Search Results (156)

Background: Nasopharyngeal carcinoma (NPC) is an epithelial malignancy arising from the nasopharyngeal mucosa. Despite treatment advances such as the use of intensity-modulated radiotherapy and immune checkpoint inhibitors, resistance remains a significant clinical challenge. Many tumours are also diagnosed at an advanced stage associated with poor prognosis. Objective: This review aims to explore the biological roles of autophagy in NPC, primarily highlighting its involvement in disease pathogenesis and treatment resistance. Methods: We performed a review of the recent literature examining the role of autophagy-related pathways in NPC pathogenesis, biomarker discovery, and therapeutic targeting. Results: Autophagy plays a dual role in NPC as it contributes to both tumour suppression and progression. It is involved in tumour initiation, metastasis, immune modulation, and treatment resistance. Autophagy-related genes such as SQSTM1, Beclin-1, and AURKA may serve as prognostic and therapeutic biomarkers. Various strategies are being investigated for their role to modulate autophagy using pharmacologic inhibitors, RNA interventions, and natural compounds. Conclusions: Further research into autophagy’s context-dependent roles in NPC may inform the development of personalised therapies and allow progress in translational and precision oncology. Full article

As the global population continues to age, the incidence of neurodegenerative diseases and neural injuries is increasing, presenting major challenges for healthcare systems. Due to the brain’s limited regenerative capacity, there is an urgent need for strategies that promote neuronal repair and functional integration. Brain-derived neurotrophic factor (BDNF) is a key regulator of synaptic plasticity and neuronal development. In this study, we investigated whether constitutive BDNF expression in human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) enhances their neurogenic and integrative potential in vitro. We found that NPCs engineered to overexpress BDNF produced neuronal cultures with increased numbers of mature and spontaneously active neurons, without altering the overall structure or organization of functional networks. Furthermore, BDNF-expressing neurons exhibited significantly greater axonal outgrowth, including directed axon extension in a compartmentalized microfluidic system, suggesting a chemoattractive effect of localized BDNF secretion. These effects were comparable to those observed with the early supplementation of recombinant BDNF. Our results demonstrate that sustained BDNF expression enhances neuronal maturation and axonal projection without disrupting network integrity. These findings support the use of BDNF not only as a therapeutic agent to improve cell therapy outcomes but also as a tool to accelerate the development of functional neural networks in vitro. Full article

Familial hypercholesterolemia (FH) is a genetic disorder marked by significantly elevated levels of low-density lipoprotein cholesterol (LDL-C) since childhood, substantially increasing the risk of premature atherosclerosis and cardiovascular disease. While dysfunction of hepatic LDL-C receptors is the main underlying cause, the gastrointestinal tract plays a key role in cholesterol homeostasis and represents an important therapeutic target. Inhibition of intestinal cholesterol absorption has emerged as an effective strategy in the management of pediatric FH, particularly in patients for whom statins may not be the ideal first-line treatment. Ezetimibe, an inhibitor of the Niemann-Pick C1-like 1 (NPC1L1) protein, has been shown to reduce LDL-C levels in children with FH, with a greater efficacy observed when used in combination with statins. Bile acid sequestrants also enhance cholesterol excretion but are often limited by gastrointestinal side effects, while dietary interventions, such as phytosterol supplementation and fiber-enriched diets, provide additional benefits in lowering LDL-C and are generally well tolerated. Emerging therapies, including microbiota-targeted strategies and novel cholesterol absorption inhibitors, show promise for expanding future treatment options. This review explores the mechanisms of intestinal cholesterol absorption and their relevance to pediatric FH. We examine key pathways, including dietary cholesterol uptake through NPC1L1, bile acid reabsorption, and cholesterol efflux mediated by ATP-binding cassette transporters, while also discussing clinical and experimental evidence on pharmacological and dietary interventions that modulate these pathways. A deeper understanding of cholesterol metabolism, the emerging role of the gut microbiota, and innovative therapeutic agents can support the development of more effective and personalized approaches to the treatment of children with FH. Full article

Background: Adaptive radiation therapy (ART) can improve prognosis for nasopharyngeal carcinoma (NPC) patients. However, the inter-individual variability in anatomical changes, along with the resulting extension of treatment duration and increased workload for the radiologists, makes the selection of eligible patients a persistent challenge in clinical practice. The purpose of this study was to predict eligible ART candidates prior to radiation therapy (RT) for NPC patients using a classification neural network. By leveraging the fusion of medical imaging and clinical data, this method aimed to save time and resources in clinical workflows and improve treatment efficiency. Methods: We collected retrospective data from 305 NPC patients who received RT at Hong Kong Queen Elizabeth Hospital. Each patient sample included pre-treatment computed tomographic (CT) images, T1-weighted magnetic resonance imaging (MRI) data, and T2-weighted MRI images, along with clinical data. We developed and trained a novel multi-modal classification neural network that combines ResNet-50, cross-attention, multi-scale features, and clinical data for multi-modal fusion. The patients were categorized into two labels based on their re-plan status: patients who received ART during RT treatment, as determined by the radiation oncologist, and those who did not. Results: The experimental results demonstrated that the proposed multi-modal deep prediction model outperformed other commonly used deep learning networks, achieving an area under the curve (AUC) of 0.9070. These results indicated the ability of the model to accurately classify and predict ART eligibility for NPC patients. Conclusions: The proposed method showed good performance in predicting ART eligibility among NPC patients, highlighting its potential to enhance clinical decision-making, optimize treatment efficiency, and support more personalized cancer care. Full article

Human induced pluripotent stem cells (iPSCs) offer immense potential as a source for cell therapy in spinal cord injury (SCI) and other diseases. The development of hypoimmunogenic, universal cells that could be transplanted to any recipient without requiring a matching donor could significantly enhance their therapeutic potential and accelerate clinical translation. To create off-the-shelf hypoimmunogenic cells, we used CRISPR-Cas9 to delete B2M (HLA class I) and CIITA (master regulator of HLA class II). Double-knockout (DKO) iPSC-derived neural progenitor cells (NPCs) evaded T-cell-mediated immune rejection in vitro and after grafting into the injured spinal cord of athymic rats and humanized mice. However, loss of HLA class I heightened susceptibility to host natural killer (NK) cell attack, limiting graft survival. To counter this negative effect, we engineered DKO NPCs to overexpress macrophage migration inhibitory factor (MIF), an NK cell checkpoint ligand. MIF expression markedly reduced NK cell-mediated cytotoxicity and improved long-term engraftment and integration of NPCs in the animal models for spinal cord injury. These findings demonstrate that MIF overexpression, combined with concurrent B2M and CIITA deletion, generates hiPSC neural derivatives that escape both T- and NK-cell surveillance. This strategy provides a scalable route to universal donor cells for regenerative therapies in SCI and potentially other disorders. Full article

Background: The geriatric nutritional risk index (GNRI), a composite metric of serum albumin and body weight, has emerged as a prognostic tool in various cancers. However, its relevance in nasopharyngeal carcinoma (NPC) patients treated with volumetric modulated arc therapy (VMAT) remains unexplored. The aim of this study was to assess the effect of the GNRI in the prediction of the prognosis of nasopharyngeal carcinoma in the era of VMAT. Methods: This retrospective study analyzed 498 newly diagnosed, non-metastatic NPC patients treated with VMAT between 2010 and 2011. The GNRI was calculated using serum albumin and body weight ratios, with receiver operating characteristic (ROC) curve analysis determining its optimal prognostic cutoff. Patients were stratified into training (70%) and validation (30%) cohorts. Cox regression identified independent prognostic factors, which were integrated into a nomogram predicting 3- and 5-year overall survival (OS). Model performance was assessed via the concordance index (C-index), calibration curves, and decision curve analysis (DCA). Results: In the study, 348 patients were included in the training cohort and 150 patients were included in the validation cohort according to a ratio of 7:3. The median follow-up was 68 months, with 5-year OS rates of 79.3%. A GNRI > 102 independently predicted improved survival (HR = 0.64; p = 0.044), alongside tumor volume, age, and N-stage. The nomogram demonstrated strong discrimination (C-index: 0.757–0.762 for training; 0.737–0.744 for validation) and calibration, aligning closely with observed survival. DCA confirmed superior clinical utility over default strategies. NPC patients treated with VMAT with a high GNRI, female sex, and a lower N-stage exhibited significantly better OS (p < 0.05). Conclusions: The GNRI is a robust prognostic marker for NPC patients receiving VMAT, reflecting the interplay of nutrition, inflammation, and treatment response. The validated nomogram provides a practical tool for individualized risk stratification, enhancing clinical decision-making in the era of precision radiotherapy. Full article

Epstein–Barr virus (EBV), a double-stranded DNA virus, is implicated in nasopharyngeal carcinoma (NPC), with particularly high incidence in regions such as southern China and Hong Kong. Although NPC is typically treated with radio- and chemotherapy, outcomes remain poor for advanced-stage diagnoses, highlighting the need for targeted therapies. This study explores the potential of CRISPR/CRISPR-associated protein 13 (Cas13) technology to target essential EBV RNA in NPC cells. Previous research demonstrated that CRISPR/Cas9 could partially reduce EBV load, but suppression was incomplete. Here, the combination of CRISPR/Cas13 with CRISPR/Cas9 shows enhanced viral clearance. Long-term EBNA1 suppression via CRISPR/Cas13 reduced the EBV genome, improved CRISPR/Cas9 effectiveness, and identified suitable AAV serotypes for delivery. Furthermore, cotreatment increased NPC cell sensitivity to 5-fluorouracil and cisplatin. These findings underscore the potential of CRISPR/Cas13 as an anti-EBV therapeutic approach, effectively targeting latent EBV transcripts and complementing existing treatments. The study suggests a promising new direction for developing anti-EBV strategies, potentially benefiting therapies for NPC and other EBV-associated malignancies. Full article

Background: Tegafur–uracil (UFT), an oral fluoropyrimidine developed in Asia, has been investigated as a maintenance or adjuvant therapy in various malignancies. Its use in head and neck cancers, however, remains limited to small retrospective studies, primarily from East Asia. Given the need for cost-effective maintenance strategies in resource-limited settings, we conducted an exploratory systematic review to evaluate the clinical utility of UFT in non-metastatic head and neck squamous cell carcinoma (HNSCC) and nasopharyngeal carcinoma (NPC). Methods: We systematically searched PubMed, EMBASE, and Cochrane Library from inception through 1 May 2025 for retrospective cohort studies evaluating UFT after definitive therapy in non-metastatic HNSCC or NPC. Study selection followed PRISMA guidelines. Given the heterogeneity of included studies, we performed a structured narrative synthesis using the SWiM (Synthesis Without Meta-analysis) framework to summarize survival outcomes, treatment settings, and clinical contexts. Results: Seven retrospective studies (four HNSCC, three NPC) involving 508 patients were included. UFT was generally administered at 300–400 mg/day for 6–12 months. Across studies, UFT use was associated with favorable disease-free and overall survival trends in high-risk subgroups, including patients with extranodal extension and persistent EBV DNA. Treatment adherence and toxicity profiles were acceptable. Conclusions: While the evidence remains limited and heterogeneous, this review highlights recurring signals of benefit associated with UFT maintenance therapy in selected high-risk patients. Prospective trials are warranted to confirm these findings and better define a possible role of UFT in maintenance therapy in some advanced non-metastatic HNSCC and NPC. Full article

Background: Nasopharyngeal carcinoma (NPC) is a rare head and neck cancer arising from the mucosal lining of the nasopharynx, for which systemic therapeutic options remain scarce, reflecting the limited characterization of its genomic profile. This study utilized a large patient-level genomic repository to characterize genetic alterations, identify potential therapeutic targets, and improve disease modeling in NPC. Methods: A retrospective analysis of NPC samples was conducted using the AACR Project GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, tumor mutational burden, and chromosomal copy number variations, with significance set at p < 0.05. Results: Frequent mutations were identified in KMT2D (20%), TP53 (16%), CYLD (9.6%), NFKBIA (6.4%), and PIK3CA (5.6%), implicating the p53, NF-κB, and PI3K pathways in NPC development. Notably, significantly distinct mutational profiles were observed based on both sex and race, with female patients exhibiting higher frequencies of PIK3C2G, ETV6, and CDKN1B mutations and non-Asian patients showing enrichment in KDM5A, CCND2, and TP53 mutations. Conclusions: This study presents a detailed genomic profile of NPC, identifying key mutations within established cancer-associated pathways. The identification of frequently mutated pathways (p53, NF-κB, and PI3K) suggests potential targets for novel therapies. Furthermore, distinct mutational landscapes in female and Asian NPC patients offer possibilities for precision therapeutic interventions. Full article

Epstein–Barr virus (EBV), a ubiquitous human herpesvirus, has been robustly linked to the pathogenesis of nasopharyngeal carcinoma (NPC). The mechanism of EBV-induced NPC involves complex interactions between viral proteins and host cell pathways. This review aims to comprehensively outline the mechanism of EBV-induced NPC and the latest advances in targeted EBV vaccines for prophylaxis and treatment. This review explores the intricate molecular mechanisms by which EBV contributes to NPC pathogenesis, highlighting viral latency, genetic and epigenetic alterations, and immune evasion strategies. It emphasizes the pivotal role of key viral proteins, including EBNA1, LMP1, and LMP2A, in carcinogenesis. Subsequently, the discussion shifts towards the development of targeted EBV vaccines, including preventive vaccines aimed at preventing primary EBV infection and therapeutic vaccines aimed at treating diagnosed EBV-related NPC. The review underscores the challenges and future directions in the field, stressing the importance of developing innovative vaccine strategies and combination therapies to improve efficacy. This review synthesizes current insights into the molecular mechanisms of EBV-induced NPC and the development of EBV-targeted vaccines, highlighting the potential use of mRNA vaccines for NPC treatment. Full article

Background/Objective: Vascular abnormalities are the primary histological changes in individuals undergoing radiotherapy for nasopharyngeal carcinoma (NPC). We sought to validate the hypothesis that the duration post-radiotherapy is linked to the progression of carotid intima-media thickness (IMT) and further explored its connection with mortality. Methods: Twenty-nine NPC patients who underwent radiotherapy and seventeen healthy controls were examined by carotid ultrasound for measurement of IMT and carotid plaque score at the common carotid artery (CCA), carotid bifurcation, and internal carotid artery, with follow-ups more than 6 years. Results: Initially, there was no discernible difference in internal carotid IMT between NPC patients and normal controls. However, a noteworthy increase in carotid IMT was observed after 6 years of radiotherapy (p < 0.0001). The carotid plaque score in NPC patients significantly exceeded that of the control group after 6 years (p < 0.0001). Linear regression demonstrated a positive correlation between carotid IMT and the duration post-radiotherapy. Logistic regression suggested that age and carotid IMT were predictors of mortality in NPC patients. Conclusions: Our study substantiates the positive correlation between carotid IMT and the duration of follow-up after radiotherapy. It found an increase in carotid IMT and plaque formation six years after radiotherapy compared to the control group. An increased carotid IMT may be correlated to an increased mortality rate and needs to be explored in future studies. Consequently, we recommend regular follow-up carotid ultrasonography for NPC patients undergoing radiation therapy. Full article

In 2024, the FDA approved fifty novel drugs, including four peptides and oligonucleotides (TIDEs) (two pepTIDEs and two oligonucleoTIDEs), highlighting their increasing importance as effective alternatives to traditional drug classes. TIDEs provide essential therapies for complex diseases, such as genetic disorders, rather than merely addressing symptoms. In addition to oligonucleotide therapeutics for various genetic conditions, peptides became the first approved treatment for Rett Syndrome in 2023 and were also used to treat Niemann–Pick disease type C (NPC) in 2024. Interestingly, among the strategies employed in recent approvals to enhance stability and/or delivery, the prodrug approach, exemplified by palopegteriparatide and pegulicianine, is emerging as a more targeted and precise therapeutic strategy. Additionally, the Enhanced Stabilization Chemistry (ESC)-GalNAc platform has been expanded for hepatic delivery of a new oligonucleotide drug, olezarsen. Furthermore, novel modifications to the ribose moiety in oligonucleotides, such as the 3′-amino substitution in imetelstat, enhance their stability. This review examines the TIDES approved in 2024 based on their chemical structure, medical targets, modes of action, administration routes, and common adverse effects. In addition, it highlights how the prodrug strategy has improved targeting efficiency and extended the half-lives of the active drugs. Full article

Elevated plasma low-density lipoprotein cholesterol (LDL-C) is associated with an increased risk for atherosclerosis and development of cardiovascular disease. An elevated plasma LDL-C concentration is the result of enhanced C synthesis, C absorption, and/or altered C homeostasis. Plasma LDL-C lowering can be achieved using pharmaceutical means. Statin therapy inhibits endogenous C synthesis and leads to a mean 40% LDL-C reduction. Ezetimibe inhibits C absorption and achieves an average 20% LDL-C reduction with a 10 mg daily intake. Phytosterol therapy is established by dietary supplements enriched in phytosterols and/or phytostanols. A dosage of 2 to 3 g a day reduces C absorption and leads to an average 10% LDL-C reduction. This dosage expresses a 10-fold increased daily intake for phytosterols or a 100-fold increased intake of phytostanols. Phytosterol- and -stanol-enriched dietary supplements are freely available in the supermarket. The majority of consumers may be healthy subjects with a plasma LDL-C in the normal range. Scientific evidence reveals that increased phytosterol intake may be associated with the development of atherosclerosis. The degree of increased risk is dependent on the patient’s genetic polymorphisms in NPC1L1 and ABCG5/G8 transport proteins as well as on the established risk reduction due to LDL-C lowering. Subjects with a normal or only slightly elevated LDL-C have only minimal LDL-C lowering and lack the compensation for the potential increased risk for atherosclerosis by phytosterols. Full article

Viral infections such as human papillomavirus (HPV) and Epstein–Barr virus (EBV) play a critical role in the onset of oropharyngeal (OPC) and nasopharyngeal cancer (NPC), respectively. Despite advancements in targeted therapies and immunotherapies, in the recurrent/metastatic setting, these tumors remain incurable diseases with poor prognosis. The development of therapeutic tumor vaccines, utilizing either neoantigens or oncoviral antigens, represents a promising addition to the cancer immunotherapy arsenal. Research on vaccine-based immunotherapy for OPC and NPC focuses on targeting viral antigens, particularly HPV E6/E7 and EBV EBNA1/LMP2. The potential for vaccine platforms, including peptide-based, DNA, RNA, and viral vector-based vaccines, to induce durable immune responses against viral antigens is reported. The early-phase clinical trials evaluating vaccine-based therapies for HPV-related OPC and EBV-related NPC revealed safety and preliminary signs of efficacy; however, further clinical trials are crucial for validation. This review provides an overview of the current landscape of vaccine-based strategies for HPV-related OPC and EBV-related NPC, discussing their biological mechanisms and immune processes involved in anti-HPV and anti-EBV vaccine treatments, with a particular focus on the immune factors that influence these therapies. Full article

DHDDS (dehydrodolichol diphosphate synthetase) and NgBR (Nogo-B Receptor) collectively form an enzymatic complex important for the synthesis of dolichol, a key component of protein N-glycosylation. Mutations in DHDDS and the gene encoding NgBR (NUS1) are associated with neurodevelopmental disorders that clinically present with epilepsy, motor impairments, and developmental delay. Previous work has demonstrated both DHDDS and NgBR can also interact with NPC2 (Niemann-Pick C (NPC) type 2), a protein which functions to traffic cholesterol out of the lysosome and, when mutated, can cause a lysosomal storage disorder (NPC disease) characterised by an accumulation of cholesterol and glycosphingolipids. Abnormal cholesterol accumulation has also been reported in cells from both individuals and animal models with mutations in NUS1, and suspected lipid storage has been shown in biopsies from individuals with mutations in DHDDS. Our findings provide further evidence for overlap between NPC2 and DHDDS disorders, showing that DHDDS patient fibroblasts have increased lysosomal volume, store cholesterol and ganglioside GM1, and have altered lysosomal Ca²⁺ homeostasis. Treatment of DHDDS cells, with the approved NPC small molecule therapy, miglustat, improves these disease-associated phenotypes, identifying a possible therapeutic option for DHDDS patients. These data suggest that treatment options currently approved for NPC disease may be translatable to DHDDS/NUS1 patients. Full article