Epigenetic Silencing of BMP6 by the SIN3A-HDAC1/2 Repressor Complex Drives Melanoma Metastasis via FAM83G/PAWS1.

Aberrant epigenetic transcriptional regulation is linked to metastasis, a primary cause of cancer-related death. Dissecting the epigenetic mechanisms controlling metastatic progression may uncover important insights to tumor biology and potential therapeutic targets. Here, we investigated the role of the SIN3A histone deacetylase 1 and 2 (SIN3A-HDAC1/2) complex in cancer metastasis. Using a mouse model of melanoma metastasis, we found that the SIN3A-HDAC1/2 transcription repressor complex silences BMP6 expression, causing increased metastatic dissemination and tumor growth via suppression of BMP6-activated SMAD5 signaling. We further discovered that FAM83G/PAWS1, a downstream effector of BMP6-SMAD5 signaling, contributes critically to metastatic progression by promoting actin-dependent cytoskeletal dynamics and cell migration. Pharmacologic inhibition of the SIN3A-HDAC1/2 complex reduced the numbers of melanoma cells in the circulation and inhibited metastatic tumor growth by inducing disseminated cell dormancy, highlighting the SIN3A-HDAC1/2 repressor complex as a potential therapeutic target for blocking cancer metastasis. IMPLICATIONS: This study identifies the novel molecular links in the metastatic progression to target cytoskeletal dynamics in melanoma and identifies the SIN3A-HDAC1/2 complex and FAM83G/PAWS1 as potential targets for melanoma adjuvant therapy.

Ceftaroline fosamil as first-line versus second-line treatment for acute bacterial skin and skin structure infections (ABSSSI) or community-acquired bacterial pneumonia (CABP).

The Clinical Assessment Program and Teflaro(®) Utilization Registry (CAPTURE) is a multicenter registry study of acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP) patients treated with ceftaroline fosamil in the US. Data for this analysis were collected between August 2011 and February 2013 at US study centres by randomly ordered chart review. Clinical success rates among ABSSSI patients were >81% when ceftaroline fosamil was used as first- or second-line therapy, including monotherapy and concurrent therapy. Among CABP patients, clinical success rates were >77% among first-line and second-line patients and patients who received first-line concurrent therapy or second line monotherapy or concurrent therapy. For CABP patients treated with ceftaroline fosamil as first-line monotherapy, the clinical success rate was 70%. Ceftaroline fosamil is an effective treatment option for patients with ABSSSI or CABP with similar clinical success rates when used as first-line or second-line treatment.

Ceftaroline fosamil for the treatment of hospital-acquired pneumonia and ventilator-associated pneumonia.

OBJECTIVES: Ceftaroline fosamil is a novel cephalosporin with bactericidal activity against common pathogens associated with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). Ceftaroline is inactive against extended-spectrum ß-lactamase-producing or AmpC-overexpressing Enterobacteriaceae and has limited activity against Pseudomonas aeruginosa. CAPTURE is a multicenter, retrospective study designed to collect information on contemporary clinical use of ceftaroline fosamil in the USA. Data on off-label use of ceftaroline fosamil for the treatment of patients with HAP/VAP between September 2013 and March 2014 are presented. METHODS: Data were collected at participating study centers by randomized selection and review of patients' charts, and included patients' demographics, disease characteristics, pathogens isolated, antibiotic treatment and clinical outcomes. Patients receiving at least four consecutive doses of ceftaroline fosamil, with data available for determination of clinical cure, comprised the evaluable population. Clinical success was defined as either clinical cure with no further need for antibiotics treatment, or clinical improvement with a switch to another antibiotic. RESULTS: A total of 40 patients were evaluated: 27 with HAP and 13 with VAP. Demographics for patients with HAP and VAP were similar (59% male, mean age of 63 years and 54% male, mean age of 58 years, respectively). The clinical success rates were 75% overall, 82% in patients with HAP and 62% in patients with VAP. Clinical success rates for patients with methicillin-resistant Staphylococcus aureus (MRSA) isolated were 58% in patients with HAP and 57% in patients with VAP. Ceftaroline fosamil was used as a second-line therapy in majority of patients (85%) with clinical success rates of 79% similar to the published literature. CONCLUSION: The CAPTURE study data support further evaluation of ceftaroline fosamil as an effective treatment option for HAP and VAP when a ceftaroline susceptible etiologic pathogen is identified, including MRSA, or as a concurrent therapy when resistant Gram-negative pathogens are suspected.

Ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia in the intensive care unit.

The Clinical Assessment Program and Teflaro(®) Utilization Registry (CAPTURE) is a multicenter study evaluating the clinical use of ceftaroline fosamil in patients with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infection. Data were collected between August 2011 and February 2013, from 398 evaluable patients receiving treatment at 33 sites in the USA. This manuscript presents data collected from patients with CABP who received care in an intensive care unit (ICU) or in general medical wards (35% and 64% of evaluable patients, respectively). The majority of ICU and general medical ward patients had underlying comorbidities (78% and 74%, respectively), with structural lung disease being the most common (42% in the ICU and 40% in general medical wards). Patients admitted to the ICU had a longer duration of stay, a longer duration of symptoms before treatment, and a longer duration of ceftaroline fosamil therapy than did general medical ward patients. Most patients treated in the ICU and in general medical wards were given ceftaroline fosamil as second-line therapy (87% and 80%, respectively). The overall rate of clinical success for patients treated with ceftaroline fosamil was 68% in the ICU and 85% in the general medical wards. Clinical success for patients receiving ceftaroline fosamil as a second-line agent was 84% in the ICU and 86% in general medical wards. These findings indicate that ceftaroline fosamil is a viable treatment option for CABP, both in the ICU and in general medical wards.

Ceftaroline Fosamil for the Treatment of Staphylococcus aureus Bacteremia Secondary to Acute Bacterial Skin and Skin Structure Infections or Community-Acquired Bacterial Pneumonia.

BACKGROUND: The Clinical Assessment Program and Teflaro® Utilization Registry is designed to collect information on the clinical use of ceftaroline fosamil in the Unites States. This report presents data on the treatment of patients with Staphylococcus aureus bacteremia (SAB) secondary to acute bacterial skin and skin structure infections (ABSSSIs) or community-acquired bacterial pneumonia (CABP). METHODS: Patients diagnosed with ABSSSI or CABP were identified through sequential review of randomly ordered charts generated from pharmacy listings from August 2011 to February 2013. Data were collected by chart review 30 days or more after completion of ceftaroline fosamil therapy. RESULTS: Secondary SAB was reported in a total of 48 of 1428 evaluable patients (27 with ABSSSI, 21 with CABP). The mean (SD) patient age was 61 (15) years. At least 1 comorbidity was recorded for 74% of patients with ABSSSI and 81% with CABP. Methicillin-resistant S. aureus was isolated from 59% of patients with ABSSSI and 76% with CABP. The mean (SD) duration of ceftaroline fosamil therapy was 5.8 (4.8) days for ABSSSI and 7.0 (3.8) days for CABP. Clinical success among all patients with SAB treated with ceftaroline fosamil was 58% (52% for SAB secondary to ABSSSI, 67% for SAB secondary to CABP). Clinical success rates of methicillin-resistant S. aureus SAB were 50% (8/16) for ABSSSI and 63% (10/16) for CABP. CONCLUSIONS: This study supports the use of ceftaroline fosamil as a viable treatment option in hospitalized patients with SAB secondary to ABSSSI or CABP. Further studies evaluating the use of ceftaroline fosamil for the treatment of SAB are warranted.

Ceftaroline fosamil for treating skin and skin structure infections or community-acquired pneumonia in patients with renal insufficiency.

The Clinical Assessment Program and Teflaro(®) Utilization Registry (CAPTURE) is a multicenter retrospective study, conducted in the USA, describing the contemporary use of ceftaroline fosamil. Ceftaroline is primarily excreted by the kidneys and the dose should be reduced in patients with moderate to severe renal insufficiency. This article describes the clinical effectiveness of ceftaroline fosamil in the treatment of acute bacterial skin and skin structure infection (ABSSSI) or community-acquired bacterial pneumonia (CABP) patients with renal insufficiency. There were 985 ABSSSI patients and 344 CABP patients, of which 22 and 31%, respectively, had renal insufficiency. Ceftaroline fosamil was mostly administered to patients as second-line therapy. Overall clinical success was 78-91% among ABSSSI or CABP patients with renal insufficiency and, overall, >50% of patients were discharged to home. Ceftaroline fosamil is an effective treatment option for ABSSSI or CABP patients with renal insufficiency.

Ceftaroline fosamil for the treatment of acute bacterial skin and skin structure infections in obese patients.

BACKGROUND: Ceftaroline fosamil is a broad-spectrum antibiotic approved by the US Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia. The Clinical Assessment Program and Teflaro Utilization Registry (CAPTURE) is a multicenter registry study of patients treated with ceftaroline fosamil in the United States for ABSSSI or community-acquired bacterial pneumonia. OBJECTIVE: To describe the clinical effectiveness of ceftaroline fosamil in the treatment of ABSSSI in obese patients [body mass index (BMI) ≥ 30] compared with patients with a normal BMI (18.5 to ≤ 24.9). METHODS: Data were collected at US study centers by randomly ordered chart review. RESULTS: Data from 261 patients with a normal BMI and 690 patients with an obese BMI were collected. The percentage of males was higher in the normal BMI than in the obese category (58.2% and 49.0%, respectively). The mean and median ages at baseline were similar. Most patients (91%) were treated on a general hospital ward, and the mean and median lengths of stay were similar between the 2 groups (approximately 11 days and 7 days, respectively). A total of 73.2% of normal BMI patients and 77.5% of obese patients were discharged to home. Rates of diabetes mellitus were 26.4% in the normal BMI group and 55.1% in the obese group. Methicillin-resistant Staphylococcus aureus was isolated from 26.1% of normal BMI patients and 20.5% of obese patients (16.4% morbidly obese subset). Mean treatment duration for all patients was 5.9 days. Of patients with a normal BMI, 57.5% received ceftaroline fosamil as monotherapy as did 63.3% of obese patients. Clinical success was high in both the normal BMI (85.1%) and the obese (89.0%) groups. CONCLUSION: Ceftaroline fosamil is an effective treatment option for obese patients with ABSSSI with a similar clinical success rate, mean and median length of stay, and discharge destination to home when compared with normal BMI patients.

Ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia in elderly patients.

The Clinical Assessment Program and Teflaro Utilization Registry (CAPTURE) is a multicenter study, assessing the contemporary use of ceftaroline fosamil in patients with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infection. This article discusses the data collected from 528 evaluable patients with CABP, from 39 sites in the United States, between August 2011 and April 2013. The majority of patients (51%) were elderly (aged ≥ 65 years), most of whom were treated in general hospital wards (70%). Approximately one quarter of elderly patients had ≥ 2 comorbidities (26%), the most common of which was structural lung disease (51%). The majority of elderly patients received ceftaroline fosamil as second-line therapy (85%), concurrently with other antibiotics (61%). Similar patterns of ceftaroline fosamil usage were noted in younger patients (aged < 65 years). Fifteen patients died (3%), 10 of whom were elderly. The overall clinical success of ceftaroline fosamil was 81% for elderly patients with CABP and 82% for younger patients. These data suggest that ceftaroline fosamil is a potentially effective treatment option for CABP in the elderly.

Contemporary use of ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia: CAPTURE study experience.

The Clinical Assessment Program and Teflaro(®) Utilization Registry (CAPTURE) is a multicenter cohort study designed to collect information on the contemporary use of ceftaroline fosamil in the US. Data collected from 398 evaluable patients with community-acquired bacterial pneumonia (CABP) (mean age 64 years) during the first 18 months of the study are presented. Most patients had co-morbidities (76%; primarily structural lung disease), and ≧2 signs and symptoms of CABP (76%). Overall clinical success was 79% which varied little with ceftaroline fosamil usage (monotherapy vs concurrent therapy; first-line vs second-line therapy). Most patients were discharged home (60%) or to another healthcare facility (35%). These data suggest that ceftaroline, in contemporary clinical use, is an effective antibiotic for the treatment of patients with CABP, including those with significant co-morbidities or who required a change of their prior antibiotic therapy.

MassSQUIRM: An assay for quantitative measurement of lysine demethylase activity.

In eukaryotes, DNA is wrapped around proteins called histones and is condensed into chromatin. Post-translational modification of histones can result in changes in gene expression. One of the most well-studied histone modifications is the methylation of lysine 4 on histone H3 (H3K4). This residue can be mono-, di- or tri-methylated and these varying methylation states have been associated with different levels of gene expression. Understanding exactly what the purpose of these methylation states is, in terms of gene expression, has been a topic of much research in recent years. Enzymes that can add (methyltransferases) and remove (demethylases) these modifications are of particular interest. The first demethylase discovered, LSD1, is the most well-classified and has been implicated in contributing to human cancers and to DNA damage response pathways. Currently, there are limited methods for accurately studying the activity of demethylases in vitro or in vivo. In this work, we present MassSQUIRM (mass spectrometric quantitation using isotopic reductive methylation), a quantitative method for studying the activity of demethylases capable of removing mono- and di-methyl marks from lysine residues. We focus specifically on LSD1 due to its potential as a prime therapeutic target for human disease. This quantitative approach will enable better characterization of the activity of LSD1 and other chromatin modifying enzymes in vitro, in vivo or in response to inhibitors.

Time trend and geographic patterns of lung adenocarcinoma in the United States, 1973-2002.

OBJECTIVE: To find the major factor explaining the substantial increase in incidence of adenocarcinoma of the lung (ADL), we observed its temporal trend, distributions in geographic areas and populations, and compared them with the distributions of air pollution and low-tar cigarette consumption in time, place, and populations. METHODS: The temporal and spatial patterns of ADL were compared with the level of nitrogen oxides (NO(x)) emissions as well as the use of low-tar cigarettes. RESULTS: Similar increasing trends followed by declining trends were seen in emission levels of NO(x) and ADL incidence rates. These trends peak about 20 years earlier for NO(x) levels than for ADL incidence. Incidence rates of ADL in high NO(x) emission areas were substantially higher than those in low NO(x) emission areas. Incidence rates of ADL in Black males are about 50% higher than in White males and can be explained by the differences in air quality related to residence site and size. CONCLUSIONS: The descriptive epidemiologic data help generate the hypothesis that long-term exposure to low-dose NO(x) may play a major role in causing steep increases in past ADL incidence rates. There is an urgent need to conduct further studies to determine whether the association is a causal relationship between long-term, low-dose exposure to NO(x) and ADL.

Human rights and the national interest: migrants, healthcare and social justice.

The UK government has recently taken steps to exclude certain groups of migrants from free treatment under the National Health Service, most controversially from treatment for HIV. Whether this discrimination can have any coherent ethical basis is questioned in this paper. The exclusion of migrants of any status from any welfare system cannot be ethically justified because the distinction between citizens and migrants cannot be an ethical one.

A novel hemoglobin-based blood substitute protects against myocardial reperfusion injury.

HBOC-201 (Biopure; Cambridge, MA) is a glutaraldehyde-polymerized bovine hemoglobin (Hb) solution that is stroma free, has lower viscosity than blood, and promotes O(2) unloading. We investigated the effects of HBOC-201 in a canine model of myocardial ischemia-reperfusion injury. Dogs were anesthetized and subjected to 90 min of regional myocardial ischemia and 270 min of reperfusion. HBOC-201 or 0.9% saline vehicle equivalent to 10% total blood volume was infused 30 min before myocardial ischemia. Hemodynamic data and peripheral blood samples were taken at baseline, 1 h of myocardial ischemia, and 1, 2, and 4 h of reperfusion. At 270 min of reperfusion, the area at risk (AAR) per left ventricle and the area of infarction (Inf) per AAR were determined. The myocardial AARs in the two study groups were similar. In addition, myocardial blood flow (as measured by radioactive microspheres) in the ischemic zone was similar between the vehicle and HBOC-201 groups. HBOC-201-infused dogs demonstrated a significant (P < 0.01) 56% reduction in Inf/AAR. Analysis of blood samples taken at 4 h of reperfusion showed a significant (P < 0.05) reduction in creatine kinase MB isoform for the HBOC-201 group. Histological analysis of the myocardium demonstrated significant (P < 0.01) reductions in neutrophil infiltration in the HBOC-201 group. These data indicate that treatment with HBOC-201 before myocardial ischemia-reperfusion reduces the extent of myocardial inflammation and ischemia-reperfusion injury in the canine myocardium.

Quantitative analysis of single- vs. multiple-set programs in resistance training.

The purpose of this study was to examine the existing research on single-set vs. multiple-set resistance training programs. Using the meta-analytic approach, we included studies that met the following criteria in our analysis: (a) at least 6 subjects per group; (b) subject groups consisting of single-set vs. multiple-set resistance training programs; (c) pretest and posttest strength measures; (d) training programs of 6 weeks or more; (e) apparently "healthy" individuals free from orthopedic limitations; and (f) published studies in English-language journals only. Sixteen studies generated 103 effect sizes (ESs) based on a total of 621 subjects, ranging in age from 15-71 years. Across all designs, intervention strategies, and categories, the pretest to posttest ES in muscular strength was (chi = 1.4 +/- 1.4; 95% confidence interval, 0.41-3.8; p < 0.001). The results of 2 x 2 analysis of variance revealed simple main effects for age, training status (trained vs. untrained), and research design (p < 0.001). No significant main effects were found for sex, program duration, and set end point. Significant interactions were found for training status and program duration (6-16 weeks vs. 17-40 weeks) and number of sets performed (single vs. multiple). The data indicated that trained individuals performing multiple sets generated significantly greater increases in strength (p < 0.001). For programs with an extended duration, multiple sets were superior to single sets (p < 0.05). This quantitative review indicates that single-set programs for an initial short training period in untrained individuals result in similar strength gains as multiple-set programs. However, as progression occurs and higher gains are desired, multiple-set programs are more effective.