Autopsy as an outcome and performance measure: three years of hospital autopsy as an instrument of clinical audit

An extensive literature documents a high prevalence of errors in clinical diagnosis discovered at autopsy. Multiple studies have suggested no significant decrease in these errors over time. Despite these findings, autopsies have dramatically decreased in frequency in the United States and many other countries. In 1994, the last year for which national U.S. data exist, the autopsy rate for all non-forensic deaths fell below 6%. The marked decline in autopsy rates from previous rates of 40\u201350% undoubtedly reflects various factors, including reimbursement issues, the attitudes of clinicians regarding the utility of autopsies in the setting of other diagnostic advances, and general unfamiliarity with the autopsy and techniques for requesting it, especially among physicians-in-training. The autopsy is valuable for its role in undergraduate and graduate medical education, the identification and characterization of new diseases, and contributions to the understanding of disease pathogenesis. Although extensive, these benefits are difficult to quantify. This review of the last three years of hospital autopsy in Lucca studied the more easily quantifiable benefits of the autopsy as a tool in performance measurement and improvement. Such benefits largely relate to the role of the autopsy in detecting errors in clinical diagnosis and unsuspected complications of treatment. It is hoped that characterizing the extent to which the autopsy provides data relevant to clinical performance measurement and improvement will help inform strategies for preserving the benefits of routinely obtained autopsies and for considering its wider use as an instrument for quality improvement

NF-κB, stem cells and breast cancer: the links get stronger

Self-renewing breast cancer stem cells are key actors in perpetuating tumour existence and in treatment resistance and relapse. The molecular pathways required for their maintenance are starting to be elucidated. Among them is the transcription factor NF-κB, which is known to play critical roles in cell survival, inflammation and immunity. Recent studies indicate that mammary epithelial NF-κB regulates the self-renewal of breast cancer stem cells in a model of Her2-dependent tumourigenesis. We will describe here the NF-κB-activating pathways that are involved in this process and in which progenitor cells this transcription factor is actually activated

Understanding the importance of selenium and selenoproteins in muscle function

Selenium is an essential trace element. In cattle, selenium deficiency causes dysfunction of various organs, including skeletal and cardiac muscles. In humans as well, lack of selenium is associated with many disorders, but despite accumulation of clinical reports, muscle diseases are not generally considered on the list. The goal of this review is to establish the connection between clinical observations and the most recent advances obtained in selenium biology. Recent results about a possible role of selenium-containing proteins in muscle formation and repair have been collected. Selenoprotein N is the first selenoprotein linked to genetic disorders consisting of different forms of congenital muscular dystrophies. Understanding the muscle disorders associated with selenium deficiency or selenoprotein N dysfunction is an essential step in defining the causes of the disease and obtaining a better comprehension of the mechanisms involved in muscle formation and maintenance

A pilot feasibility trial of alcohol screening and brief intervention in the police custody setting (ACCEPT): study protocol for a cluster randomised controlled trial

BACKGROUND: There is evidence of an association between alcohol use and offending behaviour and around a quarter of police time is spent on alcohol-related incidents. Police custody, therefore, provides an important opportunity to intervene. This pilot trial aims to investigate whether a definitive evaluation of screening and brief interventions aimed at reducing risky drinking in arrestees is acceptable and feasible in the custody suite setting. METHODS: Screening will be carried out by trained detention officers or drug and alcohol workers in four police forces across two geographical areas (North East and South West England). Detention officers (or drug and alcohol workers) will be cluster randomised to one of three conditions: screening only (control group), screening followed immediately by 10 min of manualised brief structured advice delivered by the individual responsible for screening (intervention 1) or screening followed by 10 min of manualised brief structured advice delivered by the individual responsible for screening plus the offer of a subsequent 20-min session of behaviour change counselling delivered by a trained alcohol health worker (intervention 2). Participants will be arrestees aged 18+ who screen positive on the Alcohol Use Disorders Identification Test. Participants will be followed up at 6 and 12 months post-intervention. An embedded qualitative process evaluation will explore acceptability of alcohol screening and brief intervention to staff and arrestees as well as facilitators and barriers to the delivery of such approaches in this setting. RESULTS: Recruitment is currently underway and due to end May 2015. CONCLUSION: Results from this pilot trial will determine if a definitive evaluation is possible in the future and will provide stakeholder input to its design. TRIAL REGISTRATION: Reference number: ISRCTN89291046

The acetylation of RelA in Lys310 dictates the NF-κB-dependent response in post-ischemic injury

The activation of nuclear factor kappa B (NF-κB) p50/RelA is a key event in ischemic neuronal injury, as well as in brain ischemic tolerance. We tested whether epigenetic mechanisms affecting the acetylation state of RelA might discriminate between neuroprotective and neurotoxic activation of NF-κB during ischemia. NF-κB activation and RelA acetylation were investigated in cortices of mice subjected to preconditioning brain ischemia or lethal middle cerebral artery occlusion (MCAO) and primary cortical neurons exposed to preconditioning or lethal oxygen-glucose deprivation (OGD). In mice subjected to MCAO and in cortical neurons exposed to lethal OGD, activated RelA displayed a high level of Lys310 acetylation in spite of reduced total acetylation. Also, acetylated RelA on Lys310 interacted strongly with the CREB-binding protein (CBP). Conversely, RelA activated during preconditioning ischemia appeared deacetylated on Lys310. Overexpressing RelA increased Bim promoter activity and neuronal cell death both induced by lethal OGD, whereas overexpressing the acetylation-resistant RelA-K310R, carrying a mutation from Lys310 to arginine, prevented both responses. Pharmacological manipulation of Lys310 acetylation by the sirtuin 1 activator resveratrol repressed the activity of the Bim promoter and reduced the neuronal cell loss. We conclude that the acetylation of RelA in Lys310 dictates NF-κB-dependent pro-apoptotic responses and represents a suitable target to dissect pathological from neuroprotective NF-κB activation in brain ischemia

IKKβ Regulates the Repair of DNA Double-Strand Breaks Induced by Ionizing Radiation in MCF-7 Breast Cancer Cells

Activation of the IKK-NFκB pathway increases the resistance of cancer cells to ionizing radiation (IR). This effect has been largely attributed to the induction of anti-apoptotic proteins by NFκB. Since efficient repair of DNA double strand breaks (DSBs) is required for the clonogenic survival of irradiated cells, we investigated if activation of the IKK-NFκB pathway also regulates DSB repair to promote cell survival after IR. We found that inhibition of the IKK-NFκB pathway with a specific IKKβ inhibitor significantly reduced the repair of IR-induced DSBs in MCF-7 cells. The repair of DSBs was also significantly inhibited by silencing IKKβ expression with IKKβ shRNA. However, down-regulation of IKKα expression with IKKα shRNA had no significant effect on the repair of IR-induced DSBs. Similar findings were also observed in IKKα and/or IKKβ knockout mouse embryonic fibroblasts (MEFs). More importantly, inhibition of IKKβ with an inhibitor or down-regulation of IKKβ with IKKβ shRNA sensitized MCF-7 cells to IR-induced clonogenic cell death. DSB repair function and resistance to IR were completely restored by IKKβ reconstitution in IKKβ-knockdown MCF-7 cells. These findings demonstrate that IKKβ can regulate the repair of DSBs, a previously undescribed and important IKKβ kinase function; and inhibition of DSB repair may contribute to cance cell radiosensitization induced by IKKβ inhibition. As such, specific inhibition of IKKβ may represents a more effective approach to sensitize cancer cells to radiotherapy

Deregulated expression of TANK in glioblastomas triggers pro-tumorigenic ERK1/2 and AKT signaling pathways

Signal transmission by the noncanonical IkappaB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IKKɛ, requires interaction with adapter proteins such as TRAF associated NF-κB activator (TANK). Although increased expression or dysregulation of both kinases has been described for a variety of human cancers, this study shows that deregulated expression of the TANK protein is frequently occurring in glioblastomas (GBMs). The functional relevance of TANK was analyzed in a panel of GBM-derived cell lines and revealed that knockdown of TANK arrests cells in the S-phase and prohibits tumor cell migration. Deregulated TANK expression affects several signaling pathways controlling cell proliferation and the inflammatory response. Interference with stoichiometrically assembled signaling complexes by overexpression or silencing of TANK prevented constitutive interferon-regulatory factor 3 (IRF3) phosphorylation. Knockdown of TANK frequently prevents constitutive activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). TANK-mediated ERK1/2 activation is independent from the canonical MAP kinase or ERK kinase (MEK) 1/2-mediated pathway and utilizes an alternative pathway that uses a TBK1/IKKɛ/Akt signaling axis, thus identifying a novel pathway suitable to block constitutive ERK1/2 activity.Peer reviewe

Poxvirus Protein N1L Targets the I-κB Kinase Complex, Inhibits Signaling to NF-κB by the Tumor Necrosis Factor Superfamily of Receptors, and Inhibits NF-κB and IRF3 Signaling by Toll-like Receptors

Poxviruses encode proteins that suppress host immune responses, including secreted decoy receptors for pro-inflammatory cytokines such as interleukin-1 (IL-1) and the vaccinia virus proteins A46R and A52R that inhibit intracellular signaling by members of the IL-1 receptor (IL-1R) and Toll-like receptor (TLR) family. In vivo, the TLRs mediate the innate immune response by serving as pathogen recognition receptors, whose oligomerized intracellular Toll/IL-1 receptor (TIR) domains can initiate innate immune signaling. A family of TIR domain-containing adapter molecules transduces signals from engaged receptors that ultimately activate NF-kappaB and/or interferon regulatory factor 3 (IRF3) to induce pro-inflammatory cytokines. Data base searches detected a significant similarity between the N1L protein of vaccinia virus and A52R, a poxvirus inhibitor of TIR signaling. Compared with other poxvirus virulence factors, the poxvirus N1L protein strongly affects virulence in vivo; however, the precise target of N1L was previously unknown. Here we show that N1L suppresses NF-kappaB activation following engagement of Toll/IL-1 receptors, tumor necrosis factor receptors, and lymphotoxin receptors. N1L inhibited receptor-, adapter-, TRAF-, and IKK-alpha and IKK-beta-dependent signaling to NF-kappaB. N1L associated with several components of the multisubunit I-kappaB kinase complex, most strongly associating with the kinase, TANK-binding kinase 1 (TBK1). Together these findings are consistent with the hypothesis that N1L disrupts signaling to NF-kappaB by Toll/IL-1Rs and TNF superfamily receptors by targeting the IKK complex for inhibition. Furthermore, N1L inhibited IRF3 signaling, which is also regulated by TBK1. These studies define a role for N1L as an immunomodulator of innate immunity by targeting components of NF-kappaB and IRF3 signaling pathways

The prosurvival IKK-related kinase IKKϵ integrates LPS and IL17A signaling cascades to promote Wnt-dependent tumor development in the intestine

Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikkϵ in Wnt-driven tumor development. We found that Ikkϵ was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikkϵ in b-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkϵ to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikkϵ was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding proinflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikkϵ-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikkϵ phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikkϵ to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. � 2016 American Association for Cancer Research