p53 Target Gene SMAR1 Is Dysregulated in Breast Cancer: Its Role in Cancer Cell Migration and Invasion

Tumor suppressor SMAR1 interacts and stabilizes p53 through phosphorylation at its serine-15 residue. We show that SMAR1 transcription is regulated by p53 through its response element present in the SMAR1 promoter. Upon Doxorubicin induced DNA damage, acetylated p53 is recruited on SMAR1 promoter that allows activation of its transcription. Once SMAR1 is induced, cell cycle arrest is observed that is correlated to increased phospho-ser-15-p53 and decreased p53 acetylation. Further we demonstrate that SMAR1 expression is drastically reduced during advancement of human breast cancer. This was correlated with defective p53 expression in breast cancer where acetylated p53 is sequestered into the heterochromatin region and become inaccessible to activate SMAR1 promoter. In a recent report we have shown that SMAR1 represses Cyclin D1 transcription through recruitment of HDAC1 dependent repressor complex at the MAR site of Cyclin D1 promoter. Here we show that downmodulation of SMAR1 in high grade breast carcinoma is correlated with upregulated Cyclin D1 expression. We also established that SMAR1 inhibits tumor cell migration and metastases through inhibition of TGFβ signaling and its downstream target genes including cutl1 and various focal adhesion molecules. Thus, we report that SMAR1 plays a central role in coordinating p53 and TGFβ pathways in human breast cancer

Action plans for COPD: strategies to manage exacerbations and improve outcomes

Leena Jalota,1 Vipul V Jain1,2 1Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, 2Chronic Lung Disease Program, UCSF-Fresno, Community Regional Medical Center, Fresno, CA, USA Abstract: COPD is the third-largest killer in the world, and certainly takes a toll on the health care system. Recurrent COPD exacerbations accelerate lung-function decline, worsen mortality, and consume over US$50 billion in health care spending annually. This has led to a tide of payment reforms eliciting interest in strategies reducing preventable COPD exacerbations. In this review, we analyze and discuss the evidence for COPD action plan-based self-management strategies. Although action plans may provide stabilization of acute symptomatology, there are several limitations. These include patient-centered attributes, such as comprehension and adherence, and nonadherence of health care providers to established guidelines. While no single intervention can be expected independently to translate into improved outcomes, structured together within a comprehensive integrated disease-management program, they may provide a robust paradigm. Keywords: exacerbations, self-management, integrated disease-management progra

SMAR1 and Cux/CDP modulate chromatin and act as negative regulators of the TCRβ enhancer (Eβ)

Chromatin modulation at various cis-acting elements is critical for V(D)J recombination during T and B cell development. MARβ, a matrix-associated region (MAR) located upstream of the T cell receptor β (TCRβ) enhancer (Eβ), serves a crucial role in silencing Eβ-mediated TCR activation. By DNaseI hypersensitivity assays, we show here that overexpression of the MAR binding proteins SMAR1 and Cux/CDP modulate the chromatin structure at MARβ. We further demonstrate that the silencer function of MARβ is mediated independently by SMAR1 and Cux/CDP as judged by their ability to repress Eβ-dependent reporter gene expression. Moreover, the repressor activity of SMAR1 is strongly enhanced in the presence of Cux/CDP. These two proteins physically interact with each other and colocalize within the perinuclear region through a SMAR1 domain required for repression. The repression domain of SMAR1 is separate from the MARβ binding domain and contains a nuclear localization signal and an arginine–serine (RS)-rich domain, characteristic of pre-mRNA splicing regulators. Our data suggest that at the double positive stage of T cell development, cis-acting MARβ elements recruit the strong negative regulators Cux and SMAR1 to control Eβ-mediated recombination and transcription

Supplemental intravenous crystalloids for the prevention of postoperative nausea and vomiting: quantitative review

Hypovolaemia after overnight fasting is believed to exacerbate postoperative nausea and vomiting (PONV). However, data on the efficacy of supplemental i.v. crystalloids for PONV prophylaxis are conflicting. We performed a literature search using CENTRAL, MEDLINE, EMBASE, CINAHL, and Web of Science. We included prospective randomized controlled trials that reported PONV event rates in patients receiving supplemental i.v. crystalloids or a conservative fluid regimen after elective surgery under general anaesthesia. Studies were evaluated with regard to random sequence generation, allocation concealment, blinding of participants, personnel, and outcome assessment, incomplete outcome data, and selective reporting. We identified 15 trials (n787 crystalloids; n783 conservative fluids). Compared with conservative fluids, i.v. crystalloids reduced the risk of early postoperative nausea (PON) (relative risk 0.73, 95 confidence interval 0.590.89; P0.003), late PON (0.41, 0.220.76; P0.004), and overall PON (0.66, 0.460.95; P0.02). I.V. crystalloids did not reduce the risk of early postoperative vomiting (POV) (0.66, 0.371.16; P0.16) or late POV (0.52, 0.251.11; P0.09), but did reduce overall POV (0.48, 0.290.79; P0.004). I.V. crystalloids did not reduce the risk of early PONV (0.74, 0.491.12; P0.16), but did reduce the risk of late PONV (0.27, 0.130.54; P0.001) and overall PONV (0.59, 0.420.84; P0.003). I.V. crystalloids reduced the need for antiemetic rescue treatment (0.56, 0.450.68; P0.001). In summary, supplemental i.v. crystalloids were associated with a lower incidence of several PONV outcomes. However, a number of PONV outcomes failed to reach statistical significance, perhaps due to the lack of power. Thus, studies sufficiently powered for the less frequent outcomes (e.g. POV) are required