Despite therapeutic advancements, the molecular basis of established RA remains poorly defined. Methods: In this study, we conducted an untargeted plasma proteomic analysis using two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) in samples from RA patients and healthy controls in the discovery phase. Results: Significantly (ANOVA, p ≤ 0.05, fold change > 1.5) differentially abundant proteins (DAPs) were identified. Notably, upregulated proteins included mitochondrial dicarboxylate carrier, hemopexin, and 28S ribosomal protein S18c, while CCDC124, osteocalcin, apolipoproteins A-I and A-IV, and haptoglobin were downregulated. Receiver operating characteristic (ROC) analysis identified CCDC124, osteocalcin, and metallothionein-2 with high diagnostic potential (AUC = 0.98). Proteins with the highest selected frequency were quantitatively verified by multiple reaction monitoring (MRM) analysis in the validation cohort. Bioinformatic analysis using Ingenuity Pathway Analysis (IPA) revealed the underlying molecular pathways and key interaction networks involved STAT1, TNF, and CD40. These central nodes were associated with immune regulation, cell-to-cell signaling, and hematological system development. Conclusions: Our combined proteomic and bioinformatic approaches underscore the involvement of dysregulated immune pathways in RA pathogenesis and highlight potential diagnostic biomarkers. The utility of these markers needs to be evaluated in further studies and in a larger cohort of patients. Full article

Background: Herpes zoster (HZ), resulting from the reactivation of latent varicella-zoster virus, has been increasingly observed in individuals following COVID-19. Given the shared immunological disturbances between the two conditions, this study aimed to investigate whether HZ following COVID-19 is associated with an elevated risk of renal, infectious, and autoimmune complications. Methods: This retrospective cohort study utilized data from the TriNetX global federated health network, encompassing over 9 million adults diagnosed with COVID-19 between January 2020 and January 2022. Patients who developed HZ within one year following COVID-19 diagnosis were compared to 1:1 propensity score-matched controls without HZ. Time-to-event analyses over a three-year follow-up period were conducted to estimate the risks of major adverse kidney events (MAKE; defined as acute kidney injury, dialysis dependence, or severely reduced kidney function with eGFR <30 mL/min/1.73 m²), sepsis, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), using Kaplan–Meier survival curves and Cox proportional hazards models. Results: HZ following COVID-19 was significantly associated with increased risks of all four outcomes: MAKE (HR 1.940, 95% CI: 1.866–2.017), sepsis (HR 2.362, 95% CI: 2.250–2.479), SLE (HR 2.667, 95% CI: 2.254–3.156), and RA (HR 2.484, 95% CI: 2.267–2.730). Subgroup analyses identified older age, diabetes, impaired renal function, and elevated inflammatory markers as key risk-enhancing factors. Conclusions: HZ following COVID-19 may serve as a clinical indicator of systemic immune dysregulation and is independently associated with increased long-term risks of renal, infectious, and autoimmune sequelae. Enhanced monitoring of this high-risk population is warranted. Full article

Systemic autoimmune rheumatic diseases (SARDs), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS), are traditionally characterized by chronic inflammation and immune-mediated damage to joints and other tissues. However, many patients also experience symptoms such as widespread pain, persistent fatigue, cognitive dysfunction, and autonomic disturbances that cannot be attributed directly or entirely to peripheral inflammation or structural pathology. These conditions suggest the involvement of interactions between the nervous and immune systems, which probably include both peripheral and central components. This review summarizes the current knowledge of neurological and neuroimmune mechanisms that may contribute to these symptoms in SARDs. Glial cell activation and neuroinflammation within the central nervous system (CNS), small-fiber neuropathy (SFN) affecting peripheral nociceptive pathways, central pain sensitization, and autonomic nervous system dysfunction will be discussed. In addition, the role of molecular mediators, including cytokines, neuropeptides, and microRNAs, that could potentially modulate neuroimmune signaling will be highlighted. Integrating findings from pathology, immunology, and neuroscience, this review seeks to provide a useful framework for understanding neuroimmune dysregulation in SARDs. It also highlights the clinical relevance of these mechanisms and summarizes new directions for diagnosis and treatment. Full article

The tissue renin–angiotensin system (RAS) is a regulator of oxidative and inflammatory homeostasis by balancing its pro-oxidative/pro-inflammatory axis (angiotensin II, AngII, and AngII type-1 receptor, AT1) and its anti-oxidative/anti-inflammatory axis (AngII/AT2 and ACE2/Ang1-7/Mas receptors). An RAS dysregulation contributes to diseases, including Parkinson’s disease (PD). Immune mechanisms are involved in PD. An increase in levels of pro-oxidative/pro-inflammatory autoantibodies for AT1 (AT1-AAs) and ACE2 (ACE2-AAs) has been recently observed in PD. However, it is not known whether dysregulation of autoantibodies for AT2, MasR, and the correlations among different RAS-AAs occurs in PD. In 106 controls and 117 PD patients, we used enzyme-linked immunosorbent assays to determine correlations among serum RAS-AAs, and among RAS-AAs and pro-inflammatory cytokines and 27-hydroxycholesterol. PD patients showed an increase in MasR-AAs, and a more interconnected cluster of correlations among RAS-AAs (AT1-AA, AT2-AA, MasR-AA, ACE2-AA), changes in RAS-AA networks with sex and age, and differences in networks between RAS-AAs and major PD-related pro-inflammatory cytokines and 27-hydroxycholesterol. The association between AT1-AAs and PD remained significant even after adjustment for age and other variables. This study reveals a disease-specific network of RAS autoantibodies in PD that links immune and oxidative pathways and identifies new biomarker patterns and potential therapeutic targets. Full article

Adipose tissue is essential for the regulation of insulin sensitivity and cytokine production, which are key processes in maintaining metabolic homeostasis. Previous studies have shown a link between the renin–angiotensin system (RAS) and adipose tissue dysfunction in type 2 diabetes (T2D); however, the role of RAS in prediabetes remains underexplored. This study aimed to analyze the association between RAS components and adipose tissue dysfunction in the prediabetic state. This observational, cross-sectional study was conducted between 21/05/21 and 20/05/24 and analyzed RAS markers in plasma samples. This study was conducted at King Edward Hospital, focusing on individuals from outpatient clinics. The study included non-prediabetic (NPD), prediabetic (PD), and T2D individuals (n = 40 per group) aged 25–45 years. The participants were selected based on fasting blood glucose levels and HbA1c criteria. Plasma RAS markers and adipose function markers were measured in each participant. Primary outcomes included HOMA-IR, HbA1c, and plasma levels of ACE1, Ang II, ACE2, Ang 1-7, adiponectin, adipsin, MCP-1, and HDL. PD participants had significantly altered glycaemic control (HOMA-IR: 2.1 ± 0.4 vs. 3.9 ± 0.8; HbA1c: 4.9 ± 0.4 vs. 5.9 ± 0.6) compared to NPD. Plasma ACE1 (162.0 ± 10.55 vs. 180.3 ± 7.546) and Ang II (20.26 ± 2.404 vs. 25 ± 1.752) were elevated, while adiponectin (29.08 ± 5.72 vs. 23.22 ± 4.93) and HDL (1.01 ± 0.11 vs. 0.67 ± 0.11) were reduced in PD. Alterations in RAS manifest early in prediabetes and are associated with adipose tissue dysfunction. These findings suggest that RAS dysregulation contributes to early metabolic disturbances in prediabetes. Full article

Retinoic acid (RA) exerts biological effects through RA receptors (RARs) to regulate transcription. RA also elicits rapid, RAR-independent (noncanonical) activities mediated by Cellular RA Binding Protein 1 (CRABP1) to modulate cytosolic signaling. CRABP1 functions by forming protein complexes, named CRABP1 signalosomes, to modulate signal propagation in a cell type-specific manner. This review summarizes multiple CRABP1 signalosomes and their physiological functions. CRABP1 knockout (CKO) mice develop multiple phenotypes progressively throughout the lifespan. These include altered brain function, obesity, and insulin resistance starting at young adult stages, increased vulnerability to heart failure and altered serum exosome profiles in midlife, and motor deterioration and thyroid dysfunction (hypothyroidism) in later life. The mouse Crabp1 gene is tightly regulated by multiple epigenetic mechanisms, whereas human CRABP1 gene dysregulation is associated with multiple human diseases in which age is an important factor. Further, CRABP1 expression in human and mouse thyroid glands gradually increases with aging. This underscores the clinical relevance of CRABP1 signalosomes in maintaining health and the functions of certain cells/organ systems, especially in the thyroid and during the aging process. The CRABP1 sequence is highly conserved, likely due to its functional constraint in forming various signalosomes; its tight regulation ensures proper expression of CRABP1 required for the forming of various signalosomes critical to the health and functions of multiple cell types/organ systems. Finally, CRABP1-specific (without activating RARs) signaling pathway-selective compounds have been designed. It may be an attractive therapeutic strategy to exploit these CRABP1-specific compounds to modulate selective signaling pathways in certain disease conditions, such as thyroid dysfunction, to maximize efficacy while minimizing retinoid toxicity. Full article

Noonan syndrome (NS) is a genetic disorder characterized by distinctive craniofacial and skeletal features, short stature, mild to moderate developmental impairment, and multisystem involvement, notably affecting the cardiovascular, musculoskeletal, and endocrine systems. Although abnormalities of the bone matrix, as well as osteopenia and osteoporosis, are well recognized in individuals with NS and other RASopathies, the specific impact of RAS/MAPK pathway dysregulation on bone health remains poorly understood. Objectives: The aim of this study was to evaluate bone turnover and bone remodeling markers in a cohort of children with NS, to gain further insights into the bone status of these patients. Methods: In this cross-sectional, case-control study, we analyzed 28 children (20 males) with a molecular diagnosis of NS and 35 healthy subjects (21 males), matched by age and sex. We assessed markers of bone metabolism and bone turnover (calcium, phosphate, PTH, 25(OH)-vitamin D, osteocalcin, procollagen I N-propeptide-P1NP, bone alkaline phosphatase-BALP, C-telopeptides of type I collagen-CTX) and bone remodeling (RANKL, OPG, and sclerostin). Bone mineralization was measured at the lumbar spine (L2–L4) using dual-energy X-ray absorptiometry (DEXA). Results: Serum CTX levels were significantly higher in NS patients compared to controls (1.8 ± 0.7 vs. 1.3 ± 0.5 ng/mL, p = 0.0004). RANKL levels were higher in NS patients, although the difference did not reach statistical significance. No significant differences were found for OPG, sclerostin, or other markers of bone metabolism between patients and controls. Conclusions: Children with NS exhibit increased bone resorption, as indicated by elevated CTX levels, suggesting a potential imbalance in bone remodeling processes. Further studies are warranted to better define the impact of RAS/MAPK pathway dysregulation on bone health in this population. Full article

Malignant Triton Tumors (MTTs) are rare, high-grade malignant peripheral nerve sheath tumors (MPNSTs) frequently associated with Type 1 Neurofibromatosis (NF1). NF1, an autosomal dominant disorder, predisposes approximately 10% of affected individuals to developing MPNSTs, with 50% of these tumors occurring in NF1 patients, while others arise sporadically or in association with radiation exposure. MTTs predominantly affect anatomical regions rich in large nerves, such as the limbs, spinal root, and cranial nerves. Mediastinal presentations are exceedingly rare, posing significant diagnostic and therapeutic challenges. Current treatment strategies include surgical resection, chemotherapy, radiotherapy, and lung-sparing procedures for metastatic disease. Molecular studies of MPNSTs have revealed that NF1 mutations lead to dysregulation of the RAS signalling pathway, while epigenetic alterations (e.g., SUZ12/EED mutations) further contribute to tumor progression. Dysregulated phylogenetically conserved pathways, including Wnt/beta-catenin and non-canonical SHH signalling, play a role in sarcoma progression and Schwann cell transformation. Recent advances in miRNA research highlight their involvement in tumor invasion and progression, with dysregulated miRNA expression and chromatin remodeling contributing to the pathogenesis of these neoplasms. However, the distinct molecular profiles for MTTs remain incompletely understood. Further investigation of the genetic and epigenetic landscape is essential for improving our understanding and identifying potential therapies. Herein, we present a single-center retrospective case series of three patients with an intrathoracic triton tumor treated at our University Hospital between 2000 and 2024, serving as a starting point for future insights into MPNST pathobiology. Full article

Curcumin, a major phytochemical derived from Curcuma longa, has been shown to enhance the efficacy of chemotherapeutic agents such as doxorubicin, 5-fluorouracil, and cisplatin by overcoming drug resistance, making it a promising adjunct in the treatment of glioblastoma. However, the global gene-expression changes triggered by curcumin in glioblastoma remain underexplored. In this study, we investigated the effects of curcumin on human glioblastoma (U87 MG) cells, where it significantly reduced cell viability and proliferation in a dose- and time-dependent manner and induced apoptosis without affecting senescence. Transcriptomic analysis revealed 5036 differentially expressed genes, with pathway enrichment identifying 13 dysregulated cancer-associated pathways. Notably, curcumin modulated several key regulators involved in MAPK, Ras, TGF-β, Wnt, Cytokine, and TNF signaling pathways. Several apoptosis and cell cycle-associated genes, including PRKCG, GDF7, GDF9, GDF15, GDF5, FZD1, FZD2, FZD8, AIFM3, TP53AIP1, CRD14, NIBAN3, BOK, BCL2L10, BCL2L14, BNIPL, FASLG, GZMM, TNFSF10, TNFSF11, and TNFSF4, were significantly altered. Several pro-apoptotic and anti-BCL, cell-cycle-regulated genes were modulated following curcumin treatment, emphasizing its potential role in curcumin-mediated anti-tumor effects. This study provides insight into the molecular mechanisms underlying curcumin’s action against glioblastoma. Full article

Cardiovascular diseases and cancer are the two primary causes of mortality worldwide. Although traditionally regarded as distinct pathologies, they share numerous pathophysiological mechanisms and risk factors, including chronic inflammation, insulin resistance, obesity, and metabolic dysregulation. Notably, several cancers have been identified as closely linked to cardiovascular diseases, including lung, breast, prostate, and colorectal cancers, as well as hematological malignancies, such as leukemia and lymphoma. Additionally, renal and pancreatic cancers exhibit a significant association with cardiovascular complications, partly due to shared risk factors and the cardiotoxic effects of cancer therapies. Addressing the overlapping risk factors through lifestyle modifications—such as regular physical activity, a balanced diet, and cessation of smoking and alcohol—has proven effective in reducing both CV and oncological morbidity and mortality. Furthermore, even in patients with established cancer, structured interventions targeting physical activity, nutritional optimization, and smoking cessation have been associated with improved outcomes. Beyond lifestyle modifications, pharmacological strategies play a crucial role in the prevention of both diseases. Several cardiovascular medications, including statins, aspirin, beta-blockers, and metformin, exhibit pleiotropic effects that extend beyond their primary indications, demonstrating potential anti-neoplastic properties in preclinical and observational studies. Recently, novel therapeutic agents have garnered attention for their possible cardioprotective and metabolic benefits. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is), initially developed for managing type 2 diabetes, have shown CV and renal protective effects, alongside emerging evidence of their role in modulating cancer-related metabolic pathways. Inclisiran, a small interfering RNA targeting PCSK9, effectively lowers LDL cholesterol and may contribute to reducing CV risk, with potential implications for tumor biology. Additionally, sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, has revolutionized heart failure management by improving hemodynamic parameters and exerting anti-inflammatory effects that may have broader implications for chronic disease prevention. Given the intricate interplay between CVD and cancer, further research is essential to clarify the exact mechanisms linking these conditions and assessing the potential of CV therapies in cancer prevention. This review aims to examine shared risk factors, consider the role of pharmacological and lifestyle interventions, and emphasize crucial epidemiological and mechanistic insights into the intersection of CV and oncological health. Full article

The RAS signaling pathway is one of the most commonly dysregulated pathways in urological cancers. This pathway can be regulated by RASGAPs, which catalyze the hydrolysis of RAS-GTP to RAS-GDP. As such, the loss of RASGAPs can promote the activation of the RAS signaling pathway. Dysregulation of RASGAPs significantly contributes to the progression of urological cancers, including prostate cancer, bladder cancer, and renal cell carcinoma. Furthermore, alterations in RASGAP expression may influence sensitivity to chemotherapy, radiotherapy, and targeted therapies, suggesting their potential as therapeutic targets. Despite the challenges involved, a deeper understanding of the complexity of the RAS signaling network, along with the evolution of personalized medicine, holds promise for delivering more precise and effective treatment options targeting RASGAPs in urological cancers. Full article