Description: ABSTRACT Acute lung injury (ALI) is a serious inflammatory disorder which remains the primary cause of incidence and mortality in patients with acute pulmonary inflammation. However, there is still no effective medical strategy available clinically for the improvement of ALI. Wogonin, isolated from roots of Scutellaria baicalensis Georgi, is a common medicinal herb which presents biological and pharmacological effects, including antioxidation, anti-inflammation, and anticancer. Preadministration of wogonin inhibited not only lung edema but also protein leakage into the alveolar space in murine model of lipopolysaccharide (LPS)-induced ALI. Moreover, wogonin not only reduced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)−2 but also inhibited the phosphorylation of mitogen-activated protein kinase (MAPK) induced by LPS. We further found wogonin inhibited the phosphorylation of p38 MAPK and JNK at a concentration lower than ERK. In addition, inhibition of lung edema, protein leakage, expression of iNOS and COX-2, and phosphorylation of p38 MAPK and JNK were all observed in a parallel concentration-dependent manner. These results suggest that wogonin possesses potential protective effect against LPS-induced ALI via downregulation of iNOS and COX-2 expression by blocking phosphorylation of p38 MAPK and JNK. © 2016 Wiley Periodicals, Inc. Environ Toxicol, 2016.

Description: Valproic acid (VPA), with inhibition activity mainly towards histone deacetylase (HDAC) and Glycogen Synthase Kinase (GSK)-3, and lithium, with inhibition activity mainly toward GSK-3, are both prescribed in clinical as mood-stabilizers and anticonvulsants for the control of bipolar disorder. This study aims to compare the immuno-modulation activities of VPA and lithium, especially on the differentiation and functions of dendritic cells (DC). Our data show that treatment with VPA or lithium effectively alleviated the severity of collagen-induced arthritis triggered by LPS in mice. Both agents reduced the serum level of IL-6 and IL-10 after LPS challenge in mice. VPA and lithium both induce significant down-regulation of group I CD1 expression and secretion of IL-6 during differentiation of human monocyte-derived immature DC, while they differ in the induction of CD83 and CD86 expression, secretion of IL-8, IL-10, and TNF-α. Upon stimulation of immature DC with LPS, VPA and lithium both reduced the secretion of IL-6 and TNF-α. However, only lithium significantly increased the production of IL-10, while VPA increased the production of IL-8 but substantially reduce the secretion of IL-10 and IL-23. Treatment with VPA resulted in a reduced capacity of LPS-stimulated DC to promote the differentiation of T helper 17 cells that are critical in the promotion of inflammatory responses. Taken together, our results suggest that VPA and lithium may differentially modulate inflammation through regulating the capacity of DC to mediate distinct T cell responses, and they may provide a complementary immunomodulatory effects for the treatment of inflammation-related diseases. This article is protected by copyright. All rights reserved

Description: ABSTRACT Cells switch to anaerobic glycolysis when there is a lack of oxygen during brain ischemia. Extracellular pH thus drops and such acidosis causes neuronal cell death. The fate of astrocytes, mechanical and functional partners of neurons, in acidosis is less studied. In this report we investigated the signaling in acidosis-challenged rat cortical astrocytes and whether these signals were related to mitochondrial dysfunction and cell death. Exposure to acidic pH (6.8, 6.0) caused Ca 2+ release and influx, p38 MAPK activation and Akt inhibition. Mitochondrial membrane potential was hyperpolarized after astrocytes were exposed to acidic pH as soon as 1 h and lasted for 24 h. Such mitochondrial hyperpolarization was prevented by SC79 (an Akt activator) but not by SB203580 (a p38 inhibitor) nor by cytosolic Ca 2+ chelation by BAPTA, suggesting that only the perturbation in Akt signaling was causally related to mitochondrial hyperpolarization. SC79, SB203580 and BAPTA did not prevent acidic pH-induced cell death. Acidic pH suppressed ROS production, thus ruling out the role of ROS in cytotoxicity. Interestingly, pH 6.8 caused an increase in ADP/ATP ratio and apoptosis; pH 6.0 caused a further increase in ADP/ATP ratio and necrosis. Therefore, astrocyte cell death in acidosis did not result from mitochondrial potential collapse; in case of acidosis at pH 6.0, necrosis might partly result from mitochondrial hyperpolarization and subsequent suppressed ATP production. This article is protected by copyright. All rights reserved

Description: Our previous hybrid simulation [ Shi et al. , 2013] under a radial interplanetary magnetic field (IMF) and a supercritical solar wind Mach number has shown that foreshock compressional waves originated from the quasi-parallel (Q-∥) shock are mode converted to kinetic Alfvén waves (KAWs) at the Alfvén resonance surface of the subsolar magnetopause. In this paper, three-dimensional global dayside mode conversion is investigated for cases under various solar wind conditions using the global hybrid model. The global patterns and propagations of KAWs are distinguished and presented. Under a near-critical Mach number ( M A =3), KAW structures due to mode conversion exhibit a feature of broader excitation regions in the magnetopause boundary layer (MPBL) compared to super-critical Mach number ( M A =5) shocks. For cases with an oblique IMF with supercritical Mach numbers ( M A =5), the amplitude of magnetosheath compressional waves is larger at the quasi-parallel shock (Q-∥) than at the quasi-perpendicular (Q-⊥) shock. Downstream of the Q-∥ shock, there is a general trend that the perturbations of density ( N ) and magnetic field ( B ) change from predominantly in-phase in the magnetosheath to anti-phase near the MPBL. While downstream of the Q-⊥ shock, an anti-phase relation between N and B is dominant throughout the magnetosheath and magnetopause except near the shock transition. The compressional drivers are found to reach an extended region of the magnetopause due to the combined effects of wave propagation in the plasma frame and flow convection, leading to a broad region of mode conversion at the magnetopause. Subsequently, the resulting KAWs can be carried to the regions downstream of the Q-⊥ shock owing to the ïňĆow convection at the magnetopause. The KAWs propagate poleward along the geomagnetic field lines and meanwhile are carried tailward by the ambient flows, and they are more intense in the downstream of Q-∥ shocks than downstream of Q-⊥ shocks.

Description: BACKGROUND Stereotactic radiosurgery (SRS) alone is an increasingly accepted treatment for brain metastases, but it requires adherence to frequently scheduled follow-up neuroimaging because of the risk of distant brain metastasis. The effect of disparities in access to follow-up care on outcomes after SRS alone is unknown. METHODS This retrospective study included 153 brain metastasis patients treated consecutively with SRS alone from 2010 through 2016 at an academic medical center and a safety-net hospital (SNH) located in Los Angeles, California. Outcomes included neurologic symptoms, hospitalization, steroid use and dependency, salvage SRS, salvage whole-brain radiotherapy, salvage neurosurgery, and overall survival. RESULTS Ninety-three of the 153 patients were private hospital (PH) patients, and 60 were SNH patients. The median follow-up time was 7.7 months. SNH patients received fewer follow-up neuroimaging studies (1.5 vs 3; P  = .008). In a multivariate analysis, the SNH setting was a significant risk factor for salvage neurosurgery (hazard ratio [HR], 13.65; P  〈 .001), neurologic symptoms (HR, 3.74; P  = .002), and hospitalization due to brain metastases (HR, 6.25; P  〈 .001). More clinical visits were protective against hospitalizations due to brain metastases (HR, 0.75; P  = .002), whereas more neuroimaging studies were protective against death (HR, 0.65; P  〈 .001). CONCLUSIONS SNH patients with brain metastases treated with SRS alone had fewer follow-up neuroimaging studies and were at higher risk for neurologic symptoms, hospitalization for brain metastases, and salvage neurosurgery in comparison with PH patients. Clinicians should consider the practice setting and patient access to follow-up care when they are deciding on the optimal strategy for the treatment of brain metastases. Cancer 2017; . © 2017 American Cancer Society .

Description: Oral squamous cell carcinoma (OSCC) is a common human malignant tumor with high mortality. So far, the molecular pathogenesis of OSCC remains largely unclear. Heterogeneous nuclear ribonucleoprotein (HnRNP) A1 is an important multi-function splicing factor and closely related to tumorigenesis. HnRNP A1 is overexpressed in various tumors, and promotes aerobic glycolysis and elongation of telomere, but the function of hnRNP A1 in cell cycle and proliferation remains unclear. We found that hnRNP A1 was overexpressed in OSCC tissues, and was required for the growth of OSCC cells. Moreover, hnRNP A1 was highly expressed in the G2/M cell cycle phase. Knockdown of hnRNP A1 induced G2/M arrest. DNA microarray assay result showed that hnRNP A1 regulated the expression of a number of target genes associated with G2/M phase. Moreover, hnRNP A1 controlled the alternative splicing of CDK2 exon 5. These findings suggested that hnRNP A1 plays key roles in the regulation of cell cycle progression and pathogenesis of OSCC. This article is protected by copyright. All rights reserved

Description: BACKGROUND Epithelioid inflammatory myofibroblastic sarcoma (E-IMS) is a recently established rare variant of inflammatory myofibroblastic tumor. It is characterized by a distinctive constellation of clinical, pathological, and molecular features, including a nearly exclusive intraabdominal location, strong male predilection, aggressive clinical course, predominance of epithelioid tumor cells, and Ran-binding protein 2 ( RANBP2 ) - anaplastic lymphoma kinase ( ALK ) fusion in the majority of cases. To the authors’ knowledge, the cytologic features of E-IMS have not been described to date. METHODS Cases of E-IMS that had corresponding cytology were searched. Six cytology samples (1 fine-needle aspiration sample, 2 imprint samples, and 3 effusion fluids) containing tumor cells were identified in 5 patients with E-IMS. RESULTS The cytomorphology included large monotonous epithelioid cells arranged in loose aggregates or singly, with admixed myxoid stroma, and an inflammatory background rich in neutrophils. The tumor cells had a large, round, eccentric nucleus with vesicular chromatin, prominent nucleoli, and moderate amounts of pale cytoplasm. Delicate thin-walled branching vessels traversing tumor aggregates was a prominent feature in a fine-needle aspiration sample. Immunohistochemically, ALK was positive in all 5 tumors, with a nuclear membranous staining pattern noted in 3 cases and a cytoplasmic pattern observed in the other 2 cases. ALK rearrangement was confirmed in all 5 tumors by molecular genetic studies. CONCLUSIONS The cytologic features of E-IMS recapitulate its histologic characteristics. E-IMS merits inclusion in the differential diagnosis of any intraabdominal, large epithelioid cell neoplasm. Confirmation of ALK rearrangement is advisable because patients may benefit from targeted therapies. Cancer (Cancer Cytopathol) 2015 . © 2015 American Cancer Society .

Description: Manganese-enhanced MRI studies have proven to be useful in monitoring physiological activities associated with calcium ions (Ca 2+ ) due to the paramagnetic property of the manganese ion (Mn 2+ ), which makes it an excellent probe of Ca 2+ . In this study, we developed a method in which a Mn 2+ -enhanced T 1 -map MRI could enable the monitoring of Ca 2+ influx during the early stages of intestinal ischemia–reperfusion (I/R) injury. The Mn 2+ infusion protocol was optimized by obtaining dose-dependent and time-course wash-out curves using a Mn 2+ -enhanced T 1 -map MRI of rabbit abdomens following an intravenous infusion of 50 mmol/l MnCl 2 (5–10 nmol/g body weight (BW)). In the rabbit model of intestinal I/R injury, T 1 values were derived from the T 1 maps in the intestinal wall region and revealed a relationship between the dose of the infused MnCl 2 and the intestinal wall relaxation time. Significant Mn 2+ clearance was also observed over time in control animals after the infusion of Mn 2+ at a dose of 10 nmol/g BW. This technique was also shown to be sensitive enough to monitor variations in calcium ion homeostasis in vivo after small intestinal I/R injury. The T 1 values of the intestinal I/R group were significantly lower ( P  〈 0.05) than that of the control group at 5, 10, and 15 min after Mn 2+ infusion. Our data suggest that MnCl 2 has the potential to be an MRI contrast agent that can be effectively used to monitor changes in intracellular Ca 2+ homeostasis during the early stages of intestinal I/R injury. Copyright © 2015 John Wiley & Sons, Ltd. Manganese (Mn 2+ ) acts as an excellent probe of calcium ion (Ca 2+ ) influx for monitoring Ca 2+ -associated physiological activities in a Mn 2+ -enhanced MRI (MEMRI) study. In this study, we prospectively demonstrated that Mn 2+ -enhanced T 1 -map MRI has the sensitivity to monitor variations in Ca 2+ homeostasis in vivo directly related to Ca 2+ overload in the early stage of intestinal ischemia–reperfusion injury. MEMRI provides additional information in intestinal ischemia–reperfusion injury models used to monitor disease development.

Description: Ovarian carcinosarcoma cancer is the most lethal form of gynecological malignancy, but the pathogenesis and biological function for this ovarian cancer remain unknown. We establishment the transgenic mouse model of K-ras G12D p53 loxP/loxP and found that K-ras mutation and p53 deletion within the ovarian surface epithelium gave rise to ovarian lesions with a hyperproliferation and endometrioid glandular morphology. Furthermore, double mutant ovaries formed ovarian carcinosarcomas that were high grade and poorly differentiated. Induction was widely metastatic and spread to abdominal organs including liver, spleen, and kidney at 4 wk. We also confirmed the role of K-ras G12D in ovarian cancer cell lines MCAS and PA-1 and showed that K-ras G12D overexpression strongly induced cell proliferation, migration, and invasion. The ovarian cancer model we developed recapitulates the specific tumor histomorphology and the probable mechanism of malignant transformation in endometriosis. This article is protected by copyright. All rights reserved.

Description: Although remnant cardiomyocytes (CMs) possess a certain degree of proliferative ability, efficiency is too low for cardiac regeneration after injury. In this study, we identified a distinct stage within the initiation phase of CM reprogramming before the MET process, and microarray analysis revealed the strong up-regulation of several mitosis-related genes at this stage of reprogramming. Several candidate genes were selected and tested for their ability to induce CM proliferation. Delivering a cocktail of three genes, FoxM1, Id1, and Jnk3-shRNA (FIJs), induced CMs to re-enter the cell cycle and complete mitosis and cytokinesis in vitro . More importantly, this gene cocktail increased CM proliferation in vivo and significantly improved cardiac function and reduced fibrosis after myocardial infarction. Collectively, our findings present a cocktail FIJs that may be useful in cardiac regeneration and also provide a practical strategy for probing reprogramming assays for regeneration of other tissues. The proliferation rate of remnant cardiomyocytes (CMs) is too low for cardiac regeneration after injury. Here, a gene cocktail is defined to induce CMs to efficiently proliferate, while improving cardiac function after myocardial infarction in mice.