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Caspase-4 (CASP4) is a member of the inflammatory caspase subfamily and promotes inflammation. Here, we report that CASP4 in lung adenocarcinoma cells contributes to both tumor progression via angiogenesis and tumor hyperkinesis and tumor cell killing in response to high interferon (IFN)-γ levels. We observe that elevated CASP4 expression in the primary tumor is associated with cancer progression in patients with lung adenocarcinoma. Further, CASP4 knockout attenuates tumor angiogenesis and metastasis in subcutaneous tumor mouse models. CASP4 enhances the expression of genes associated with angiogenesis and cell migration in lung adenocarcinoma cell lines through nuclear factor kappa-light chain-enhancer of activated B cell signaling without stimulation by lipopolysaccharide or tumor necrosis factor. CASP4 is induced by endoplasmic reticulum stress or IFN-γ via signal transducer and activator of transcription 1. Most notably, lung adenocarcinoma cells with high CASP4 expression are more prone to IFN-γ-induced pyroptosis than those with low CASP4 expression. Our findings indicate that the CASP4 level in primary lung adenocarcinoma can predict metastasis and responsiveness to high-dose IFN-γ therapy due to cancer cell pyroptosis. Our findings indicate that the CASP4 level in primary lung adenocarcinoma can predict metastasis and responsiveness to high-dose IFN-γ therapy due to cancer cell pyroptosis. [ABSTRACT FROM AUTHOR]

Introduction: Sarcopenia is a complication of Chronic Obstructive Pulmonary Disease (COPD) that negatively affects physical activity and quality of life. However, the underlying mechanism by which COPD affects skeletal muscles remains to be elucidated. Therefore, we investigated the association between oxidative stress and structural alterations in muscles in elastase-induced emphysema mouse models. Materials and methods: Twelve-week-old male C57BL/6J mice were treated with either intratracheal porcine pancreatic elastase (PPE) dissolved in saline, or saline alone. The mice were euthanized 12 weeks after treatment, and the lungs and limb muscles were used for protein analysis of oxidative stress, p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway and muscle atrophy signaling pathway related with oxidative stress. Furthermore, C57BL/6J mice treated with PPE or saline were analyzed for the effects of oral administration of astaxanthin or p38 inhibitor. Results: The weight of the soleus muscle, proportion of type I muscle fibers, and cross-sectional areas of muscle fibers in the PPE group were lower than those in the control group. Oxidative stress marker levels in the PPE group were elevated in skeletal muscles. The p38 MAPK signaling pathway was activated in the soleus muscles, leading to the activation of the ubiquitin–proteasome system and autophagy. Astaxanthin and p38 inhibitors attenuated alterations in muscle structure through the deactivation of the p38 MAPK signaling pathway. Conclusions: This study provides first evidence in COPD mouse model that oxidative stress trigger a series of muscle structural changes. Our findings suggest a novel target for sarcopenia in COPD. [ABSTRACT FROM AUTHOR]

Systematic geochronology and geochemistry were performed on the volcanic rocks in the Ganhe area, northern Great Xing'an Range, northeastern China. Zircon U–Pb data indicate that there are three periods of volcanism in the Ganhe area, namely the Manketouebo Formation (166.3 ± 2.5 Ma), Manitu Formation (155.2 ± 1.4 Ma), and Baiyingaolao Formation (123.3 ± 1.0 Ma). The rhyolites of Manketouebo Formation and Baiyingaolao Formation exhibit chemical affinities to A-type granites, implying an extensional environment. Their geochemical features indicate that they are the result of the partial melting of the crust. The andesites of Manitu Formation exhibit chemical affinities to the magmatic rocks associated with a subduction zone. Their geochemical features indicate that they were generated by partial melting of a mantle wedge that had been metasomatized by subduction fluids or subducted oceanic slab. According to the geochemical features of coeval igneous rocks from the northern Great Xing'an Range and its adjacent areas, we propose that the Manketouebo Formation was generated in a continental back-arc extensional setting caused by the subduction of the Mongolia-Okhotsk plate, the Manitu Formation was related to the subduction zone metasomatism caused by the southward subduction of Mongolia-Okhotsk plate, and the Baiyingaolao Formation was generated in a continental back-arc extensional setting caused by the westward subduction of Paleo-Pacific slab or a post-collisional extensional setting after the closure of Mongolia-Okhotsk Ocean. [ABSTRACT FROM AUTHOR]

The roles of endogenous nitric oxide (NO) derived from the entire NO synthases (NOSs) system have yet to be fully elucidated. We addressed this issue in mice in which all three NOS isoforms were deleted. Under basal conditions, the triple n/i/eNOSs−/− mice displayed significantly longer mean alveolar linear intercept length, increased alveolar destructive index, reduced lung elastic fiber content, lower lung field computed tomographic value, and greater end-expiratory lung volume as compared with wild-type (WT) mice. None of single NOS−/− or double NOSs−/− genotypes showed such features. These findings were observed in the triple n/i/eNOSs−/− mice as early as 4 weeks after birth. Cyclopaedic and quantitative comparisons of mRNA expression levels between the lungs of WT and triple n/i/eNOSs−/− mice by cap analysis of gene expression (CAGE) revealed that mRNA expression levels of three Wnt ligands and ten Wnt/β-catenin signaling components were significantly reduced in the lungs of triple n/i/eNOSs−/− mice. These results provide the first direct evidence that complete disruption of all three NOS genes results in spontaneous pulmonary emphysema in juvenile mice in vivo possibly through down-regulation of the Wnt/β-catenin signaling pathway, demonstrating a novel preventive role of the endogenous NO/NOS system in the occurrence of pulmonary emphysema. [ABSTRACT FROM AUTHOR]

Joint contracture leads to major patient discomfort. Metformin, one of the most extensively used oral drugs against type 2 diabetes has recently been found to suppress tissue fibrosis as well. However, its role in suppressing tissue fibrosis in joint contractures remains unknown. In this study, we examined the role of metformin treatment in suppressing joint capsular fibrosis and the most effective time of its administration. Joint capsular fibrosis was induced by immobilizing the knee joints of mice using splints and tapes. Metformin was administered intraperitoneally every alternate day after immobilization. Histological and immunohistochemical changes and expression of fibrosis-related genes were evaluated. Metformin treatment significantly suppressed fibrosis in joint capsules based on histological and immunohistochemical evaluation. Joint capsular tissue from metformin-treated mice also showed decreased expression of fibrosis-related genes. Early, but not late, metformin administration showed the same effect on fibrosis suppression in joint capsule as the whole treatment period. The expression of fibrosis-related genes was most suppressed in mice administered with metformin early. These studies demonstrated that metformin treatment can suppress joint capsular fibrosis and the most effective time to administer it is early after joint immobilization; a delay of more than 2 weeks of administration is less effective. [ABSTRACT FROM AUTHOR]

The Middle Triassic Laojiagou porphyry Mo deposit is located in the Xilamulun metallogenic belt, along the northern margin of the North China Craton (NCC). Molybdenum mineralization is associated with a monzogranite porphyry and occurs primarily in quartz veins and veinlets hosted in wall rocks affected by potassic, silicic, sericitic, and propylitic alteration. The ore-forming process is divided into three stages, characterized by veinlets comprising molybdenite + pyrite + quartz (stage I), pyrite + chalcopyrite + molybdenite + quartz (stage II), and pyrite + quartz (sulfide-poor) (stage III). We identify three fluid inclusion types in quartz grains: carbonic (C-type), liquid-rich two-phase (L-type), and rare vapor-rich two-phase (V-type) inclusions. Microthermometric results indicate that an initial high-temperature (> 350 °C) and low-salinity (< 10 wt% NaCl equiv.) CO2-rich fluid evolved to a low-temperature (< 280 °C) and CO2-poor fluid, comprising dominantly of meteoric water. Hydrogen and oxygen isotopes indicate that initial ore-forming fluids were magmatic and became progressively mixed with meteoric water (stage I δ18OH2O = 4.4–4.8‰ and δDH2O = − 105.8 to − 101.5‰). Zircon U–Pb dating indicates that the monzogranite porphyry formed at 232.2 ± 3.6 Ma (MSWD = 0.88). The porphyry has high SiO2, K2O, and Al2O3 and low MgO and CaO concentrations and is classified as high-K calc-alkaline and weakly peraluminous. All samples are enriched in light rare earth and large-ion lithophile elements and depleted in high-field-strength elements. Our results indicate that the Laojiagou porphyry Mo deposit formed in the Middle Triassic, associated with post-orogenic extension following closure of the Palaeo-Asian Ocean. [ABSTRACT FROM AUTHOR]

Background: Asthma is characterized by airflow limitation with chronic airway inflammation, hyperresponsiveness and mucus hypersecretion. NO is generated by three nitric oxide synthase (i/n/eNOSs) isoforms, but conflicting results have been reported using asthmatic mice treated with NOSs inhibitors and NOS-knockout mice. To elucidate the authentic role of NO/NOSs in asthma, we used asthmatic mice lacking all NOSs (n/i/eNOS). Methods: Wild-type and n/i/eNOS mice were sensitized and challenged with ovalbumin. Pathological findings and expressions of interferon (IFN)-γ, interleukin (IL)-4, -5, -10, -13 and chemokines in the lung were evaluated. Results: Decreased eosinophilic inflammation, bronchial thickening and mucus secretion, IL-4, -5 and -13, monocyte chemoattractant protein-1, eotaxin-1 and thymus and activation-regulated chemokine expressions were observed in n/i/eNOS mice compared to wild-type, but expressions of IFN-γ and IL-10 were similar. Conclusion: Using asthmatic n/i/eNOS mice, NO plays important roles in accelerating bronchial eosinophilic inflammation and mucus hypersecretion in the pathophysiology of asthma. [ABSTRACT FROM AUTHOR]

The polypeptide N-acetylgalactosaminyltransferase (GalNAc-Ts) family of enzymes regulates the critical initial steps of mucin-type O-glycosylation. Among GalNAc-Ts that may significantly influence cancer biology, thus affecting cell differentiation, adhesion, invasion, and/or metastasis, GalNAc-T3 exhibits a high expression in several human cancers, closely associated with tumor progression and a poor prognosis. However, the expression pattern of GalNAc-T3 in oral squamous cell carcinoma (OSCC) remains obscure. Since postoperative recurrence of even early stage OSCC (ESOSCC) occurs at an early phase, significantly affecting their clinical course and worse outcome, the identification of clinically significant accurate biomarkers is needed. Therefore, we investigated the correlation between the immunohistochemical GalNAc-T3 expression and various clinicopathological characteristics and recurrence using 110 paraffin-embedded tumor samples obtained from patients with surgically resected ESOSCC (T1-2N0). Recurrence was recognized in 37 of 110 (33.6 %) patients. The GalNAc-T3 expression was considered to be strongly positive when 20 % or more of the cancer cells showed positive cytoplasmic staining. Consequently, a strong expression of GalNAc-T3 was observed in 40 patients (36.4 %), showing a close relationship to poor differentiation, the presence of lymphatic and vascular invasion, and recurrence. Univariate and multivariate analyses further demonstrated that the patients with a strong GalNAc-T3+ status had markedly lower disease-free survival (DFS) rates, especially within the first 2 years postoperatively. Therefore, GalNAc-T3 might play a role in the pathogenesis of ESOSCC recurrence, and its immunohistochemical detection potentially predicts a shorter DFS and may be a useful parameter for providing clinical management against ESOSCC in the early postoperative phase. [ABSTRACT FROM AUTHOR]

High-mobility group box (HMGB) proteins are ubiquitous, abundant nuclear non-histone chromosomal proteins that play a critical role in binding to distorted DNA structures and subsequently regulating DNA transcription, replication, repair, and recombination. Both HMGB1 and HMGB2 exhibit a high expression in several human cancers and are closely associated with tumor progression and a poor prognosis. However, the expression patterns of these molecules in pancreatic ductal adenocarcinoma (PDAC) remain to be elucidated. As most cases of postoperative relapse of PDAC occur within the first 2 years, the clinical significance of accurate biomarkers is needed. Therefore, we investigated the correlation between the immunohistochemical HMGB1 and HMGB2 expression and the clinicopathological characteristics and prognosis using 62 paraffin-embedded tumor samples obtained from patients with surgically resected PDAC. The HMGB1/2 expression was considered to be positive when 10 % or more of the cancer cells showed positive nuclear, not merely cytoplasmic, staining. Consequently, the expression of HMGB1/2 was observed in 54 (87.1 %) and 31 (50.0 %) patients, respectively. Unexpectedly, a positive HMGB1 expression was found to have a significantly close relationship with a negative HMGB2 expression. The univariate and multivariate analyses demonstrated that the patients with a HMGB1+ and HMGB2− status had markedly lower disease-specific survival rates, especially within the first 2 years postoperatively, whereas those with a HMGB1+ status alone did not. Therefore, the combination of a HMGB1+ and HMGB2− expression potentially predicts a poor prognosis in patients with PDAC, and these new biomarkers may be useful parameters for clinical management in the early postoperative phase. [ABSTRACT FROM AUTHOR]

The Angeer Yinwula Pb-Zn deposit of Inner Mongolia, China, is located in the Erlianhot-Dongwuqi metallogenic belt, which is considered to be the eastern part of the Central Asian Orogenic Belt. We used the ore geology, fluid inclusion, isotopes, and zircon U-Pb geochronology to elucidate the genesis and tectonic setting of the deposit. The deposit belongs to the moderate-temperature hydrothermal-vein type, and most of the ore bodies occurred in the quartz diorite intrusions and silty slate country rocks of the Devonian Angeer Yinwula Group. Fluid inclusion petrography and microthermometry results show that the inclusions that developed in the different mineralization stages changed from the LV type (vapor-rich two-phase) + S type (daughter-mineral-bearing three-phase) + VL type (liquid-rich two-phase) to the VL type + LV type and eventually evolved into the VL type, and the ore-forming fluids changed from a moderate-temperature and moderate- to high-salinity, boiling fluid system to a low-temperature and low-salinity H2O-NaCl system. The isotope (C, H, O, S) characteristics suggest that the ore-forming fluids were derived from a magmatic source, and the lead was derived from a deep-seated mantle-derived magma and also included some crustal material. The LA-ICP-MS zircon U-Pb age of the quartz diorite is 152.0 ± 1.5 Ma, which is the best estimate for the age of mineralization of the deposit. Overall, we suggest that the deposit formed in a Late Jurassic Paleo-Pacific Plate subduction setting, although this hypothesis needs to be further tested by conducting computational simulations in the field of emerging computational geosciences. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a lifestyle-related disease that develops in middle-aged and older adults, often due to smoking habits, and has been noted to cause bone fragility. COPD is a risk factor for osteoporosis and fragility fracture, and a high prevalence of osteoporosis and incidence of vertebral fractures have been shown in patients with COPD. Findings of lung tissue analysis in patients with COPD are primarily emphysema with a loss of alveolar septal walls, and the severity of pulmonary emphysema is negatively correlated with thoracic spine bone mineral density (BMD). On the other hand, epidemiological studies on COPD and fracture risk have reported a BMD-independent increase in fracture risk; however, verification in animal models and human bone biopsy samples has been slow, and the essential pathogenesis has not been elucidated. The detailed pathological/molecular mechanisms of musculoskeletal complications in patients with COPD are unknown, and basic research is needed to elucidate the mechanisms. This paper discusses the impacts of COPD on bone strength, focusing on findings in animal models in terms of bone microstructure, bone metabolic dynamics, and material properties. [ABSTRACT FROM AUTHOR]