ABSTRACT
Head and Neck Squamous Cell Carcinoma (HNSCC) remains a significant health burden due to tumor heterogeneity and treatment resistance, emphasizing the need for improved biological understanding and tailored therapies. This study enrolled 31 HNSCC patients for the establishment of patient-derived tumor organoids (PDOs), which faithfully maintained genomic features and histopathological traits of primary tumors. Long-term culture preserved key characteristics, affirming PDOs as robust representative models. PDOs demonstrated predictive capability for cisplatin treatment responses, correlating ex vivo drug sensitivity with patient outcomes. Bulk and single-cell RNA sequencing unveiled molecular subtypes and intratumor heterogeneity (ITH) in PDOs, paralleling patient tumors. Notably, a hybrid epithelial-mesenchymal transition (hEMT)-like ITH program is associated with cisplatin resistance and poor patient survival. Functional analyses identified amphiregulin (AREG) as a potential regulator of the hybrid epithelial/mesenchymal state. Moreover, AREG contributes to cisplatin resistance via EGFR pathway activation, corroborated by clinical samples. In summary, HNSCC PDOs serve as reliable and versatile models, offer predictive insights into ITH programs and treatment responses, and uncover potential therapeutic targets for personalized medicine.
ABSTRACT
Objective To study the spatial distribution characteristics of liver cancer in Guangxi so as to provide evidence for the development of congol and prevention on liver cancer.Methods The average eight year morbidity was computed,using the rates of liver cancer in 2000-2007.The spatial statistics module of GIS was used to conduct spatial autocorrelation analysis.and the disease mapping Was drawn,using the Map Info 8.0 software.Results The average morbidity rate Was clustered in Guangxi in the past eight years.with Moran's I index as 0.34 and P value below 0.01.G index appeared to be 0.77 and the Pvalue Was below 0.01.Moran's I correlogram lifled up in four spaces,specifically,the cluster took place in both nlacro-scale(one to three spatial intervals,45 to 135 km real Scale)and micro-scale(16 to 18 spatial intervals,720 to 800 km real scale).When the spatial interval became 14 and real scale was 60 km.the spatial distribution of liver cancer showed the most intensive autocorrelation.Most of the regions with high morbidity would be clustered in the southwest and southern parts,along the Coastal areas of Guangxi while the regions with low morbidity clustered in the northern part of Guangxi.Conclusion Liver cancer was found un-randorely distributed and geographitally clustered in Guangxi in 2000-2007.
ABSTRACT
<p><b>OBJECTIVE</b>To investigate effect of inhibiting melatonin biosynthesis on activities of protein kinase A (PKA), glycogen synthase kinase-3 (GSK-3) and tau phosphorylation at PS214 and M4 epitopes using haloperidol, a specific inhibitor of 5-hydroxyindole-O-methyltransferase.</p><p><b>METHODS</b>Brain ventricular and intraperitoneal injections were used for haloperidol administration, Western blots for tau phosphorylation, 32P-labeling for PKA and GSK-3 activity, and high performance liquid chromatograph for detection of serum melatonin levels.</p><p><b>RESULTS</b>Haloperidol injection through the lateral ventricle and intraperitoneal reinforcement significantly stimulated PKA activity with a concurrent hyperphosphorylation of tau at M4 (Thr231/Ser235) and PS214 (Ser214) sites. Prior treatment of the rats using melatonin supplement for one week and reinforcement during the haloperidol administration arrested PKA activity and attenuated tau hyperphosphorylation. GSK-3 activity showed no obvious change after haloperidol injection, however, melatonin supplements and reinforcements during haloperidol infusion inactivated basal activity of GSK-3.</p><p><b>CONCLUSION</b>Decreased melatonin may be involved in Alzheimer-like tau hyperphosphorylation, and overactivation of PKA may play a crucial role in this process.</p>