Although the role of TGF-β in tumor progression has been studied extensively, its impact on drug delivery in tumors remains far from understood. In this study, we examined the effect of TGF-β blockade on the delivery and efficacy of conventional therapeutics and nanotherapeutics in orthotopic mammary carcinoma mouse models. We used both genetic (overexpression of sTβRII, a soluble TGF-β type II receptor) and pharmacologic (1D11, a TGF-β neutralizing antibody) approaches to block TGF-β signaling. In two orthotopic mammary carcinoma models (human MDA-MB-231 and murine 4T1 cell lines), TGF-β blockade significantly decreased tumor growth and metastasis. TGF-β blockade also increased the recruitment and incorporation of perivascular cells into tumor blood vessels and increased the fraction of perfused vessels. Moreover, TGF-β blockade normalized the tumor interstitial matrix by decreasing collagen I content. As a result of this vessel and interstitial matrix normalization, TGF-β blockade improved the intratumoral penetration of both a low-molecular-weight conventional chemotherapeutic drug and a nanotherapeutic agent, leading to better control of tumor growth.breast cancer | vessel normalization | drug delivery B reast cancer is the second leading cause of cancer death in women, with most fatalities resulting from a failure to control metastatic disease with systemically administered therapies. In addition to the induction of cellular resistance mechanisms (decreased apoptosis, increased drug efflux, etc.), impaired intratumoral drug delivery is an important physiological factor contributing toward chemoresistance (1, 2). TGF-β is an important regulator of normal mammary gland development and function, as well as of the progression of mammary carcinomas (3-8). Although the role of TGF-β in tumor progression and metastasis has been studied extensively, little is known about its impact on drug delivery.Transport of a therapeutic agent from the circulation to cancer cells is a three-step process. Systemically administered drugs must (i) travel to different regions within a tumor via the vascular network; (ii) cross the vessel wall; and finally (iii) diffuse through the interstitial space to reach the tumor cells, with each step being hindered by the presence of an abnormal vasculature and/or matrix (1, 2, 9, 10). Tumor blood vessels are structurally and functionally abnormal, characterized by increased permeability and heterogeneous perfusion. Poor vascular perfusion decreases drug delivery and, as a result, impairs the efficacy of blood-borne antitumor agents (1, 11). In addition, the dense collagen-rich interstitial matrix further hinders drug transport to tumor cells-a feature especially relevant to larger therapeutics, such as nanoparticles (1-100 nm) (1, 10, 12, 13). The dense collagen matrix also contributes to solid stress, which compresses tumor vessels (14). Hence, depleting collagen will reduce stress and open up compressed vessels. TGF-β is a negative regulator of pericyte recruitment during blood vessel stab...

The relationship between physicians and nurses in the delivery of anesthesia care is politically and financially charged, and hotly debated. Against this backdrop, federal regulators have proposed dropping a Medicare requirement that nurse anesthetists be supervised by a physician. Proponents note that the new regulations would resolve inconsistencies between Medicare supervisory requirements and state law, while opponents voice concerns for patient safety. This Issue Brief describes the current controversy, and summarizes a newly published study that suggests differences in patient outcomes depending on the nature and level of anesthesiologist involvement in surgical care. License This work is licensed under a Creative Commons Attribution-No Derivative Works 4.0 License.

Background:Epithelial–mesenchymal transition (EMT) is a crucial programme in cancer metastasis. Epidermal growth factor (EGF) is a key inducer of EMT, and Ezrin has an important role in this process. However, how Ezrin is activated and whether it mediates EGF-induced EMT in tongue squamous cell carcinomas (TSCCs) through activating NF-κB remains obscure.Methods:We used two TSCC cell lines as a cell model to study invasion and EMT in vitro, and used nude mice xenografts model to evaluate metastasis of TSCC cells. Finally, we evaluated the level of pEzrin Tyr353, nuclear p65 and EMT markers in TSCC clinical samples.Results:Ezrin Tyr353 was phosphorylated through Akt (but not ERK1/2, ROCK1) pathway, and lead to the activation of NF-κB in EGF-treated TSCC cells. Akt and NF-κB inhibitors blocked EGF-induced EMT, and suppressed invasion and migration of TSCC cells. In vivo, silencing Ezrin significantly suppressed EGF-enhanced metastasis of TSCC xenografts. Finally, high levels of expression of pEzrin Tyr353, nuclear p65, vimentin and low level of expression of E-cadherin were correlated with cancer metastasis and poor patient prognosis.Conclusion:Our data suggest that Akt/Ezrin Tyr353/NF-κB pathway regulates EGF-induced EMT and metastasis inTSCC, and Ezrin may serve as a therapeutic target to reverse EMT in tongue cancers and prevent TSCC progression.

Proliferation and epithelial–mesenchymal transition (EMT) of lens epithelium cells (LECs) may contribute to anterior subcapsular cataract (ASC) and posterior capsule opacification (PCO), which are important causes of visual impairment. Histone deacetylases (HDACs)-mediated epigenetic mechanism has a central role in controlling cell cycle regulation, cell proliferation and differentiation in a variety of cells and the pathogenesis of some diseases. However, whether HDACs are involved in the regulation of proliferation and EMT in LECs remain unknown. In this study, we evaluated the expression profile of HDAC family (18 genes) and found that class I and II HDACs were upregulated in transforming growth factor β2 (TGFβ2)-induced EMT in human LEC lines SRA01/04 and HLEB3. Tricostatin A (TSA), a class I and II HDAC inhibitor, suppressed the proliferation of LECs by G1 phase cell cycle arrest not only through inhibition of cyclin/CDK complexes and induction of p21 and p27, but also inactivation of the phosphatidylinositol-3-kinase/Akt, p38MAPK and ERK1/2 pathways. Meanwhile, TSA strongly prevented TGFβ2-induced upregulation of fibronectin, collagen type I, collagen type IV, N-cadherin, Snail and Slug. We also demonstrated that the underlying mechanism of TSA affects EMT in LECs through inhibiting the canonical TGFβ/Smad2 and the Jagged/Notch signaling pathways. Finally, we found that TSA completely prevented TGFβ2-induced ASC in the whole lens culture semi-in vivo model. Therefore, this study may provide a new insight into the pathogenesis of ASC and PCO, and suggests that epigenetic treatment with HDAC inhibitors may be a novel therapeutic approach for the prevention and treatment of ASC, PCO and other fibrotic diseases.

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The mechanism regulating the gastrointestinal epithelial barrier remains poorly understood. We herein demonstrate that Absent in melanoma-2 (AIM2) contributes to the maintenance of intestinal barrier integrity and defense against bacterial infection. AIM2-deficient mice displayed an increased susceptibility to mucosal but not systemic infection by Salmonella typhimurium, indicating a protective role for AIM2 in the gastrointestinal tract. In a Salmonella colitis model, compared with wild-type mice, AIM2(-/-) mice exhibited more severe body weight loss, intestinal damage, intestinal inflammation, and disruption of basal and activated epithelial cell turnover. In vivo and in vitro data showed that AIM2 restricted the early epithelial paracellular invasion of Salmonella and decreased epithelial permeability. The decreased epithelial barrier in AIM2(-/-) mice might be attributed to the altered expression of tight junction proteins that contribute to epithelial integrity. AIM2 promoted the expression of tight junction proteins through Akt activation. Together, these results suggest that AIM2 is required for maintaining the integrity of the epithelial barrier.

A regulator of the protein phosphatase 2A (PP2A), a4, has been implicated in a variety of functions that regulate many cellular processes. To explore the role of a4 in human cell transformation and tumorigenesis, we show that a4 is highly expressed in human cells transformed by chemical carcinogens including benzo(a)pyrene, aflatoxin B 1 , N-methyl-N 0 -nitro-N-nitrosoguanidine, nickel sulfate and in several hepatic and lung cancer cell lines. In addition, overexpression of a4 was detected in 87.5% (74/80) of primary hepatocellular carcinomas, 84.0% (21/25) of primary lung cancers and 81.8% (9/11) of primary breast cancers, indicating that a4 is ubiquitously highly expressed in human cancer. Functional studies revealed that elevated a4 expression results in an increase in cell proliferation, promotion of cell survival and decreased PP2A-attributable activity. Importantly, ectopic expression of a4 permits non-transformed human embryonic kidney cells (HEKTER) and L02R cells to form tumors in immunodeficient mice. Furthermore, we show that the highly expressed a4 in transformed cells or human tumors is not regulated by DNA hypomethylation. A microRNA, miR-34b, that suppresses the expression of a4 through specific binding to the 3 0 -untranslated region of a4 is downregulated in transformed or human lung tumors. Taken together, these observations identify that a4 possesses an oncogenic function. Reduction of PP2A activity due to an enhanced a4-PP2A interaction contributes directly to chemical carcinogen-induced tumorigenesis.

The study was aimed at detecting the expression of a newly found oncogene, astrocyte elevated gene-1 (AEG-1), in renal cell carcinoma (RCC) and its correlation with histopathologic features and the survival of patients. Real-time reverse transcription-PCR and Western blot showed markedly higher expression of AEG-1 in 8 cases of RCC tissue compared with the paired normal tissue from the same patient. The expression level of AEG-1 was also increased in four RCC cell lines in contrast with normal tubular epithelial human kidney cells 2 (HK-2) at both mRNA and protein levels. Furthermore, immunohistochemistry analysis showed highly expressed AEG-1 in 96 of 102 (94.1%) cases of paraffin-embedded archival RCC tissue. Statistical analysis showed a significant correlation of AEG-1 expression with tumor grade (P <0.001), clinical staging (P = 0.003), T classification (P = 0.003) as well as metastasis classification (P=0.032). The means for survival time of low AEG-1 expression group was 76.98m while high AEG-1expression group was 60.94m. Our results suggest that AEG-1 protein is overexpressed in RCC and plays an important role in tumor differentiation and progression. High AEG-1 expression is closely associated with poor prognosis.