Related Articles

Propranolol induced G0/G1/S phase arrest and apoptosis in melanoma cells via AKT/MAPK pathway.

Oncotarget. 2016 10 18;7(42):68314-68327

Authors: Zhou C, Chen X, Zeng W, Peng C, Huang G, Li X, Ouyang Z, Luo Y, Xu X, Xu B, Wang W, He R, Zhang X, Zhang L, Liu J, Knepper TC, He Y, McLeod HL

Abstract
Both preclinical and epidemiology studies associate β-adrenoceptors-blockers (β-blockers) with activity against melanoma. However, the underlying mechanism is still unclear, especially in acral melanoma. In this study, we explored the effect of propranolol, a non-selective β-blocker, on the A375 melanoma cell line, two primary acral melanoma cell lines (P-3, P-6) and mice xenografts. Cell viability assay demonstrated that 50μM-400μM of propranolol inhibited viability in a concentration and time dependent manner with an IC50 ranging from 65.33μM to 148.60μM for 24h -72h treatment, but propranolol (less than 200μM) had no effect on HaCaT cell line. Western blots showed 100μM propranolol significantly reduced the expression of Bcl-2 while increasing the expressions of Bax, cytochrome c, cleaved capase-9 and cleaved caspase-3, and down-regulated the levels of p-AKT, p-BRAF, p-MEK1/2 and p-ERK1/2 in melanoma cells, after a 24h incubation. The in vivo data confirmed the isolation results. Mice received daily ip. administration of propranolol at the dose of 2 mg/kg for 3 weeks and the control group was treated with the same volume of saline. The mean tumor volume at day 21 in A375 xenografts was 82.33 ± 3.75mm3vs. 2044.67 ± 54.57mm3 for the propranolol-treated mice and the control group, respectively, and 31.66 ± 4.67 mm3vs. 1074.67 ± 32.17 mm3 for the P-3 xenografts. Propranolol also reduced Ki67, inhibited phosphorylation of AKT, BRAF, MEK1/2 and ERK1/2 in xenografts. These are the first data to demonstrate that propranolol might inhibit melanoma by activating the intrinsic apoptosis pathway and inactivating the MAPK and AKT pathways.

PMID: 27582542 [PubMed - indexed for MEDLINE]

Evaluation of adipokines in children with cystic fibrosis.

Endokrynol Pol. 2018 Feb 21;:

Authors: Machura E, Szczepańska M, Świętochowska E, Halkiewicz F, Barć-Czarnecka M, Ziora K, Ziora D

Abstract
INTRODUCTION: Patients with CF present numerous pathological conditions such as malnutrition, depletion of fat-free mass, metabolic disturbances (abnormal glucose metabolism, increased insulin resistance, chronic energy deficit, local and chronic inflammation), which could affect or be associated with altered adipokines concentrationMaterial and Methods: We aimed in this study to investigate the levels of selected adipokines such as resistin, apelin, adiponectin to demonstrate their application as possible markers of inflammation.
RESULTS: Serum level of resistin was higher (p<0.001) and adiponectin - lower (p=0.02) in CF children than in healthy children. There was no difference in serum apelin level between two examined groups. However, values of adiponectin/BMI and apelin/BMI ratios in CF did not differ significantly from controls. Higher values of resistin/BMI ratio in CF in comparison to controls were observed Serum resistin/adiponectin ratio was significantly higher in CF patients than in controls (p<0.0001). Resistin/BMI ratio correlated negatively with FEV1 (R:-48,p<0.043). Serum resistin/adiponectin ratio correlated negatively with FEV1/FVC (R:-49, p=0.04), Adipokines showed no correlation with BMI and BMI-SDS, glucose, total cholesterol, and LDL-, HDL-cholesterol, triglyceride serum levels. Spirometric parameters FEV1, FVC, VC correlated negatively with serum glucose levels (R: -0.55, p<0.018; R: -0.65 p<0.0025; R:-0.76, p<0.0008 respectively). FEV1 and FVC correlated positively with BMI-SDS (R:0.58, p<0.01; R:0.5, p<0.036, respectively).
CONCLUSIONS: A significant increase in resistin concentration expressed also as resistin/BMI, and resistin/adiponectin ratios, observed in children with CF may suggests that this adipokine is involved in the inflammatory process underlying the disease and is related to worse spirometric parameters describing airways obstruction.

PMID: 29465158 [PubMed - as supplied by publisher]

Related Articles

The Prevalence and Risk of Fecal Incontinence in Patients with Cystic Fibrosis: Nothing to Sneeze At.

Dig Dis Sci. 2018 Feb 21;:

Authors: Whitehead WE

PMID: 29464584 [PubMed - as supplied by publisher]

Related Articles

Varying susceptibility of clinical and environmental Scedosporium isolates to chemical oxidative stress in conidial germination.

Arch Microbiol. 2018 Feb 20;:

Authors: Staerck C, Godon C, Bouchara JP, Fleury MJJ

Abstract
Scedosporium species are opportunistic pathogens causing a great variety of infections in both immunocompetent and immunocompromised individuals. The Scedosporium genus ranks the second among the filamentous fungi colonizing the airways of patients with cystic fibrosis (CF), after Aspergillus fumigatus, and most species are capable to chronically colonize the respiratory tract of these patients. Nevertheless, few data are available regarding evasion of the inhaled conidia to the host immune response. Upon microbial infection, macrophages and neutrophils release reactive oxygen species (ROS). To colonize the respiratory tract, the conidia need to germinate despite the oxidative stress generated by phagocytic cells. Germination of spores from different clinical or environmental isolates of the major Scedosporium species was investigated in oxidative stress conditions. All tested species showed susceptibility to oxidative stress. However, when comparing clinical and environmental isolates, differences in germination capabilities under oxidative stress conditions were seen between species as well as within each species. Among environmental isolates, Scedosporium aurantiacum isolates were the most resistant to oxidative stress whereas Scedosporium dehoogii were the most susceptible. Overall, the differences observed between Scedosporium species in the capacity to germinate under oxidative stress conditions could explain their varying prevalence and pathogenicity.

PMID: 29464281 [PubMed - as supplied by publisher]

Related Articles

Functional analyses of the RsmY and RsmZ small non-coding regulatory RNAs in Pseudomonas aeruginosa.

J Bacteriol. 2018 Feb 20;:

Authors: Janssen KH, Diaz MR, Golden M, Graham JW, Sanders W, Wolfgang MC, Yahr TL

Abstract
Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen with distinct acute and chronic virulence phenotypes. Whereas acute virulence is typically associated with expression of a type III secretion system (T3SS), chronic virulence is characterized by biofilm formation. Many of the phenotypes associated with acute and chronic virulence are inversely regulated by RsmA and RsmF. RsmA and RsmF are both members of the CsrA family of RNA-binding proteins and regulate protein synthesis at the post-transcriptional level. RsmA activity is controlled by two small, non-coding regulatory RNAs (RsmY and RsmZ). Bioinformatic analyses suggest that RsmY and RsmZ each have 3-4 putative RsmA bindings sites. Each predicted binding site contains of a GGA sequence presented in the loop portion of a stem-loop structure. RsmY/RsmZ regulate RsmA, and possibly RsmF, by sequestering them from target mRNAs. In this study, we used SHAPE chemistry to determine the secondary structures of RsmY and RsmZ, and functional assays to characterize the contribution of each GGA site to RsmY/RsmZ activity. Our data indicate that RsmA has two preferential binding sites on RsmY and RsmZ, while RsmF has one preferential binding site on RsmY and two sites on RsmZ. Despite sharing a common consensus site, RsmF binding properties are more restrictive when compared to RsmA.IMPORTANCE CsrA homologs are present in many bacteria. The opportunistic pathogen Pseudomonas aeruginosa uses RsmA and RsmF system to inversely regulate factors associated with acute and chronic virulence phenotypes. RsmA has a higher affinity for RsmY and RsmZ when compared to RsmF. The goal of this study was to understand the differential binding properties of RsmA and RsmF using the RsmY and RsmZ regulatory sRNAs as a model. Mutagenesis of the predicted RsmA/RsmF binding sites on RsmY and RsmZ revealed similarities in the sites required to control RsmA and RsmF activity in vivo. Whereas binding by RsmA was relatively tolerant of binding site mutations, RsmF was sensitive to disruption to all but two of the sites, further demonstrating that the requirements for RsmF binding activity in vivo and in vitro are more stringent than those for RsmA.

PMID: 29463606 [PubMed - as supplied by publisher]

Related Articles

A Slippery Cause of a Slimy Problem: Mucin Induction by an Esterified Lipid.

Am J Respir Cell Mol Biol. 2017 12;57(6):633-634

Authors: Randell SH, Zeldin DC

PMID: 29192828 [PubMed - indexed for MEDLINE]

Related Articles

Roles for Myoepithelial Cells in the Formation and Maintenance of Submucosal Glands.

Am J Respir Cell Mol Biol. 2017 06;56(6):685-686

Authors: Carraro G, Stripp BR

PMID: 28569595 [PubMed - indexed for MEDLINE]

Related Articles

Workflow Challenges of Enterprise Imaging: HIMSS-SIIM Collaborative White Paper.

J Digit Imaging. 2016 Oct;29(5):574-82

Authors: Towbin AJ, Roth CJ, Bronkalla M, Cram D

Abstract
With the advent of digital cameras, there has been an explosion in the number of medical specialties using images to diagnose or document disease and guide interventions. In many specialties, these images are not added to the patient's electronic medical record and are not distributed so that other providers caring for the patient can view them. As hospitals begin to develop enterprise imaging strategies, they have found that there are multiple challenges preventing the implementation of systems to manage image capture, image upload, and image management. This HIMSS-SIIM white paper will describe the key workflow challenges related to enterprise imaging and offer suggestions for potential solutions to these challenges.

PMID: 27527613 [PubMed - indexed for MEDLINE]

Related Articles

SCN3A deficiency associated with increased seizure susceptibility.

Neurobiol Dis. 2017 Jun;102:38-48

Authors: Lamar T, Vanoye CG, Calhoun J, Wong JC, Dutton SBB, Jorge BS, Velinov M, Escayg A, Kearney JA

Abstract
Mutations in voltage-gated sodium channels expressed highly in the brain (SCN1A, SCN2A, SCN3A, and SCN8A) are responsible for an increasing number of epilepsy syndromes. In particular, mutations in the SCN3A gene, encoding the pore-forming Nav1.3 α subunit, have been identified in patients with focal epilepsy. Biophysical characterization of epilepsy-associated SCN3A variants suggests that both gain- and loss-of-function SCN3A mutations may lead to increased seizure susceptibility. In this report, we identified a novel SCN3A variant (L247P) by whole exome sequencing of a child with focal epilepsy, developmental delay, and autonomic nervous system dysfunction. Voltage clamp analysis showed no detectable sodium current in a heterologous expression system expressing the SCN3A-L247P variant. Furthermore, cell surface biotinylation demonstrated a reduction in the amount of SCN3A-L247P at the cell surface, suggesting the SCN3A-L247P variant is a trafficking-deficient mutant. To further explore the possible clinical consequences of reduced SCN3A activity, we investigated the effect of a hypomorphic Scn3a allele (Scn3aHyp) on seizure susceptibility and behavior using a gene trap mouse line. Heterozygous Scn3a mutant mice (Scn3a+/Hyp) did not exhibit spontaneous seizures nor were they susceptible to hyperthermia-induced seizures. However, they displayed increased susceptibility to electroconvulsive (6Hz) and chemiconvulsive (flurothyl and kainic acid) induced seizures. Scn3a+/Hyp mice also exhibited deficits in locomotor activity and motor learning. Taken together, these results provide evidence that loss-of-function of SCN3A caused by reduced protein expression or deficient trafficking to the plasma membrane may contribute to increased seizure susceptibility.

PMID: 28235671 [PubMed - indexed for MEDLINE]

Funding Opportunity PA-18-676 from the NIH Guide for Grants and Contracts. The Office of Research on Womens Health (ORWH) announces the availability of administrative supplements to support interdisciplinary, transdisciplinary and multidisciplinary research focused on the effect of sex/gender influences at the intersection of a number of social determinants, including but not limited to: race/ethnicity, socioeconomic status, education, health literacy and other social determinants in human health and illness. This research includes preclinical, clinical and behavioral studies with the specific purpose to provide Administrative Supplements to active NIH parent grants for one year to address health disparities among women of populations in the US who are understudied, underrepresented and underreported in biomedical research. The proposed research must address an area specified within Objective 3.9 (Goal 3.0) of the NIH Strategic Plan for Research on Womens Health (http://orwh.od.nih.gov/research/strategicplan/index.asp) which states: Examine health disparities among women stemming from differences in such factors as race and ethnicity, socioeconomic status, gender identity, and urban-rural living, as they influence health, health behaviors, and access to screening and therapeutic interventions. Projects must include a focus on one or more NIH-designated health disparities populations, which include Blacks/African Americans, Hispanics/Latinos, American Indians/Alaska Natives, Asian Americans, Native Hawaiians and other Pacific Islanders, socioeconomically disadvantaged populations, underserved rural populations, and sexual and gender minorities (SGM). Combinations of one or more populations is also encouraged, e.g. socioeconomically disadvantaged sexual and gender minorities.

Funding Opportunity RFA-RM-18-005 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites an application from the Program Directors/Principal Investigators of the Coordination and Evaluation Center (CEC), which is currently supporting the research being performed for the Enhancing the Diversity of the NIH-Funded Workforce Program. This program, known as the Diversity Program Consortium (DPC), consists of three integrated initiatives: Building Infrastructure Leading to Diversity (BUILD), the National Research Mentoring Network (NRMN) and the CEC. The CEC will continue to organize the activities required for the attainment of program-wide goals and to measure the agreed upon hallmarks of success at the student, faculty, and institutional level. The CEC will employ and refine the processes developed in the previous funding period to assess the impact of BUILD and NRMN activities on attainment of the hallmarks. The CEC will coordinate the collection of data from the DPC, assess the data in an ongoing way, provide feedback, and facilitate an iterative process of program adjustment to maximize the research of BUILD and NRMN. The CEC should also focus on the dissemination of effective strategies for enhancing the diversity of the biomedical research workforce and for transitioning into a sustainable model for evaluating diversity enhancing programs beyond the funding cycle.

Notice NOT-OD-18-142 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-18-674 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to support observational or intervention research focused on reducing cancer health disparities in tobacco use in the United States. Specifically, this FOA is intended to stimulate scientific inquiry focused on innovative tobacco control policies. Applicants may propose projects in which the primary outcome of interest is on reducing tobacco use cancer health disparities in vulnerable populations by utilizing tobacco prevention and control strategies. The long-term goal of this FOA is to reduce cancer health disparities in health outcomes thereby reducing the excess disease burden of tobacco use within these groups. Applicants submitting applications related to health economics are encouraged to consult NOT-OD-16-025 to ensure that the research projects align with NIH mission priorities in health economics research.

Funding Opportunity PAR-18-675 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to support observational or intervention research focused on reducing cancer health disparities in tobacco use in the United States. Specifically, this FOA is intended to stimulate scientific inquiry focused on innovative tobacco control policies. Applicants may propose projects in which the primary outcome of interest is on reducing tobacco use cancer health disparities in vulnerable populations by utilizing tobacco prevention and control strategies. The long-term goal of this FOA is to reduce cancer health disparities in health outcomes thereby reducing the excess disease burden of tobacco use within these groups. Applicants submitting applications related to health economics are encouraged to consult NOT-OD-16-025 to ensure that the research projects align with NIH mission priorities in health economics research.

Funding Opportunity PAR-18-669 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement is to provide continuing support for specific pathogen free (SPF) macaque colonies previously funded under the auspices of PAR-14-066. Breeding colonies are essential to sustain Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) research. Pedigree SPF macaques are free of certain viruses, which can confound the results of AIDS-related investigations or present a risk to the personnel who care for the animals. The SPF macaques are genetically characterized for major histocompatibility (MHC) class I types as defined MHC classes are critical in determining immune responses to HIV/AIDS infections.

Notice NOT-AA-18-004 from the NIH Guide for Grants and Contracts

Notice NOT-DA-18-062 from the NIH Guide for Grants and Contracts

Notice NOT-DA-18-008 from the NIH Guide for Grants and Contracts

Notice NOT-GM-18-018 from the NIH Guide for Grants and Contracts

Notice NOT-OD-18-125 from the NIH Guide for Grants and Contracts