Esophageal squamous cell carcinoma (ESCC) is a world-wide prevalent cancer, which is particularly common in certain regions of Asia. Here we report the whole-exome or targeted deep sequencing of 139 paired ESCC cases, and analysis of somatic copy number variations (SCNV) of over 180 ESCCs. We identified novel significantly mutated genes such as FAT1, FAT2, ZNF750 and KMT2D, in addition to previously discovered ones (TP53, PIK3CA and NOTCH1). Further SCNV evaluation, immunohistochemistry and biological analysis suggested their functional relevance in ESCC. Notably, RTK-MAPK-PI3K pathways, cell cycle and epigenetic regulation are frequently dysregulated by multiple molecular mechanisms in this cancer. Moreover, our approaches uncovered many novel druggable candidates, and XPO1 was further explored as a therapeutic target because of its mutation and protein overexpression. Together, our integrated study unmasks a number of novel genetic lesions in ESCC and provides an important molecular foundation for understanding esophageal tumors and developing therapeutic targets.
The prognostic significance of tumor-associated FOXP3(+) regulatory T cells (Tregs) and CD8(+) cytotoxic T lymphocytes (CTLs) in invasive breast carcinomas is studied. Tregs and CTLs were assessed by immunohistochemistry in 1270 cases of invasive breast carcinoma for their associations with patient survival, histopathologic features, and molecular subtypes. Infiltrates of Tregs and CTLs were observed within tumor bed and in the tissue surrounding tumor. Within tumor bed, increased infiltration of Tregs and CTLs was significantly more common in those with unfavorable histologic features, including high histologic grade and negative ER and PR status. In addition, high density Treg infiltration was also associated with tumor HER2 overexpression, decreased overall survival (OS) and progression-free survival (PFS). In tissue surrounding tumor, in contrast, high CTL/Treg ratio was found to be significantly associated with improved OS and PFS. These prognostic associations were confirmed by multivariate analysis. Furthermore, the density of Treg infiltrates within tumors was inversely correlated with the prognosis of the molecular subtypes of tumors. The ratio of CTL/Treg infiltrates in the surrounding tissue was also significantly higher in luminal than non-luminal subtypes of carcinoma. The prognostic significances of Tregs and CTLs in breast carcinoma depend on their relative density and location. The density of intratumoral Treg infiltrates and the peritumoral CTL/Treg ratio are independent prognostic factors and correlated with the prognosis of the molecular subtypes of breast carcinoma, which may serve as potential target for stratifying immunotherapy to battle against the aggressive subtypes of breast carcinoma.
Atherosclerosis is a leading cause of vascular diseases worldwide. Whereas antioxidative therapy has been considered promising for the treatment of atherosclerosis in view of a critical role of reactive oxygen species (ROS) in the pathogenesis of atherosclerosis, currently available antioxidants showed considerably limited clinical outcomes. Herein, we hypothesize that a broad-spectrum ROS-scavenging nanoparticle can serve as an effective therapy for atherosclerosis, taking advantage of its antioxidative stress activity and targeting effects. As a proof of concept, a broad-spectrum ROS-eliminating material was synthesized by covalently conjugating a superoxide dismutase mimetic agent Tempol and a hydrogen-peroxide-eliminating compound of phenylboronic acid pinacol ester onto a cyclic polysaccharide β-cyclodextrin (abbreviated as TPCD). TPCD could be easily processed into a nanoparticle (TPCD NP). The obtained nanotherapy TPCD NP could be efficiently and rapidly internalized by macrophages and vascular smooth muscle cells (VSMCs). TPCD NPs significantly attenuated ROS-induced inflammation and cell apoptosis in macrophages, by eliminating overproduced intracellular ROS. Also, TPCD NPs effectively inhibited foam cell formation in macrophages and VSMCs by decreasing internalization of oxidized low-density lipoprotein. After intravenous (i.v.) administration, TPCD NPs accumulated in atherosclerotic lesions of apolipoprotein E-deficient (ApoE) mice by passive targeting through the dysfunctional endothelium and translocation via inflammatory cells. TPCD NPs significantly inhibited the development of atherosclerosis in ApoE mice after i.v. delivery. More importantly, therapy with TPCD NPs afforded stabilized plaques with less cholesterol crystals, a smaller necrotic core, thicker fibrous cap, and lower macrophages and matrix metalloproteinase-9, compared with those treated with control drugs previously developed for antiatherosclerosis. The therapeutic benefits of TPCD NPs mainly resulted from reduced systemic and local oxidative stress and inflammation as well as decreased inflammatory cell infiltration in atherosclerotic plaques. Preliminary in vivo tests implied that TPCD NPs were safe after long-term treatment via i.v. injection. Consequently, TPCD NPs can be developed as a potential antiatherosclerotic nanotherapy.
Inflammatory cytokines, especially tumor necrosis factor a (TNF-a), have been shown to inhibit osteogenic differentiation of mesenchymal stem cells (MSCs) and bone formation in estrogen deficiency-induced osteoporosis, but the mechanism responsible remains poorly understood. MicroRNAs (miRNAs) have been shown to regulate MSC differentiation. Here, we identified a novel mechanism whereby TNF-a, suppressing the functional axis of a key miRNA (miR-21) contributes to estrogen deficiency-induced osteoporosis. In this study, we screened differentially expressed miRNAs in MSCs derived from estrogen deficiency-induced osteoporosis and found miR-21 was significantly downregulated. miR-21 was suppressed by TNF-a during the osteogenesis of MSCs. Furthermore, miR-21 was confirmed to promote the osteoblast differentiation of MSCs by repressing Spry1, which can negatively regulate the osteogenic differentiation of MSCs. Upregulating miR-21 partially rescued TNF-a-impaired osteogenesis of MSCs. Blocking TNF-a ameliorated the inflammatory environment and significantly enhanced bone formation with increased miR-21 expression and suppressed Spry1 expression in ovariectomized (OVX) mice. Our results revealed a novel function for miR-21 and suggested that suppressed miR-21 may contribute to impaired bone formation by elevated TNF-a in estrogen deficiency-induced osteoporosis. This study may indicate a molecular basis for novel therapeutic strategies against osteoporosis and other inflammatory bone diseases. ß
Pancreatic cancer is an aggressive malignancy that is generally refractory to chemotherapy, thus posing experimental and clinical challenges. In this study, the antiproliferative effect of the triterpenoid compound cucurbitacin B was tested in vitro and in vivo against human pancreatic cancer cells. Dose-response studies showed that the drug inhibited 50% growth of seven pancreatic cancer cell lines at 10 À7 mol/L, whereas clonogenic growth was significantly inhibited at 5 Â 10 À8 mol/L. Cucurbitacin B caused dose-and timedependent G 2 -M-phase arrest and apoptosis of pancreatic cancer cells. This was associated with inhibition of activated JAK2, STAT3, and STAT5, increased level of p21 WAF1 even in cells with nonfunctional p53, and decrease of expression of cyclin A, cyclin B1, and Bcl-XL with subsequent activation of the caspase cascade. Interestingly, the combination of cucurbitacin B and gemcitabine synergistically potentiated the antiproliferative effects of gemcitabine on pancreatic cancer cells. Moreover, cucurbitacin B decreased the volume of pancreatic tumor xenografts in athymic nude mice by 69.2% (P < 0.01) compared with controls without noticeable drug toxicities. In vivo activation of JAK2/STAT3 was inhibited and expression of Bcl-XL was decreased, whereas caspase-3 and caspase-9 were up-regulated in tumors of drug-treated mice. In conclusion, we showed for the first time that cucurbitacin B has profound in vitro and in vivo antiproliferative effects against human pancreatic cancer cells, and the compound may potentate the antiproliferative effect of the chemotherapeutic agent gemcitabine. Further clinical studies are necessary to confirm our findings in patients with pancreatic cancer.
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