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Composto e composição farmacêutica
No full text[[abstract]]COMPOSTO, COMPOSIÇÃO FARMACÊUTICA, E, MÉTODO DE TRATAMENTO DE UMA CONDIÇÃO ASSOCIADA A CÉLULAS CONTENDO FOSFATIDILSERINA INVERSA São aqui definidos compostos de dipicolilamina da Fórmula (I). São também reveladas composições farmacêuticas contendo íons metálicos e estes compostos. Além disso, é revelado um método para o tratamento de uma condição associada a células contendo fosfatidilserina inversa, com estes compostos
[[alternative]]Pyrazole compounds
No full text[[abstract]]본 발명은 말초의 카나비노이드 1 수용체에 의한 질병을 치료하는데 유용한 본 명세서에 설명된 화학식 (I)의 피라졸 화합물에 관한 것이다. 또한, 본 발명은 이러한 화합물의 사용과 관련된 약제 조성물 및 방법에 관한 것이다
Downregulation of PAX1 in OSCC Enhances Stemness and Immunosuppression via IFIT1 and PD-L1 Pathways
No full text[[abstract]]ObjectiveOur study investigated how arecoline-induced extracellular vesicle (EV) secretion suppresses PAX1 protein production through DNA hypermethylation and examined whether PAX1 downregulation enhances cancer stemness and immunosuppression in the tumor microenvironment.Materials and MethodsEVs were isolated from SAS/TW2.6 cancer cell lines using ultracentrifugation and identified using transmission electron microscopy. PAX1 DNA methylation was tested in an ISO17025-certified lab, with and without EV pretreatment. Stemness and epithelial-mesenchymal transition markers were assessed by western blotting and 3D culture. PAX1, IFIT1, and PD-L1 co-expression were examined through immunofluorescence. Flow cytometry detected various T cells.ResultsArecoline-induced EVs enhanced PAX1 methylation, suppressing its tumor-suppressive function. Reduced PAX1 mRNA in OSCCs was linked to larger tumors, nodal metastasis, late-stage disease, areca quid chewing, and poor survival. Downregulated PAX1 protein negatively correlated with IFIT1 and PD-L1 expression. Reduced PAX1 promoted stemness via the IFIT1 pathway, increasing PD-L1 secretion and aiding immune evasion. PD-L1 expression correlated with Treg and CD8+ T cell levels in OSCC tissues, and the CD4+/CD8+ T cell ratio was lower in OSCC patients than in controls.ConclusionArecoline-induced EV production, which influences PAX1/IFIT1/PD-L1 function, may serve as a reliable biomarker for targeted therapy in OSCC patients
Efficacy and safety of surgical management for Rathke's cleft cysts in pediatric patients: a systematic review and meta-analysis
No full text[[abstract]]Rathke's cleft cysts (RCCs) are benign, cystic lesions that account for less than 5% of cases in the pediatric population. While asymptomatic RCCs often require only conservative management, symptomatic cases may necessitate surgical intervention. Advances in surgical techniques have improved the safety of these procedures. This comprehensive review and single-arm meta-analysis evaluates the outcomes of surgical management in pediatric patients. PubMed, Embase, and Web of Science were systematically searched for studies documenting RCC resection in pediatric patients (< 18 years). Outcomes of interest included symptomatic improvement (headache, visual impairment, endocrinopathy), postoperative complications, postoperative diabetes insipidus (DI), recurrence, and reoperation rate. Heterogeneity was assessed using I-2 statistics, and a random-effects model was adopted. Twelve studies were included in the final analysis. The pooled proportion of headache improvement was 84% (95% CI: 73%-91%), with 65% of patients achieving complete resolution. Improvement of visual symptoms occurred in 87% of cases (95% CI: 63%-96%). The rate of improvement of endocrinopathy after surgery had an overall pooled rate of 48% (95% CI: 29%-69%). The rate of postoperative complications was 8% (95% CI: 4%-13%), and the incidence of new postoperative DI was 28% (95% CI: 18%-40%). The pooled incidence of cyst recurrence was 16% (95% CI: 11%-23%), while the incidence of reoperation was 14% (95% CI: 8%-24%).Surgery for RCC in pediatric patients offers high rates of symptomatic improvement for headaches and visual impairments, though improvement for endocrinopathy tends to be moderate. The procedure generally has a low risk of postoperative complications, but the incidence of new-onset DI is notable. While many patients experienced complete headache resolution, surgery should not be solely indicated for headache management. Surgical decisions must prioritize objective clinical factors, such as cyst characteristics, neurological impact, and endocrine dysfunction. Additionally, recurrence and reoperation rates are observed, highlighting the need for careful consideration of potential risks and individualized treatment planning. Future research should focus on refining surgical techniques and assessing long-term outcomes to optimize treatment strategies for pediatric RCC patients
Mealtime experiences during Aml/Mds treatment: Longitudinal qualitative study preliminary results
No full text[[abstract]]Older adults (aged ≥60) with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) face varied experiences related to eating and mealtimes during treatment with hypomethylating agents and Venetoclax (HMA+VEN). Family/friend carepartners may provide extensive support to patients during this time and undergo challenges of their own. A gap exists in our understanding of eating and mealtime experiences over time, and how this affects quality of life (QOL); further information is crucial to guide patients, clinicians and carepartners in their management. We aimed to understand patient’s eating and mealtime experiences with AML/MDS and their carepartners during Cycles 1 and 2 of HMA+VEN treatment, the efforts made to address challenges, and the impacts on QOL. We conducted semi-structured interviews with 11 older adult patients and ten carepartners at Cycles 1 and 2 and conducted directed content analysis with the Adaptive Leadership Framework for Chronic Illness. We identified five preliminary categories: (1) adaptive challenges for patients in eating and mealtimes, (2) changes with eating and mealtimes over Cycles 1 and 2, (3) adaptive challenges for carepartners in care of patients, (4) how they collaboratively address challenges, and (5) the impact of experiences or changes in eating and mealtimes on QOL. Findings highlight and expand our knowledge of eating/mealtime experiences during chemotherapy for patients with AML/MDS and carepartners, including their experiences with appetite loss, adaptations of meals, and the extensive involvement of carepartners. These findings may guide future intervention development to support symptom management, enhance support and services, and maintain QOL
[[alternative]]Targeted sputum sequencing for rapid and broad drug resistance of <i>Mycobacterium tuberculosis</i>
No full text[[abstract]]PurposeRapid detection of drug resistance in Mycobacterium tuberculosis (Mtb) from clinical samples facilitates the timely provision of optimal treatment regimens for tuberculosis (TB) patients.MethodsIn November, 2023, the WHO released its second catalogue of resistance-conferring mutations in Mtb. Utilizing this information, we developed a single 17-plex PCR assay covering 16 key resistance genes and modified thermo-protection buffer to amplify 30 kbp DNA directly from sputum samples for nanopore sequencing. We implemented our protocol using rapid barcoding for sequencing with both a Flongle and a MinION flow cell.ResultsThe single multiplex PCR assay was successfully validated on clinical sputum samples using the thermo-protection buffer. The protocol was applied to both Flongle and MinION flow cells, analyzing 12 and 40 samples, respectively. Data analysis suggested that optimal performance could be achieved by processing 6 and 12 samples with similar microscope staining scores on these two platforms. This approach facilitated rapid antimicrobial resistance (AMR) predictions directly from sputum on the day of collection or the following day, with a cost of less than $35 per sample. Compared to AMR predictions based on whole-genome sequencing (WGS) using Mykrobe and TBProfiler, our amplicon-based analysis tool, ARapidTb, demonstrated superior resistance detection capabilities. When analyzing publicly available nanopore WGS datasets for 442 isolates, ARapidTb achieved agreement rates of 95.8% and 98.0%, outperforming Mykrobe (89.4% and 98.3%) and TBProfiler (75.6% and 89.8%).ConclusionsOur study significantly reduces the time required for drug resistance detection, enabling quicker initiation of appropriate treatments and potentially improving patient outcomes and TB management
Concentrations, composition profiles, and in vitro–in silico-based mixture risk assessment of bisphenol A and its analogs in plant-based foods
No full text[[abstract]]The substitution of bisphenol A (BPA) with structurally similar analogs has raised concerns due to their comparable estrogenic activities. Considering the high consumption of plant-based foods, assessing the risks posed by bisphenols (BPs) in such dietary sources is essential. However, limited exposure and animal toxicological data on BP analogs hinder comprehensive risk assessments. This study investigated 16 BPs in 23 plant-based foods from Taiwan and estimated their dietary exposure across age groups. High-throughput toxicokinetic modeling was used to convert in vitro ToxCast estrogen receptor (ER) bioactive concentrations into human-equivalent points of departure (PODs), which were compared to PODs derived from animal studies and applied to assess mixture risks through the margin of exposure based on the common ER pathway. In total, 7 BPs were detected, and most samples (85.9 %) contained detectable concentrations. Total concentrations of the 7 BPs (∑7BP) ranged from 0.06 ± 0.11 ng/g to 26.60 ± 72.18 ng/g, with BPA being the most predominant (63 % of the mean ∑7BP concentrations), followed by bisphenol S (19 %) and 4,4-bisphenol F (13 %). In vitro–in silico-derived PODs were comparable to or even more protective than in vivo animal-derived PODs. For most population groups, combined exposure to multiple BPs from plant-based foods is generally not a risk concern for ER pathway perturbation, although potential concerns in worst-case scenarios cannot be excluded. This study advances the understanding of the dietary risks associated with BP mixtures and illustrates the potential of in vitro–in silico approaches for assessing human health risks from environmental contaminants
Burdens of type 2 diabetes and cardiovascular disease attributable to sugar-sweetened beverages in 184 countries
No full text[[abstract]]The consumption of sugar-sweetened beverages (SSBs) is associated with type 2 diabetes (T2D) and cardiovascular diseases (CVD). However, an updated and comprehensive assessment of the global burden attributable to SSBs remains scarce. Here we estimated SSB-attributable T2D and CVD burdens across 184 countries in 1990 and 2020 globally, regionally and nationally, incorporating data from the Global Dietary Database, jointly stratified by age, sex, educational attainment and urbanicity. In 2020, 2.2 million (95% uncertainty interval 2.0–2.3) new T2D cases and 1.2 million (95% uncertainty interval 1.1–1.3) new CVD cases were attributable to SSBs worldwide, representing 9.8% and 3.1%, respectively, of all incident cases. Globally, proportional SSB-attributable burdens were higher among men versus women, younger versus older adults, higher- versus lower-educated adults, and adults in urban versus rural areas. By world region, the highest SSB-attributable percentage burdens were in Latin America and the Caribbean (T2D: 24.4%; CVD: 11.3%) and sub-Saharan Africa (T2D: 21.5%; CVD: 10.5%). From 1990 to 2020, the largest proportional increases in SSB-attributable incident T2D and CVD cases were in sub-Saharan Africa (+8.8% and +4.4%, respectively). Our study highlights the countries and subpopulations most affected by cardiometabolic disease associated with SSB consumption, assisting in shaping effective policies and interventions to reduce these burdens globally
First detection of the S989P+V1016G+D1763Y haplotype and expansion of voltage-gated sodium channel mutations in Aedes aegypti in Taiwan in 2016-2023
No full text[[abstract]]BACKGROUND: Aedes aegypti transmits various arthropod-borne diseases such as dengue, posing a significant burden to public health in tropical and subtropical regions. Pyrethroid-based control strategies are effective in managing this vector; however, the development of insecticide resistance has hindered these efforts. Hence, long-term monitoring of insecticide resistance in mosquito populations is crucial for effective vector and disease control. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we identified insecticide resistance due to a voltage-gated sodium channel (vgsc) mutation in Ae. aegypti in Taiwan between 2016 and 2023. In total, 1,761 field-caught Ae. aegypti samples from Tainan, Kaohsiung, and Pingtung were genotyped. The frequencies of S989P, V1016G, T1520I, F1534C, and D1763Y amino acid variants increased over the surveillance period. A T1520I mutation was detected for the first time and has since rapidly spread throughout Taiwan. The triple-mutant haplotype PGTFY was first documented in Ae. aegypti. Moreover, the unmutated haplotype vanished in Taiwan, suggesting that the vgsc mutations were fixed in local populations of Ae. aegypti. Five resistance-associated genotypes, SVTCD/SVTCD, SGTFY/PGTFD, SVTCD/SGTFY, PGTFD/PGTFD, and SVTCD/PGTFD, exhibited an increased frequency and accounted for 76% of the total field population. We also detected the resistant genotype SVICD/PGTFD, and its frequency increased 13-fold in the field between 2016 and 2023. Moreover, we also observed that mutations differed geographically, with S989P mainly found in Kaohsiung and V1016G in Kaohsiung and Pingtung. The frequency of T1520I was noticeably higher in Kaohsiung, and D1763Y occurred mainly in Tainan. CONCLUSIONS/SIGNIFICANCE: The emergence and expansion of mutations along with the disappearance of wild-type mosquitoes in Taiwan underscores the threat of resistance and difficulty of mosquito control in Taiwan as well as globally. This study determined the insecticide resistance status of Ae. aegypti in Taiwan, and the findings will be helpful for resistance monitoring in areas where pyrethroids are used to control Ae. aegypti
[[alternative]]2 fused bicyclic pyrimidine compounds as aurora kinase inhibitors
No full text[[abstract]]내셔날 헬스 리서치 인스티튜트 (TW