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Purpose: Cell-surface receptor-targeted magnetic iron oxide nanoparticles provide molecular magnetic resonance imaging contrast agents for improving specificity of the detection of human cancer. Experimental Design:The present study reports the development of a novel targeted iron oxide nanoparticle using a recombinant peptide containing the amino-terminal fragment of urokinasetype plasminogen activator (uPA) conjugated to magnetic iron oxide nanoparticles amino-terminal fragment conjugated-iron oxide (ATF-IO).This nanoparticle targets uPA receptor, which is overexpressed in breast cancer tissues. Results: ATF-IO nanoparticles are able to specifically bind to and be internalized by uPA receptor^expressing tumor cells. Systemic delivery of ATF-IO nanoparticles into mice bearing s.c. and i.p. mammary tumors leads to the accumulation of the particles in tumors, generating a strong magnetic resonance imaging contrast detectable by a clinical magnetic resonance imaging scanner at a field strength of 3 tesla. Target specificity of ATF-IO nanoparticles showed by in vivo magnetic resonance imaging is further confirmed by near-IR fluorescence imaging of the mammary tumors using near-IR dye-labeled amino-terminal fragment peptides conjugated to iron oxide nanoparticles. Furthermore, mice administered ATF-IO nanoparticles exhibit lower uptake of the particles in the liver and spleen compared with those receiving nontargeted iron oxide nanoparticles. Conclusions: Our results suggest that uPA receptor^targeted ATF-IO nanoparticles have potential as molecularly targeted, dual modality imaging agents for in vivo imaging of breast cancer.Breast cancer is the most common type of cancer and the second leading cause of cancer-related death among women. Novel approaches for the detection of primary and metastatic breast cancers are urgently needed to increase the survival of patients. A promising strategy to improve the specificity and sensitivity of cancer imaging is to use biomarker target -specific imaging probes (1 -3) for image-based diagnosis and treatment monitoring. Currently, targeted radionuclide probes have been used for cancer detection by positron emission tomography or single photon emission tomography (2, 4, 5). Although nuclear imaging modalities show a high sensitivity, they lack good resolution and anatomic localization of the tumor lesion and require complicated and expensive radiochemistry. In addition, the half-life of the radiotracer often limits the ability for dynamic and time-resolved imaging and may not be able to capture the biomarker-targeting agent to reach and accumulate in the tumor. Magnetic resonance imaging offers a high spatial resolution and three-dimensional anatomic details and has been widely used in clinical oncology imaging. Recently, breast magnetic resonance imaging was recommended by the American Cancer Society as a screening approach, adjunct to mammography, for the early detection of breast cancer in women at high risk for this disease (6). Although breast cancer magnetic reson...

Disparity in life expectancy for females and both black and Hispanic males, compared with males and white males, respectively, persists and should be addressed.

Dopamine (DA) type 1 receptor (D1R) signaling in the striatum presumably regulates neuronal excitability and reward-related behaviors through PKA. However, whether and how D1Rs and PKA regulate neuronal excitability and behavior remain largely unknown. Here, we developed a phosphoproteomic analysis method to identify known and novel PKA substrates downstream of the D1R and obtained more than 100 candidate substrates, including Rap1 GEF (Rasgrp2). We found that PKA phosphorylation of Rasgrp2 activated its guanine nucleotide-exchange activity on Rap1. Cocaine exposure activated Rap1 in the nucleus accumbens in mice. The expression of constitutively active PKA or Rap1 in accumbal D1R-expressing medium spiny neurons (D1R-MSNs) enhanced neuronal firing rates and behavioral responses to cocaine exposure through MAPK. Knockout of Rap1 in the accumbal D1R-MSNs was sufficient to decrease these phenotypes. These findings demonstrate a novel DA-PKA-Rap1-MAPK intracellular signaling mechanism in D1R-MSNs that increases neuronal excitability to enhance reward-related behaviors.

Importance Over 1.4 million male circumcisions are performed annually in U.S. medical settings. However, population-based estimates of male circumcision associated adverse events are lacking. Objectives To estimate the incidence rate of male circumcision associated adverse events, and assess whether adverse event rates differed by age at circumcision. Design We selected 41 possible male circumcision adverse events based on literature review and medical billing codes. We estimated a likely risk window for incidence calculation for each male circumcision adverse event based on pathogenesis. We used 2001 – 2010 data from SDIhealth, a large administrative claims dataset, to conduct a retrospective cohort study. Setting SDIhealth provided administrative claims data from inpatient and outpatient U.S. medical settings. Main outcome measures For each adverse event, we calculated incidence per million male circumcisions. We compared incidence risk ratio and incidence rate difference for: a) circumcised vs. uncircumcised newborn males, and b) males circumcised at ≤1 year, 1–9 years, or ≥10 years of age. An adverse event was considered probably related to male circumcision if the incidence risk ratio significantly exceeded one at p<0.05 or occurred only in circumcised males. Results Records were available for 1,400,920 circumcised males, 93.3% as newborns. Of the 41 possible male circumcision adverse events, 16 (39%) were probable. Incidence of total male circumcision adverse event was slightly less than half percent. Rates of potentially serious male circumcision adverse events ranged from 0.76 per million male circumcision (95% CI: 0.10 – 5.43) for stricture of male genital organs to 703.23 per million male circumcision (95% CI: 659.22 – 750.18) for repair of incomplete circumcision. Compared to males circumcised at ≤1 year of age, the incidence was approximately 20- and 10-fold greater for males circumcised between 1 – 9 years and those ≥10 years of age, respectively. Conclusions and Relevance male circumcision had a relatively low incidence of adverse events overall, especially if the procedure was performed during the first year of life, but rose 10–20 fold when performed after infancy.

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A novel method called kinase-interacting substrate screening based on affinity beads coated with the kinase of interest identifies phosphorylation sites for Rho-kinase and others, which reveals that Rho-kinase substrate Scrib plays a crucial role in the regulation of subcellular contractility by assembling with Rho-kinase and Shroom2.

-Excessive accumulation of reactive oxygen species (ROS), catalyzed by the NADPH oxidases (NOX), is involved in the pathogenesis of ischemia-reperfusion (I/R) injury. The underlying epigenetic mechanism remains elusive. -We evaluated the potential role of megakaryocytic leukemia 1, or MKL1, as a bridge linking epigenetic activation of NOX to ROS production and cardiac ischemia-reperfusion injury. -Following I/R injury, MKL1 deficient (KO) mice exhibited smaller myocardial infarction along with improved heart function compared to wild type (WT) littermates. Similarly, pharmaceutical inhibition of MKL1 with CCG-1423 also attenuated myocardial infarction and improved heart function in mice. Amelioration of I/R injury as a result of MKL1 deletion or inhibition was accompanied by reduced ROS and In response to I/R, MKL1 levels were specifically elevated in macrophages, but not in cardiomyocytes, in the heart. Of note, macrophage-specific deletion (MφcKO), instead of cardiomyocyte-restricted ablation (CMcKO), of MKL1 in mice led to similar improvements of infarct size, heart function, and myocardial ROS generation. Reporter assay and ChIP assay revealed that MKL1 directly bound to the promoters of NADPH oxidase (NOX) genes to activate NOX transcription. Mechanistically, MKL1 recruited the histone acetyltransferase MOF to modify the chromatin structure surrounding the NOX promoters. Knockdown of MOF in macrophages blocked hyoxia/re-oxygenation-induced NOX transactivation and ROS accumulation. Of importance, pharmaceutical inhibition of MOF with MG-149 significantly down-regulated NOX1/NOX4 expression, dampened ROS production, and normalized myocardial function in mice exposed to I/R injury. Finally, administration of a specific NOX1/4 inhibitor GKT137831 dampened ROS generation and rescued heart function following I/R in mice. -Our data delineate an MKL1-MOF-NOX axis in macrophages that contributes to I/R injury and as such have provided novel therapeutic targets in the treatment of ischemic heart disease.