Search Results (3,185)

Background/Objectives: The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand crosslinks and maintenance of genomic stability. Germline loss of FA pathway function in the inherited Fanconi anemia syndrome leads to increased DNA damage and a range of clinical phenotypes, including a heightened risk of head and neck squamous cell carcinoma (HNSCC). Non-synonymous FA gene mutations are also observed in up to 20% of sporadic HNSCCs. The mechanistic target of rapamycin (mTOR) is known to stimulate cell growth, anabolic metabolism including protein synthesis, and survival following genotoxic stress. Methods/Results: Here, we demonstrate that FA− deficient (FA−) HNSCC cells exhibit elevated intracellular amino acid levels, increased total protein content, and an increase in protein synthesis indicative of enhanced translation. These changes are accompanied by hyperactivation of the mTOR effectors translation initiation factor 4E Binding Protein 1 (4E-BP1) and ribosomal protein S6. Treatment with the mTOR inhibitor rapamycin reduced the phosphorylation of these targets and blocked translation specifically in FA− cells but not in their isogenic FA− proficient (FA+) counterparts. Rapamycin-mediated mTOR inhibition sensitized FA− but not FA+ cells to rapamycin under nutrient stress, supporting a therapeutic metabolism-based vulnerability in FA− cancer cells. Conclusions: These findings uncover a novel role for the FA pathway in suppressing mTOR signaling and identify mTOR inhibition as a potential strategy for targeting FA− HNSCCs. Full article

The management of acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, critically relies on thiopurine therapy, such as 6-mercaptopurine (6-MP), during the maintenance phase. However, significant inter-individual response variety and high risk of myelosuppression often disrupt therapy efficacy. Pharmacogenetics offer crucial strategies to personalized therapy. While thiopurine methyltransferase (TPMT) was initially the primary focus, the discovery of nudix hydrolase 15 (NUDT15) appears as a more comprehensive determinant of thiopurine intolerance. This review aims to consolidate and critically evaluate the advancement achieved in unraveling the biological mechanism and clinical significance of NUDT15 pharmacogenetics in thiopurine therapy. Foundational studies showed the vital role of NUDT15 in the detoxification of active thiopurines, with common genetic variants (for instance, p. Arg139Cys) significantly disrupting its activity, leading to the accumulation of toxic metabolites. Observational studies consistently associated NUDT15 variants with severe myelosuppression, notably in Asian populations. Recent randomized controlled trials (RCTs) confirmed that NUDT15 genotype-guided dosing effectively reduces thiopurine-induced toxicity without interfering with the therapeutic outcome. Despite these advancements, challenges remain present, including the incomplete characterization of rare variants, limited data in the diverse Asian populations, and the need for standardized integration with metabolite monitoring. In conclusion, NUDT15 pharmacogenetics is essential for improving patient safety and thiopurine dosage optimization in the treatment of ALL. For thiopurine tailored medicine to be widely and fairly implemented, future research should focus on increasing genetic data across different populations, improving the dose adjustment algorithm, and harmonizing therapeutic guidelines. Full article

Macrophage-mediated inflammation is known to be involved in the epithelial–mesenchymal transition (EMT) of various types of cancer. This makes macrophage-derived inflammatory factors prime targets for the development of new treatments. This study uncovers the therapeutic potential and action mechanism of DAB-2-28, a small-molecule derived from para-aminobenzoic acid, in the treatment of breast cancer. The luminal MCF-7 and the triple-negative MDA-MB-231 cancer cell lines used in this study represent, respectively, breast cancers in which the differentiation states are related to the epithelial phenotype of the mammary gland and breast cancers expressing a highly aggressive mesenchymal phenotype. In MCF-7 cells, soluble factors from macrophage-conditioned media (CM-MØ) induce a characteristic morphology of mesenchymal cells with an upregulated expression of Snail1, a mesenchymal marker, as opposed to a decrease in the expression of E-cadherin, an epithelial marker. DAB-2-28 does not affect the differential expression of Snail1 and E-cadherin in response to CM-MØ, but negatively impacts other hallmarks of EMT by decreasing invasion and migration capacities, in addition to MMP9 expression and gelatinase activity, in both MCF-7 and MDA-MB-231 cells. Moreover, DAB-2-28 inhibits the phosphorylation of key pro-EMT transcriptional factors, such as NFκB, STAT3, SMAD2, CREB, and/or AKT proteins, in breast cancer cells exposed to different EMT inducers. Overall, our study provides evidence suggesting that inhibition of EMT initiation or maintenance is a key mechanism by which DAB-2-28 can exert anti-tumoral effects in breast cancer cells. Full article

Biological extracellular vesicles in tear fluids, such as exosomes, are thought to have physiological functions in the management of healthy ocular surface epithelium, including corneal epithelium. However, the physiological roles of tear extracellular vesicles in the ocular surface remain unclear. In this study, we investigated the physiological function of tear extracellular vesicles in mouse tear fluids in the ocular surface epithelium in vitro. Morphological analysis of the isolated extracellular vesicles from mouse tear fluids was performed using nanoparticle tracking analysis and transmission electron microscopy. The identified particles were characterised by immunoblotting for exosomal markers. After confirming the uptake of tear exosomes in cultured corneal epithelial cells, gene expression changes in mouse cultured corneal epithelial cells after tear exosome treatment were analysed. Immunostaining analysis was performed to confirm cell proliferation in the cultured corneal epithelial cells with tear exosome treatment. Tear fluids from mice contain nanoparticles with exosome-like morphologies, which express the representative exosomal markers CD9 and TSG101. The extracellular vesicles can be taken up by cultivated murine corneal epithelial cells in vitro and induce expression changes in genes related to the cell cycle, cell membranes, microtubules, and signal peptides. Treatment with the tear extracellular vesicles promoted cell proliferation of cultured murine corneal epithelial cells. Our study provides evidence that murine tear fluids contain extracellular vehicles like exosomes and they may contribute to the maintenance of the physiological homeostatic environment of the ocular surface. Full article

While horizontal roughing filters (HRFs) remain widely acclaimed for their exceptional efficiency in water treatment, especially in developing countries, they are inherently susceptible to clogging, which necessitates timely maintenance interventions. Conventional methods for managing clogging in HRFs typically involve evaluating filter head loss coefficients against established water quality standards. This study utilizes artificial neural network (ANN) for the prediction of clogging duration and effluent turbidity in HRF equipment. The ANN was configured with two outputs, the clogging duration and effluent turbidity, which were predicted concurrently. Effluent turbidity was modeled to enhance the network’s learning process and improve the accuracy of clogging prediction. The network steps of the iterative training process of ANN used different types of input parameters, such as influent turbidity, filtration rate, pH, conductivity, and effluent turbidity. The training, in addition, optimized network parameters such as learning rate, momentum, and calibration of neurons in the hidden layer. The quantities of the dataset accounted for up to 70% for training and 30% for testing and validation. The optimized structure of ANN configured in a 4-8-2 topology and trained using the Levenberg–Marquardt (LM) algorithm achieved a mean square error (MSE) of less than 0.001 and R-coefficients exceeding 0.999 across training, validation, testing, and the entire dataset. This ANN surpassed models of scaled conjugate gradient (SCG) and obtained a percentage of average absolute deviation (%AAD) of 9.5. This optimal structure of ANN proved to be a robust tool for tracking the filter clogging duration in HRF equipment. This approach supports proactive maintenance and operational planning in HRFs, including data-driven scheduling of backwashing based on predicted clogging trends. Full article

CNOT2, a central component of the CCR4-NOT transcription complex subunit 2, plays a pivotal role in the regulation of gene expression and metabolism. CNOT2 is involved in various cellular processes, including transcriptional regulation, mRNA deadenylation, and the modulation of mRNA stability. CNOT2 specifically contributes to the structural integrity and enzymatic activity of the CCR4-NOT complex with transcription factors and RNA-binding proteins. Recent studies have elucidated its involvement in cellular differentiation, immune response modulation, and the maintenance of genomic stability. Abnormal regulation of CNOT2 has been implicated in a spectrum of pathological conditions, including oncogenesis, neurodegenerative disorders, and metabolic dysfunctions. This review comprehensively examines the interplay between CNOT2 and p53, elucidating their collaborative and antagonistic interactions in various cellular contexts. CNOT2 is primarily involved in transcriptional regulation, mRNA deadenylation, and the modulation of mRNA stability, thereby influencing diverse biological processes such as cell proliferation, apoptosis, and differentiation. Conversely, p53 is renowned for its role in maintaining genomic integrity, inducing cell cycle arrest, apoptosis, and senescence in response to cellular stress and DNA damage. Emerging evidence suggests that CNOT2 can modulate p53 activity through multiple mechanisms, including the regulation of p53 mRNA stability and the modulation of p53 target gene expression. The dysregulation of CNOT2 and p53 interactions has been implicated in the pathogenesis and progression of various cancers, highlighting their potential as therapeutic targets. Additionally, CNOT2 regulates c-Myc, a well-known oncogene, in cancer cells. This review shows the essential roles of CNOT2 in maintaining cancer cellular homeostasis and explores its interactions within the CCR4-NOT complex that influence transcriptional and post-transcriptional regulation. Furthermore, we investigate the potential of CNOT2 as a biomarker and therapeutic target across various disease states, highlighting its significance in disease progression and treatment responsiveness. Full article

Rural roads are critical for connecting isolated communities to essential services such as education and health and administrative services, as well as production and market opportunities in low-income countries. More than 70% of movements of people and goods in Sub-Saharan Africa are heavily reliant on rural transport systems, using both motorised but mainly alternative means of transport. However, rural roads often suffer from poor construction due to the use of low-strength, in situ soils and limited financial resources, leading to premature failures and subsequent traffic disruptions with significant economic losses. This study investigates the use of rice husk ash (RHA), a waste byproduct from rice production, as a sustainable supplement to Ordinary Portland Cement (OPC) for soil stabilisation in order to increase durability and sustainability of rural roads, hence limit recurrent maintenance needs and associated transport costs and challenges. To conduct this study, soil samples collected from Mulungushi, Zambia, were treated with combinations of 6–10% OPC and 10–15% RHA by weight. Laboratory tests measured maximum dry density (MDD), optimum moisture content (OMC), and California Bearing Ratio (CBR) values; the main parameters assessed to ensure the quality of road construction soils. Results showed that while the MDD did not change significantly and varied between 1505 kg/m³ and 1519 kg/m³, the OMC increased hugely from 19.6% to as high as 26.2% after treatment with RHA. The CBR value improved significantly, with the 8% OPC + 10% RHA mixture achieving the highest resistance to deformation. These results suggest that RHA can enhance the durability and sustainability of rural roads and hence improve transport systems and subsequently improve socioeconomic factors in rural areas. Full article

Objectives: This study explored perceptions, experiences, and outcomes associated with the choice of insulin therapies among pediatric patients with type 1 diabetes mellitus (T1D). Methods: This study included 20 adolescents (8 male and 12 female) with T1D, with a mean age of 15.05 ± 0.91 years, a mean diabetes duration of 5.19 ± 1.2 years, and a mean most recent HbA1c of 7.03 ± 0.16%. Ten of the participants were using an insulin pump (n = 10) and another 10 had either refused (n = 7) or discontinued (n = 3) insulin pump therapy. A qualitative inductive method was employed, using in-depth individual interviews. The interview material was transcribed verbatim and grounded theory was used to analyze the verbal material. Results: Four main thematic categories were identified from the narrations that captured both common and divergent perceptions of insulin pump users versus non-users: (1) adjusting to the lifelong diagnosis, (2) exposing diabetes versus hiding it, (3) becoming autonomous and integrating insulin pump therapy into daily life, and (4) worrying over the pump. The third theme, capturing autonomy and integration, surfaced as the core thematic category of this study. Conclusions: This grounded theory study revealed that, by using insulin pump therapy, adolescent T1D patients can enhance their autonomy and facilitate the integration of insulin treatment into their life. This study identified processes that inform diabetes education and contribute to ameliorating gaps in the uptake and maintenance of pump therapy in pediatric care. Full article

Background: The identification of pathogenic variants in the Breast Cancer Genes 1 and 2 (BRCA1/2) is a critical predictive biomarker for poly (ADP-ribose) polymerase inhibitor (PARPi) therapy in epithelial ovarian cancer (EOC). The aim of this study is to define real-world rates and determinants of germline and somatic BRCA1/2 testing and subsequent PARPi utilisation in Australia using a national clinical quality registry. Methods: This multi-centre cohort study analysed data from 1503 women with non-mucinous EOC diagnosed between May 2017 and July 2022, captured by the Australian National Gynae-Oncology Registry (NGOR). We evaluated rates of germline and somatic testing and PARPi use, using multivariate logistic regression to identify associated clinical and demographic factors. Results: Overall germline and somatic testing rates were 68% and 32%, respectively. For the high-grade serous ovarian cancer (HGSOC) cohort, rates were higher, at 78% and 39%, respectively. Germline testing was significantly less likely for women aged >80 years (OR 0.49), those in regional areas (OR 0.61), and those receiving single-modality treatment. Somatic testing uptake increased significantly following public reimbursement for PARPi (p = 0.004). Among eligible women with a newly diagnosed BRCA pathogenic variant and advanced disease (n = 110), 52% commenced first-line maintenance PARPi. Conclusions: This national study offers valuable insights into Australian ovarian cancer care, highlighting opportunities to enhance testing equity for older women (aged >80) and regional patients. Furthermore, it identifies the translation of a positive test into PARPi therapy as a complex area that warrants further collaborative investigation to optimise patient outcomes. Full article

Pain following orthodontic treatment is the chief complaint of patients undergoing this form of treatment. Although the use of diode lasers has been suggested for pain reduction, the mechanism of laser-induced analgesic effects remains unclear. Neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP), contribute to the transmission and maintenance of inflammatory pain. Heat shock protein (HSP) 70 plays a protective role against various stresses, including orthodontic forces. This study aimed to examine the effects of diode laser irradiation on neuropeptides and HSP 70 expression in periodontal tissues induced by experimental tooth movement (ETM). For inducing ETM for 24 h, 50 g of orthodontic force was applied using a nickel–titanium closed-coil spring to the upper left first molar and the incisors of 20 male Sprague Dawley rats (7 weeks old). The right side without ETM treatment was considered the untreated control group. In 10 rats, diode laser irradiation was performed on the buccal and palatal sides of the first molar for 90 s with a total energy of 100.8 J/cm². A near-infrared (NIR) laser with a 808 nm wavelength, 7 W peak power, 560 W average power, and 20 ms pulse width was used for the experiment. We measured the number of facial groomings and vacuous chewing movements (VCMs) in the ETM and ETM + laser groups. Immunohistochemical staining of the periodontal tissue with SP, CGRP, and HSP 70 was performed. The number of facial grooming and VCM periods significantly decreased in the ETM + laser group compared to the ETM group. Moreover, the ETM + laser group demonstrated significant suppression of SP, CGRP, and HSP 70 expression. These results suggest that the diode laser demonstrated analgesic effects on ETM-induced pain by inhibiting SP and CGRP expression, and decreased HSP 70 expression shows alleviation of cell damage. Thus, although further validation is warranted for human applications, an NIR diode laser can be used for reducing pain and neuropeptide markers during orthodontic tooth movement. Full article

Background: Intravenous vancomycin remains a key agent in the treatment of complex orthopedic infections, particularly those involving methicillin-resistant Staphylococcus aureus (MRSA). However, its use is associated with significant risks, most notably nephrotoxicity. Despite guideline recommendations, standardized dosing and monitoring protocols are often absent in orthopedic settings, leading to inconsistent therapeutic drug exposure and preventable adverse events. This study evaluated the clinical impact of implementing a structured standard operating procedure (SOP) for intravenous vancomycin therapy in orthopedic inpatients. Methods: We conducted a single-center, pre-post cohort study at a university orthopedic department. The intervention consisted of a standard operating procedure (SOP) for intravenous vancomycin therapy, which mandated weight-based loading doses, renal function-adjusted maintenance dosing, trough level monitoring, and defined dose adjustments. Patients treated before SOP implementation (n = 58) formed the control group; those treated under the SOP (n = 56) were prospectively included. The primary outcome was the incidence of vancomycin-associated acute kidney injury (VA-AKI) defined by KDIGO Stage 1 criteria. Secondary outcomes included therapeutic trough level attainment and infusion-related or ototoxic adverse events. Results: All patients in the post-SOP group received a loading dose (100% vs. 31% pre-SOP, p < 0.001). The range of measured vancomycin trough levels narrowed substantially after SOP implementation (7.1–36.2 mg/L vs. 4.0–80.0 mg/L). The proportion of patients reaching therapeutic trough levels increased, although this was not statistically significant. Most notably, VA-AKI occurred in 17.2% of patients in the control group, but in none of the patients after SOP implementation (0%, p = 0.0013). No cases of ototoxicity were observed in either group. Infusion-related reactions decreased after the implementation of the SOP, though not significantly. Conclusions: The introduction of a structured vancomycin protocol significantly reduced adverse drug events and improved dosing control in orthopedic inpatients. Incorporating such protocols into routine practice represents a feasible and effective strategy to strengthen antibiotic stewardship and clinical quality in surgical disciplines. Full article

Skin aging is characterized by compromised epidermal homeostasis and dermo-epidermal junction (DEJ) integrity, resulting in reduced stem cell potential and impaired tissue regeneration. This study investigated the effects of Andrographis paniculata extract (APE) on keratinocyte stem cells (KSCs) and DEJ composition in human skin. Using human skin explants and cell culture models, we demonstrated that APE treatment enhances DEJ composition by increasing Collagen IV and Laminin production while decreasing MMP-9 expression, without altering epidermal structure or differentiation. In the same model, APE preserved stemness potential by upregulating markers related to niche components (collagen XVII and β1-integrin), proliferation (Ki-67 and KRT15), and stem cell capacity (Survivin and LRIG1). In vitro studies revealed that APE selectively stimulated KSC proliferation without affecting transit amplifying cells and promoted Collagen IV and Laminin secretion, particularly in KSCs. Furthermore, in a co-culture model simulating a compromised DEJ (UVB-induced), APE increased Laminin production in KSCs, suggesting a protective effect against photo-damage. These findings indicate that APE enhances DEJ composition and preserves stem cell potential, highlighting its promise as a candidate for skin anti-aging strategies targeting stem cell maintenance and extracellular matrix stability to promote skin regeneration and repair. Full article

Background/Objectives: The consumption of opioids is a public health problem that significantly affects quality of life. In Spain, 7585 people are enrolled in the Methadone Maintenance Programme (MMP), which is an effective intervention with a low adherence rate. In this study, factors associated with the quality of life of MMP users, especially perceived social support and treatment adherence, were analysed. We hypothesised that low levels of adherence and social support would be associated with poorer quality of life. Methods: This was a cross-sectional observational study with an analytical approach. Quality of life (WHOQoL-BREF), perceived social support (DUKE-UNC-11), and treatment adherence (MMAS-8) among MMP users were studied, and data on sociodemographic and clinical characteristics were collected through ad hoc questionnaires and a review of electronic medical records. Linear and logistic regression models were used. Results: A total of 70 individuals were included in this study. The mean age was 56.9 years, and 83% of the participants were male. The perceived quality of life was low in the four domains evaluated (range of 47.4–48.2). A total of 38.57% of the participants had low perceived social support. Treatment adherence was low or moderate in 77.1% of the participants. Greater perceived social support was associated with better quality of life in all domains (p < 0.05). Quality of social life was negatively associated with the use of nonbenzodiazepine neuroleptics and HIV status. Treatment adherence was lower in insulin therapy users. Conclusions: Social support is a key determinant of the quality of life of MMP users. Health policies should promote social support networks as a strategy to improve the well-being of this population. Full article

This study aimed to evaluate the impact of preoperative anti-VEGF injections on pars plana vitrectomy (PPV) outcomes in patients with proliferative diabetic retinopathy (PDR). Material and methods: We analysed 232 eyes with proliferative diabetic vitreoretinopathy treated with posterior vitrectomy. There were 112 women and 120 men. The patients were divided into two groups of 116 eyes each. In 116 eyes (study group), an anti-VEGF injection was administered 3 to 5 days before vitrectomy. The control eyes were not injected with anti-VEGF due to systemic contraindications to anti-VEGF treatment or lack of patient consent. All participants underwent pars plana vitrectomy with silicone oil injection. The oil was removed within 2–3 months after PPV. Results: At 2 years of observation, after removal of silicone oil, visual acuity (VA) was 0.24 ± 0.27 logMAR in the study and 0.37 ± 0.45 logMAR in the control group (p = 0.003). Intraocular pressure was 16.84 ± 6.25 mmHg in the study group and 17.78 ± 6.22 mmHg in the control group (p = 0.04). The mean duration of surgery was 47.62 ± 9.87 and 50.05 ± 9.41 min in the study and control groups, respectively (p = 0.02). The size of intraoperative haemorrhage was 0.97 ± 0.86 dd in the study group and 1.51 ± 1.22 dd in the control group (p = 0.003). The frequency of surgery-induced retinal breaks was 0.34 ± 0.56 in the study group and 0.56 ± 0.76 in the control group (p = 0.003). The recurrence rate of retinal detachment was 0.05 ± 0.22 in the study group and 0.1 ± 0.31 in the control group (p = 0.15). Conclusions: Preoperative anti-VEGF therapy shortens the duration of surgery, reduces complications, and improves long-term outcomes in terms of visual acuity and maintenance of normal eye function. Full article

The advancement of non-thermal disinfection technologies represents a critical pathway for ensuring food safety, meeting environmental sustainability requirements, and meeting consumer preferences for clean-label products. This study systematically evaluated the combined preservation effect of ultrasonic-assisted slightly acidic electrolyzed water (US+SAEW) on mirror carp fillets during refrigeration. Results demonstrated that US+SAEW exhibited superior antimicrobial efficacy compared to individual US or SAEW, achieving reductions of 0.73, 0.74, and 0.79 log CFU/g in total viable counts (TVC), Aeromonas bacteria, and lactic acid bacteria counts compared to the control, respectively. Furthermore, the combined intervention significantly suppressed microbial proliferation throughout the refrigeration period while simultaneously delaying protein and lipid degradation/oxidation induced by spoilage bacteria, thereby inhibiting the formation of alkaline nitrogenous compounds. Consequently, lower levels of pH, total volatile basic nitrogen (TVB-N), protein carbonyl, and thiobarbituric acid reactive substances (TBARS) were observed in US+SAEW compared to the other treatments. Multimodal characterization through low-field nuclear magnetic resonance (LF-NMR), texture, and color analysis confirmed that US+SAEW effectively preserved quality characteristics, extending the shelf life of mirror carp fillets by four days. This study provides a novel non-thermal preservation strategy that combines microbial safety maintenance with quality retention, offering particular advantages for thermolabile food. Full article