A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer

Anthracyclines are used in over 50% of childhood cancer treatment protocols, but their clinical usefulness is limited by anthracycline-induced cardiotoxicity (ACT) manifesting as asymptomatic cardiac dysfunction and congestive heart failure in up to 57% and 16% of patients, respectively. Candidate gene studies have reported genetic associations with ACT, but these studies have in general lacked robust patient numbers, independent replication or functional validation. Thus, the individual variability in ACT susceptibility remains largely unexplained. We performed a genome-wide association study in 280 patients of European ancestry treated for childhood cancer, with independent replication in similarly treated cohorts of 96 European and 80 non-European patients. We identified a nonsynonymous variant (rs2229774, p.Ser427Leu) in RARG highly associated with ACT (P = 5.9 × 10(-8), odds ratio (95% confidence interval) = 4.7 (2.7-8.3)). This variant alters RARG function, leading to derepression of the key ACT genetic determinant Top2b, and provides new insight into the pathophysiology of this severe adverse drug reaction.

Genetic variants in SLC22A17 and SLC22A7 are associated with anthracycline-induced cardiotoxicity in children

AIM To identify novel variants associated with anthracycline-induced cardiotoxicity and to assess these in a genotype-guided risk prediction model. PATIENTS & METHODS Two cohorts treated for childhood cancer (n = 344 and 218, respectively) were genotyped for 4578 SNPs in drug ADME and toxicity genes. RESULTS Significant associations were identified in SLC22A17 (rs4982753; p = 0.0078) and SLC22A7 (rs4149178; p = 0.0034), with replication in the second cohort (p = 0.0071 and 0.047, respectively). Additional evidence was found for SULT2B1 and several genes related to oxidative stress. Adding the SLC22 variants to the prediction model improved its discriminative ability (AUC 0.78 vs 0.75 [p = 0.029]). CONCLUSION Two novel variants in SLC22A17 and SLC22A7 were significantly associated with anthracycline-induced cardiotoxicity and improved a genotype-guided risk prediction model, which could improve patient risk stratification.

Kinetic simulation of neutral∕ionized gas and electrically charged dust in the coma of comet 67P∕Churyumov-Gerasimenko

The cometary coma is a unique phenomenon in the solar system being a planetary atmosphere influenced by little or no gravity. As a comet approaches the sun, the water vapor with some fraction of other gases sublimate, generating a cloud of gas, ice and other refractory materials (rocky and organic dust) ejected from the surface of the nucleus. Sublimating gas molecules undergo frequent collisions and photochemical processes in the near���nucleus region. Owing to its negligible gravity, comets produce a large and highly variable extensive dusty coma with a size much larger than the characteristic size of the cometary nucleus. The Rosetta spacecraft is en route to comet 67P/Churyumov‐Gerasimenko for a rendezvous, landing, and extensive orbital phase beginning in 2014. Both, interpretation of measurements and safety consideration of the spacecraft require modeling of the comet’s dusty gas environment. In this work we present results of a numerical study of multispecies gaseous and electrically charged dust environment of comet Chyuryumov‐Gerasimenko. Both, gas and dust phases of the coma are simulated kinetically. Photolytic reactions are taken into account. Parameters of the ambient plasma as well as the distribution of electric/magnetic fields are obtained from an MHD simulation [1] of the coma connected to the solar wind. Trajectories of ions and electrically charged dust grains are simulated by accounting for the Lorentz force and the nucleus gravity.

Effect of the Tiger Stripes on the water vapor distribution in Enceladus' exosphere

The jet activity emanating from Enceladus' exosphere south pole region observed by Cassini is a subject of intensive study. The in situ and remote sensing observations performed since 2005 triggered an active modeling campaign. Such modeling is essential for better understanding of the measurements performed by individual instruments as well as to link them for a more complete picture of the volatile and ice grain distribution in Enceladus' exosphere. This paper is focused on the investigation of the effect that diffuse gas sources along the Tiger Stripes have on distribution of the water vapor in Enceladus' exosphere using the updated version of our multiplume model. We have found that accounting for the gas production by Tiger Stripes is critical for interpretation of the Cassini data. According to our calculations, sources along the Tiger Stripes (apart from those originally identified by Spitale and Porco (2007)) must contribute about 23–32% to the total plume source rate, which varies in the range of (6.4–29) ×1027 s−1. The effect of the previously unidentified source suggested in the paper is found to be critical for explaining the Ultraviolet Imaging Spectrograph 2007 and 2010 observations in the whole range of the elapsed times.

Inventory of the volatiles on comet 67P/Churyumov-Gerasimenko from Rosetta/ROSINA

Context. The ESA Rosetta spacecraft (S/C) is tracking comet 67P/Churyumov-Gerasimenko in close vicinity. This prolonged encounter enables studying the evolution of the volatile coma composition. Aims. Our work aims at comparing the diversity of the coma of 67P/Churyumov-Gerasimenko at large heliocentric distance to study the evolution of the comet during its passage around the Sun and at trying to classify it relative to other comets. Methods. We used the Double Focussing Mass Spectrometer (DFMS) of the ROSINA experiment on ESA’s Rosetta mission to determine relative abundances of major and minor volatile species. This study is restricted to species that have previously been detected elsewhere. Results. We detect almost all species currently known to be present in cometary coma with ROSINA DFMS. As DFMS measured the composition locally, we cannot derive a global abundance, but we compare measurements from the summer and the winter hemisphere with known abundances from other comets. Differences between relative abundances between summer and winter hemispheres are large, which points to a possible evolution of the cometary surface. This comet appears to be very rich in CO2 and ethane. Heavy oxygenated compounds such as ethylene glycol are underabundant at 3 AU, probably due to their high sublimation temperatures, but nevertheless, their presence proves that Kuiper belt comets also contain complex organic molecules.

Comparison of proximal femur and vertebral body strength improvements in the FREEDOM trial using an alternative finite element methodology

Denosumab reduced the incidence of new fractures in postmenopausal women with osteoporosis by 68% at the spine and 40% at the hip over 36 months compared with placebo in the FREEDOM study. This efficacy was supported by improvements from baseline in vertebral (18.2%) strength in axial compression and femoral (8.6%) strength in sideways fall configuration at 36 months, estimated in Newtons by an established voxel-based finite element (FE) methodology. Since FE analyses rely on the choice of meshes, material properties, and boundary conditions, the aim of this study was to independently confirm and compare the effects of denosumab on vertebral and femoral strength during the FREEDOM trial using an alternative smooth FE methodology. Unlike the previous FE study, effects on femoral strength in physiological stance configuration were also examined. QCT data for the proximal femur and two lumbar vertebrae were analyzed by smooth FE methodology at baseline, 12, 24, and 36 months for 51 treated (denosumab) and 47 control (placebo) subjects. QCT images were segmented and converted into smooth FE models to compute bone strength. L1 and L2 vertebral bodies were virtually loaded in axial compression and the proximal femora in both fall and stance configurations. Denosumab increased vertebral body strength by 10.8%, 14.0%, and 17.4% from baseline at 12, 24, and 36 months, respectively (p < 0.0001). Denosumab also increased femoral strength in the fall configuration by 4.3%, 5.1%, and 7.2% from baseline at 12, 24, and 36 months, respectively (p < 0.0001). Similar improvements were observed in the stance configuration with increases of 4.2%, 5.2%, and 5.2% from baseline (p ≤ 0.0007). Differences between the increasing strengths with denosumab and the decreasing strengths with placebo were significant starting at 12 months (vertebral and femoral fall) or 24 months (femoral stance). Using an alternative smooth FE methodology, we confirmed the significant improvements in vertebral body and proximal femur strength previously observed with denosumab. Estimated increases in strength with denosumab and decreases with placebo were highly consistent between both FE techniques.

Evidence for an Ancestral Association of Human Coronavirus 229E with Bats.

UNLABELLED We previously showed that close relatives of human coronavirus 229E (HCoV-229E) exist in African bats. The small sample and limited genomic characterizations have prevented further analyses so far. Here, we tested 2,087 fecal specimens from 11 bat species sampled in Ghana for HCoV-229E-related viruses by reverse transcription-PCR (RT-PCR). Only hipposiderid bats tested positive. To compare the genetic diversity of bat viruses and HCoV-229E, we tested historical isolates and diagnostic specimens sampled globally over 10 years. Bat viruses were 5- and 6-fold more diversified than HCoV-229E in the RNA-dependent RNA polymerase (RdRp) and spike genes. In phylogenetic analyses, HCoV-229E strains were monophyletic and not intermixed with animal viruses. Bat viruses formed three large clades in close and more distant sister relationships. A recently described 229E-related alpaca virus occupied an intermediate phylogenetic position between bat and human viruses. According to taxonomic criteria, human, alpaca, and bat viruses form a single CoV species showing evidence for multiple recombination events. HCoV-229E and the alpaca virus showed a major deletion in the spike S1 region compared to all bat viruses. Analyses of four full genomes from 229E-related bat CoVs revealed an eighth open reading frame (ORF8) located at the genomic 3' end. ORF8 also existed in the 229E-related alpaca virus. Reanalysis of HCoV-229E sequences showed a conserved transcription regulatory sequence preceding remnants of this ORF, suggesting its loss after acquisition of a 229E-related CoV by humans. These data suggested an evolutionary origin of 229E-related CoVs in hipposiderid bats, hypothetically with camelids as intermediate hosts preceding the establishment of HCoV-229E. IMPORTANCE The ancestral origins of major human coronaviruses (HCoVs) likely involve bat hosts. Here, we provide conclusive genetic evidence for an evolutionary origin of the common cold virus HCoV-229E in hipposiderid bats by analyzing a large sample of African bats and characterizing several bat viruses on a full-genome level. Our evolutionary analyses show that animal and human viruses are genetically closely related, can exchange genetic material, and form a single viral species. We show that the putative host switches leading to the formation of HCoV-229E were accompanied by major genomic changes, including deletions in the viral spike glycoprotein gene and loss of an open reading frame. We reanalyze a previously described genetically related alpaca virus and discuss the role of camelids as potential intermediate hosts between bat and human viruses. The evolutionary history of HCoV-229E likely shares important characteristics with that of the recently emerged highly pathogenic Middle East respiratory syndrome (MERS) coronavirus.

Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death.

The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.

Interferon response of the cystic fibrosis bronchial epithelium to major and minor group rhinovirus infection

Rhinoviruses (RVs) are associated with exacerbations of cystic fibrosis (CF), asthma and COPD. There is growing evidence suggesting the involvement of the interferon (IFN) pathway in RV-associated morbidity in asthma and COPD. The mechanisms of RV-triggered exacerbations in CF are poorly understood. In a pilot study, we assessed the antiviral response of CF and healthy bronchial epithelial cells (BECs) to RV infection, we measured the levels of IFNs, pattern recognition receptors (PRRs) and IFN-stimulated genes (ISGs) upon infection with major and minor group RVs and poly(IC) stimulation. Major group RV infection of CF BECs resulted in a trend towards a diminished IFN response at the level of IFNs, PRRs and ISGs in comparison to healthy BECs. Contrary to major group RV, the IFN pathway induction upon minor group RV infection was significantly increased at the level of IFNs and PRRs in CF BECs compared to healthy BECs.

Endoscopic Biopsy for Intra- and Paraventricular Tumors: Rates of Complications, Mortality, and Tumor Cell Dissemination

Background and Study Aim Intra- and paraventricular tumors are frequently associated with cerebrospinal fluid (CSF) pathway obstruction. Thus the aim of an endoscopic approach is to restore patency of the CSF pathways and to obtain a tumor biopsy. Because endoscopic tumor biopsy may increase tumor cell dissemination, this study sought to evaluate this risk. Patients, Materials, and Methods Forty-four patients who underwent endoscopic biopsies for ventricular or paraventricular tumors between 1993 and 2011 were included in the study. Charts and images were reviewed retrospectively to evaluate rates of adverse events, mortality, and tumor cell dissemination. Adverse events, mortality, and tumor cell dissemination were evaluated. Results Postoperative clinical condition improved in 63.0% of patients, remained stable in 30.4%, and worsened in 6.6%. One patient (2.2%) had a postoperative thalamic stroke leading to hemiparesis and hemineglect. No procedure-related deaths occurred. Postoperative tumor cell dissemination was observed in 14.3% of patients available for follow-up. Conclusions For patients presenting with occlusive hydrocephalus due to tumors in or adjacent to the ventricular system, endoscopic CSF diversion is the procedure of first choice. Tumor biopsy in the current study did not affect safety or efficacy.

Retraction

Vareille M, Kieninger E, Alves MP, et al. Impaired type I and type III interferon induction and rhinovirus control in human cystic fibrosis airway epithelial cells. Thorax 2012;67:517-25. This article has been retracted. In our article recently published in Thorax, we described a novel mechanism explaining the increased susceptibility of patients with cystic fibrosis (CF) to rhinovirus infections, namely defective interferon type I and III production by CF airway epithelial cells. In experiments performed after publication of the article we were unable to consistently replicate our findings of deficient interferon type I and III production by CF airway epithelial cells upon rhinovirus infection. In the light of these results, we carried out detailed investigations of the data reported in the above manuscript and regrettably found evidence of deliberate manipulation of experimental data by the first author Dr M. Vareille. This manipulation was accompanied in some instances by absence of original data files. The manipulation/original data absence involved data presented in most, if not all of the figures, thus we wish to fully retract the paper and apologise to the readers of Thorax and to the scientific community for the inconvenience this has caused. We also checked data published by our group in manuscripts on which Dr Vareille was a co-author and found that data published in these manuscripts had not been manipulated. These two manuscripts, whose data and conclusions we stand by are: Edwards MR, Regamey N, Vareille M, et al. Impaired innate interferon induction in severe therapy resistant atopic asthmatic children. Mucosal Immunol 2013;6:797–806. doi: 10.1038/mi.2012.118. and Kieninger E, Vareille M, Kopf BS, et al. Lack of an exaggerated inflammatory response on virus infection in cystic fibrosis. Eur Respir J 2012;39:297–304. doi: 10.1183/09031936.00054511. Dr. Vareille has received a letter from the Secretary General of the University of Bern condemning her scientific misconduct as a severe offence against the rules of scientific integrity. Her current employers have also been informed. All co-authors of the publication including Dr. Vareille concur with the retraction statement.

Recommendations for Genetic Testing to Reduce the Incidence of Anthracycline-induced Cardiotoxicity

AIM Anthracycline-induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline-based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence-based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk. METHODS We followed a standard guideline development process; including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group. RESULTS RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B - moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow-up, as well as therapeutic options within the current standard of clinical practice. CONCLUSIONS Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT.