Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest human malignancies with poor patient outcomes often resulting from delayed diagnosis. Therefore, early diagnosis can lead to a better prognosis and improved outcomes. In this study, we have developed a novel conjugate complex of plectin/integrin-targeted bispecific molecular probe , termed Gd-Cy7-PTP/RGD, to be used for magnetic resonance/near-infrared imaging (MRI/NIRF) of pancreatic cancer in vivo . This bispecific molecular probe comprises four parts: Gd(III) for MRI, cyanine 7 (Cy7) for NIRF, the peptide PTP for binding to plectin-1 specifically overexpressed on the surface of PDAC cells, and the peptide RGD for targeting integrin widely expressed on pancreatic duct epithelial cells and angiogenesis . Remarkably, the combination of PTP and RGD greatly increased the targeting efficiency in vitro and in vivo compared to that of either single peptide. Moreover, such bispecific molecular probes target pancreatic neoplasms and angiogenesis simultaneously, producing a “multi-level” targeting effect confirmed by immunofluorescence testing in vitro and in vivo . Under the guidance of MRI/NIRF dual-modality imaging, NIRF-guided delineation of surgical margins during operations was successfully achieved in orthotopic pancreatic cancer. This study promotes further exploration of bispecific molecular probes for clinical application.
ObjectiveThis study aimed to characterize molecular subtypes of Papillary thyroid carcinoma (PTC) and identify novel therapeutic targets and potential therapeutic compounds.MethodsWe performed integrative analysis of TCGA data, including consensus clustering, mutational profiling, copy number variation (CNV) analysis, functional enrichment (GO and GSEA), and immune microenvironment assessment (CIBERSORT). Validation utilized GEO datasets. The biological function of Plectin (PLEC) was investigated through expression analysis (TCGA, GEO, qRT-PCR and IHC), association with clinical parameters, and functional experiments such as siRNA knockdown or overexpression of PLEC in TPC-1 and B-CPAP cell lines assessing cell growth, proliferation, apoptosis, and migration both in vitro and in vivo. Drug candidates targeting PLEC were screened (DGIdb and DrugMap) and validated via molecular docking, dynamics simulations (RMSD, RMSF and Rg), and rescue experiments. Favorable biosafety was tested by ELISA kits and H&E staining.ResultsConsensus clustering revealed four stable molecular subtypes (A1-A4) with distinct mutational landscapes (e.g., prevalent BRAF mutations (59%), subtype-specific alterations in CAND1/PCDH11X (A1) and PTEN (A4)), CNV gains (e.g., A1: 2p16.1/19p13.3), and immune features (A3 enriched in immune pathways). PLEC is up-regulated in PTC tissues compared with non-tumor thyroid tissues and was associated with lymph node metastasis, histological type, and residual tumor status in TCGA-THCA. Knockdown of PLEC significantly suppressed PTC cell growth, proliferation, and migration while inducing apoptosis. Whereas PLEC overexpression partially reversed these phenotypes. Among FDA-approved drugs predicted to target PLEC, Troglitazone exhibited the lowest binding affinity (-7.5 kcal/mol). Troglitazone’s anti-tumor effects (inhibiting proliferation/migration, inducing apoptosis) were partially reversed by PLEC overexpression, suggesting that PLEC may participate in Troglitazone-associated anti-PTC effects.ConclusionThese findings identify PLEC as a candidate molecule associated with aggressive PTC phenotypes and provide preliminary evidence supporting its biological relevance, although larger independent cohorts are required to validate its clinical significance.
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