Abstract Objective Clinical immunohistochemistry plays an increasingly important role in pathologic diagnosis. We investigated the usefulness of an immunohistochemical panel of glypican-3 (GPC3), hepatocyte paraffin antigen-1 (HepPar-1), arginase-1 (Arg-1), cytokeratin-19 (CK19), and human epithelial membrane antigen (EMA) for the differential diagnosis of liver tumors. Methods Two hundred and thirty-five immunohistochemical sections of hepatocellular carcinoma (HCC; 120 cases), intrahepatic cholangiocarcinoma (ICC; 50 cases), combined hepatocellular and cholangiocarcinoma (CHC; 17 cases), metastatic adenocarcinoma (20 cases), and benign liver lesions (28 cases) were obtained from the Department of Pathology at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. The sensitivity and specificity of the combined biomarkers GPC3/HepPar-1/Arg-1/CK19/EMA for the differential diagnosis of HCC, ICC, and CHC were calculated and analyzed retrospectively. Results The combined biomarkers GPC3 + /CK19 - had the highest specificity (98.3%) for diagnosing HCC, with a sensitivity of 60.0%. The specificity of GPC3-/HepPar-1 - /Arg-1 - /CK19 + /EMA + for diagnosing ICC was 93.0%, with a sensitivity of 76.0%. The specificity of GPC3 + /HepPar-1 + /Arg-1 + /CK19 + /EMA + for diagnosing CHC was 95.9%, with a sensitivity of 52.9%. Conclusion The combined biomarkers GPC3/HepPar-1/Arg-1/CK19/EMA greatly improved the specificity of liver tumor diagnosis. We believe that clinical pathological work could improve the original determination of liver nodules.
Abstract Background Owing to the advances in diagnosis and therapy, survival or remission rates for lymphoma have improved prominently. Apart from the lymphoma- and chemotherapy-related somatic symptom burden, increasing attention has been drawn to the health-related quality of life. The application of 18 F-fluorodeoxyglucose positron emission tomography-computed tomography ( 18 F-FDG PET/CT) has been routinely recommended for the staging and response assessment of FDG-avid lymphoma. However, up till now, only a few researches have investigated the brain metabolic impairments in patients with pre-treatment lymphoma. The determination of the lymphoma-related metabolic brain pattern would facilitate exploring the tailored therapeutic regimen to alleviate not only the physiological, but also the psychological symptoms. In this retrospective study, we aimed to establish the diffuse large B-cell lymphoma-related pattern (DLBCLRP) of metabolic brain network and investigate the correlations between DLBCLRP and several indexes of the staging and response assessment. Results The established DLBCLRP was characterized by the increased metabolic activity in bilateral cerebellum, brainstem, thalamus, striatum, hippocampus, amygdala, parahippocampal gyrus and right middle temporal gyrus and by the decreased metabolic activity in bilateral occipital lobe, parietal lobe, anterior cingulate gyrus, midcingulate cortex and medial frontal gyrus. Significant difference in the baseline expression of DLBCLRP was found among complete metabolic response (CMR), partial metabolic response (PMR) and progressive metabolic disease (PMD) groups ( P < 0.01). DLBCLRP expressions were also significantly or tended to be positively correlated with international prognostic index (IPI) ( r s = 0.306, P < 0.05), lg(total metabolic tumor volume, TMTV) ( r = 0.298, P < 0.05) and lg(total lesion glycolysis, TLG) ( r = 0.233, P = 0.064). Though no significant correlation of DLBCLRP expression was found with Ann Arbor staging or tumor SUV max ( P > 0.05), the post-treatment declines of DLBCLRP expression were significantly positively correlated with Ann Arbor staging ( r s = 0.284, P < 0.05) and IPI ( r s = 0.297, P < 0.05). Conclusions The proposed DLBCLRP would lay the foundation for further investigating the cerebral dysfunction related to DLBCL itself and/or treatments. Besides, the expression of DLBCLRP was associated with the tumor burden of lymphoma, implying a potential biomarker for prognosis.
Rationale: Clinical application of mesenchymal stem cells (MSCs) and MSC-derived exosomes (MSC-Exos) to alleviate myocardial ischemia/reperfusion (I/R) injury is compromised by the low cell engraftment rate and uncontrolled exosomal content.As one of their active ingredients, single-component microRNA therapy may have more inherent advantages.We sought to find an ideal microRNA candidate and determine whether it could reproduce the cardioprotective effects of MSCs and MSC-Exos.Methods: Cardiac function and myocardial remodeling in MSC, MSC-Exo, or microRNA oligonucleotide-treated mouse hearts were investigated after I/R injury.The effects of microRNA oligonucleotides on cardiac cells (macrophages, cardiomyocytes, fibroblasts, and endothelial cells) and their downstream mechanisms were confirmed.Large animals were also employed to investigate the safety of microRNA therapy. Results:The results showed that microRNA-125a-5p (miR-125a-5p) is enriched in MSC-Exos, and intramyocardial delivery of their modified oligonucleotides (agomir) in mouse I/R myocardium, as well as MSCs or MSC-Exos, exerted obvious cardioprotection by increasing cardiac function and limiting adverse remodeling.In addition, miR-125a-5p agomir treatment increased M2 macrophage polarization, promoted angiogenesis, and attenuated fibroblast proliferation and activation, which subsequently contributed to the improvements in cardiomyocyte apoptosis and inflammation.Mechanistically, Klf13, Tgfbr1, and Daam1 are considered the targets of miR-125a-5p for regulating the function of macrophages, fibroblasts, and endothelial cells, respectively.Similar results were observed following miR-125a-5p agomir treatment in a porcine model, with no increase in the risk of arrhythmia or hepatic, renal, or cardiac toxicity.Conclusions: This targeted microRNA delivery presents an effective and safe strategy as a stem cell and exosomal therapy in I/R cardiac repair.
Glypican-3 (GPC3) is a key member of the glypican family that is expressed on the cell surface by a glycosyl-phosphatidyl-inositol (GPI) anchor. It plays a significant role in hepatocellular carcinoma (HCC) development, angiogenesis, and metastasis. Most HCC overexpress GPC3, whereas little GPC3 can be detected in normal adult liver and benign liver lesions. Therefore, it is important to understand the function of GPC3 in HCC tumor development as the GPC3 ligand may facilitate detection of HCC. In this study, a 12-mer peptide with the sequence of DHLASLWWGTEL (denoted as TJ12P1) was identified by screening a phage display peptide library that demonstrated ideal GPC3 binding affinity. We used TJ12P1 conjugated with near-infrared fluorescent (NIFR) dye Cy5.5 for tumor imaging. After intravenous injection of the imaging agent, TJ12P1, xenografts of high GPC3 expressing hepatocellular carcinoma cell line, HepG2, demonstrated significantly higher tumor accumulation (tumor/muscle ratio: 3.98 ± 0.36) than those of low GPC3 expressing prostate cancer cell line, PC3 (tumor/muscle ratio: 2.03 ± 0.23). More importantly, GPC3 expression in tumor samples of patients could be visualized using TJ12P1, suggesting the potential use of this peptide as a probe for HCC detection. Our study has successfully identified a promising GPC3-binding peptide ligand for detecting the GPC3 expression in HCC not only in vitro but also in vivo by its noninvasive imaging.
Myopathy is an adverse effect of telbivudine. We describe a case of telbivudine-induced myopathy visualized on FDG PET/CT in a 75-year-old man with history of chronic HBV infection and hepatocellular carcinoma. FDG PET/CT images demonstrate no abnormal uptake characteristic of hypermetabolic malignancy. However, intense hypermetabolic activity in muscles of the abdominal wall was noted. Three months after telbivudine withdrawal, a second FDG PET/CT showed normal muscle activity in the abdominal wall.
Positron emission tomography (PET) is a promising modality for early diagnosis, accurate detection, and staging of hepatocellular carcinoma (HCC). Hereby, a dual-specific probe targeting Glypican-3 (GPC3) and prostate-specific membrane antigen (PSMA) was evaluated for HCC PET imaging. The probe was prepared by conjugating TJ12P2, a GPC3-targeting peptide previously reported by our group, to a highly potent PSMA inhibitor via a polyethylene glycol linker and further tethered to the 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator. The resultant probe, NOTA-TJ12P2-PSMA, abbreviated as T2P, was labeled with gallium-68 and fluorine-18, respectively, and evaluated in murine HCC models of various levels of GPC3 and PSMA expression. Targeting specificity was confirmed by blocking studies. The synthesized [
Anin vivoandin vitrotwo-step phage display screening approach to identify Glypican-3 targeting peptides for the detection of hepatocellular carcinoma with low normal liver uptake.
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