Long-term safety study of infliximab in moderate-to-severe chronic obstructive pulmonary disease

SummaryRationaleThere was an increased number of malignancies in infliximab-treated (5.7%) over placebo-treated (1.3%) patients in a 44-week, phase 2 clinical study of 234 patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).ObjectivesTo collect malignancy and mortality data from completed clinical studies of infliximab in COPD treatment.MethodsThe multicenter, observational Remicade Safety Under Long-Term Study in COPD (RESULTS COPD) collected malignancy and mortality data every six months for five years from patients who received ≥1 study-agent dose in a phase 2 study. Co-primary endpoints were the number of patients with malignancy and the number of deaths. Secondary endpoints included the number of patients with a malignancy according to malignancy type.ResultsThere was a gap period between the end of the phase 2 study and the initiation of RESULTS COPD, during which six malignancies and 14 deaths were reported spontaneously for the 107 (45.7%) of 234 patients with long-term safety information. Twenty-eight patients (overall 12.0%; placebo 10.4%, infliximab 12.7%) reported malignancies, including 12 patients during RESULTS COPD. Twenty-six patients (overall 11.1%; placebo 9.1%, infliximab 12.1%) died, including nine during RESULTS COPD. Lung cancer was the most common malignancy type (placebo n = 2; infliximab n = 10).ConclusionsThe greater proportion of malignancies observed with infliximab versus placebo in a phase 2 study diminished over the long-term follow-up. Due to the observational nature, limited patient participation, potential reporting bias from the interim spontaneous reporting period, and unblinding of all patients, more definitive conclusions cannot be drawn.Trial Registration Number: NCT00056264

Coumarins and pyranocoumarins, potential novel pharmacophores for inhibition ofmeasles virus replication

A series of coumarin and pyranocoumarin analogues were evaluated in vitro for antiviral efficacy against measles virus (MV), strain Chicago. Of the 22 compounds tested for inhibition, six were found to have selectivity indices greater than 10. These were compounds 5-hydroxy-7-propionyloxy- 4-propylcoumarin (2a), 5,7-bis(tosyloxy)-4- propylcoumarin (7); 5-hydroxy-4-propyl-7-tosyloxy- coumarin (8); 6,6-dimethyl-9-propionyloxy-4- propyl-2H,6H-benzo[1,2-b:3,4-b′]dipyran-2-one (9); 6,6-dimethyl-9-pivaloyloxy-4-propyl-2H,6Hbenzo[ 1,2-b:3,4-b′]dipyran-2-one (10); and 7,8-cis- 10,11,12-trans-4-propyl-6,6,10,11-tetramethyl- 7,8,9-trihydroxy-2H,6H,12H-benzo[1,2-b:3,4-b′:5,6- b′′]tripyran-2-one (18). Three of the active drugs were propyl coumarin analogues (2a, 7 and 8), two were dipyranone or chromeno-coumarins (9 and 10), and one was a benzotripyranone with a coumarin nucleus (18). Some appeared to be rather specific and potent inhibitors of MV with EC50 values ranging from 0.2 to 50 μg/ml and the majority of the EC50 values being less than 5 μg/ml. The compounds inhibited an additional nine strains of MV, and in virucidal tests the drugs did not physically disrupt the virion to inhibit virus replication. The inhibitory activity for one of the compounds tested (7) was somewhat dependent on virus concentration and it was still active when added to cells up to 24 h after virus exposure. When used in combination with ribavirin, compound 7 appeared not to profoundly affect the antiviral efficacy of ribavirin or its cell-associated toxicity. However, a slightly antagonistic MVinhibitory effect was observed at the highest concentration of ribavirin used in combination with most concentrations of compound 7 tested. This and related compounds may be valuable leads in the development of a potent and selective class of MV inhibitors that could be used in future in the clinic

Molecular Mechanism of Capacitative Calcium Entry Deficits in Familial Alzheimer’s Disease

Poster PresentationPresenilin (PS) is the catalytic subunit of the gamma-secretase which is responsible for the cleavage of amyloid precursor protein to form beta amyloid (Aβ). Mutations in PS associated with familial Alzheimer’s disease (FAD) increase the Aβ plaques formation in the brain and cause neurodegeneration. Apart from this, FAD-linked PS mutations have been demonstrated to disrupt intracellular calcium (Ca2+) regulation. Accumulating evidence suggests that Ca2+ disruption may play a proximal role in the AD pathogenesis. Mutant PS exaggerated Ca2+ release from the endoplasmic reticulum (ER). It also attenuated Ca2+ entry through the capacitative Ca2+ entry (CCE) pathway, yet, the mechanism is not fully understood. Using a human neuroblast cell line SH-SY5Y and Ca2+ imaging technique, we observed CCE deficits in FAD-linked PS1-M146L retroviral infected cell. The attenuation of CCE in PS1 mutant cells was not mediated by the down-regulation of STIM1 and Orai1 expression, the known essential molecular players in the CCE pathway. Instead, we identified a molecular interaction between PS and STIM1 proteins by immunoprecipitation. On the other hand, immunofluorescence staining showed a significant reduction in puncta formation after ER Ca2+ depleted by thapsigargin in cells infected with PS1-M146L as compared to the wild type PS1 infected cells. Taken together, our results suggest a molecular mechanism for the CCE deficits in FAD associated with PS1 mutations. The interaction of mutant PS1 with STIM1 exerts a negative impact on its oligomerization and/or its interaction with Orai1. Our results may suggest molecular targets for the development of therapeutic agents that help to treat the disease.published_or_final_versio

Regulation of microRNA biosynthesis and expression in 2102Ep embryonal carcinoma stem cells is mirrored in ovarian serous adenocarcinoma patients

<p>Abstract</p> <p>Background</p> <p>Tumours with high proportions of differentiated cells are considered to be of a lower grade to those containing high proportions of undifferentiated cells. This property may be linked to the differentiation properties of stem cell-like populations within malignancies. We aim to identify molecular mechanism associated with the generation of tumours with differing grades from malignant stem cell populations with different differentiation potentials. In this study we assessed microRNA (miRNA) regulation in two populations of malignant Embryonal Carcinoma (EC) stem cell, which differentiate (NTera2) or remain undifferentiated (2102Ep) during tumourigenesis, and compared this to miRNA regulation in ovarian serous carcinoma (OSC) patient samples.</p> <p>Methods</p> <p>miRNA expression was assessed in NTera2 and 2102Ep cells in the undifferentiated and differentiated states and compared to that of OSC samples using miRNA qPCR.</p> <p>Results</p> <p>Our analysis reveals a substantial overlap between miRNA regulation in 2102Ep cells and OSC samples in terms of miRNA biosynthesis and expression of mature miRNAs, particularly those of the miR-17/92 family and clustering to chromosomes 14 and 19. In the undifferentiated state 2102Ep cells expressed mature miRNAs at up to 15,000 fold increased levels despite decreased expression of miRNA biosynthesis genes Drosha and Dicer. 2102Ep cells avoid differentiation, which we show is associated with consistent levels of expression of miRNA biosynthesis genes and mature miRNAs while expression of miRNAs clustering to chromosomes 14 and 19 is deemphasised. OSC patient samples displayed decreased expression of miRNA biosynthesis genes, decreased expression of mature miRNAs and prominent clustering to chromosome 14 but not 19. This indicates that miRNA biosynthesis and levels of miRNA expression, particularly from chromosome 14, are tightly regulated both in progenitor cells and in tumour samples.</p> <p>Conclusion</p> <p>miRNA biosynthesis and expression of mature miRNAs, particularly the miR-17/92 family and those clustering to chromosomes 14 and 19, are highly regulated in both progenitor cells and tumour samples. Strikingly, 2102Ep cells are not simply malfunctioning but respond to differentiation specifically, a mechanism that is highly relevant to OSC samples. Our identification and future manipulation of these miRNAs may facilitate generation of lower grade malignancies from these high-grade cells.</p

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Analysis of the 10q11 Cancer Risk Locus Implicates MSMB and NCOA4 in Human Prostate Tumorigenesis

Genome-wide association studies (GWAS) have established a variant, rs10993994, on chromosome 10q11 as being associated with prostate cancer risk. Since the variant is located outside of a protein-coding region, the target genes driving tumorigenesis are not readily apparent. Two genes nearest to this variant, MSMB and NCOA4, are strong candidates for mediating the effects of rs109939934. In a cohort of 180 individuals, we demonstrate that the rs10993994 risk allele is associated with decreased expression of two MSMB isoforms in histologically normal and malignant prostate tissue. In addition, the risk allele is associated with increased expression of five NCOA4 isoforms in histologically normal prostate tissue only. No consistent association with either gene is observed in breast or colon tissue. In conjunction with these findings, suppression of MSMB expression or NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells. These data suggest that germline variation at chromosome 10q11 contributes to prostate cancer risk by influencing expression of at least two genes. More broadly, the findings demonstrate that disease risk alleles may influence multiple genes, and associations between genotype and expression may only be observed in the context of specific tissue and disease states

Pattern of injury mortality by age-group in children aged 0–14 years in Scotland, 2002–2006, and its implications for prevention

<p>Abstract</p> <p>Background</p> <p>Knowledge of the epidemiology of injuries in children is essential for the planning, implementation and evaluation of preventive measures but recent epidemiological information on injuries in children both in general and by age-group in Scotland is scarce. This study examines the recent pattern of childhood mortality from injury by age-group in Scotland and considers its implications for prevention.</p> <p>Methods</p> <p>Routine mortality data for the period 2002–2006 were obtained from the General Register Office for Scotland and were analysed in terms of number of deaths, mean annual mortality rates per 100,000 population, leading causes of death, and causes of injury death. Mid-year population estimates were used as the denominator. Chi-square tests were used to determine statistical significance.</p> <p>Results</p> <p>186 children aged 0–14 died from an injury in Scotland during 2002–06 (MR 4.3 per 100,000). Injuries were the leading cause of death in 1–14, 5–9 and 10–14 year-olds (causing 25%, 29% and 32% of all deaths respectively). The leading individual causes of injury death (0–14 years) were pedestrian and non-pedestrian road-traffic injuries and assault/homicide but there was variation by age-group. Assault/homicide, fire and suffocation caused most injury deaths in young children; road-traffic injuries in older ones. Collectively, intentional injuries were a bigger threat to the lives of under-15s than any single cause of unintentional injury. The mortality rate from assault/homicide was highest in infants (<1 year) and decreased with increasing age. Children aged 5–9 were significantly less likely to die from an injury than 0–4 or 10–14 year-olds (p < 0.05). Suicide was an important cause of injury mortality in 10–14 year-olds.</p> <p>Conclusion</p> <p>Injuries continue to be a leading cause of death in childhood in Scotland. Variation in causes of injury death by age-group is important when targeting preventive efforts. In particular, the threats of assault/homicide in infants, fire in 1–4 year-olds, pedestrian injury in 5–14 year-olds, and suicide in 10–14 year-olds need urgent consideration for preventive action.</p

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse