Cancer stem cells (CSCs) are now recognized as one of the major root causes of therapy failure and tumor recurrence in hepatocellular carcinoma (HCC). Early studies in the field focused primarily on ...the intrinsic regulators of CSC maintenance, but in recent years, mounting evidence has demonstrated the presence and role of extrinsic regulators in the tumor microenvironment (TME) in the control of liver CSCs. In addition to direct interaction with cellular components, noncellular components, including the extracellular matrix, hypoxia, nutrient deprivation, and secreted molecules within the tumor stroma and hepatitis viruses, also play a critical role in shaping the CSC niche. In this review, we highlight how various noncellular components in the TME play a role in regulating CSCs and how CSCs secrete components to interact with the TME to generate their own niche, working hand in hand to drive tumor physiology in HCC. In addition, we describe the potential clinical applications of these findings and propose perspectives on future research of noncellular components in the liver CSC niche.
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BFBNIB, FZAB, GIS, IJS, KILJ, OILJ, SBCE, SBMB, UPUK
Abstract
Tumor lineage plasticity, considered a hallmark of cancer, denotes the phenomenon in which tumor cells co-opt developmental pathways to attain cellular plasticity, enabling them to evade ...targeted therapeutic interventions. However, the underlying molecular events remain largely elusive. Our recent study identified CD133/Prom1 in hepatocellular carcinoma (HCC) tumors to mark proliferative tumor-propagating cells with cancer stem cell-like properties, that follow a dedifferentiation trajectory towards a more embryonic state. Here we show SPINK1 to strongly associate with CD133 + HCC, and tumor dedifferentiation. Enhanced transcriptional activity of SPINK1 is mediated by promoter binding of ELF3, which like CD133, is found to increase following 5-FU and cisplatin treatment; while targeted depletion of CD133 will reduce both ELF3 and SPINK1. Functionally, SPINK1 overexpression promotes tumor initiation, self-renewal, and chemoresistance by driving a deregulated EGFR-ERK-CDK4/6-E2F2 signaling axis to induce dedifferentiation of HCC cells into their ancestral lineages. Depleting SPINK1 function by neutralizing antibody treatment or in vivo lentivirus-mediated
Spink1
knockdown dampens HCC cancer growth and their ability to resist chemotherapy. Targeting oncofetal SPINK1 may represent a promising therapeutic option for HCC treatment.
Nasopharyngeal carcinoma (NPC) is an Epstein‐Barr virus (EBV)‐associated epithelial malignancy. The high expression of BART‐miRNAs (miR‐BARTs) during latent EBV infection in NPC strongly supports ...their pathological importance in cancer progression. Recently, we found that several BART‐miRNAs work co‐operatively to modulate the DNA damage response (DDR) by reducing Ataxia‐telangiectasia‐mutated (ATM) activity. In this study, we further investigated the role of miR‐BARTs on DDR. The immunohistochemical study showed that the DNA repair gene, BRCA1, is consistently down‐regulated in primary NPCs. Using computer prediction programs and a series of reporter assays, we subsequently identified the negative regulatory role of BART2‐3p, BART12, BART17‐5p and BART19‐3p in BRCA1 expression. The ectopic expression of these four miR‐BARTs suppressed endogenous BRCA1 expression in EBV‐negative epithelial cell lines, whereas BRCA1 expression was enhanced by repressing endogenous miR‐BARTs activities in C666‐1 cells. More importantly, suppressing BRCA1 expression in nasopharyngeal epithelial cell lines using miR‐BART17‐5p and miR‐BART19‐3p mimics reduced the DNA repair capability and increased the cell sensitivity to the DNA‐damaging chemotherapeutic drugs, cisplatin and doxorubicin. Our findings suggest that miR‐BARTs play a novel role in DDR and may facilitate the development of effective NPC therapies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
HCC is an aggressive disease with poor clinical outcome. Understanding the mechanisms that drive cancer stemness, which we now know is the root cause of therapy failure and tumor recurrence, is ...fundamental for designing improved therapeutic strategies. This study aims to identify molecular players specific to CD133 + HCC to better design drugs that can precisely interfere with cancer stem cells but not normal stem cell function.
Transcriptome profiling comparison of epithelial-specific "normal" CD133 + cells isolated from fetal and regenerating liver against "HCC" CD133 + cells isolated from proto-oncogene-driven and inflammation-associated HCC revealed preferential overexpression of SERPINA12 in HCC but not fetal and regenerating liver CD133 + cells. SERPINA12 upregulation in HCC is tightly associated with aggressive clinical and stemness features, including survival, tumor stage, cirrhosis, and stemness signatures. Enrichment of SERPINA12 in HCC is mediated by promoter binding of the well-recognized β-catenin effector TCF7L2 to drive SERPINA12 transcriptional activity. Functional characterization identified a unique and novel role of endogenous SERPINA12 in promoting self-renewal, therapy resistance, and metastatic abilities. Mechanistically, SERPINA12 functioned through binding to GRP78, resulting in a hyperactivated AKT/GSK3β/β-catenin signaling cascade, forming a positive feed-forward loop. Intravenous administration of rAAV8-shSERPINA12 sensitized HCC cells to sorafenib and impeded the cancer stem cell subset in an immunocompetent HCC mouse model.
Collectively, our findings revealed that SERPINA12 is preferentially overexpressed in epithelial HCC CD133 + cells and is a key contributor to HCC initiation and progression by driving an AKT/β-catenin feed-forward loop.
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BFBNIB, FZAB, GIS, IJS, KILJ, OILJ, SBCE, SBMB, UPUK
Virtual reality (VR) technology is one of the promising directions for rehabilitation, especially cognitive rehabilitation. Previous studies demonstrated successful rehabilitation in motor, ...cognitive, and sensorial functions using VR. The objective of this review is to summarize the current designs and evidence on immersive rehabilitation interventions using VR on cognitive- or behavioral-related eating disorders, which was mapped using a VREHAB framework. Two authors independently searched electronic databases, including PubMed, Web of Science, Scopus, CINAHL, EMBASE, and Cochrane Library. Ten (
= 10) articles were eligible for review. Treatments for anorexia nervosa and binge eating disorder/bulimia nervosa were reported through enhanced/experimental cognitive behavior therapy (ECT), cue exposure therapy (CET), and body exposure therapy (BET) via the virtual environment. Some studies reported that the VR effects were superior or comparable to traditional treatments, while the effects may last longer using VR technology. In addition, VR was perceived as acceptable and feasible among patients and therapists and could be valuable for supplementing existing therapies, relieving manpower and caregiver burdens. Future studies may consider incorporating haptic, smell, and biofeedback to improve the experience, and thus the effects of the treatments for the users.
Aspiration caused by dysphagia is a prevalent problem that causes serious health consequences and even death. Traditional diagnostic instruments could induce pain, discomfort, nausea, and radiation ...exposure. The emergence of wearable technology with computer-aided screening might facilitate continuous or frequent assessments to prompt early and effective management. The objectives of this review are to summarize these systems to identify aspiration risks in dysphagic individuals and inquire about their accuracy. Two authors independently searched electronic databases, including CINAHL, Embase, IEEE Xplore
Digital Library, PubMed, Scopus, and Web of Science (PROSPERO reference number: CRD42023408960). The risk of bias and applicability were assessed using QUADAS-2. Nine (n = 9) articles applied accelerometers and/or acoustic devices to identify aspiration risks in patients with neurodegenerative problems (e.g., dementia, Alzheimer's disease), neurogenic problems (e.g., stroke, brain injury), in addition to some children with congenital abnormalities, using videofluoroscopic swallowing study (VFSS) or fiberoptic endoscopic evaluation of swallowing (FEES) as the reference standard. All studies employed a traditional machine learning approach with a feature extraction process. Support vector machine (SVM) was the most famous machine learning model used. A meta-analysis was conducted to evaluate the classification accuracy and identify risky swallows. Nevertheless, we decided not to conclude the meta-analysis findings (pooled diagnostic odds ratio: 21.5, 95% CI, 2.7-173.6) because studies had unique methodological characteristics and major differences in the set of parameters/thresholds, in addition to the substantial heterogeneity and variations, with sensitivity levels ranging from 21.7% to 90.0% between studies. Small sample sizes could be a critical problem in existing studies (median = 34.5, range 18-449), especially for machine learning models. Only two out of the nine studies had an optimized model with sensitivity over 90%. There is a need to enlarge the sample size for better generalizability and optimize signal processing, segmentation, feature extraction, classifiers, and their combinations to improve the assessment performance.
(https://www.crd.york.ac.uk/prospero/), identifier (CRD42023408960).
An experiment coupled with a computational analysis was conducted to investigate the effectiveness of surgical masks, which include KF94 and ASTM Level 1, in an indoor environment. The KF94 mask ...sample shows the highest filtration efficiency (99.9%) in the analysis. The simulation is consistent with the experimental results as the concentration of sodium chloride (NaCl) droplets is ＜ 4% on average in the room. The ultraviolet-C (UVC) irradiation and dry heating samples are shown to retain the highest filtration efficiencies (＞ 97%) after 3 disinfection treatment cycles. All methods (boiling, steaming, ethanol treatment, and dry heating) effectively reduce the S. aureus load by 99.99%. The UVC irradiation shows exposure to 450 μW cm^(-2) for 10 minutes can effectively eliminate all S. aureus on the mask materials. Simulation shows the reduction in overall NaCl and carbon dioxide (CO_2) levels is directly proportional to the filtration efficiency and the effectiveness of reused masks is also directly proportional to the filtration efficiency. The proxy indicator (CO_2) for aerosol particles demonstrates that very fine respiratory droplets can penetrate the mask after reaching a steady state. The CO_2 concentration increase shows that aerosol particles are accumulated under adequate ventilation and further pose the risk of infection. The NaCl droplets (2%) simulation shows that respiratory droplets have infiltrated the mask, but the mask demonstrates a higher ability to block the NaCl droplets and prevent their penetration. The findings suggest a need to revise the existing regulation of the control policy.
Biomechanical studies play an important role in understanding the pathophysiology of sleep disorders and providing insights to maintain sleep health. Computational methods facilitate a versatile ...platform to analyze various biomechanical factors in silico, which would otherwise be difficult through in vivo experiments. The objective of this review is to examine and map the applications of computational biomechanics to sleep-related research topics, including sleep medicine and sleep ergonomics. A systematic search was conducted on PubMed, Scopus, and Web of Science. Research gaps were identified through data synthesis on variants, outcomes, and highlighted features, as well as evidence maps on basic modeling considerations and modeling components of the eligible studies. Twenty-seven studies (n = 27) were categorized into sleep ergonomics (n = 2 on pillow; n = 3 on mattress), sleep-related breathing disorders (n = 19 on obstructive sleep apnea), and sleep-related movement disorders (n = 3 on sleep bruxism). The effects of pillow height and mattress stiffness on spinal curvature were explored. Stress on the temporomandibular joint, and therefore its disorder, was the primary focus of investigations on sleep bruxism. Using finite element morphometry and fluid–structure interaction, studies on obstructive sleep apnea investigated the effects of anatomical variations, muscle activation of the tongue and soft palate, and gravitational direction on the collapse and blockade of the upper airway, in addition to the airflow pressure distribution. Model validation has been one of the greatest hurdles, while single-subject design and surrogate techniques have led to concerns about external validity. Future research might endeavor to reconstruct patient-specific models with patient-specific loading profiles in a larger cohort. Studies on sleep ergonomics research may pave the way for determining ideal spine curvature, in addition to simulating side-lying sleep postures. Sleep bruxism studies may analyze the accumulated dental damage and wear. Research on OSA treatments using computational approaches warrants further investigation.
Nasopharyngeal carcinoma (NPC) is a common malignancy endemic in South‐East Asia. Functional magnetic resonance imaging (fMRI) has been used for prompt detection of treatment response before visible ...morphological changes in NPC treatment. Among different fMRI techniques, diffusion‐weighted imaging (DWI) and dynamic contrast enhancement (DCE) were proved to be more successful in NPC treatment response assessment whilst the application of magnetic resonance spectroscopy (MRS) remains questionable. Apart from discussing the imaging technique, time points for post‐treatment response assessments are recommended. Four instead of three months is recommended for prompt identification of non‐ or partial responders and 6–9 months post‐treatment multiparametric MRI is also recommended for effective confirmation of complete responding individuals to avoid residual disease. For future advancement, in addition to the post‐treatment response assessment, continuous or longitudinal assessment on the treatment response with the use of magnetic resonance simulator (MR‐simulator) or magnetic resonace imaging guided linear accelerator (MR‐Linac) tailor‐made for radiotherapy (RT) maybe feasible. Longitudinal assessments or predictive radiomics modeling allow spotting out the possibility of treatment failure before the completion or even before the start of treatments. Adaptive instead of salvage treatments can then be prepared, thus reducing the damage and side effects of consecutive cytotoxic treatments.
This paper summarized three functional magnetic resonance imaging techniques mostly discussed and applied in the field of radiotherapy treatment assessment of nasopharyngeal carcinoma, including diffusion‐weighted imaging, dynamic contrast enhancement, and magnetic resonance spectroscopy.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK, VSZLJ
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