Donor engrafted clonal hematopoiesis of indeterminate potential in allogeneic hematopoietic stem cell transplantation

Introduction: Clonal hematopoiesis of indeterminate (CHIP) describes the presence of hemato-logic cancer-associated somatic mutations in at least 4% of peripheral nucleated blood cells in the absence of further criteria for hematological malignancies. The main project investigated CHIP in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). Due to continuously growing numbers of older patients undergoing allogeneic HSCT, the proportion of older donors has been increasing, too, since siblings are often eligible donors. This is accompanied by a higher CHIP prevalence among donors as the prevalence increases in an age dependent manner. Since CHIP is known to be associated with adverse conditions such as cardiovascular diseases or hematologic cancers, our study investigated the effects of transplanted donor-CHIP on the clinical outcome of hematopoietic stem cell transplant recipients systematically. A side project addressed CHIP in the context of (radio-)chemotherapy in solid tumor patients and additionally studied the cell of origin and distribution patterns of CHIP-mutations among the hemato-poietic differentiation tree in non-cancer patients. A second side project focused on CHIP in the setting of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis. Methods: DNA samples from peripheral blood were tested for CHIP using paired-end sequenc-ing. Sequencing data were analyzed using a customized bioinformatic pipeline and statistically tested for clinical associations. Results: 80/500 stem dell donors were tested positive for CHIP (16%). Transplantation of do-nor-CHIP to the recipient was associated with a higher cumulative incidence of chronic graft-versus-host disease and a lower cumulative incidence of relapse/progression. Also, an elevated risk for the development of a donor cell leukemia was observed. However, non-relapse mortality and overall survival were not affected by CHIP-status. In the setting of solid tumor patients CHIP was linked to a more frequent chemotherapy dose reduction. After exclusion of solely DNMT3A-mutated patients CHIP was also associated with a higher need for red blood cell transfusions. Lin-CD34+CD38- hematopoietic stem cells were identified as cells of origin and expansion of CHIP-clones showed a bias towards the myeloid compartment and natural killer cells. In AAV patients an unexpectedly high CHIP prevalence of 30.4% (34/112) was observed. Also, the renal and nervous system were less frequently affected in CHIP+ individuals. Conclusion: Our results provide evidence for new clinical associations of CHIP and extend reported findings linking CHIP with aberrant immune response in inflammatory diseases. Trans-plantation of donor-CHIP does not affect overall survival after HSCT and therefore appears safe.Klonale Hämatopoese von unbestimmtem Potential (clonal hematopoiesis of indeterminate potential, CHIP) beschreibt das Vorkommen von Blutkrebs-assoziierten, somatischen Mutationen in mindestens 4% der kernhaltigen peripheren Blutzellen, ohne dabei weitere Kriterien für hämatologische Neoplasien zu erfüllen. Das Hauptprojekt untersuchte CHIP im Kontext von allogenen hämatopoetischen Stammzelltransplantationen (HSZT). Aufgrund der stetig zunehmenden Zahl älterer Patient*innen, die sich einer allogenen HSZT unterziehen, nimmt auch der Anteil älterer Spender*innen zu, da Verwandte häufig geeignete Spender*innen darstellen. Diese Entwicklung wird begleitet von einer höheren Prävalenz von CHIP unter den Spender*innen, da die Prävalenz altersabhängig zunimmt. Da CHIP mit Gesundheitsrisiken wie kardiovaskulären Erkrankungen oder hämatologischen Neoplasien assoziiert ist, wurden die Auswirkungen von transplantierter Spender-CHIP auf den klinischen Verlauf von Empfänger*innen einer HSZT systematisch untersucht. Ein Nebenprojekt befasste sich mit CHIP im Kontext solider Tumoren unter Einfluss von (Radio-)Chemotherapie sowie mit der Ursprungszelle und Verteilungsmustern von CHIP-Mutationen während der hämatopoetischen Differenzierung in nicht-onkologischen Patient* innen. Ein weiteres Nebenprojekt untersuchte die Rolle von CHIP im Setting von antineutrophilen zytoplasmatischen Antikörpern (ANCA)-assoziierten Vaskulitiden. Methoden: DNA-Proben aus peripherem Blut wurden mittels paired-end-Sequenzierung auf CHIP getestet. Die Sequenzierdaten wurden mittels einer angepassten bioinformatorischen Pipeline ausgewertet und anschließend statistisch auf klinische Assoziationen untersucht. Ergebnisse: 80/500 Stammzellspendern wurden positiv auf CHIP getestet (16%). Die Transplantation von Spender-CHIP war in den Empfänger*innen assoziiert mit einer höheren kumulativen Inzidenz für chronische Graft-versus-Host-Reaktionen sowie mit einer niedrigeren kumulativen Inzidenz für Rezidive/Progress. Zudem bestand ein erhöhtes Risiko für die Entwicklung von Spenderzellleukämien. Die therapiebedingte Mortalität und das Gesamtüberleben wurden jedoch durch den CHIP-Status nicht beeinflusst. In Patient*innen mit soliden Tumoren war CHIP mit einer häufigeren Reduktion der Chemotherapiedosis verbunden. Unter Ausschluss von einzig im Gen DNMT3A mutierten Patient*innen, war CHIP mit einem höheren Bedarf an Erythrozytentransfusionen assoziiert. Als Ursprungszelle wurden Lin-CD34+CD38- hämatopoetische Stammzellen identifiziert und es zeigte sich eine Expansion der CHIP-Klone zugunsten der myeloischen Zellreihe sowie natürlicher Killerzellen. Für AAV-Patient*innen wurde erstmalig eine unerwartet hohe CHIP-Prävalenz von 30.4% (34/112) nachgewiesen. Zudem ging CHIP mit einer geringeren renalen und neuronalen Beteiligung einher. Schlussfolgerung: Unserer Ergebnisse weisen auf neue klinische Assoziationen von CHIP hin und erweitern Kenntnisse über die Rolle von CHIP im Rahmen fehlgesteuerter Immunantworten bei chronisch entzündlichen Erkrankungen. Die Übertragung einer Spender-CHIP scheint das Gesamtüberleben nach HSZT nicht zu beeinflussen und wirkt somit sicher

Influence of transport and ocean ice extent on biogenic aerosol sulfur in the Arctic atmosphere

The recent decline in sea ice cover in the Arctic Ocean could affect the regional radiative forcing via changes in sea ice-atmosphere exchange of dimethyl sulfide (DMS) and biogenic aerosols formed from its atmospheric oxidation, such as methanesulfonic acid (MSA). This study examines relationships between changes in total sea ice extent north of 70 degrees N and atmospheric MSA measurement at Alert, Nunavut, during 1980-2009; at Barrow, Alaska, during 1997-2008; and at Ny-Alesund, Svalbard, for 1991-2004. During the 1980-1989 and 1990-1997 periods, summer (July-August) and June MSA concentrations at Alert decreased. In general, MSA concentrations increased at all locations since 2000 with respect to 1990 values, specifically during June and summer at Alert and in summer at Barrow and Ny-Alesund. Our results show variability in MSA at all sites is related to changes in the source strengths of DMS, possibly linked to changes in sea ice extent as well as to changes in atmospheric transport patterns. Since 2000, a late spring increase in atmospheric MSA at the three sites coincides with the northward migration of the marginal ice edge zone where high DMS emissions from ocean to atmosphere have previously been reported. Significant negative correlations are found between sea ice extent and MSA concentrations at the three sites during the spring and June. These results suggest that a decrease in seasonal ice cover influencing other mechanisms of DMS production could lead to higher atmospheric MSA concentrations

Organosulfate Formation in Biogenic Secondary Organic Aerosol

Organosulfates of isoprene, α-pinene, and β-pinene have recently been identified in both laboratory-generated and ambient secondary organic aerosol (SOA). In this study, the mechanism and ubiquity of organosulfate formation in biogenic SOA is investigated by a comprehensive series of laboratory photooxidation (i.e., OH-initiated oxidation) and nighttime oxidation (i.e., NO3-initiated oxidation under dark conditions) experiments using nine monoterpenes (α-pinene, β-pinene, d-limonene, l-limonene, α-terpinene, γ-terpinene, terpinolene, Δ3-carene, and β-phellandrene) and three monoterpenes (α-pinene, d-limonene, and l-limonene), respectively. Organosulfates were characterized using liquid chromatographic techniques coupled to electrospray ionization combined with both linear ion trap and high-resolution time-of-flight mass spectrometry. Organosulfates are formed only when monoterpenes are oxidized in the presence of acidified sulfate seed aerosol, a result consistent with prior work. Archived laboratory-generated isoprene SOA and ambient filter samples collected from the southeastern U.S. were reexamined for organosulfates. By comparing the tandem mass spectrometric and accurate mass measurements collected for both the laboratory-generated and ambient aerosol, previously uncharacterized ambient organic aerosol components are found to be organosulfates of isoprene, α-pinene, β-pinene, and limonene-like monoterpenes (e.g., myrcene), demonstrating the ubiquity of organosulfate formation in ambient SOA. Several of the organosulfates of isoprene and of the monoterpenes characterized in this study are ambient tracer compounds for the occurrence of biogenic SOA formation under acidic conditions. Furthermore, the nighttime oxidation experiments conducted under highly acidic conditions reveal a viable mechanism for the formation of previously identified nitrooxy organosulfates found in ambient nighttime aerosol samples. We estimate that the organosulfate contribution to the total organic mass fraction of ambient aerosol collected from K-puszta, Hungary, a field site with a similar organosulfate composition as that found in the present study for the southeastern U.S., can be as high as 30%

Terpenylic Acid and Related Compounds from the Oxidation of α-Pinene: Implications for New Particle Formation and Growth above Forests

Novel secondary organic aerosol (SOA) products from the monoterpene α-pinene with unique dimer-forming properties have been identified as lactone-containing terpenoic acids, i.e., terpenylic and 2-hydroxyterpenylic acid, and diaterpenylic acid acetate. The structural characterizations were based on the synthesis of reference compounds and detailed interpretation of mass spectral data. Terpenylic acid and diaterpenylic acid acetate are early oxidation products generated upon both photooxidation and ozonolysis, while 2-hydroxyterpenylic acid is an abundant SOA tracer in ambient fine aerosol that can be explained by further oxidation of terpenylic acid. Quantum chemical calculations support that noncovalent dimer formation involving double hydrogen bonding interactions between carboxyl groups of the monomers is energetically favorable. The molecular properties allow us to explain initial particle formation in laboratory chamber experiments and are suggested to play a role in new particle formation and growth above forests, a natural phenomenon that has fascinated scientists for more than a century

Updating Carbon Density and Opportunity Cost Parameters in Deforesting Regions in the GCOMAP Model

This paper explores the economics of carbon density and carbon pricing in forestry and in deforested areas. According to a footnote, this paper was commissioned by the [United Kingdom] Office of Climate Change as background work to its report 'Climate Change: Financing Global Forests' (the Eliasch Review)

Bell Diagonal and Werner state generation: entanglement, non-locality, steering and discord on the IBM quantum computer

We propose the first correct special-purpose quantum circuits for preparation of Bell-diagonal states (BDS), and implement them on the IBM Quantum computer, characterizing and testing complex aspects of their quantum correlations in the full parameter space. Among the circuits proposed, one involves only two quantum bits but requires adapted quantum tomography routines handling classical bits in parallel. The entire class of Bell-diagonal states is generated, and a number of characteristic indicators, namely entanglement of formation, CHSH non-locality, steering and discord, are experimentally evaluated over the full parameter space and compared with theory. As a by-product of this work we also find a remarkable general inequality between "quantum discord" and "asymmetric relative entropy of discord": the former never exceeds the latter. We also prove that for all BDS the two coincide.Comment: 18 pages, 21 figure

GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation

COPI is a key mediator of protein trafficking within the secretory pathway. COPI is recruited to the membrane primarily through binding to Arf GTPases, upon which it undergoes assembly to form coated transport intermediates responsible for trafficking numerous proteins, including Golgi-resident enzymes. Here, we identify GORAB, the protein mutated in the skin and bone disorder gerodermia osteodysplastica, as a component of the COPI machinery. GORAB forms stable domains at the trans-Golgi that, via interactions with the COPI-binding protein Scyl1, promote COPI recruitment to these domains. Pathogenic GORAB mutations perturb Scyl1 binding or GORAB assembly into domains, indicating the importance of these interactions. Loss of GORAB causes impairment of COPI-mediated retrieval of trans-Golgi enzymes, resulting in a deficit in glycosylation of secretory cargo proteins. Our results therefore identify GORAB as a COPI scaffolding factor, and support the view that defective protein glycosylation is a major disease mechanism in gerodermia osteodysplastica.Peer reviewe

Macaque models of human infectious disease.

Macaques have served as models for more than 70 human infectious diseases of diverse etiologies, including a multitude of agents-bacteria, viruses, fungi, parasites, prions. The remarkable diversity of human infectious diseases that have been modeled in the macaque includes global, childhood, and tropical diseases as well as newly emergent, sexually transmitted, oncogenic, degenerative neurologic, potential bioterrorism, and miscellaneous other diseases. Historically, macaques played a major role in establishing the etiology of yellow fever, polio, and prion diseases. With rare exceptions (Chagas disease, bartonellosis), all of the infectious diseases in this review are of Old World origin. Perhaps most surprising is the large number of tropical (16), newly emergent (7), and bioterrorism diseases (9) that have been modeled in macaques. Many of these human diseases (e.g., AIDS, hepatitis E, bartonellosis) are a consequence of zoonotic infection. However, infectious agents of certain diseases, including measles and tuberculosis, can sometimes go both ways, and thus several human pathogens are threats to nonhuman primates including macaques. Through experimental studies in macaques, researchers have gained insight into pathogenic mechanisms and novel treatment and vaccine approaches for many human infectious diseases, most notably acquired immunodeficiency syndrome (AIDS), which is caused by infection with human immunodeficiency virus (HIV). Other infectious agents for which macaques have been a uniquely valuable resource for biomedical research, and particularly vaccinology, include influenza virus, paramyxoviruses, flaviviruses, arenaviruses, hepatitis E virus, papillomavirus, smallpox virus, Mycobacteria, Bacillus anthracis, Helicobacter pylori, Yersinia pestis, and Plasmodium species. This review summarizes the extensive past and present research on macaque models of human infectious disease

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Characterization and source identification of fine particulate matter in urban Beijing during the 2015 Spring Festival

The Spring Festival (SF) is the most important holiday in China for family reunion and tourism. During the 2015 SF an intensive observation campaign of air quality was conducted to study the impact of the anthropogenic activities and the dynamic characteristics of the sources. During the study period, pollution episodes frequently occurred with 12 days exceeding the Chinese Ambient Air Quality Standards for 24-h average PM2.5 (75 μg/m3), even 8 days with exceeding 150 μg/m3. The daily maximum PM2.5 concentration reached 350 μg/m3 while the hourly minimum visibility was <0.8 km. Three pollution episodes were selected for detailed analysis including chemical characterization and diurnal variation of the PM2.5 and its chemical composition, and sources were identified using the Positive Matrix Factorization model. The first episode occurring before the SF was characterized by more formation of SO42− and NO3− and high crustal enrichment factors for Ag, As, Cd, Cu, Hg, Pb, Se and Zn and seven categories of pollution sources were identified, whereby vehicle emission contributed 38% to the PM2.5. The second episode occurring during the SF was affected heavily by large-scale firework emissions, which led to a significant increase in SO42−, Cl−, OC, K and Ba; these emissions were the largest contributor to the PM2.5 accounting for 36%. During the third episode occurring after the SF, SO42−, NO3−, NH4+ and OC were the major constituents of the PM2.5 and the secondary source was the dominant source with a contribution of 46%. The results provide a detailed understanding on the variation in occurrence, chemical composition and sources of the PM2.5 as well as of the gaseous pollutants affected by the change in anthropogenic activities in Beijing throughout the SF. They highlight the need for limiting the firework emissions during China's most important traditional festival