Search Results (141)

Background: The acquisition of adaptive skills is critical for independence and participation in activities of daily living (ADL). While caregiver perceptions provide valuable insights, most studies on autistic participation have focused on older children and relied on one-time clinic-based assessments. As a result, little is known about how autistic toddlers function in their natural environments across time. Ecological momentary assessment (EMA) is a real-time, context-sensitive method in which parents can report behaviors at multiple time points in the child’s natural environment. This pilot study aimed to examine ADL independence in autistic toddlers compared to their typically developing (TD) peers, to assess the feasibility of using EMA in early childhood, and to compare EMA-based assessments with a one-time standardized report. Methods: 23 autistic toddlers and 28 TD toddlers (aged 18–40 months) participated in the study. Parents completed a one-time report on the self-care scales of the Pediatric Evaluation of Disability Inventory (PEDI) and the Functional Independence Measure for Children (WeeFIM) and then rated their child’s independence on the WeeFIM twice a day for two weeks via their smartphones. Results: EMA was feasible with high response rates (ASD: 91.1%, TD: 88.55%). Autistic toddlers showed different participation profiles, with less independent performance in ADL compared to TD peers. In the autism group, the average EMA scores (M = 16.53, SD = 6.58) were significantly higher than the one-time WeeFIM scores (M = 13.74, SD = 5.23), t (22) = 3.23, p < 0.01, suggesting underreporting in single-time assessments. In contrast, no such difference was found in the TD group. Significant positive correlations were found between the EMA mean and the one-time WeeFIM scores in both groups (r > 0.80), indicating convergent validity. In the autism group only, greater variability in EMA was moderately associated with higher functional independence (r = 0.46, p < 0.01). Conclusions: These findings indicate that autistic toddlers demonstrated higher levels of participation in their natural environment than reflected by the one-time assessment, emphasizing the limitations of single-time-point evaluations. This underscores the importance of collecting data across multiple time points to accurately assess adaptive functioning and ADL participation. The EMA technique demonstrated in this study provides exploratory evidence of feasibility as an ecologically valid approach to assessing functional independence in autistic toddlers, offering a richer and more context-sensitive alternative to traditional one-time clinical assessments. Full article

Epithelial ovarian cancer (EOC) remains one of the deadliest gynecologic malignancies, largely due to late diagnosis and treatment resistance. The main objective of this study is to identify and validate CDK1 as a high-confidence therapeutic target in EOC and to assess the dual-target inhibitory potential of the natural compound Naringin against both CDK1 and its regulator WEE1. This study employed an integrative pipeline combining transcriptomic profiling, protein–protein interaction network analysis, machine learning, and molecular simulations to identify key oncogenic regulators in EOC. CDK1 emerged as a central hub gene, exhibiting strong association with poor prognosis and signaling convergence. CDK1 overexpression correlated with adverse survival outcomes and robust involvement in critical oncogenic pathways. Molecular docking and dynamics simulations assessed the binding efficacy of seven compounds with CDK1 and WEE1, with Naringin showing high-affinity binding, stable complex formation, and minimal predicted toxicity. This study underscores the power of computational-experimental integration in accelerating oncology drug discovery, providing visual and quantitative evidence that systematically connect the study’s aim to its findings. Full article

Extensive research on homologous-recombination-deficient (HRD) tumors has led to advancements in targeted therapies, such as PARP inhibitors (PARPis). Around 50% of high-grade serous ovarian cancer (HGSOC) cases exhibit HR deficiency, but understanding the remaining half, referred to as homologous-recombination-proficient (HRP) tumors, is limited. This review explores existing knowledge regarding HGSOC patients with HRP tumors and offers insights into potential targets for innovative treatments. Patients with HRP tumors do not experience the same benefits from PARPi and have poorer survival outcomes compared to those with HRD tumors. CCNE1 amplification is a common, well-established molecular feature in HGSOC HRP tumors, occurring in about 20% of cases. Targeting CCNE1 amplification and/or overexpression shows promise with emerging therapies like CDK2 or Wee1 inhibitors. Additionally, approaches using immunotherapy and antibody–drug conjugates could represent promising targets for HRP patients. This review also covers lesser-known molecular features in HRP tumors, such as fold-back inversions and CARM1 amplification and/or overexpression, as well as HRD tumors that acquire HR proficiency (BRCA1/2 reversion mutations, demethylation of BRCA1 and RAD51C). We also discuss controversial topics regarding HRP tumors and limitations of HRD detection. Addressing this need is critical to reduce toxicity and improve disease management. Full article

Tempol is a synthetic antioxidant that shows promise in preclinical cancer studies by inhibiting growth and inducing apoptosis. Given that the Mitogen-Activated Protein Kinase (MAPK) and Protein Kinase B/Mammalian Target of Rapamycin (Akt/mTOR) signaling pathways are frequently dysregulated in gastric and colon cancers and contribute to their progression, we investigated Tempol’s anti-cancer potential in HT29 (colon) and CRL-1739 (gastric) cancer cells. Cells were treated with 2 mM Tempol for 48 h, with untreated cells as controls. We evaluated apoptosis (Bax, cleaved caspase-3, and Bcl-2), key signaling pathway activity (p-ERK, p-JNK, p-AKT, and p-mTOR), and levels of stress- and apoptosis-related proteins (WEE1, GADD153, GRP78, and AIF). Tempol significantly increased pro-apoptotic Bax and cleaved caspase-3 (p < 0.0001) and decreased anti-apoptotic Bcl-2 (p < 0.0001) in both cell lines. Furthermore, Tempol markedly reduced the activity of p-ERK, p-JNK, p-AKT, and p-mTOR (p < 0.0001) and significantly increased the protein levels of WEE1, GADD153, GRP78, and AIF (p < 0.0001). Tempol treatment also led to a significant increase in total oxidant status and a decrease in total antioxidant status. In conclusion, our findings suggest that Tempol exhibits its anti-cancer activity through multiple interconnected mechanisms, primarily inducing apoptosis and oxidative stress, while concurrently suppressing pro-survival signaling pathways. These results highlight Tempol’s potential as a therapeutic agent for gastric and colon cancers. Full article

The paper presents the financial potential of recycling waste electronic equipment (WEE) in the form of printed circuit boards, hard drives, and lithium-ion batteries. Metal contents in selected types of WEE were presented, as well as their price and importance from an environmental, economic, and geopolitical perspective using indicators of relative supply risk and abiotic depletion potential (ADP). The potential benefits that recycling can bring to the company and the environment were presented. Furthermore, the mass balance and value of recovered metals were estimated for southern Poland, and potential possibilities for the management of the remaining separation products were presented. Finally, verified physical recycling methods for the presented WEE were described. Full article

WEE1 kinase is a crucial cell cycle regulatory protein that controls the timing of mitotic entry. WEE1, via inhibition of Cyclin-dependent Kinase 1 (CDK1) and Cyclin-dependent Kinase 2 (CDK2), governs the G2-M checkpoint by inhibiting entry into mitosis. The state of balance between WEE family kinases and CDC25C phosphatases restricts CDK1/CycB activity. The WEE kinase family consists of WEE1, PKMYT1, and WEE2 (WEE1B). WEE1 and PKMYT1 regulate entry into mitosis during cell cycle progression, whereas WEE2 governs cell cycle progression during meiosis. Recent studies have identified WEE1 as a potential therapeutic target in several cancers, including therapy-resistant triple-negative breast cancer. Adavosertib’s clinical promise was challenged by inter-individual variations in response and side effects. Because of these promising preclinical outcomes, other WEE1 kinase inhibitors (Azenosertib, SC0191, IMP7068, PD0407824, PD0166285, WEE1-IN-5, Zedoresertib, WEE1-IN-8, and ATRN-1051) are being developed, with several currently being evaluated in clinical trials or as an adjuvant to chemotherapies. Preclinical studies show WEE1 inhibitors induce MHC class 1 antigens and STING when given as combination therapies, suggesting potential additional therapeutic opportunities. Reliable predictors of clinical responses based on mechanistic insights remain an important unmet need. Herein, we review the role of WEE1 inhibition therapy in breast cancer. Full article

Cervical cancer remains a major threat to women’s health, with advanced cases often exhibiting recurrence and metastasis due to cancer stem cells driving therapy resistance. This study evaluated fenbendazole (FBZ), a repurposed veterinary anthelmintic, for its antitumor activity dual targeting cervical cancer cells (CCCs) and cervical cancer stem cells (CCSCs). CD133⁺CD44⁺ CCSCs were isolated from HeLa and C-33 A cell lines via immunomagnetic sorting and validated for stemness. Cell proliferation, cell cycle and apoptosis, and protein expression were detected by MST assay, flow cytometry, and Western blot analysis, respectively. FBZ dose-dependently inhibited proliferation, induced G2/M arrest, and triggered apoptosis in both CCCs and CCSCs. Mechanistically, FBZ upregulated cyclin B1 and phosphorylation of cdc25C-Ser198, while downregulating Wee1, phosphorylation of CDK1, and phosphorylation of cdc25C-Ser216, collectively enforcing G2/M blockade. In vivo, FBZ (100 mg/kg) significantly suppressed tumor growth in xenograft models without weight loss, contrasting with cisplatin-induced toxicity. Survival analysis revealed 100% survival in FBZ-treated mice versus 40% in cisplatin and 0% in untreated controls. These findings demonstrate FBZ’s unique ability to simultaneously target bulk tumor cells and therapy-resistant CCSCs via cell cycle disruption, supported by its preclinical safety and efficacy, positioning it as a promising therapeutic candidate for cervical cancer. Full article

Cancer cell spheroids autonomously form in the ascites fluid and are considered a conduit for epithelial ovarian cancer metastasis within the peritoneal cavity. Spheroids are homotypic, avascular 3D structures that acquire resistance to anoikis to remain viable after cellular detachment. We used in vitro spheroid model systems to interrogate pathways critical for spheroid cell proliferation, distinct from those driving monolayer cancer cell proliferation. Using the 105C and KOC-7c human ovarian clear cell carcinoma (OCCC) cell lines, which have distinct proliferative phenotypes as spheroids but the same prototypical OCCC gene mutation profile of constitutively activated AKT signaling with the loss of ARID1A, we revealed therapeutic targets that efficiently kill cells in spheroids. RNA-seq analyses compared the transcriptome of 3-day monolayer and spheroid cells from these lines and identified the characteristics of dormant spheroid cell survival, which included the G2/M checkpoint, autophagy, and other stress pathways induced in 105C spheroids, in sharp contrast to the proliferating spheroid cells of the KOC-7c cell line. Next, we assessed levels of various G2/M checkpoint regulators and found a consistent reduction in steady-state levels of checkpoint regulators in dormant spheroid cells, but not proliferative spheroids. Our studies showed that proliferative spheroid cells were sensitive to Wee1 inhibition by AZD1775, but the dormant spheroid cells showed a degree of resistance to AZD1775, both in terms of EC50 values and spheroid reattachment abilities. Thus, we identified biomarkers of dormant spheroids, including the G2/M checkpoint regulators Wee1, Cdc25c, and PLK1, and showed that, when compared to proliferating spheroid cells, the transcriptome of dormant OCCC spheroids is a source of therapeutic targets. Full article

Women entrepreneurs in small to medium enterprises (SMEs) in emerging countries play an essential role in the economy of developing countries such as Indonesia. Drawing on the resource-based view and entrepreneurship effectuation theory, this study examines how women’s entrepreneurial effectuation (WEE) modeled as a higher-order construct (HOC) comprising its four dimensions (LOCs)—namely, flexibility, experimentation, affordable loss, and pre-commitment—can influence employee performance (EMPRF) mediated by structural (STREM) and psychological empowerment (PSYEM). Using a disjointed two-stage PLS-SEM approach with data from 218 female SME employees, our results confirm that flexibility is the most salient effectuation dimension. WEE strongly predicts both STREM and PSYEM but shows no direct impact on EMPRF, highlighting that effectuation must be activated via empowerment mechanisms. PSYEM emerges as the strongest mediator of WEE on EMPRF, with STREM also contributing significantly and being amplified by gender equality practices; market orientation, by contrast, fails to moderate any paths. Theoretically, these findings enrich resource-based view (RBV) theory by integrating entrepreneurial effectuation dimensions and empowerment as human resource capabilities that generate inimitable performance gains. Practically, they suggest that women-led SMEs should integrate effectuation heuristics with targeted empowerment programs to realize the full potential of their human capital. Full article

Background: Silver–Russell syndrome (SRS) is a genetic disorder characterized by prenatal and postnatal growth retardation. Affected individuals commonly present with low birth weight, intrauterine growth restriction, postnatal short stature, hemihypotrophy, characteristic facial features, and body asymmetry. Methods: This study includes 24 Taiwanese children with SRS aged 2 years to 13 years and 3 months who were recruited at MacKay Memorial Hospital and other Taiwan hospitals between January 2013 and December 2024. Functional independence was assessed using the Functional Independence Measure for Children (WeeFIM) to evaluate self-care, mobility, and cognition domains. Results: The mean total WeeFIM score was 106.9 ± 23.2 (range: 54–126), with mean self-care, mobility, and cognition scores of 44.4 ± 13.8 (maximum 56), 32.4 ± 5.1 (maximum 35), and 30.2 ± 6.0 (maximum 35), respectively. The results of the restricted cubic spline analysis reveal a clear positive linear correlation before school age (approximately 72 months), followed by a plateau (p for nonlinearity < 0.05). Traceable molecular data were available for thirteen participants, of whom nine (69%) had loss of methylation at chromosome 11p15 (11p15LOM), and four (31%) had maternal uniparental disomy of chromosome 7 (upd(7)mat). Of the 24 children, 46% required assistance with bathing, which was strongly correlated with self-care ability and body height. In contrast, most of the children had independence in mobility tasks such as walking and stair climbing. However, some required support in cognitive tasks, including problem-solving, comprehension, and expression. Overall, the included children reached a functional plateau later than the normative population, with the greatest delays in self-care and mobility domains. Conclusions: This study highlights that Taiwanese children with SRS require support in self-care and cognitive tasks. Functional independence in self-care and mobility domains was positively associated with body height. The WeeFIM questionnaire effectively identified strengths and limitations, emphasizing the need for individualized support in daily activities. Full article

Most intensive swine production systems use invasive practices that increase stress and compromise animal welfare. Apparently, the way in which animals respond to stress is sexually dimorphic. To cope with stress and improve the life of animals, environmental enrichment (EE) is used. The objective of the study was to evaluate how EE and weaning affect the behavior and cortisol levels of barrows and female piglets. Forty piglets were divided into two groups: (1) WEE: piglets that received EE from birth until 21 days of age and whose mothers received EE from week six of gestation until farrowing; (2) NEE: piglets for whom neither them nor their mothers received EE. Cortisol fecal metabolites and frequency, latency and duration of behaviors associated with stress were evaluated and compared before and after weaning. Before weaning, WEE barrows showed less inactive and ingestion behaviors and shorter duration of aggression (p < 0.05), while WEE females showed longer duration of aggression and higher frequency of ingestion behavior (p < 0.05). After weaning, WEE barrows and NEE females had higher cortisol levels, and NEE females showed longer duration of aggression (p < 0.05). In conclusion, piglets’ response to EE and the way they learnt to cope with stress were sexually dimorphic. Full article

The poor prognosis for high-grade serous ovarian cancer (HGSOC), the dominant subtype of ovarian cancer, reflects its aggressive nature, late diagnosis, and the highest mortality rate among all gynaecologic cancers. Apart from late diagnosis, the main reason for the poor prognosis and its unsuccessful treatment is primarily the emergence of chemoresistance to carboplatin. Although there is a good response to primary treatment, the disease recurs in 80% of cases, at which point it is largely resistant to carboplatin. The introduction of novel targeted therapies in the second decade of the 21st century has begun to transform the treatment of HGSOC, although their impact on overall survival remains unsatisfactory. Targeting the specific pathways known to be abnormally activated in HGSOC is especially difficult due to the molecular diversity of its subtypes. Moreover, a range of molecular changes are associated with acquired chemoresistance, e.g., reversion of BRCA1 and BRCA2 germline alleles. In this review, we examine the advantages and disadvantages of approved targeted therapies, including bevacizumab, PARP inhibitors (PARPis), and treatments targeting cells with neurotrophic tyrosine receptor kinase (NTRK), B-rapidly accelerated fibrosarcoma (BRAF), and rearranged during transfection (RET) gene alterations, as well as antibody–drug conjugates. Additionally, we explore promising new targets under investigation in ongoing clinical trials, such as immune checkpoint inhibitors, anti-angiogenic agents, phosphatidylinositol-3-kinase (PI3K) inhibitors, Wee1 kinase inhibitors, and ataxia telangiectasia and Rad3-related protein (ATR) inhibitors for platinum-resistant disease. Despite the development of new targeted therapies, carboplatin remains the fundamental medicine in HGSOC therapy. The correct choice of treatment strategy for better survival of patients with advanced HGSOC should therefore include a prediction of patients’ risks of developing chemoresistance to platinum-based chemotherapy. Moreover, effective targeted therapy requires the selection of patients who are likely to derive clinical benefit while minimizing potential adverse effects, underscoring the essence of precision medicine. Full article

Background/Objectives: This study explores the potential of LB-100 (a protein phosphatase 2A—PP2A inhibitor) combined with adavosertib (a WEE1 kinase inhibitor) and doxorubicin (DOX), to overcome multidrug resistance (MDR) in cancer cells and enhance treatment efficacy. Methods: We evaluated LB-100 combinations with adavosertib and DOX in patient-derived glioblastoma and non-small cell lung carcinoma cells (NSCLCs) using a real-time cell analyzer. Effectiveness was also assessed through immunofluorescence assay, and interactions were analyzed via SynergyFinder+. We also examined P-glycoprotein (P-gp) expression and drug resistance genes’ expression in MDR glioblastoma and NSCLCs after LB-100 treatment, as well as LB-100 sensitizing effect on DOX and DOX accumulation. Results: LB-100 significantly boosts the effectiveness of adavosertib and DOX after multiple applications. It also enhances these drugs’ cytotoxicity in a single application without acting synergistically. Additionally, LB-100 reduces P-gp expression in MDR glioblastoma and NSCLCs, sensitizing them to DOX and increasing its accumulation. Conclusions: LB-100 enhances the effectiveness of drugs against MDR cancer cells, presenting a promising strategy to overcome drug resistance in glioblastoma and NSCLCs through P-gp modulation. Full article