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헤테로사이클릭 화합물 및 이의 용도
No full text[[abstract]]화학식 I의 헤테로사이클릭 화합물이 본원에 개시되어 있다. 또한, 상기 헤테로사이클릭 화합물 중 하나를 함유하는 약제학적 조성물이 개시되어 있다. 조혈모세포(hematopoietic stem cells, HSC) 및 내피 전구세포(endothelial progenitor cells, EPC)를 말초 혈액 순환에 동원하고, 조직 손상, 암, 염증성 질환 및 자가면역질환을 치료하기 위해 상기 헤테로사이클릭 화합물 중 하나를 사용하는 방법이 또한 개시되어 있다
雜環化合物及其用途
No full text[[abstract]]本文提供一种式(I)的杂环化合物，也公开了一种包含该杂环化合物之一的药物组合物。更进一步公开了使用该杂环化合物之一用于驱动造血干细胞和内皮前驱细胞进入周边循环的方法，以及用于治疗组织伤害、癌症、发炎性疾病、和自体免疫疾病的方法
二甲基吡啶胺衍生物及其醫藥用途
No full text[[abstract]]本發明提供一種式(I)的二甲基吡啶胺化合物，另提供一種包含金屬離子和這類化合物的藥物組合物，再提供一種使用這類化合物治療與含磷脂質絲胺酸進出的細胞相關病症的方法
Pyrazole compounds
No full text[[abstract]]Compounds of formula (I): wherein R1, R2, R3, R4, R5, and X are defined herein. Also disclosed are pharmaceutical compositions and methods related to use of these compounds
[[alternative]]Heterocyclic compounds and use thereof
No full text[[abstract]]화학식 (I)의 헤테로사이클릭 화합물이 본원에 기재된다. 또한 상기 헤테로사이클릭 화합물을 함유하는 약학적 조성물과 조혈 줄기세포 및 내피 전구 세포를 말초 순환 내로 동원하기 위해 상기 헤테로사이클릭 화합물을 사용하는 방법이 개시된다. 상기 헤테로사이클릭 화합물로 조직 손상, 암, 염증 질환 및 자가면역 질환을 치료하는 방법이 더 제공된다
Reprogramming dysfunctional dendritic cells by a versatile catalytic dual oxide antigen-captured nanosponge for remotely enhancing lung metastasis immunotherapy
No full text[[abstract]]Dendritic cells (DCs) play a crucial role in initiating antitumor immune responses. However, in the tumor environment, dendritic cells often exhibit impaired antigen presentation and adopt an immunosuppressive phenotype, which hinders their function and reduces their ability to efficiently present antigens. Here, a dual catalytic oxide nanosponge (DON) doubling as a remotely boosted catalyst and an inducer of programming DCs to program immune therapy is reported. Intravenous delivery of DON enhances tumor accumulation via the marginated target. At the tumor site, DON incorporates cerium oxide nanozyme (CeO2)-coated iron oxide nanocubes as a peroxide mimicry in cancer cells, promoting sustained ROS generation and depleting intracellular glutathione, i.e., chemodynamic therapy (CDT). Upon high-frequency magnetic field (HFMF) irradiation, CDT accelerates the decomposition of H2O2 and the subsequent production of more reactive oxygen species, known as Kelvin's force laws, which promote the cycle between Fe3+/Fe2+ and Ce3+/Ce4+ in a sustainable active surface. HFMF-boosted catalytic DON promotes tumors to release tumor-associated antigens, including neoantigens and damage-associated molecular patterns. Then, the porous DON acts as an antigen transporter to deliver autologous tumor-associated antigens to program DCs, resulting in sustained immune stimulation. Catalytic DON combined with the immune checkpoint inhibitor (anti-PD1) in lung metastases suppresses tumors and improves survival over 40 days
Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells
No full text[[abstract]]Background and aimsOncogenic KRAS mutations are present in approximately 90% of pancreatic ductal adenocarcinoma (PDAC). However, Kras mutation alone is insufficient to transform precancerous cells into metastatic PDAC. This study investigates how KRAS-mutated epithelial cells acquire the capacity to escape senescence or even immune clearance, thereby progressing to advanced PDAC.MethodsSingle-cell RNA sequencing and analysis of primary PDAC tumors were conducted. Genetically engineered pancreas-specific Kras-mutated, dual specificity phosphatase-2 (Dusp2) knockout mouse models were established. Human and mouse primary pancreatic cancer cell lines were used for in vitro assessment of cancer characteristics. Tumor progression was studied via pancreas orthotopic and portal vein injection in the immune-competent mice. Clinical relevance was validated by digital spatial transcriptomic analysis of PDAC tumors.ResultsKras mutation induces the formation of pancreatic intraepithelial neoplasia (PanIN), these lesions also exhibit significant apoptotic signals. Single-cell RNA sequencing identified a subset of ERKactiveDUSP2low cells continuing to expand from early to advanced stage PDAC. In vitro and in vivo studies reveal that early infiltrating macrophage-derived tissue inhibitor of metallopeptidase 1 (TIMP-1) is the key factor in maintaining the ERKactiveDUSP2low cell population in a CD63-dependent manner. The ERKactiveDUSP2low cancer cells further exacerbate macrophage-mediated cancer malignancy, including loss of epithelial trait, increased lymphangiogenesis, and immune escape. Digital spatial profiling analysis of PDAC samples demonstrates the colocalization of TIMP-1high macrophages and CD63high cancer cells. The presence of TIMP-1high macrophages and CD63high epithelial cells correlates with poor prognosis in PDAC.ConclusionsOur study reveals the vicious cycle between early infiltrating macrophages and pancreatic cancer cells, providing a mechanistic insight into the dynamic regulation directing pancreatic cancer progression
CXCR4 antagonist-loaded nanoparticles reprogram the tumor microenvironment and enhance immunotherapy in hepatocellular carcinoma
No full text[[abstract]]Hepatocellular carcinoma (HCC) is a leading cause of cancer death that has limited treatment options for advanced stages. Although PD-1 inhibitors such as nivolumab and pembrolizumab have been approved for advanced HCC treatment, their effectiveness is often hampered by the immunosuppressive tumor microenvironment (TME), which is due to hypoxia-driven CXCL12/CXCR4 axis activation. In this study, we developed 807-NPs, lipid-coated tannic acid (TA) nanoparticles that encapsulate BPRCX807, a potent CXCR4 antagonist to target HCC. 807-NPs enhance the pharmacokinetics and improve the tumor availability of BPRCX807 without causing systemic toxicity. Our findings show that 807-NPs block the CXCR4/CXCL12 pathway, inhibiting Akt and mTOR activation in HCC cells and M2 macrophages and promoting their repolarization toward the antitumor M1 phenotype. In orthotopic murine HCC models, systemic administration of 807-NPs significantly remodeled the immunosuppressive TME by reprogramming tumor-associated macrophages (TAMs) toward an immunostimulatory phenotype and promoting cytotoxic T-cell infiltration into tumors. This led to suppressed primary tumor growth and metastasis, while enhancing the efficacy of cancer immunotherapies, including PD-1 blockade and whole-cancer cell vaccines, by promoting T-cell activation. Our work demonstrates the potential of using nanotechnology to deliver CXCR4 antagonists for cancer immunotherapy
Addressing healthcare disparities and improving osteoporosis management in rural communities: A cluster randomized control trial
No full text[[abstract]]Rural communities face healthcare challenges. This study assessed a multicomponent intervention to improve hospital visits and anti-osteoporosis medication (AOM) treatment rates. A total of 567 patients were randomized into three groups. Results showed significant improvements in hospital attendance and AOM treatment in intervention groups compared to usual care group. PURPOSE: Rural communities face limited healthcare access, financial constraints, and transportation barriers leading to health disparities. This study examined interventions that reduced health disparities in increasing the outpatient attendance and treatment rate of anti-osteoporosis medication (AOM), while identifying factors contributing to therapy refusal in rural communities. METHODS: A total of 567 patients were randomized at the community level into three groups: multicomponent integrated care (MIC), osteoporosis care only (OC), and usual care (UC). Fracture Risk Assessment Tool and dual-energy X-ray absorptiometry scans were used to evaluate the osteoporosis and osteoporotic fracture risk. High- and moderate-risk patients were advised to pursue further hospital-based assessments and treatment. Both the MIC and OC groups received five interventions to address rural barriers, including specialist access, disease education, overcoming transportation barriers, peer support, and dedicated case managers. However, UC excluded transportation assistance, peer support, and case management. Outcomes measured included outpatient attendance, AOM treatment rates, and factors affecting hospital assessment refusal, analyzed via multivariable logistic modeling. RESULTS: In the MIC group, 73.3% of patients attended the outpatient clinic and 58.6% received AOM. In the OC group, 81% patients attended and 69.3% received AOM. Conversely, in the UC group, only 4.1% attended and received AOM. Significant differences in attendance and AOM rates were found between the MIC and UC groups and between the OC and UC groups (p < .001 for both). Common barriers included beliefs that treatment was unnecessary and lack of hospital access. Risk factors hindering outpatient attendance include male sex, low education, low budget, multiple disabilities, and osteopenia diagnosis. CONCLUSION: Addressing transportation barriers and implementing dedicated case management are crucial for improving healthcare access among rural patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT05104034
Environmental exposures related to gut microbiota among children with asthma: A pioneer study in Taiwan
No full text[[abstract]]Gut microbiota plays a crucial role in human health and can be influenced by environmental factors. While past studies have examined the impact of the environment on gut microbiota, vulnerable populations have often been overlooked. This study aimed to investigate the association between environmental exposures, air pollution and greenspace, and gut microbiota in asthmatic children. Data were collected during the recovery period for 41 eligible children. Air pollution was estimated using an ensemble learning model that combined regression and machine-learning algorithms, while greenspace was quantified using the normalized difference vegetation index (NDVI) and green land-cover data. The lag effects of exposures were assessed within defined buffer zones surrounding each child's residence. A generalized additive model was applied to examine associations. Results revealed a marginally significant negative association between 1-day lag exposure to NO₂ and gut microbiota indices, such as observed bacteria (Coef.: -1.130; 95 %CI -2.287, 0.027) and bacterial richness (Coef.: -2.420; 95 %CI -4.987, 0.146). The 8-day lagged average exposure to PM(2.5) and O₃ also showed negative impacts on bacterial diversity. In contrast, the 1-month lagged average exposure to greenspace was positively associated with microbiota indices. Air pollution and greenspace were also linked to specific bacterial abundances, such as Streptococcus. This study underscores the need for further research on how environmental factors may influence immunity in asthmatic children by altering gut microbiota