Clinical experience with the novel histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in patients with relapsed lymphoma

Preclinical studies indicate that vorinostat (suberoylanilide hydroxamic acid or SAHA) inhibits histone deacetylase (HDAC) activity, increases acetylated histones H2a, H2b, H3, and H4, and thereby induces differentiation and apoptosis in a variety of tumour cell lines, including murine erythroleukaemia, human bladder transitional cell carcinoma, and human breast adenocarcinoma. On the basis of these favourable preclinical findings, vorinostat has been selected as a candidate for clinical development with the potential to treat patients with selected malignances, including Hodgkin's disease and non-Hodgkin's lymphomas. Phase I clinical trials in patients with haematological malignances and solid tumours showed that both intravenous (i.v.) and oral formulations of vorinostat are well tolerated, can inhibit HDAC activity in peripheral blood mononuclear cells and tumour tissue biopsies, and produce objective tumour regression and symptomatic improvement with little clinical toxicity. The dose-limiting toxicities (DLT) of i.v. vorinostat were primarily haematologic and were rapidly reversible within 4–5 days of therapy cessation. In contrast, the DLT for oral vorinostat were primarily non-haematologic (including dehydration, anorexia, diarrhoea, fatigue) and were also rapidly reversible, usually within 3 days. Further research is warranted to optimise the dosing schedule for vorinostat, particularly with respect to dose, timing of administration, and duration of therapy, and to fully delineate the mechanism(s) of antitumour effect of vorinostat in various types of malignances. Several phase II studies are currently ongoing in patients with haematological malignances and solid tumours

Realization of a Tunable Artificial Atom at a Supercritically Charged Vacancy in Graphene

The remarkable electronic properties of graphene have fueled the vision of a graphene-based platform for lighter, faster and smarter electronics and computing applications. One of the challenges is to devise ways to tailor its electronic properties and to control its charge carriers. Here we show that a single atom vacancy in graphene can stably host a local charge and that this charge can be gradually built up by applying voltage pulses with the tip of a scanning tunneling microscope (STM). The response of the conduction electrons in graphene to the local charge is monitored with scanning tunneling and Landau level spectroscopy, and compared to numerical simulations. As the charge is increased, its interaction with the conduction electrons undergoes a transition into a supercritical regime 6-11 where itinerant electrons are trapped in a sequence of quasi-bound states which resemble an artificial atom. The quasi-bound electron states are detected by a strong enhancement of the density of states (DOS) within a disc centered on the vacancy site which is surrounded by halo of hole states. We further show that the quasi-bound states at the vacancy site are gate tunable and that the trapping mechanism can be turned on and off, providing a new mechanism to control and guide electrons in grapheneComment: 18 pages and 5 figures plus 14 pages and 15 figures of supplementary information. Nature Physics advance online publication, Feb 22 (2016

Patient-Reported Outcome questionnaires for hip arthroscopy: a systematic review of the psychometric evidence

Abstract Background Hip arthroscopies are often used in the treatment of intra-articular hip injuries. Patient-reported outcomes (PRO) are an important parameter in evaluating treatment. It is unclear which PRO questionnaires are specifically available for hip arthroscopy patients. The aim of this systematic review was to investigate which PRO questionnaires are valid and reliable in the evaluation of patients undergoing hip arthroscopy. Methods A search was conducted in Pubmed, Medline, CINAHL, the Cochrane Library, Pedro, EMBASE and Web of Science from 1931 to October 2010. Studies assessing the quality of PRO questionnaires in the evaluation of patients undergoing hip arthroscopy were included. The quality of the questionnaires was evaluated by the psychometric properties of the outcome measures. The quality of the articles investigating the questionnaires was assessed by the COSMIN list. Results Five articles identified three questionnaires; the Modified Harris Hip Score (MHHS), the Nonarthritic Hip Score (NAHS) and the Hip Outcome Score (HOS). The NAHS scored best on the content validity, whereas the HOS scored best on agreement, internal consistency, reliability and responsiveness. The quality of the articles describing the HOS scored highest. The NAHS is the best quality questionnaire. The articles describing the HOS are the best quality articles. Conclusions This systematic review shows that there is no conclusive evidence for the use of a single patient-reported outcome questionnaire in the evaluation of patients undergoing hip arthroscopy. Based on available psychometric evidence we recommend using a combination of the NAHS and the HOS for patients undergoing hip arthroscopy.</p

Outcome Predictors of Pediatric Extracorporeal Cardiopulmonary Resuscitation

Extracorporeal cardiopulmonary resuscitation (ECPR) allows clinicians to potentially rescue pediatric patients unresponsive to traditional cardiopulmonary resuscitation (CPR). Clinical and laboratory variables predictive of survival to hospital discharge are beginning to emerge. In this retrospective, historical cohort case series, clinical, and laboratory data from 31 pediatric patients (<21 years of age) receiving ECPR from March 2000 to April 2006 at our university-affiliated, tertiary-care children’s hospital were statistically analyzed in an attempt to identify variables predictive of survival to hospital discharge. Seven patients survived to hospital discharge (23%), and 24 patients died. Survival was independent of gender, age, and CPR duration. ECPR survival was, however, associated with a lower pre-ECPR phosphorus concentration (P = 0.002) and a lower pre-ECPR creatinine concentration (P = 0.05). A classification tree analysis, using, in part, a pre-ECPR phosphorus concentration threshold and a CPR ABG base excess concentration threshold, yielded a 96% nominal accuracy of predicting survival to hospital discharge or death. A large, multicenter, prospective cohort study aimed at validating these predictive variables is needed to guide appropriate ECPR patient selection. This study reveals the potential survival benefit of ECPR for pediatric patients, regardless of CPR duration prior to ECPR cannulation

Pyrimidine biosynthesis is not an essential function for trypanosoma brucei bloodstream forms

&lt;p&gt;Background: African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is essential to the parasite.&lt;/p&gt; &lt;p&gt;Methodology/Principal Findings: Pyrimidine requirements for growth were investigated using strictly pyrimidine-free media, with or without single added pyrimidine sources. Growth rates of wild-type bloodstream form Trypanosoma brucei brucei were unchanged in pyrimidine-free medium. The essentiality of the de novo pyrimidine biosynthesis pathway was studied by knocking out the PYR6-5 locus that produces a fusion product of orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase). The pyrimidine auxotroph was dependent on a suitable extracellular pyrimidine source. Pyrimidine starvation was rapidly lethal and non-reversible, causing incomplete DNA content in new cells. The phenotype could be rescued by addition of uracil; supplementation with uridine, 2′deoxyuridine, and cytidine allowed a diminished growth rate and density. PYR6-5−/− trypanosomes were more sensitive to pyrimidine antimetabolites and displayed increased uracil transport rates and uridine phosphorylase activity. Pyrimidine auxotrophs were able to infect mice although the infection developed much more slowly than infection with the parental, prototrophic trypanosome line.&lt;/p&gt; &lt;p&gt;Conclusions/Significance: Pyrimidine salvage was not an essential function for bloodstream T. b. brucei. However, trypanosomes lacking de novo pyrimidine biosynthesis are completely dependent on an extracellular pyrimidine source, strongly preferring uracil, and display reduced infectivity. As T. brucei are able to salvage sufficient pyrimidines from the host environment, the pyrimidine biosynthesis pathway is not a viable drug target, although any interruption of pyrimidine supply was lethal.&lt;/p&gt

Stable isotopes and mtDNA reveal niche segregation but no evidence of intergradation along a habitat gradient in the Lesser Whitethroat complex (Sylvia curruca; Passeriformes; Aves)

Niche segregation plays a critical role in the speciation process, but determining the extent to which taxa are geographically or ecologically isolated is challenging. In this study, we use stable isotopes of carbon (δ13C), nitrogen (δ15N), hydrogen (δ2H) and oxygen (δ18O) to test for ecological differences among taxa in the Lesser Whitethroat Sylvia curruca complex. Analysis of mitochondrial DNA (mtDNA) revealed 6 distinct haplotype groups, which conform to at least 5 distinct taxa. Stable isotopes provided insight into geographical and broad-scale ecological differences among haplotypes. The most striking isotope differences were between the populations inhabiting Siberian boreal forest (S. c. blythi) from the one inhabiting semi-desert in Kazakhstan (S. c. halimodendri). It is generally assumed that these two populations form a morphological cline along a gradient from mesic to xeric habitat. Our sample includes a large proportion of morphologically intermediate individuals that appear to represent a hybrid population. However, in all of these, there is strict correspondence between haplotype and isotope signature, suggesting an ecological division on the breeding grounds between all our samples of these two taxa. The lack of ecologically intermediate individuals among our sample of morphologically intermediate ones thus speaks against the existence of a cline. The two taxa blythi and halimodendri emerge as potential models for the study of the early stages of the speciation process. While differences in stable isotopes may be largely influenced by geography, we also demonstrate how, in specific instances (such as the alleged cline reported here), they may be used to evaluate niche segregation between taxa, providing information of importance for determination of species limits

DNA microarray profiling of genes differentially regulated by the histone deacetylase inhibitors vorinostat and LBH589 in colon cancer cell lines

<p>Abstract</p> <p>Background</p> <p>Despite the significant progress made in colon cancer chemotherapy, advanced disease remains largely incurable and novel efficacious chemotherapies are urgently needed. Histone deacetylase inhibitors (HDACi) represent a novel class of agents which have demonstrated promising preclinical activity and are undergoing clinical evaluation in colon cancer. The goal of this study was to identify genes in colon cancer cells that are differentially regulated by two clinically advanced hydroxamic acid HDACi, vorinostat and LBH589 to provide rationale for novel drug combination partners and identify a core set of HDACi-regulated genes.</p> <p>Methods</p> <p>HCT116 and HT29 colon cancer cells were treated with LBH589 or vorinostat and growth inhibition, acetylation status and apoptosis were analyzed in response to treatment using MTS, Western blotting and flow cytometric analyses. In addition, gene expression was analyzed using the Illumina Human-6 V2 BeadChip array and Ingenuity^®Pathway Analysis.</p> <p>Results</p> <p>Treatment with either vorinostat or LBH589 rapidly induced histone acetylation, cell cycle arrest and inhibited the growth of both HCT116 and HT29 cells. Bioinformatic analysis of the microarray profiling revealed significant similarity in the genes altered in expression following treatment with the two HDACi tested within each cell line. However, analysis of genes that were altered in expression in the HCT116 and HT29 cells revealed cell-line-specific responses to HDACi treatment. In addition a core cassette of 11 genes modulated by both vorinostat and LBH589 were identified in both colon cancer cell lines analyzed.</p> <p>Conclusion</p> <p>This study identified HDACi-induced alterations in critical genes involved in nucleotide metabolism, angiogenesis, mitosis and cell survival which may represent potential intervention points for novel therapeutic combinations in colon cancer. This information will assist in the identification of novel pathways and targets that are modulated by HDACi, providing much-needed information on HDACi mechanism of action and providing rationale for novel drug combination partners. We identified a core signature of 11 genes which were modulated by both vorinostat and LBH589 in a similar manner in both cell lines. These core genes will assist in the development and validation of a common gene set which may represent a molecular signature of HDAC inhibition in colon cancer.</p

Long-term effects of an inpatient weight-loss program in obese children and the role of genetic predisposition-rationale and design of the LOGIC-trial

<p>Abstract</p> <p>Background</p> <p>The prevalence of childhood obesity has increased worldwide, which is a serious concern as obesity is associated with many negative immediate and long-term health consequences. Therefore, the treatment of overweight and obesity in children and adolescents is strongly recommended. Inpatient weight-loss programs have shown to be effective particularly regarding short-term weight-loss, whilst little is known both on the long-term effects of this treatment and the determinants of successful weight-loss and subsequent weight maintenance.</p> <p>The purpose of this study is to evaluate the short, middle and long-term effects of an inpatient weight-loss program for children and adolescents and to investigate the likely determinants of weight changes, whereby the primary focus lies on the potential role of differences in polymorphisms of adiposity-relevant genes.</p> <p>Methods/Design</p> <p>The study involves overweight and obese children and adolescents aged 6 to 19 years, who participate in an inpatient weight-loss program for 4 to 6 weeks. It started in 2006 and it is planned to include 1,500 participants by 2013. The intervention focuses on diet, physical activity and behavior therapy. Measurements are taken at the start and the end of the intervention and comprise blood analyses (DNA, lipid and glucose metabolism, adipokines and inflammatory markers), anthropometry (body weight, height and waist circumference), blood pressure, pubertal stage, and exercise capacity. Physical activity, dietary habits, quality of life, and family background are assessed by questionnaires. Follow-up assessments are performed 6 months, 1, 2, 5 and 10 years after the intervention: Children will complete the same questionnaires at all time points and visit their general practitioner for examination of anthropometric parameters, blood pressure and assessment of pubertal stage. At the 5 and 10 year follow-ups, blood parameters and exercise capacity will be additionally measured.</p> <p>Discussion</p> <p>Apart from illustrating the short, middle and long-term effects of an inpatient weight-loss program, this study will contribute to a better understanding of inter-individual differences in the regulation of body weight, taking into account the role of genetic predisposition and lifestyle factors.</p> <p>Trial Registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01067157">NCT01067157</a>.</p

Histone deacetylase inhibitor, butyrate, attenuates lipopolysaccharide-induced acute lung injury in mice

<p>Abstract</p> <p>Background</p> <p>Histone deacetylase (HDAC) inhibitors, developed as promising anti-tumor drugs, exhibit their anti-inflammatory properties due to their effects on reduction of inflammatory cytokines.</p> <p>Objective</p> <p>To investigate the protective effect of butyrate, a HDAC inhibitor, on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice.</p> <p>Methods</p> <p>ALI was induced in Balb/c mice by intratracheally instillation of LPS (1 mg/kg). Before 1 hour of LPS administration, the mice received butyrate (10 mg/kg) orally. The animals in each group were sacrificed at different time point after LPS administration. Pulmonary histological changes were evaluated by hematoxylin-eosin stain and lung wet/dry weight ratios were observed. Concentrations of interleukin (IL)-1β and tumor necrosis factor (TNF)-α in bronchoalveolar lavage fluid (BALF) and concentrations of nitric oxide (NO) and myeloperoxidase (MPO) activity in lung tissue homogenates were measured by enzyme-linked immunosorbent assay (ELISA). Expression of nuclear factor (NF)-κB p65 in cytoplasm and nucleus was determined by Western blot analysis respectively.</p> <p>Results</p> <p>Pretreatment with butyrate led to significant attenuation of LPS induced evident lung histopathological changes, alveolar hemorrhage, and neutrophils infiltration with evidence of reduced MPO activity. The lung wet/dry weight ratios, as an index of lung edema, were reduced by butyrate administration. Butyrate also repressed the production of TNF-α, IL-1β and NO. Furthermore, the expression of NF-κB p65 in nucleus was markedly suppressed by butyrate pretreatment.</p> <p>Conclusions</p> <p>Butyrate had a protective effect on LPS-induced ALI, which may be related to its effect on suppression of inflammatory cytokines production and NF-κB activation.</p