Search Results (391)

Most patients with non-small-cell lung cancer (NSCLC) present with advanced/metastatic disease at diagnosis, and molecular profiling is critical in guiding treatment decisions. This retrospective cohort study aimed to characterize EGFR mutations (EGFRm) in advanced/metastatic NSCLC patients, treatment patterns, and real-world outcomes. Adults diagnosed between 2018 and 2021 and treated at a Comprehensive Care Center were included. Time-to-event outcomes were analyzed using the Kaplan–Meier method. A total of 110 patients were included, with a median age of 69.0 years (range, 37–93), 76.4% female, and 83.2% non-smokers. About 97.3% had adenocarcinomas, with 93.6% at stage IV, 40.9% with ≥ three metastatic sites (brain metastases in 24.5%), 33.6% ECOG 2–4, and 58.2% with an EGFR exon-19 deletion. A minority started supportive care or curative-intent treatment, and 81.8% underwent first-line palliative systemic therapy (TKIs, 91.1%; chemotherapy, 8.9%). Median real-world overall survival (rwOS) was 18.9 months (95% CI, 13.8–28.1). Worse rwOS was observed in patients with ECOG 2–4 versus ECOG 0–1 (10.3 vs. 22.8 months; HR 1.82, 95% CI 1.17–2.85; p = 0.008) and in patients with exon-21 L858R versus exon 19 deletions (15.8 vs. 24.2 months; HR 1.59, 95% CI 1.00–2.54; p = 0.048). In patients treated with palliative systemic treatment, median progression-free survival was 10.9 months (95% CI, 8.8–13.6). This study provides important insights regarding real-world characteristics, treatment patterns, and outcomes from a cohort of EGFRm advanced/metastatic NSCLC patients. Full article

There has been a great need for replacing combustion-powered vehicles with electric vehicles (EV), and fully electric cars are meant to replace combustion engine cars. This has led to considerable research into improving the performance of EVs, especially via electric motor voltage control. A wide range of optimization algorithms have been used as traditional approaches, but the dynamic parameters of electric motors, impacted by temperature and different driving cycles, continue to be a problem. This study introduces an improved version of the Parrot Optimizer (IPO) aimed at enhancing voltage regulation in EVs. The algorithm can intelligently adjust certain motor parameters for adaptive management to maintain performance based on different situations. To ensure a stable and sustainable power supply for the powertrain of the EV, a photovoltaic (PV) system is used with energy storage batteries. Such an arrangement seeks to deliver permanent electric energy, a solution to traditional grid electricity reliance. This demonstrates the effectiveness of IPO, with the resultant motor performance remaining optimal despite parameter changes. It is also illustrated that energy production, by integrating PV systems, prevents excessive voltage line drops and thus voltage imbalances. The proposed intelligent controller is verified based on multiple simulations, demonstrating and ensuring significant improvements in EV efficiency and reliability. Full article

Immunotherapy has emerged as a key modality in cancer treatment, yet its effectiveness varies significantly among patients, often due to the metabolic stress imposed by the tumor microenvironment. Hypoxia, a major factor in the tumor microenvironment, results from the high metabolic rate of tumor cells and inadequate vascularization, impairing immune cells’ function and potentially influencing gene expression profiles. Despite the widespread use of quantitative real-time PCR in immunological studies, to the best of our knowledge, data on reference gene stability in human peripheral blood mononuclear cells under hypoxic conditions is limited. In our study, we assessed the expression stability of commonly used reference genes (S18, HPRT, IPO8, RPL13A, SDHA, PPIA, and UBE2D2) in both non-stimulated and CD3/CD28-activated peripheral blood mononuclear cells cultured under normoxic, hypoxic (1% O₂), and chemically induced hypoxic conditions for 24 h. Analysis using four different algorithms—delta Ct, geNorm, NormFinder, and BestKeeper—identified RPL13A, S18, and SDHA as the most suitable reference genes for human peripheral blood mononuclear cells under hypoxic conditions. In contrast, IPO8 and PPIA were found to be the least suitable housekeeping genes. The study provides essential insights into the stability of reference genes in peripheral blood mononuclear cells under hypoxic conditions, a critical but understudied aspect of immunological research. Given the significant impact of hypoxia on T cell metabolism and function in the tumor microenvironment, selecting reliable reference genes is crucial for accurate gene expression analysis. Our findings will be valuable for future studies investigating hypoxia-driven metabolic reprogramming in immune cells, ultimately contributing to a better understanding of T cell responses in cancer immunotherapy. Full article

This study examines the deferred tax valuation allowance disclosures of a sample of venture-capital-backed IPO firms that incurred a net operating loss (NOL) in the period prior to their public offering (IPO). I find that 82 percent of these firms record an allowance that reduces the associated deferred tax asset to zero, that the choice to record the allowance is largely driven by a firm’s history of losses, and that the allowance is associated with lower future book income. I further propose a new explanation for the presence of the allowance: the Section 382 ownership change limitation, which can cause firms to record an allowance independent of their past profitability or expectations about future earnings. I find that firms consider this limitation when recording the allowance, and that controlling for it can enhance the signal regarding future income. Full article

Thyroid carcinogenesis has multiple hallmarks, including evasion of tumor suppressors. Reactivation of wild-type p53 function is the ultimate goal in cancer therapy, which requires an understanding of the p53 suppression mechanism specific to the cancer type. MiR-7-5p and IPO7 are implicated in the pathogenesis of several human diseases. This work aims to investigate the role of miR-7-5p and IPO7 in p53 regulation in papillary thyroid cancer (PTC) cells. Primary cultured thyroid cells and FFPE thyroid tissues from PTC and benign cases were used. Functional experiments were performed by transfection with IPO7 siRNA or miR-7-5p mimic/inhibitor, followed by apoptosis and luciferase reporter assays, immunoblot assays, and RT-PCR. The expression and subcellular localization of IPO7, p53, MDM2, and ribosomal proteins (RPL11 and RPL5) were studied by immunofluorescence staining and confocal microscopy. The results show that IPO7 is overexpressed in PTC and regulated by miR-7-5p. Modulation of IPO7 expression in cultured thyroid cells altered the nucleocytoplasmic shuttling of p53, MDM2, RPL11, and RPL5, in addition to the p53 protein level and activity. The expression pattern of IPO7, p53, and MDM2 in cultured thyroid cells and clinical thyroid tissue specimens confirmed the association between IPO7 overexpression and reduced p53 stability in PTC. In conclusion, the data here show that p53 level and activity are differentially controlled in malignant and benign thyroid cells through miR-7-5P/IPO7-mediated regulation of RP-MDM2-p53 nucleocytoplasmic trafficking. In PTC, downregulation of miR-7-5p with consequent overexpression of IPO7 might be a protective mechanism used by cancer cells to evade p53 growth suppression during carcinogenesis. Full article

The COVID-19 pandemic highlighted the need for rapid, cost-effective tools to monitor transmission and immune response. We developed two novel paper-based colorimetric biosensors using glutaraldehyde as a protein dye—its first use in this context. Glutaraldehyde reacts with amino groups to generate a brown color, enabling detection of SARS-CoV-2 antibodies. Wathman filter paper was functionalized with (3-aminopropyl)triethoxysilane (APTES) to immobilize virus-like particles (VLPs) and nucleocapsid protein (N-protein) as biorecognition elements. Upon incubation with antibody-containing samples, glutaraldehyde enabled colorimetric detection using RGB analysis in ImageJ software. Both sensors showed a linear correlation between antibody concentration and RGB values in buffer and serum. The VLP sensor responded linearly within the range of 1.0–20 µg/mL (green coordinate) in 500-fold diluted serum and the N-protein sensor from 1.0–40 µg/mL (blue coordinate) in 250-fold diluted serum. Both sensors demonstrated good selectivity, with glucose causing up to 18% interference. These biosensors represent a paradigm shift, as they provide a sensitive, user-friendly, and cost-effective option for semi-quantitative serological analysis. Furthermore, their versatility goes beyond the detection of SARS-CoV-2 antibodies and suggests broader applicability for various molecular targets. Full article

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor with a dismal prognosis despite advances in multimodal treatment. Conventional therapies fail to achieve durable responses due to GBM’s molecular heterogeneity and capacity to evade therapeutic pressures. Epigenetic alterations have emerged as critical contributors to GBM pathobiology, including aberrant DNA methylation, histone modifications, and non-coding RNA (ncRNA) dysregulation. These mechanisms drive oncogenesis, therapy resistance, and immune evasion. This scoping review evaluates the current state of knowledge on epigenetic modifications in GBM, synthesizing findings from original articles and preclinical and clinical trials published over the last decade. Particular attention is given to MGMT promoter hypermethylation status as a biomarker for temozolomide (TMZ) sensitivity, histone deacetylation and methylation as modulators of chromatin structure, and microRNAs as regulators of pathways such as apoptosis and angiogenesis. Therapeutically, epigenetic drugs, like DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis), appear as promising approaches in preclinical models and early trials. Emerging RNA-based therapies targeting dysregulated ncRNAs represent a novel approach to reprogram the tumor epigenome. Combination therapies, pairing epigenetic agents with immune checkpoint inhibitors or chemotherapy, are explored for their potential to enhance treatment response. Despite these advancements, challenges such as tumor heterogeneity, the blood–brain barrier (BBB), and off-target effects remain significant. Future directions emphasize integrative omics approaches to identify patient-specific targets and refine therapies. This article thus highlights the potential of epigenetics in reshaping GBM treatment paradigms. Full article

The Parrot Optimizer (PO) is a new optimization algorithm based on the behaviors of trained Pyrrhura Molinae parrots. In this paper, an improved PO (IPO) is proposed for solving global optimization problems and training the multilayer perceptron. The basic PO is enhanced by using three improvements, which are aerial search strategy, modified staying behavior, and improved communicating behavior. The aerial search strategy is derived from Arctic Puffin Optimization and is employed to enhance the exploration ability of PO. The staying behavior and communicating behavior of PO are modified using random movement and roulette fitness–distance balance selection methods to achieve a better balance between exploration and exploitation. To evaluate the optimization performance of the proposed IPO, twelve CEC2022 test functions and five standard classification datasets are selected for the experimental tests. The results between IPO and the other six well-known optimization algorithms show that IPO has superior performance for solving complex global optimization problems. The results between IPO and the other six well-known optimization algorithms show that IPO has superior performance for solving complex global optimization problems. In addition, IPO has been applied to optimize a multilayer perceptron model for classifying the oral English teaching quality evaluation dataset. An MLP model with a 10-21-3 structure is constructed for the classification of evaluation outcomes. The results show that IPO-MLP outperforms other algorithms with the highest classification accuracy of 88.33%, which proves the effectiveness of the developed method. Full article

Introduction: Previous neuroimaging studies have reported structural brain alterations and local network hyperexcitability in terms of increased slow-wave electroencephalography (EEG) activity in patients with borderline personality disorder (BPD). In particular, intermittent rhythmic delta and theta activity (IRDA/IRTA) has drawn attention in mental health contexts due to its links with metabolic imbalances, neuronal stress, and emotional dysregulation—processes that are highly pertinent to BPD. These functional disturbances may be reflected in corresponding structural brain changes. The current study investigated cortical thickness and subcortical volumes in BPD and examined their associations with IRDA/IRTA events per minute, symptom severity, and neuropsychological measures. Methods: Seventy female BPD patients and 36 age-matched female healthy controls (HC) were included (for clinical EEG comparisons even 72 patients were available). IRDA/IRTA rates were assessed using an automatic independent component analyses (ICA) approach. T1-weighted MRI data were obtained using a MAGNETOM Prisma 3T system and analyzed with FreeSurfer (version 7.2) for subcortical structures and CAT12 for cortical thickness and global volume measurements. Psychometric assessments included questionnaires such as Borderline Symptom List (BSL-23) and Inventory of Personality Organization (IPO). Neuropsychological performance was evaluated with the Test for Attentional Performance (TAP), Culture Fair Intelligence Test (CFT-20-R), and Verbal Learning and Memory Test (VLMT). Results: Between-group comparisons exhibited no significant increase in IRDA/IRTA rates or structural abnormalities between the BPD and HC group. However, within the BPD group, cortical thickness of the right isthmus of the cingulate gyrus negatively correlated with the IRDA/IRTA difference (after minus before hyperventilation, HV; p < 0.001). Furthermore, BPD symptom severity (BSL-23) and IPO scores positively correlated with the thickness of the right rostral anterior cingulate cortex (p < 0.001), and IPO scores were associated with the thickness of the right temporal pole (p < 0.001). Intrinsic alertness (TAP) significantly correlated with relative cerebellar volume (p = 0.01). Discussion: While no group-level structural abnormalities were observed, correlations between EEG slowing, BPD symptom severity, and alertness with cortical thickness and/or subcortical volumes suggest a potential role of the anterior cingulate cortex, temporal pole, and cerebellum in emotion regulation and cognitive functioning in BPD. Future research employing multimodal EEG-MRI approaches may provide deeper insights into the neural mechanisms underlying BPD and guide personalized therapeutic strategies. Full article

Background and Clinical Significance: Intermediate- to high-risk Myelodysplastic Syndrome (MDS), according to the Revised International Prognostic Scoring System (IPSS-M), confers a high risk of progression into acute myeloid leukemia. Treatment with hypomethylating agents, including azacitidine and decitabine, represents the current standard of care. In eligible patients, hypomethylating agents are used as a bridge for allogeneic stem cell transplantation, currently the only curative approach in these malignancies. The most common side effects of hypomethylating agents are myelosuppression, cutaneous injection site reactions (when azacitidine is given subcutaneously), and gastrointestinal symptoms. Uncommon, disabling, and long-lasting side effects represent a threat to effective treatment in this group of patients. Case Presentation: We describe the case of a 49-year-old male patient with IPSS-M intermediate-risk MDS, intended to receive first-line treatment with azacitidine followed by allogeneic stem cell transplantation. The first, late-onset azacitidine reaction was observed 48 h after the first exposure, with cutaneous and respiratory toxicity, followed by the late-onset recurrence of symptoms after azacitidine withdrawal and decitabine introduction. Conclusions: This case highlights atypical, disabling, and long-lasting drug reactions to two hypomethylating agents, with the persistence of hypersensitivity manifestations months after medication withdrawal. Full article

Background/Objectives: The methylation of the hypermethylated oncological region (THOR) of human telomerase reverse transcriptase (hTERT) may forecast tumour aggressiveness. This pilot study aimed to evaluate THOR methylation as a potential biomarker for recurrence/malignant transformation in salivary gland pleomorphic adenomas (PA). Methods: THOR methylation was assessed by quantitative pyrosequencing in 96 parotid tissue samples (benign and malignant), including non-neoplastic parotid tissue, PA, recurrent PA (rPA), and carcinomas, along with their adjacent tissues. TERT promoter mutations (TPMs) were analysed by Sanger sequencing. Results: THOR methylation significantly differed across the seven groups. Malignant tissues showed higher THOR methylation than non-neoplastic tissues, whereas benign tumours showed no significant difference from non-neoplastic tissue. THOR methylation in rPA was closer to carcinoma than to normal tissue, similar in rPA and tissues adjacent to rPA, and higher in tissues adjacent to carcinomas than in non-neoplastic tissues. A subset of PA-adjacent tissues showed epigenetic alterations, suggesting an increased risk of recurrence or malignant transformation (5–15%). No TPMs were detected. Conclusions: THOR methylation may add information to differentiate normal from carcinogenic tissues and, as such, may be included in a biomarkers panel. Epigenetic alterations in PA-adjacent tissues with normal histology highlight the need for improved diagnostic markers. Full article

Trigeminal somatosensory-evoked potentials (TSEPs) provide valuable insight into neural responses to oral stimuli. This study investigates TSEP recording methods and their impact on interpreting results in clinical settings to improve the development process of neurostimulation-based therapies. The experiments and results presented here aim at identifying appropriate stimulation characteristics to design an active dental prosthesis capable of contributing to restoring the lost neurosensitive connection between the teeth and the brain. Two methods of TSEP acquisition, traditional and occluded, were used, each conducted by a different volunteer. Traditional TSEP acquisition involves stimulation at different sites with varying parameters to achieve a control base. In contrast, occluded TSEPs examine responses acquired under low- and high-force bite conditions to assess the influence of periodontal mechanoreceptors and muscle activation on measurements. Traditional TSEPs demonstrated methodological feasibility with satisfactory results despite a limited subject pool. However, occluded TSEPs presented challenges in interpreting results, with responses deviating from expected norms, particularly under high force conditions, due to the simultaneous occurrence of stimulation and dental occlusion. While traditional TSEPs highlight methodological feasibility, the occluded approach highlights complexities in outcome interpretation and urges caution in clinical application. Previously unreported results were achieved, which underscores the importance of conducting further research with larger sample sizes and refined protocols in order to strengthen the reliability and validity of TSEP assessments. Full article

With the widespread adoption of electric vehicles (EVs), optimizing their charging and discharging strategies to improve energy efficiency and extend battery life has become a focal point of current research. Traditional charging and discharging strategies often fail to adequately consider the battery’s state of health (SOH), resulting in accelerated battery aging and decreased efficiency. In response, this paper proposes a safe reinforcement learning–based optimization method for EV charging and discharging strategies, aimed at minimizing charging and discharging costs while accounting for battery SOH. First, a novel battery health status prediction model based on physics-informed hybrid neural networks (PHNN) is designed. Then, the EV charging and discharging decision-making problem, considering battery health status, is formulated as a constrained Markov decision process, and an interior-point policy optimization (IPO) algorithm based on long short-term memory (LSTM) neural networks is proposed to solve it. The algorithm filters out strategies that violate constraints by introducing a logarithmic barrier function. Finally, the experimental results demonstrate that the proposed method significantly enhances battery life while maintaining maximum economic benefits during the EV charging and discharging process. This research provides a novel solution for intelligent and personalized charging strategies for EVs, which is of great significance for promoting the sustainable development of new energy vehicles. Full article

Aberrant glycosylation is a hallmark of cancer, offering opportunities to enhance clinical decision-making and enable precise targeting of cancer cells. Nevertheless, alterations in the bladder urothelial carcinoma (BLCA) N-glycome remain poorly characterized. Here, we used in situ N-deglycosylation and mass spectrometry, revealing a marked enrichment of oligomannose-type N-glycans in non-invasive Ta tumors, which diminished with disease progression. A complementary analysis of The Cancer Genome Atlas (TCGA) transcriptomic data revealed downregulation of the key mannosidases in BLCA, suggesting a mechanistic basis for oligomannose accumulation, though this requires further validation. Then, targeted glycoproteomic profiling identified potential stage-specific carriers of oligomannoses. Exploratory functional annotation suggests stage-dependent differences among detected glycoproteins, ranging from metabolic regulation in Ta tumors to oxidative stress adaptation in muscle-invasive disease, highlighting glycosylation’s contribution to tumor progression. Furthermore, myeloperoxidase (MPO) was enriched in more aggressive stages. Spatial validation confirmed MPO overexpression in tumor-infiltrating immune cells and its correlation with oligomannose content. Importantly, high MPO expression combined with low mannosidase levels was linked to poor survival, suggesting biological relevance. This study suggests a dynamic, stage-specific N-glycome in BLCA and identifies oligomannose-bearing glycoproteins as exploratory leads for biomarker and therapeutic target discovery, providing a N-glycomic resource for further investigation towards glycan-based precision oncology. Full article

Background/Objectives: Pediatric gonadal tumors are rare tumors, and germ cell tumors (GCTs) are the most common subgroup. GCTs are heterogeneous tumors and have different subtypes that can be either benign or malignant. Therefore, extensive sampling of the resected tumor is required to obtain an accurate diagnosis. Higher harmonic generation microscopy (HHGM) is an innovative imaging technique that enables rapid visualization of fresh tissue without the need for preparation or staining. This makes it particularly valuable for sample selection, as the tissue can be reused for further analysis. This study aims to evaluate the accuracy of pathologists detecting normal gonadal tissue, germ cell tumors, and other pediatric gonadal tumors in HHGM images. Methods: Twenty-eight samples of twenty-two patients with a germ cell tumor or other gonadal tumor were imaged with the HHG microscope and subsequently processed for histology. Overview images of the samples were made in 10 s per mm², and high-quality images in 1 min per mm². A multi-observer study was performed with five expert pathologists. Results: Pathologists were able to differentiate between tumor and non-tumor tissue with an accuracy of 75% (21/28) on the HHGM images versus an accuracy of 89% (25/28) on the corresponding histology. Discrepancies mainly concerned teratoma cases for HHGM as well as H&E, indicating that sampling errors of these heterogeneous tumors affected the outcomes of this study adversely. Conclusions: Although the sample size was limited by the rarity of these tumors, our data show that HHGM is a promising technique for the rapid assessment of pediatric gonadal tumor samples, particularly in evaluating their representativeness. Full article