Immune dysregulation in myelodysplastic syndrome

Myelodysplastic syndrome (MDS) represents one of the most challenging health-related problems in the elderly. Characterized by dysplastic morphology in the bone marrow in association with ineffective hematopoiesis, pathophysiological causes of this disease are diverse including genetic abnormalities within myeloid progenitors, altered epigenetics, and changes in the bone marrow microenvironment. The concept that T-cell mediated autoimmunity contributes to bone marrow failure has been widely accepted due to hematologic improvement after immunosuppressive therapy (IST) in a subset of patients. Currently, IST for MDS primarily involves anti-thymocyte globulin (ATG)-based regimens in which responsiveness is strongly associated with younger (under 60 years) age at disease onset. In such cases, progressive cytopenia may occur as a consequence of expanded self-reactive CD8+ cytotoxic T lymphocytes (CTLs) that suppress hematopoietic progenitors. Although most hematologists agree that IST can offer durable hematologic remission in younger patients with MDS, an international clinical study and a better understanding of the molecular mechanisms contributing to the expansion of self-reactive CTLs is crucial. In this review, data accumulated in the US, Europe, and Asia will be summarized to provide insight and direction for a multi-center international trial

Engineering moral machines

This article provides a short report on a recent Dagstuhl Seminar on “Engineering Moral Agents”. Imbuing robots and autonomous systems with ethical norms and values is an increasingly urgent challenge, given rapid developments in, for example, driverless cars, unmanned air vehicles (drones), and care assistant robots. Seminar participants discussed two immediate problems. A challenge for philosophical research is the formalisation of ethics in a format that lends itself to machine implementation; a challenge for computer science and robotics is the actual implementation of moral reasoning and conduct in autonomous systems. This article reports on these two challenges

Atomically Thin Al2 O3 Films for Tunnel Junctions

Metal-insulator-metal tunnel junctions are common throughout the microelectronics industry. The industry standard AlOx tunnel barrier, formed through oxygen diffusion into an Al wetting layer, is plagued by internal defects and pinholes which prevent the realization of atomically thin barriers demanded for enhanced quantum coherence. In this work, we employ in situ scanning tunneling spectroscopy along with molecular-dynamics simulations to understand and control the growth of atomically thin Al2O3 tunnel barriers using atomic-layer deposition. We find that a carefully tuned initial H2O pulse hydroxylated the Al surface and enabled the creation of an atomically thin Al2O3 tunnel barrier with a high-quality M-I interface and a significantly enhanced barrier height compared to thermal AlOx. These properties, corroborated by fabricated Josephson junctions, show that atomic-layer deposition Al2O3 is a dense, leak-free tunnel barrier with a low defect density which can be a key component for the next generation of metal-insulator-metal tunnel junctions

Impact of baseline cytogenetic findings and cytogenetic response on outcome of high-risk myelodysplastic syndromes and low blast count AML treated with azacitidine

•Cytogenetic findings are strong predictor for survial in AZA-treated MDS patients.•Isolated del(7q) had similar survival as patients with normal karyotype.•Cytogenetic abnormalities don’t predict response to AZA.•Achieving cytogenetic response has a limited effect on outcomes in AZA-treated patients. Karyotype according to the revised IPSS is a strong independent prognostic factor for overall survival (OS) in myelodysplastic syndromes (MDS), however established in untreated patients. The prognostic impact of cytogenetics and cytogenetic response (CyR) in MDS patients receiving azacitidine (AZA) remains uncertain. We examined the prognostic value of baseline cytogenetics and CyR for overall response rate (ORR) and OS in 702 AZA-treated higher risk MDS and low blast count acute myeloid leukemia (AML), including 493 (70%) with abnormal karyotype. None of the cytogenetic abnormalities had significant impact on ORR (43.9%) or complete response (15.35%), except 3q abnormalities and complex karyotypes, which were associated with a lower ORR. OS differed significantly across all R-IPSS cytogenetic subgroups (p<10−4) but patients with non complex del(7q) had similar survival as patients with normal cytogenetics. CyR was achieved in 32% of the 281 evaluable patients with abnormal cytogenetics, was complete (CCyR) in 71 (25.3%) patients. We found no correlation between hematological response and cytogenetic response and 21% of the patients with CCyR did not achieve morphological response. In the 281 patients, we found no impact of CyR on survival, but when restricting to MDS (ie: <20% marrow blasts) achievement of CCyR was associated with better OS

TP53 and MDM2 single nucleotide polymorphisms influence survival in non-del(5q) myelodysplastic syndromes

Abstract:P53 is a key regulator of many cellular processes and is negatively regulated by the human homolog of murine double minute-2 (MDM2) E3 ubiquitin ligase. Single nucleotide polymorphisms (SNPs) of either gene alone, and in combination, are linked to cancer susceptibility, disease progression, and therapy response. We analyzed the interaction of TP53 R72P and MDM2 SNP309 SNPs in relationship to outcome in patients with myelodysplastic syndromes (MDS). Sanger sequencing was performed on DNA isolated from 208 MDS cases. Utilizing a novel functional SNP scoring system ranging from +2 to -2 based on predicted p53 activity, we found statistically significant differences in overall survival (OS) (p = 0.02) and progression-free survival (PFS) (p = 0.02) in non-del(5q) MDS patients with low functional scores. In univariate analysis, only IPSS and the functional SNP score predicted OS and PFS in non-del(5q) patients. In multivariate analysis, the functional SNP score was independent of IPSS for OS and PFS. These data underscore the importance of TP53 R72P and MDM2 SNP309 SNPs in MDS, and provide a novel scoring system independent of IPSS that is predictive for disease outcome

Cytogenetic and molecular predictors of response in patients with myeloid malignancies without del[5q] treated with lenalidomide

<p>Abstract</p> <p>Background</p> <p>While lenalidomide (LEN) shows high efficacy in myelodysplastic syndromes (MDS) with del[5q], responses can be also seen in patients presenting without del[5q]. We hypothesized that improved detection of chromosomal abnormalities with new karyotyping tools may better predict response to LEN.</p> <p>Design and methods</p> <p>We have studied clinical, molecular and cytogenetic features of 42 patients with MDS, myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes and secondary acute myeloid leukemia (sAML) without del[5q] by metaphase cytogenetics (MC) who underwent therapy with LEN.</p> <p>Results</p> <p>Fluorescence in situ hybridization (FISH) or single nucleotide polymorphism array (SNP-A)-based karyotyping marginally increased the diagnostic yield over MC, detecting 2/42 (4.8%) additional cases with del[5q], one of whom were responded to LEN. Responses were more often observed in patients with a normal karyotype by MC (60% vs abnormal MC; 17%, <it>p </it>= .08) and those with gain of chromosome 8 material by either of all 3 karyotyping methods (83% vs all other chromosomal abnormalities; 44% <it>p </it>= .11). However, 5 out of those 6 patients received combined LEN/AZA therapy and it may also suggest those with gain of chromosome 8 material respond well to AZA. The addition of FISH or SNP-A did not improve the predictive value of normal cytogenetics by MC. Mutational analysis of <it>TET2, UTX, CBL, EZH2, ASXL1, TP53, RAS, IDH1/2</it>, and <it>DNMT-3A </it>was performed on 21 of 41 patients, and revealed 13 mutations in 11 patients, but did not show any molecular markers of responsiveness to LEN.</p> <p>Conclusions</p> <p>Normal karyotype and gain of chromosome 8 material was predictive of response to LEN in non-del[5q] patients with myeloid malignancies.</p

Observing atmospheric formaldehyde (HCHO) from space: validation and intercomparison of six retrievals from four satellites (OMI, GOME2A, GOME2B, OMPS) with SEAC(4)RS aircraft observations over the southeast US

Formaldehyde (HCHO) column data from satellites are widely used as a proxy for emissions of volatile organic compounds (VOCs), but validation of the data has been extremely limited. Here we use highly accurate HCHO aircraft observations from the NASA SEAC4RS (Studies of Emissions, Atmospheric Composition, Clouds and Climate Coupling by Regional Surveys) campaign over the southeast US in August&ndash;September 2013 to validate and intercompare six retrievals of HCHO columns from four different satellite instruments (OMI, GOME2A, GOME2B and OMPS; for clarification of these and other abbreviations used in the paper, please refer to Appendix A) and three different research groups. The GEOS-Chem chemical transport model is used as a common intercomparison platform. All retrievals feature a HCHO maximum over Arkansas and Louisiana, consistent with the aircraft observations and reflecting high emissions of biogenic isoprene. The retrievals are also interconsistent in their spatial variability over the southeast US (r &thinsp;=&thinsp; 0.4&ndash;0.8 on a 0.5&deg; &thinsp;&times;&thinsp; 0.5&deg;  grid) and in their day-to-day variability (r &thinsp;=&thinsp; 0.5&ndash;0.8). However, all retrievals are biased low in the mean by 20&ndash;51 %, which would lead to corresponding bias in estimates of isoprene emissions from the satellite data. The smallest bias is for OMI-BIRA, which has high corrected slant columns relative to the other retrievals and low scattering weights in its air mass factor (AMF) calculation. OMI-BIRA has systematic error in its assumed vertical HCHO shape profiles for the AMF calculation, and correcting this would eliminate its bias relative to the SEAC4RS data. Our results support the use of satellite HCHO data as a quantitative proxy for isoprene emission after correction of the low mean bias. There is no evident pattern in the bias, suggesting that a uniform correction factor may be applied to the data until better understanding is achieved.</p

Impacts of the Denver Cyclone on regional air quality and aerosol formation in the Colorado Front Range during FRAPPE 2014

We present airborne measurements made during the 2014 Front Range Air Pollution and Photochemistry Experiment (FRAPP&Eacute;) project to investigate the impacts of the Denver Cyclone on regional air quality in the greater Denver area. Data on trace gases, non-refractory submicron aerosol chemical constituents, and aerosol optical extinction (&beta;ext) at &lambda; &thinsp;=&thinsp; 632 nm were evaluated in the presence and absence of the surface mesoscale circulation in three distinct study regions of the Front Range: In-Flow, Northern Front Range, and the Denver metropolitan area. Pronounced increases in mass concentrations of organics, nitrate, and sulfate in the Northern Front Range and the Denver metropolitan area were observed during the cyclone episodes (27&ndash;28 July) compared to the non-cyclonic days (26 July, 2&ndash;3 August). Organic aerosols dominated the mass concentrations on all evaluated days, with a 45 % increase in organics on cyclone days across all three regions, while the increase during the cyclone episode was up to &thinsp;&sim;&thinsp; 80 % over the Denver metropolitan area. In the most aged air masses (NOx / NOy &thinsp;&lt;&thinsp; 0.5), background organic aerosols over the Denver metropolitan area increased by a factor of &sim;&thinsp; 2.5 due to transport from Northern Front Range. Furthermore, enhanced partitioning of nitric acid to the aerosol phase was observed during the cyclone episodes, mainly due to increased abundance of gas phase ammonia. During the non-cyclone events,&nbsp;&beta;ext&nbsp;displayed strong correlations (r &thinsp;=&thinsp; 0.71) with organic and nitrate in the Northern Front Range and only with organics (r &thinsp;=&thinsp; 0.70) in the Denver metropolitan area, while correlation of&nbsp;&beta;ext during the cyclone was strongest (r &thinsp;=&thinsp; 0.86) with nitrate over Denver. Mass extinction efficiency (MEE) values in the Denver metropolitan area were similar on cyclone and non-cyclone days despite the dominant influence of different aerosol species on&nbsp;&beta;ext. Our analysis showed that the meteorological patterns associated with the Denver Cyclone increased aerosol mass loadings in the Denver metropolitan area mainly by transporting aerosols and/or aerosol precursors from the northern regions, leading to impaired visibility and air quality deterioration.</p

Aerosol optical extinction during the Front Range Air Pollution and Photochemistry Experiment (FRAPP) 2014 summertime field campaign, Colorado, USA

Summertime aerosol optical extinction (&beta;ext) was measured in the Colorado Front Range and Denver metropolitan area as part of the Front Range Air Pollution and Photochemistry &Eacute;xperiment (FRAPP&Eacute;) campaign during July&ndash;August 2014. An Aerodyne cavity attenuated phase shift particle light extinction monitor (CAPS-PMex) was deployed to measure&nbsp;&beta;ext&nbsp;(at average relative humidity of 20 &plusmn; 7 %) of submicron aerosols at &lambda;&thinsp;=&thinsp;632 nm at 1 Hz. Data from a suite of gas-phase instrumentation were used to interpret&nbsp;&beta;ext&nbsp;behavior in various categories of air masses and sources. Extinction enhancement ratios relative to CO (&Delta;&beta;ext ∕ &Delta;CO) were higher in aged urban air masses compared to fresh air masses by &thinsp;&sim;&thinsp; 50 %. The resulting increase in &Delta;&beta;ext ∕ &Delta;CO for highly aged air masses was accompanied by formation of secondary organic aerosols (SOAs). In addition, the impacts of aerosol composition on&nbsp;&beta;ext&nbsp;in air masses under the influence of urban, natural oil and gas operations (O&amp;G;), and agriculture and livestock operations were evaluated. Estimated non-refractory mass extinction efficiency (MEE) values for different air mass types ranged from 1.51 to 2.27 m2 g-1, with the minimum and maximum values observed in urban and agriculture-influenced air masses, respectively. The mass distribution for organic, nitrate, and sulfate aerosols presented distinct profiles in different air mass types. During 11&ndash;12 August, regional influence of a biomass burning event was observed, increasing the background&nbsp;&beta;ext and estimated MEE values in the Front Range.</p