BackgroundInterleukin-27 signaling is mediated by the JAK-STAT pathway via activation of STAT1 and STAT3, which have tumor suppressive and oncogenic activities, respectively. Epithelial–mesenchymal transition (EMT) and angiogenesis are key processes in carcinogenesis. Although IL-27 has been shown to have potent anti-tumor activity in various cancer models, the role of IL-27 in EMT and angiogenesis is poorly understood. In this study, we investigated the role of IL-27 in regulating EMT and angiogenesis through modulation of the STAT pathways in human non-small cell lung carcinoma (NSCLC) cells.MethodsSTAT activation following IL-27 exposure was measured in human NSCLC cell lines. Expression of epithelial (E-cadherin, γ-catenin) and mesenchymal (N-cadherin, vimentin) markers were assessed by Western blot analysis. Production of pro-angiogenic factors (VEGF, IL-8/CXCL8, CXCL5) were examined by ELISA. Cell motility was examined by an in vitro scratch and transwell migration assays. Selective inhibitors of STAT1 (STAT1 siRNAs) and STAT3 (Stattic) were used to determine whether both STAT1 and STAT3 are required for IL-27 mediated inhibition of EMT and secretion of angiogenic factors.ResultsOur results demonstrate that IL-27 stimulation in NSCLC resulted in 1) STAT1 and STAT3 activation in a JAK-dependent manner, 2) development of epithelial phenotypes, including a decrease in the expression of a transcriptional repressor for E-cadherin (SNAIL), and mesenchymal marker (vimentin) with a reciprocal increase in the expression of epithelial markers, 3) inhibition of cell migration, and 4) reduced production of pro-angiogenic factors. STAT1 inhibition in IL-27–treated cells reversed the IL-27 effect with resultant increased expression of Snail, vimentin and the pro-angiogenic factors. The inhibition of STAT3 activation had no effect on the development of the epithelial phenotype.ConclusionIL-27 induces mesenchymal to epithelial transition and inhibits the production of pro-angiogenic factors in a STAT1–dominant pathway. These findings highlight the importance of STAT1 in repressing lung carcinogenesis and describe a new anti-tumor mechanism of IL-27.

We report our multidisciplinary experience with primary chest wall sarcomas that included induction therapy in the majority of high-risk soft tissue and bony sarcomas and desmoid tumors. Despite aggressive preoperative treatments, acceptable surgical results with low morbidity and mortality can be achieved. Neoadjuvant systemic therapy may reduce local and distant recurrence and improve overall survival.

A low-frequency variant of sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SVEP1), an extracellular matrix protein, is associated with risk of coronary disease in humans independent of plasma lipids. Despite a robust statistical association, if and how SVEP1 might contribute to atherosclerosis remained unclear. Here, using Mendelian randomization and complementary mouse models, we provide evidence that SVEP1 promotes atherosclerosis in humans and mice and is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque. VSMCs also interact with SVEP1, causing proliferation and dysregulation of key differentiation pathways, including integrin and Notch signaling. Fibroblast growth factor receptor transcription increases in VSMCs interacting with SVEP1 and is further increased by the coronary disease–associated SVEP1 variant p.D2702G. These effects ultimately drive inflammation and promote atherosclerosis. Together, our results suggest that VSMC-derived SVEP1 is a proatherogenic factor and support the concept that pharmacological inhibition of SVEP1 should protect against atherosclerosis in humans.

The middle ear transmits sound efficiently from the air in the ear canal (EC) to the fluid filled cochlea. In gerbil, middle ear transmission produces a constant pressure gain between the EC and the cochlea of ~ 25 dB from 2 to 40 kHz, and a delay-like phase corresponding to a ~25 -30 μs delay. The mechanisms by which the air-born signal is collected and delivered to the cochlea are not thoroughly understood, and the source of the delay is controversial. We investigated these issues by observing ossicular motion along a single line of sight, roughly parallel to the EC and perpendicular to the stapes footplate. Measurements were made at the umbo, the lateral process of the manubrium, across the malleus-incus joint, at the long process of the incus, and the stapes head. While the overall delay between EC pressure and stapes velocity was fairly constant with frequency, subcomponents of the delay were frequency dependent. Up to ~ 17 kHz, most of the overall delay was between the EC and umbo with a much smaller contribution along the ossicles, whereas in the range from ~17 to 30 kHz, more of the overall delay was along the ossicles.

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An immune tolerant tumor microenvironment promotes immune evasion of lung cancer. Agents that antagonize immune tolerance will thus aid the fight against this devastating disease. Members of the tumor necrosis factor receptor (TNFR) family modulate the magnitude, duration and phenotype of immune responsiveness to antigens. Among these, GITR expressed on immune cells functions as a key regulator in inflammatory and immune responses. Here, we evaluate the GITR agonistic antibody (DTA-1) as a mono-therapy and in combination with therapeutic vaccination in murine lung cancer models. We found that DTA-1 treatment of tumor-bearing mice increased: (i) the frequency and activation of intratumoral natural killer (NK) cells and T lymphocytes, (ii) the antigen presenting cell (APC) activity in the tumor, and (iii) systemic T-cell specific tumor cell cytolysis. DTA-1 treatment enhanced tumor cell apoptosis as quantified by cleaved caspase-3 staining in the tumors. DTA-1 treatment increased expression of IFNγ, TNFα and IL-12 but reduced IL-10 levels in tumors. Furthermore, increased anti-angiogenic chemokines corresponding with decreased pro-angiogenic chemokine levels correlated with reduced expression of the endothelial cell marker Meca 32 in the tumors of DTA-1 treated mice. In accordance, there was reduced tumor growth (8-fold by weight) in the DTA-1 treatment group. NK cell depletion markedly inhibited the antitumor response elicited by DTA-1. DTA-1 combined with therapeutic vaccination caused tumor rejection in 38% of mice and a 20-fold reduction in tumor burden in the remaining mice relative to control. Mice that rejected tumors following therapy developed immunological memory against subsequent re-challenge. Our data demonstrates GITR agonist antibody activated NK cell and T lymphocyte activity, and enhanced therapeutic vaccination responses against lung cancer.

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Background. Transcatheter aortic valve replacement (TAVR) and transcatheter mitral valve replacement expose operators to radiation. These procedures differ primarily in whether they are performed via a transfemoral (TF) or an alternative access (AA) approach. This study compared operator radiation exposure during transcatheter valve implantation when performed via a TF vs an AA approach, when performed in a catheterization lab vs a hybrid operating room (OR), and investigated the potential benefit of disposable shielding. Methods. Dosimeters were worn during TAVR-TF (n = 50) and TAVR-AA (n = 31) procedures by operators. All TAVR-AA procedures were performed in a hybrid OR and TF procedures were performed in either catheterization labs (n = 16) or a hybrid OR (n = 34). Disposable radiation shielding pads (RADPAD; Worldwide Innovations and Technologies, Inc, Kansas City) or a placebo were added in a randomized, blinded fashion. Results. Team radiation exposure was higher after TAVR-AA vs TAVR-TF (median 15.1 mRad [interquartile range: IQR 8.6, 32.4] vs 5.5 mRad [IQR 2.4, 9.8], P < .001). TAVR-TF procedures required the same amount of fluoroscopy time regardless of where they were performed (20.3 ± 7.4 min in hybrid OR vs 19.0 ± 6.4 min in catheterization lab, P = .55). However, radiation exposure for TAVR-TF remained higher when performed in a hybrid OR (median 9.0 mRad [IQR 4.5, 11.9] vs 2.2 mRad [IQR 1.3, 2.8], P < .001). Radiation exposure was greatest for TAVR-AA (median 15.1 mRad [IQR 8.6, 32.4]). The use of RADPAD did not decrease radiation exposure (median 9.0 mRad [IQR 4.5, 14.7] vs 9.4 mRad [IQR 2.8, 19.5], P = .82). Conclusions. Procedures performed in the hybrid OR were associated with higher operator radiation exposure. In comparison with the TF approach, AA cases had the highest levels of operator radiation. This is particularly important in cases of transcatheter mitral valve replacement that can only be done via an AA approach. The use of disposable radiation shielding in this series did not attenuate operator radiation exposure. Radiation shielding within hybrid ORs should be scrutinized in an effort to remain on par with that found within catheterization labs.