Showing papers by "Gdańsk Medical University published in 2012"

Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal

Abstract: Activation of tissue mast cells (MCs) and their abnormal growth and accumulation in various organs are typically found in primary MC disorders also referred to as mastocytosis. However, increasing numbers of patients are now being informed that their clinical findings are due to MC activation (MCA) that is neither associated with mastocytosis nor with a defined allergic or inflammatory reaction. In other patients with MCA, MCs appear to be clonal cells, but criteria for diagnosing mastocytosis are not met. A working conference was organized in 2010 with the aim to define criteria for diagnosing MCA and related disorders, and to propose a global unifying classification of all MC disorders and pathologic MC reactions. This classification includes three types of ‘MCA syndromes’ (MCASs), namely primary MCAS, secondary MCAS and idiopathic MCAS. MCA is now defined by robust and generally applicable criteria, including (1) typical clinical symptoms, (2) a substantial transient increase in serum total tryptase level or an increase in other MC-derived mediators, such as histamine or prostaglandin D2, or their urinary metabolites, and (3) a response of clinical symptoms to agents that attenuate the production or activities of MC mediators. These criteria should assist in the identification and diagnosis of patients with MCAS, and in avoiding misdiagnoses or overinterpretation of clinical symptoms in daily practice. Moreover, the MCAS concept should stimulate research in order to identify and exploit new molecular mechanisms and therapeutic targets.

Sensing the Environment: Regulation of Local and Global Homeostasis by the Skin's Neuroendocrine System

Abstract: 1.1. General overview The strategic location of the skin as the barrier between the environment and internal milieu determines its critical function in the preservation of body homeostasis, and ultimately organism survival (Slominski, 2005, Slominski and Wortsman, 2000, Slominski et al., 2000c, Zmijewski and Slominski, 2011). It also exposes skin to numerous pathological agents, processes, and events. Thus, the capability to locally recognize, discriminate and integrate various signals within a highly heterogeneous environment, and to immediately launch appropriate responses, is a vital property of skin (Slominski and Wortsman, 2000). These skin functions are integrated into the skin immune, pigmentary, epidermal and adnexal systems, and are in continuous communication with the systemic immune, neural and endocrine systems (Arck et al., 2006, Slominski, 2009c, Slominski et al., 2004c, Slominski and Wortsman, 2000, Slominski et al., 2007a, Stenn and Paus, 2001). These fundamental functions results from the location of the skin, which is the largest body’s organ, at the interphase between external and internal environment, requiring development of efficient sensory and effector capabilities to differentially react to changes in external environment. They are represented by inducible production of biologically active compounds (hormones, neurohormones and neurotransmitters) that act both locally and at the systemic levels (Fig. 1). Figure 1 Skin senses changes in the environment through cutaneous neuroendocrine system, which computes and translates the received information into chemical, physical and biological messengers that regulate global (A and B) and local (B) homeostasis. These signals ... The skin being continuously exposed to many external biological or environmental factors (acute transfers of solar, thermal or chemical energy), had to evolve optimal mechanism(s) to protect, restore or maintain local and global homeostasis in relation to hostile environment (Slominski et al., 1993b, Slominski and Pawelek, 1998, Slominski and Wortsman, 2000, Slominski et al., 2000c). We have proposed that precise coordination and execution of these responses are mediated by a cutaneous neuroendocrine system, which also is able to reset the body homeostatic adaptation mechanisms (Slominski and Wortsman, 2000). Superimposed on this is the impact of psychological stress on skin physiology and pathology, placed in the context of the bidirectional brain-skin communication (Arck et al., 2006, Slominski, 2005a, Slominski et al., 2008b). To summarize, in reaction to changing external and also internal environment, the skin can generate signals to produce rapid (neural) or slow (humoral or immune) responses at the local and systemic levels (Fig. 1). Coordination between these local and systemic responses is mediated by the skin neuroendocrine system (Slominski and Wortsman, 2000a), which employs local equivalents of the hypothalamo-pituitary-adrenal axis (HPA) (Slominski et al., 2007a), hypothalamo-pituitary-thyroid (HPT) axis (Pisarchik and Slominski, 2002, van Beek et al., 2008), catecholaminergic (Schallreuter et al., 1997), serotoninergic, melatoninergic (Slominski et al., 2008a, Slominski et al., 2005c), cholinergic (Grando, 2006, Grando et al., 2006), steroidogenic (Slominski et al., 2008b) and secosteroidogenic (Bikle, 2010, Holick, 2003, Slominski et al., 2010) systems (Fig. 2). Given their common embryonic origins, it is not surprising that skin shares numerous mediators with the CNS and endocrine system. Recent research has revealed that skin also harbors a complex opioidogenic (Grando et al., 1995, Slominski et al., 2011c) and canabinnoidogenic (Biro et al., 2009) systems, which role in the maintenance of cutaneous homeostasis is currently being intensively explored. Figure 2 Skin neuroendocrine system follows the algorithms of classical neuroendocrine or endocrine systems. It also forms a natural platform of signal exchange between internal organs and environment. For this purpose skin cells not only are subjected to neurohormonal ... In this monograph we will discuss the role of various components of the skin neuroendocrine system in sensing the environment with subsequent regulation of local and global homeostasis with a main focus on the algorithms of classical neuroendocrine axes.

Administration of CD4+CD25highCD127− Regulatory T Cells Preserves β-Cell Function in Type 1 Diabetes in Children

Abstract: OBJECTIVE Type 1 diabetes is a condition in which pancreatic islets are destroyed by self-reactive T cells. The process is facilitated by deficits in the number and suppressive activity of regulatory T cells (Tregs). Here, we show for the first time that the infusion of autologous Tregs prolongs remission in recently diagnosed type 1 diabetes in children. RESEARCH DESIGN AND METHODS We have administered Tregs in 10 type 1 diabetic children (aged 8–16 years) within 2 months since diagnosis. In total, 4 patients received 10 × 106 Tregs/kg body wt and the remaining 6 patients received 20 × 106 Tregs/kg body wt. The preparation consisted of sorted autologous CD3+CD4+CD25highCD127− Tregs expanded under good manufacturing practice conditions. RESULTS No toxicity of the therapy was noted. A significant increase in the percentage of Tregs in the peripheral blood has been observed since the day of infusion. These patients were followed along with matched type 1 diabetic patients not treated with Tregs. Half a year after type 1 diabetes onset (4–5 months after Treg infusion), 8 patients treated with Tregs still required <0.5 UI/kg body wt of insulin daily, with 2 patients out of insulin completely, whereas the remission was over in the nontreated group. In addition, plasma C-peptide levels were significantly higher in the treated group as compared with those not treated. CONCLUSIONS This study shows that the administration of Tregs is safe and tolerable in children with recent-onset type 1 diabetes.

L-tyrosine and L-dihydroxyphenylalanine as hormone-like regulators of melanocyte functions.

Abstract: There is evidence that L-tyrosine and L-dihydroxyphenylalanine (L-DOPA), besides serving as substrates and intermediates of melanogenesis, are also bioregulatory agents acting not only as inducers and positive regulators of melanogenesis but also as regulators of other cellular functions. These can be mediated through action on specific receptors or through non-receptor-mediated mechanisms. The substrate induced (L-tyrosine and/or L-DOPA) melanogenic pathway would autoregulate itself as well as regulate the melanocyte functions through the activity of its structural or regulatory proteins and through intermediates of melanogenesis and melanin itself. Dissection of regulatory and autoregulatory elements of this process may elucidate how substrate-induced autoregulatory pathways have evolved from prokaryotic or simple eukaryotic organisms to complex systems in vertebrates. This could substantiate an older theory proposing that receptors for amino acid-derived hormones arose from the receptors for those amino acids, and that nuclear receptors evolved from primitive intracellular receptors binding nutritional factors or metabolic intermediates.

Structural and biochemical characteristics of various white adipose tissue depots.

Abstract: It is now widely accepted that white adipose tissue (WAT) is not merely a fuel storage organ, but also a key component of metabolic homoeostatic mechanisms. Apart from its major role in lipid and glucose metabolism, adipose tissue is also involved in a wide array of other biological processes. The hormones and adipokines, as well as other biologically active agents released from fat cells, affect many physiological and pathological processes. WAT is neither uniform nor inflexible because it undergoes constant remodelling, adapting the size and number of adipocytes to changes in nutrients' availability and hormonal milieu. Fat depots from different areas of the body display distinct structural and functional properties and have disparate roles in pathology. The two major types of WAT are visceral fat, localized within the abdominal cavity and mediastinum, and subcutaneous fat in the hypodermis. Visceral obesity correlates with increased risk of insulin resistance and cardiovascular diseases, while increase of subcutaneous fat is associated with favourable plasma lipid profiles. Visceral adipocytes show higher lipogenic and lipolytic activities and produce more pro-inflammatory cytokines, while subcutaneous adipocytes are the main source of leptin and adiponectin. Moreover, adipose tissue associated with skeletal muscles (intramyocellular and intermuscular fat) and with the epicardium is believed to provide fuels for skeletal and cardiac muscle contraction. However, increased mass of either epicardial or intermuscular adipose tissue correlates with cardiovascular risk, while the presence of the intramyocellular fat is a risk factor for the development of insulin resistance. This review summarizes results of mainly human studies related to the differential characteristics of various WAT depots.

ESH Position Paper: Renal denervation ^ an interventional therapy of resistant hypertension

Abstract: Experts from the European Society of Hypertension prepared this position paper in order to summarize current evidence, unmet needs and practical recommendations on the application of percutaneous transluminal ablation of renal nerves [renal denervation (RDN)] as a novel therapeutic strategy for the treatment of resistant hypertension. The sympathetic nervous activation to the kidney and the sensory afferent signals to the central nervous system represent the targets of RND. Clinical studies have documented that catheter-based RDN decreases both efferent sympathetic and afferent sensory nerve traffic leading to clinically meaningful systolic and diastolic blood pressure (BP) reductions in patients with resistant hypertension. This position statement intends to facilitate a better understanding of the effectiveness, safety, limitations and issues still to be addressed with RDN.

Rapid screening of antibiotic toxicity in an automated microdroplet system

Abstract: We report an automated microfluidic platform for ‘digitally’ screening the composition space of droplets containing cocktails of small molecules and demonstrate the features of this system by studying epistatic interactions between antibiotics and Escherichia coli ATCC 25922. This system has several key characteristics: (i) it uses small (<100 μL) samples of liquids and suspensions of bacteria that are introduced directly into the chip; (ii) it generates a sequence of droplets with compositions, including reagents and bacterial cell suspensions that are programmed by the user; (iii) it exports the sequence of droplets to an external segment of tubing that is subsequently disconnected for incubation and storage; and (iv) after incubation of bacteria in droplets, the droplets are injected into a second device equipped with an in-line fiber optic spectrophotometer that measures cell growth. The system generates and fuses droplets with precise (<1% in standard deviation) control of liquid volumes and of the concentrations of input substrates. We demonstrate the application of this technology in determining the minimum inhibitory concentration and pair-wise interactions of ampicillin, tetracycline, and chloramphenicol against E. coli. The experiments consumed small volumes of reagents and required minutes to create the droplets and several hours for their incubation and analysis.

EuraHS: the development of an international online platform for registration and outcome measurement of ventral abdominal wall hernia repair.

Abstract: Although the repair of ventral abdominal wall hernias is one of the most commonly performed operations, many aspects of their treatment are still under debate or poorly studied. In addition, there is a lack of good definitions and classifications that make the evaluation of studies and meta-analyses in this field of surgery difficult. Under the auspices of the board of the European Hernia Society and following the previously published classifications on inguinal and on ventral hernias, a working group was formed to create an online platform for registration and outcome measurement of operations for ventral abdominal wall hernias. Development of such a registry involved reaching agreement about clear definitions and classifications on patient variables, surgical procedures and mesh materials used, as well as outcome parameters. The EuraHS working group (European registry for abdominal wall hernias) comprised of a multinational European expert panel with specific interest in abdominal wall hernias. Over five working group meetings, consensus was reached on definitions for the data to be recorded in the registry. A set of well-described definitions was made. The previously reported EHS classifications of hernias will be used. Risk factors for recurrences and co-morbidities of patients were listed. A new severity of comorbidity score was defined. Post-operative complications were classified according to existing classifications as described for other fields of surgery. A new 3-dimensional numerical quality-of-life score, EuraHS-QoL score, was defined. An online platform is created based on the definitions and classifications, which can be used by individual surgeons, surgical teams or for multicentre studies. A EuraHS website is constructed with easy access to all the definitions, classifications and results from the database. An online platform for registration and outcome measurement of abdominal wall hernia repairs with clear definitions and classifications is offered to the surgical community. It is hoped that this registry could lead to better evidence-based guidelines for treatment of abdominal wall hernias based on hernia variables, patient variables, available hernia repair materials and techniques.

Hypertension and atrial fibrillation: diagnostic approach, prevention and treatment. Position paper of the Working Group "Hypertension Arrhythmias and Thrombosis" of the European Society of Hypertension

Abstract: Hypertension is the most common cardiovascular disorder and atrial fibrillation is the most common clinically significant arrhythmia. Both these conditions frequently coexist and their prevalence increases rapidly with aging. There are different risk factors and clinical conditions predisposing to the development of atrial fibrillation, but due its high prevalence, hypertension is still the main risk factor for the development of atrial fibrillation. Several pathophysiologic mechanisms (such as structural changes, neurohormonal activation, fibrosis, atherosclerosis, etc.) have been advocated to explain the onset of atrial fibrillation. The presence of atrial fibrillation per se increases the risk of stroke but its coexistence with high blood pressure leads to an abrupt increase of cardiovascular complications. Different risk models are available for the risk stratification and the prevention of thromboembolism in patients with atrial fibrillation. In all of them hypertension is present and is an important risk factor. Antihypertensive treatment may contribute to reduce this risk, and it seems some classes are superior to others in the prevention of new-onset atrial fibrillation and prevention of stroke. Antithrombotic treatment with warfarin is effective in the prevention of thromboembolic events, although quite recently, new classes of anticoagulants that do not require international normalized ratio monitoring have been introduced with promising results.

Position paper on the management of patients with obstructive sleep apnea and hypertension: joint recommendations by the European Society of Hypertension, by the European Respiratory Society and by the members of European COST (COoperation in Scientific and Technological research) ACTION B26 on obstructive sleep apnea.

Abstract: This article is aimed at addressing the current state of the art in epidemiology, pathophysiology, diagnostic procedures and treatment options for appropriate management of obstructive sleep apnea (OSA) in cardiovascular (particularly hypertensive) patients, as well as for the management of cardiovascular diseases (particularly arterial hypertension) in OSA patients. The present document is the result of the work done by a panel of experts participating in the European Union COST (COoperation in Scientific and Technological research) ACTION B26 on OSA, with the endorsement of the European Respiratory Society (ERS) and the European Society of Hypertension (ESH). These recommendations are particularly aimed at reminding cardiovascular experts to consider the occurrence of sleep-related breathing disorders in patients with high blood pressure. They are at the same time aimed at reminding respiration experts to consider the occurrence of hypertension in patients with respiratory problems at night.

Age-Related Somatic Structural Changes in the Nuclear Genome of Human Blood Cells

Abstract: Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we describe age-related accumulation of copy-number variation in the nuclear genomes in vivo and frequency changes for both megabase- and kilobase-range variants. Megabase-range aberrations were found in 3.4% (9 of 264) of subjects ≥60 years old; these subjects included 78 MZ twin pairs and 108 single-born individuals. No such findings were observed in 81 MZ pairs or 180 single-born subjects who were ≤55 years old. Recurrent region- and gene-specific mutations, mostly deletions, were observed. Longitudinal analyses of 43 subjects whose data were collected 7–19 years apart suggest considerable variation in the rate of accumulation of clones carrying structural changes. Furthermore, the longitudinal analysis of individuals with structural aberrations suggests that there is a natural self-removal of aberrant cell clones from peripheral blood. In three healthy subjects, we detected somatic aberrations characteristic of patients with myelodysplastic syndrome. The recurrent rearrangements uncovered here are candidates for common age-related defects in human blood cells. We anticipate that extension of these results will allow determination of the genetic age of different somatic-cell lineages and estimation of possible individual differences between genetic and chronological age. Our work might also help to explain the cause of an age-related reduction in the number of cell clones in the blood; such a reduction is one of the hallmarks of immunosenescence.

Epithelial-mesenchymal transition: a hallmark in metastasis formation linking circulating tumor cells and cancer stem cells.

Abstract: The occurrence of either regional or distant metastases is an indicator of poor prognosis for cancer patients. The mechanism of their formation has not yet been fully uncovered, which limits the possibility of developing new therapeutic strategies. Nevertheless, the discovery of circulating tumor cells (CTCs), which are responsible for tumor dissemination, and cancer stem cells (CSCs), required for tumor growth maintenance, shed light on the metastatic cascade. It seems that CTCs and CSCs are not necessarily separate populations of cancer cells, as CTCs generated in the process of epithelial-mesenchymal transition (EMT) can bear features characteristic of CSCs. This article describes the mechanisms of CTC and CSC formation and characterizes their molecular hallmarks. Moreover, we present different types of EMT occurring in physiological and pathological conditions, and we demonstrate its crucial role in providing CTCs with a CSC phenotype. The article delineates molecular changes acquired by cancer cells undergoing EMT that facilitate metastasis formation. Deeper understanding of those processes is of fundamental importance for the development of new strategies of early cancer detection and effective cancer treatment approaches that will be translated into clinical practice.

Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: further evidence for disease course-related immune alterations?

Abstract: Certain cytokines have been identified in the peripheral blood as trait markers of schizophrenia, while others are considered relapse-related state markers. Furthermore, data from peripheral blood, cerebrospinal fluid (CSF) and nuclear imaging studies suggest that (1) blood-brain barrier (BBB) dysfunction (e.g., immigration of lymphocytes into brain tissue and intrathecal antibody production) correlates with the development of negative symptoms, while (2) the brain's mononuclear phagocyte system (microglial cells) is activated during acute psychosis. Based on these neuroinflammatory hypotheses, we have quantified the numerical density of immunostained CD3+ T-lymphocytes, CD20+ B-lymphocytes, and HLA-DR+ microglial cells in the posterior hippocampus of 17 schizophrenia patients and 11 matched controls. Disease course-related immune alterations were considered by a separate analysis of residual (prevailing negative symptoms, n=7) and paranoid (prominent positive symptoms, n=10) schizophrenia cases. Higher densities of CD3+ and CD20+ lymphocytes were observed in residual versus paranoid schizophrenia (CD 3: left: P=0.047, right: P=0.038; CD20: left: P=0.020, right: P=0.010) and controls (CD3: left: P=0.057, right: P=0.069; CD20: left: P=0.008, right: P=0.006). In contrast, HLA-DR+ microglia were increased in paranoid schizophrenia versus residual schizophrenia (left: P=0.030, right: P=0.012). A similar trend emerged when this group was compared to controls (left: P=0.090, right: P=0.090). BBB impairment and infiltration of T cells and B cells may contribute to the pathophysiology of residual schizophrenia, while microglial activation seems to play a role in paranoid schizophrenia. The identification of diverse immune endophenotypes may facilitate the development of distinct anti-inflammatory schizophrenia therapies to normalize BBB function, (auto)antibody production or microglial activity.

CMV and Immunosenescence: from basics to clinics

Abstract: Alone among herpesviruses, persistent Cytomegalovirus (CMV) markedly alters the numbers and proportions of peripheral immune cells in infected-vs-uninfected people. Because the rate of CMV infection increases with age in most countries, it has been suggested that it drives or at least exacerbates "immunosenescence". This contention remains controversial and was the primary subject of the Third International Workshop on CMV & Immunosenescence which was held in Cordoba, Spain, 15-16th March, 2012. Discussions focused on several main themes including the effects of CMV on adaptive immunity and immunosenescence, characterization of CMV-specific T cells, impact of CMV infection and ageing on innate immunity, and finally, most important, the clinical implications of immunosenescence and CMV infection. Here we summarize the major findings of this workshop.

Bridging the gap between the immune and glutamate hypotheses of schizophrenia and major depression: Potential role of glial NMDA receptor modulators and impaired blood–brain barrier integrity

Abstract: Objectives. Previous studies have suggested that the pathogenesis of schizophrenia and major depression involves an altered peripheral immune system. It is not clear, however, whether such changes are associated with corresponding neuroinflammatory responses and disturbances of neurotransmission. Methods. This paper reviews the current state of knowledge about the involvement of immune alterations in schizophrenia and major depression and a possible link to disturbances of glutamatergic transmission. Results. Inflammatory endogenous modulators of the NMDA receptor, the kynurenine pathway metabolites, are potential candidates for such a link. Studies of the blood and cerebrospinal fluid have suggested a schizophrenia-related upregulation of the NMDA receptor antagonist kynurenic acid in astrocytes, analogous to the ketamine psychosis model. Conversely, it has been proposed that there is depression-related microglial synthesis of the NMDA receptor agonist quinolinic acid, which is consistent with the observation that ketamine has therapeutic effects in major depression. Few publications have studied NMDA receptor modulating kynurenines in the brain, however. Conclusions. Future research on the cerebral cell-type specific distribution of kynurenine metabolites and their brain-regional concentration imbalances will be required to connect peripheral immune changes, the hypotheses of blood–brain barrier dysfunction and glial pathology with concepts of altered neurotransmission in schizophrenia and major depression. Read More: http://informahealthcare.com/doi/abs/10.3109/15622975.2011.583941

Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research

Abstract: Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.

Pathogenesis and classification of eosinophil disorders: a review of recent developments in the field

Abstract: Eosinophils and their products play an essential role in the pathogenesis of various reactive and neoplastic disorders. Depending on the underlying disease, molecular defect and involved cytokines, hypereosinophilia may develop and may lead to organ damage. In other patients, persistent eosinophilia is accompanied by typical clinical findings, but the causative role and impact of eosinophilia remain uncertain. For patients with eosinophil-mediated organ pathology, early therapeutic intervention with agents reducing eosinophil counts can be effective in limiting or preventing irreversible organ damage. Therefore, it is important to approach eosinophil disorders and related syndromes early by using established criteria, to perform all appropriate staging investigations, and to search for molecular targets of therapy. In this article, we review current concepts in the pathogenesis and evolution of eosinophilia and eosinophil-related organ damage in neoplastic and non-neoplastic conditions. In addition, we discuss classifications of eosinophil disorders and related syndromes as well as diagnostic algorithms and standard treatment for various eosinophil-related disorders.

Bone-Related Complications and Quality of Life in Advanced Breast Cancer: Results from a Randomized Phase III Trial of Denosumab versus Zoledronic Acid

Abstract: Purpose: Denosumab was shown to be superior to zoledronic acid in preventing skeletal related events (SRE) in patients with breast cancer and bone metastases in a randomized, double-blind phase III study. We evaluated further results from this study related to skeletal complications and health-related quality of life (HRQoL).Experimental Design: Patients were randomized 1:1 to receive subcutaneous denosumab 120 mg (n = 1,026) and intravenous placebo, or intravenous zoledronic acid 4 mg (n = 1,020) and subcutaneous placebo every 4 weeks. Analyses reported here include the proportion of patients with one or multiple on-study SREs, time to first radiation to bone, time to first SRE or hypercalcemia of malignancy, and change in HRQoL (functional assessment of cancer therapy–general).Results: Fewer patients receiving denosumab than zoledronic acid had an on-study SRE (31% vs. 36%, P = 0.006). The incidence of first radiation to bone was 12% (n = 123) with denosumab versus 16% (n = 162) with zoledronic acid. Denosumab prolonged the time to first radiation to bone by 26% versus zoledronic acid (HR, 0.74; 95% confidence interval [CI], 0.59–0.94, P = 0.012) and prolonged the time to first SRE or hypercalcemia of malignancy by 18% (HR, 0.82; 95% CI, 0.70–0.95; P = 0.007). Ten percent more patients had a clinically meaningful improvement in HRQoL with denosumab relative to zoledronic acid, regardless of baseline pain levels.Conclusions: Denosumab was superior to zoledronic acid in reducing bone-related complications of metastatic breast cancer and maintained HRQoL, providing an efficacious, well-tolerated treatment option for patients with bone metastases from breast cancer. Clin Cancer Res; 18(17); 4841–9. ©2012 AACR.

Increased MET and HGF gene copy numbers are associated with trastuzumab failure in HER2-positive metastatic breast cancer.

Abstract: To investigate whether copy number gain of MET or hepatocyte growth factor (HGF) affect trastuzumab sensitivity in HER2-positive metastatic breast cancer (MBC). We analysed 130 HER2-positive MBC treated with trastuzumab-based therapy. MET and HGF gene copy numbers (GCN) were assessed by fluorescence in situ hybridisation (FISH) in primary breast cancer samples. Receiver operating characteristic analysis was applied to find the best cutoff point for both MET and HGF GCN. MET FISH-positive cases (N=36, mean ⩾3.72) had a significantly higher trastuzumab failure rate (44.4% vs 16.0%; P=0.001) and a significantly shorter time to progression (5.7 vs 9.9 months; HR 1.74; P=0.006) than MET FISH-negative cases (N=94, mean <3.72). Hepatocyte growth factor GCN was evaluated in 84 cases (64.6%). Receiver operating characteristic analysis identified 33 HGF FISH-positive patients (mean HGF GCN ⩾3.01). HGF FISH-positive status was significantly associated with higher risk of failure (30.3% vs 7.8%; P=0.007) as compared with HGF FISH-negative cases (N=51, mean <3.01). MET and HGF FISH-positive status was highly correlated (P<0.001) and combination of both biomarkers did not increase predictive value of either considered separately. High GCNs of MET and HGF associate with an increased risk of trastuzumab-based therapy failure in HER2-positive MBC.

Prevalence of monogenic diabetes amongst Polish children after a nationwide genetic screening campaign

Abstract: Aims/hypothesis The aim of this study was to study dynamic changes in the prevalence of different types of diabetes in paediatric populations in Poland, with a specific focus on monogenic diabetes (MD).

Mechanisms of toxicity of amorphous silica nanoparticles on human lung submucosal cells in vitro: protective effects of fisetin.

Abstract: There is growing evidence that amorphous silica nanoparticles (SiO₂-NP) can cause an inflammatory response in the lung. We studied in vitro the effects of exposing human lung submucosal cells to SiO₂-NP of various sizes (10, 150, and 500 nm) for 2-24 h. Cell survival, reactive oxygen species (ROS), malondialdehyde (MDA) levels, cytokine production, inflammatory gene expression, and genotoxicity were measured after exposure of Calu-3 cells to 10SiO₂-NP in the presence or absence of the flavanoid fisetin and an antioxidant enzyme catalase. The exposure of Calu-3 cells to 10SiO₂-NP resulted in (1) increased cytotoxicity and cell death in a time- and concentration-dependent manner, with a lethal concentration (LC₅₀) of 9.7 μg/mL after 24 h; (2) enhanced gene expression of interleukin (IL)-6, IL-8, and matrix metalloproteinase-9; (3) a significant correlation between increases in MDA and cytotoxicity at 18 h; (4) ROS production; (5) IL-6 and IL-8 release; and (6) up-regulation of the pro-apoptotic genes, p53 and caspase-3. Cell death and inflammatory reactions were attenuated by fisetin and catalase. We observed that 150- and 500SiO₂-NP exerted no toxic effects on Calu-3 cells. In conclusion, the nanotoxicity of amorphous 10SiO₂-NP on submucosal cells is associated with inflammation, the release of ROS leading to apoptosis, and decreased cell survival. The nanotoxic effects of 10SiO₂-NP can be decreased by fisetin and catalase treatment, implicating oxidative stress in this injury.