Tissue hypoxia is a characteristic property of cervical cancers that makes tumors resistant to chemo- and radiation therapy. Erythropoietin (Epo) is a hypoxia-inducible stimulator of erythropoiesis. Acting via its receptor (EpoR), Epo up-regulates bcl-2 and inhibits apoptosis of erythroid cells and rescues neurons from hypoxic damage. In addition to human papillomavirus infection, increased bcl-2 expression and decreased apoptosis are thought to play a role in the progression of cervical neoplasia. Using reverse transcriptase-polymerase chain reaction and Western blotting we showed that HeLa and SiHa cervical carcinoma cells and human cervical carcinomas express EpoR, and that hypoxia enhances EpoR expression. Exogenous Epo stimulated tyrosine phosphorylation and inhibited the cytotoxic effect of cisplatin in HeLa cervical carcinoma cells. Using immunohistochemistry, we examined the expression of Epo, EpoR, p16, hypoxia-inducible factor (HIF)-1alpha, and bcl-2 in benign and dysplastic cervical squamous epithelia and invasive squamous cell carcinomas (ISCCs). EpoR expression in benign epithelia was confined to the basal cell layers, whereas in dysplasias it increasingly appeared in more superficial cell layers and showed a significant correlation with severity of dysplasia. Diffuse EpoR expression was found in all ISCCs. Expression of Epo and HIF-1alpha was increased in dysplasias compared to benign epithelia. Focal Epo and HIF-1alpha expression was seen near necrotic areas in ISCCs, and showed correlation in their spatial distribution. Significant correlation was found between expression of EpoR, and p16 and bcl-2 in benign and dysplastic squamous epithelia. Our results suggest that increased expression of Epo and EpoR may play a significant role in cervical carcinogenesis and tumor progression. Hypoxia-inducible Epo signaling may play a significant role in the aggressive behavior and treatment resistance of hypoxic cervical cancers.

The late Cenozoic extensional basins in Yunnan Province (southwestern China), which are kinematically linked with the regional strike-slip faults, can provide meaningful constraints on the fault activity history and tectonic evolution of the southeast margin of the Tibetan Plateau (SEMTP), and further on the geodynamic evolution of the Tibetan Plateau. However, this has been severely impeded by the lack of precise age constraints on the timing of fault activity. To better constrain the timing of fault activity and the tectonic rotation of SEMTP, we undertook a high-resolution magnetostratigraphic study on the Xiaolongtan Formation in the Xiaolongtan Basin, which is located at the southern tip of the Xianshuihe-Xiaojiang fault and is well-known by the presence of hominoid Lufengpithecus keiyuanensis. Rock magnetic experiments indicate that magnetite is the main remanence carrier. Correlation to the geomagnetic polarity timescale was achieved by combining magnetostratigraphic and biostratigraphic data. Our correlation suggests that the Xiaolongtan Formation sedimentary sequence spans from Chron C5Ar.1r to Chron C5n.2n, which indicates that the age of the Xiaolongtan Formation ranges from 10 Ma to 12.7 Ma, and that the ages of the two sedimentary layers possibly bearing the hominoid L. keiyuanensis are~11.6 Ma or~12.5 Ma. The basal age of the sediments is 12.7 Ma, which indicates that the activation of the southern Xianshuihe-Xiaojiang fault was initiated at this time. The overall mean paleomagnetic direction (D = 353.2°, I = 34.2°, α 95 = 2.1°, n = 166) documents a counter-clockwise vertical axis rotation of −8 ± 3°with respect to Eurasia, which is the response to the activity of the left-lateral Xianshuihe-Xiaojiang Fault.

Background: Pyroptosis is a form of cell death triggered by proinflammatory signals. Recent studies have reported that oxidized phospholipids function as caspase-11 agonists to induce noncanonical inflammasome activation in immune cells. As the levels of oxidized phospholipids derived from ox-LDL are largely elevated in atherosclerotic lesions, this study sought to determine whether oxidized lipids trigger pyroptosis and subsequent inflammation in the pathogenesis of atherosclerosis.Methods and Results: In our current study, after integrating transcriptomic data available from the Gene Expression Omnibus with data from hyperlipidemic mice and ox-LDL-treated peritoneal macrophages, we discovered that caspase-4/11-gasdermin D-associated inflammatory signaling was significantly activated. Consistently, the mRNA expression of caspase-4 and gasdermin D was upregulated in peripheral blood mononuclear cells from patients with coronary heart disease. In particular, the expression of caspase-4 was closely associated with the severity of lesions in the coronary arteries. An in vivo study showed that caspase-11-gasdermin D activation occurred in response to a high-fat/high-cholesterol (HFHC) diet in ApoE−/− mice, while caspase-11 deletion largely attenuated the volume and macrophage infiltration of atherosclerotic lesions. An in vitro mechanistic study showed that caspase-11-mediated inflammation occurred partly via gasdermin D-mediated pyroptosis in macrophages. Suppressing gasdermin D in HFHC-fed ApoE−/− mice via delivery of an adeno-associated virus markedly decreased lesion volume and infiltrating macrophage numbers.Conclusion: Caspase-11-gasdermin D-mediated pyroptosis and the subsequent proinflammatory response in macrophages are involved in the pathogenesis of atherosclerosis. Therefore, targeting the caspase 11-gasdermin D may serve as an alternative strategy for the treatment of atherosclerosis.