ALBERT

Description: Author Posting. © American Meteorological Society, 2016. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 97 (2016): 1859–1884, doi:10.1175/BAMS-D-14-00197.1.

Description: Air–Sea Interactions in the Northern Indian Ocean (ASIRI) is an international research effort (2013–17) aimed at understanding and quantifying coupled atmosphere–ocean dynamics of the Bay of Bengal (BoB) with relevance to Indian Ocean monsoons. Working collaboratively, more than 20 research institutions are acquiring field observations coupled with operational and high-resolution models to address scientific issues that have stymied the monsoon predictability. ASIRI combines new and mature observational technologies to resolve submesoscale to regional-scale currents and hydrophysical fields. These data reveal BoB’s sharp frontal features, submesoscale variability, low-salinity lenses and filaments, and shallow mixed layers, with relatively weak turbulent mixing. Observed physical features include energetic high-frequency internal waves in the southern BoB, energetic mesoscale and submesoscale features including an intrathermocline eddy in the central BoB, and a high-resolution view of the exchange along the periphery of Sri Lanka, which includes the 100-km-wide East India Coastal Current (EICC) carrying low-salinity water out of the BoB and an adjacent, broad northward flow (∼300 km wide) that carries high-salinity water into BoB during the northeast monsoon. Atmospheric boundary layer (ABL) observations during the decaying phase of the Madden–Julian oscillation (MJO) permit the study of multiscale atmospheric processes associated with non-MJO phenomena and their impacts on the marine boundary layer. Underway analyses that integrate observations and numerical simulations shed light on how air–sea interactions control the ABL and upper-ocean processes.

Description: This work was sponsored by the U.S. Office of Naval Research (ONR) in an ONR Departmental Research Initiative (DRI), Air–Sea Interactions in Northern Indian Ocean (ASIRI), and in a Naval Research Laboratory project, Effects of Bay of Bengal Freshwater Flux on Indian Ocean Monsoon (EBOB). ASIRI–RAWI was funded under the NASCar DRI of the ONR. The Indian component of the program, Ocean Mixing and Monsoons (OMM), was supported by the Ministry of Earth Sciences of India.

Description: 2017-04-22

Description: The Convective Transport of Active Species in the Tropics (CONTRAST) experiment was conducted from Guam (13.5°N, 144.8°E) during January–February 2014. Using the NSF/NCAR Gulfstream V research aircraft, the experiment investigated the photochemical environment over the tropical western Pacific (TWP) warm pool, a region of massive deep convection and the major pathway for air to enter the stratosphere during Northern Hemisphere (NH) winter. The new observations provide a wealth of information for quantifying the influence of convection on the vertical distributions of active species. The airborne in situ measurements up to 15-km altitude fill a significant gap by characterizing the abundance and altitude variation of a wide suite of trace gases. These measurements, together with observations of dynamical and microphysical parameters, provide significant new data for constraining and evaluating global chemistry–climate models. Measurements include precursor and product gas species of reactive halogen compounds that impact ozone in the upper troposphere/lower stratosphere. High-accuracy, in situ measurements of ozone obtained during CONTRAST quantify ozone concentration profiles in the upper troposphere, where previous observations from balloonborne ozonesondes were often near or below the limit of detection. CONTRAST was one of the three coordinated experiments to observe the TWP during January–February 2014. Together, CONTRAST, Airborne Tropical Tropopause Experiment (ATTREX), and Coordinated Airborne Studies in the Tropics (CAST), using complementary capabilities of the three aircraft platforms as well as ground-based instrumentation, provide a comprehensive quantification of the regional distribution and vertical structure of natural and pollutant trace gases in the TWP during NH winter, from the oceanic boundary to the lower stratosphere.

Description: Key Points Daratumumab is effective against T-ALL in human xenograft models. CD38 is a novel target with broad potential in the treatment of T-ALL.

Description: Introduction: Primitive extranodal lymphomas are a heterogeneous group of malignant lymphoid hematological developed from the mucosa-associated lymphoid tissue (MATL) or sites that have acquired MALT after repeated stimulation. The particularity of this type of affection reside: the access to diagnosis which is difficult and therapeutic approach which respond to the ATB, antiviral, surgery and RT. They represent 24-48% of lymph node lymphomas and they are increasing. The incidence of lymphoma is growing in the world, it is approximately 16.8 / 105inhabitants. In Algeria in 2012, the incidence of lymph node lymphomas in adults was 2.24 / 100,000. Lymphomas Diffuse large B-cell phenotype (DLBCL) represent 50-60% of lymphomas, it is the most common histological type. Goals of the study: 1-analyze the epidemiological characteristics (gender, age, geographical distribution, annual incidence). 2- Identify anatomical sites. 3- Specify the clinical and prognostic features Patients and methods: It's is a multicenter, retrospective study over a period between 2010-2014. The study population included all pts over 15 years and having an extranodal DLBCL at 18 hematology centers and 4 cancer centers. Data were collected on data sheets distributed to the various services involved in the study. The diagnosis is made on the histological examination of a biopsy of the affected organ. The clinical, biological and imaging results allowed us to classify and identify prognostic factors for pts. Results: Among 1057 sheets of extranodal lymphomas, the type DLBCL is specified in 562 (53%) cases, distributed in 325 men and 237 women (sex ratio M/F: 1.36). The average age at diagnosis is 51 years (16-88) with a peak in the age group 50-60 years. The overall annual incidence of 0.31/105 inhabitants/year and the specific incidence for patients over 15 years is 0.42 / 105inhabitants/year. PS 0-1: 323 / 543pts (60%). Number of pts (pts) by place of care: Annaba 65, Sétif: 60, CAC Constantine: 53, Tizi Ouzou: 49, Blida Cac: 41, CMPC-hematology: 40, Tlemcen: 30, Beni- Méssous- hematology: 29, CAC CPMC: 24, EHUOran: 23, hematology CAC Batna: 22, CHU Oran: 19, HMRUO: 17, Blida-hematology: 16, HCA:16, SBA: 15, CAC Béni-Messous: 14, EPH Mascara: 10, HMRU Oran: 9, Bejaia: 7, hematology CHU Batna: 2, hematology Cne:1. Number of cases according to anatomical localisation: Stomach: 180, Intestine: 31, Colon 12, Tonsils: 70, Cavum: 31, nasal cavities: 11, Bones: 43, mediastinum: 41, SNC: 29, Skin: 25, Rate / MO :15, Thyroid: 12, soft Parties: 10, Breast: 6, lung / pleural: 5, Liver: 5, Others: 36. The clinical symptomatology is very heterogeneous, specifically of the affected organ. Clinical stage is specified in 549 cases, according to Ann Arbor: SCIE: 272 (49%), SCIIE: 149 (27%), SCIIIE: 31 (6%), SCIV: 97 (18%). The International Prognostic Index adjusted for age (IPIaa) include: for pts less than 60 years: Low (F): 70 (23%), lower intermediate (IF): 130 (43%), intermediate high (IE) : 69 (23%), high (H): 32 (11%); for over 60 years Topics: F: 33 (23%), MI: 53 (37%) IE: 41 (28%), E: 17 (12%). Comments: As with other types of lymphoma, there is a male predominance and a peak incidence in the age group 50-60 years. The higher number of pts in the center and east of the country is probably related to a denser population in these regions. The histological type DLBCL at 53% is in agreement whith what it is conventionally reported. The incidence of 0.31/105inhabitants/year extranodal DLBCL is lower than the overall nodal DLBCL, however, the incidence of extranodal NHL is rarely determined. The number of cases of extranodal lymphomas described in this study is certainly below the actual number because this group of disorders is supported by various specialties related to the location of lymphoma. Extranodal lymphomas has a clinical polymorphism, but it is recognized that gastric and tonsillar locations are the most common, the other despite their rarity, require attention from management. This type of lymphoma is characterized by a preponderance of localized stages unlike ganglion lymphomas where the extended stages predominate. Likewise distribution by IPIaa not exceeding one pejorative factor is more common. Conclusion: Extranodal DLBCL are rare, they are characterized by a diversity clinicopathological that challenges us to homogenization of their treatment in multidisciplinary level. Disclosures No relevant conflicts of interest to declare.

Description: A grand challenge from the wind energy industry is to provide reliable forecasts on mountain winds several hours in advance at microscale (∼100 m) resolution. This requires better microscale wind-energy physics included in forecasting tools, for which field observations are imperative. While mesoscale (∼1 km) measurements abound, microscale processes are not monitored in practice nor do plentiful measurements exist at this scale. After a decade of preparation, a group of European and U.S. collaborators conducted a field campaign during 1 May–15 June 2017 in Vale Cobrão in central Portugal to delve into microscale processes in complex terrain. This valley is nestled within a parallel double ridge near the town of Perdigão with dominant wind climatology normal to the ridges, offering a nominally simple yet natural setting for fundamental studies. The dense instrument ensemble deployed covered a ∼4 km × 4 km swath horizontally and ∼10 km vertically, with measurement resolutions of tens of meters and seconds. Meteorological data were collected continuously, capturing multiscale flow interactions from synoptic to microscales, diurnal variability, thermal circulation, turbine wake and acoustics, waves, and turbulence. Particularly noteworthy are the extensiveness of the instrument array, space–time scales covered, use of leading-edge multiple-lidar technology alongside conventional tower and remote sensors, fruitful cross-Atlantic partnership, and adaptive management of the campaign. Preliminary data analysis uncovered interesting new phenomena. All data are being archived for public use.

Description: The authors report the interaction between Down syndrome, a major genetic leukemia predisposition condition, and inherited genetic alleles associated with increased susceptibility to childhood acute lymphoblastic leukemia.

Description: Key Points Ph-like ALL is characterized by a diverse array of genetic alterations activating cytokine receptor and tyrosine kinase signaling. Pediatric patients with Ph-like ALL can be identified in real time for effective treatment stratification.

Description: Introduction. Prior studies have described a subset of B-progenitor ALL cases with a distinct gene expression profile and/or deletions involving ERG (encoding the ETS family member v-ets avian erythroblastosis virus E26 oncogene), however the relationship of these alterations and their role in leukemogenesis are poorly understood. We performed integrated genomic and epigenetic analyses, biochemical studies and leukemogenesis assays to define the genetic basis of this form of ALL. Methods. We studied 1674 childhood, adolescent and young adult B-progenitor ALL cases with microarray gene expression profiling and/or RNA-sequencing data to enable the identification of ERG ALL by unsupervised clustering and predictive analysis of microarrays. Detailed genomic analysis was performed for 144 ERG ALL cases, including whole genome (N=38), exome (n=46) and/or RNA-sequencing (n=57) cases, and single nucleotide polymorphism array analysis. Epigenetic profiling, including whole genome bisulfite sequencing, chromatin immunoprecipitation and sequencing for ERG and histone modifications and ATAC-sequencing were performed for a subset of 8 xenografted ERG tumors and reference cell lines. ERG transcript expression was measured by analysis of RNA-seq analysis and quantitative RT-PCR assays, and by interrogation of TCGA and PCGP RNA-seq data. The function of ERG isoforms was evaluated by EMSA and transcriptional reporter assays, immunofluoresence, colony forming assays and retroviral bone marrow transplant assays. Results. One hundred and forty four cases (8.6%) of B-ALL cases exhibited a distinct gene expression profile and lacked known chromosomal rearrangements (ERG ALL). Such cases had favorable outcome. Eighty cases (55.6%) had focal deletions of ERG with no evidence of oncogenic or chimeric ERG fusions. The deletions were most commonly heterozygous and involving exons 3-7 (n=27) or 3-9 (n=22) of 10 coding exons, and less commonly involving exon 1, or a larger region of the gene. No ERG deletions were identified in non-ERG ALL. Two cases harbored missense mutations in the ETS domain. Analysis of whole genome and exome sequencing data of 71 cases identified a high frequency of alterations of lymphoid transcription factors (46.5%; IKZF1 36.7%, PAX5 11.3%); mutation of transcription factors otherwise uncommon in ALL (21%; MYC, MYCBP2, MGA, ZEB2, GATA3); activation of signaling pathways, most commonly NRAS or KRAS (35.2%); cell cycle regulation (22.5%); and epigenetic modifiers (56.3%), most commonly KMT2D, SETD2, ARID2 and NCOR1. Notably, the five year event-free survival of ERG ALL cases with IKZF1 alterations exceeded 85% in both St Jude and Children's Oncology Group cohorts. We observed striking transcriptional deregulation at the ERG locus. Most (51/56) ERG- deleted cases expressed an ERG isoform encoded by a novel exon in intron 6 that splices in frame to distal exons, resulting in expression of a truncated C-terminal ERG protein that lacks the pointed and central regulatory domains, but retains the ETS and transactivation domain (ERGalt). ERGalt was also present in most (36/44) cases lacking an ERG deletion, and was strongly associated with presence of ERGalt protein in leukemic cells. We also identified expression of an Antisense Long non-coding RNA associated with the ERG locus (ALE) in ERG ALL. ERGalt and ALE were absent, or uncommonly expressed at very low levels in non-ERG ALL. ERGalt was absent, and ALE rarely expressed in non-ALL PCGP and TCGA samples. ERGalt and point mutant ERG were retained in the nucleus, bound DNA targets and acted as competitive inhibitors of wild type (WT) ERG in transcriptional reporter assays. Lineage-negative Arf -null bone marrow cells transduced with ERG WT induced an aggressive erythro-megakaryoblastic leukemia; in contrast ERGalt induced an immature lymphoid progenitor leukemia. Conclusions. Genomic alterations drive aberrant transcription of ERG, resulting on expression of a truncated, C-terminal oncogenic ERG protein. This represents a novel mechanism of transcription factor deregulation in leukemia. As a subset of ERG ALL cases lack ERG deletion, and as IKZF1 alterations are not associated with inferior outcome in this form of ALL, diagnostic approaches must incorporate gene expression profiling in addition to identification of ERG and IKZF1 alterations to accurately identify this form of leukemia. Disclosures Evans: Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Voorhees:Oncopeptides: Consultancy; Onyx Pharmaceuticals: Research Funding; GSK: Consultancy; Oncopeptides: Research Funding; Janssen: Research Funding; A Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy; Millennium Pharmaceuticals: Consultancy, Research Funding; Acetylon Pharmaceuticals, Inc.: Research Funding; Novartis: Consultancy; Array BioPharma: Consultancy; GSK: Research Funding; Celgene: Research Funding. Hunger:Spectrum Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Sigma Tau: Consultancy; Merck: Equity Ownership. Mullighan:Incyte: Consultancy; Amgen: Honoraria.

Description: Introduction: Although recent studies have refined the classification of B-progenitor and T-lineage acute lymphoblastic leukemia into gene-expression based subgroups, a comprehensive integration of significantly mutated genes and pathways for each subgroup is needed to understand disease etiology. Methods: We studied 2789 children, adolescents and young adults (AYA) with newly diagnosed B-ALL (n=2,322 cases) or T-ALL (n=467) treated on Children's Oncology Group (n=1,872) and St. Jude Children's Research Hospital trials (n=917). The cohort comprised childhood NCI standard-risk (41.8%; age range 1-9.99 yrs, WBC ≤ 50,000/ml), childhood NCI high-risk (44.5%; age range ≥10 to 15.99 yrs) and AYA (9.9%; age range 16-30.7 yrs). Genomic analysis was performed on tumor and matched-remission samples using whole transcriptome sequencing (RNA-seq; tumor only; n=1,922), whole exome sequencing (n=1,659), whole genome sequencing (n=757), and single nucleotide polymorphism array (n=1,909). Results: For B-ALL, 2104 cases (90.6%) were classified into 26 subgroups based on RNA-seq gene expression data and aneuploidy or other gross chromosomal abnormalities (iAMP21, Down syndrome, dicentric), deregulation of known transcription factors by rearrangement or mutation (PAX5 P80R, IKZF1 N159Y), or activation of kinase alterations (Ph+, Ph-like). For T-ALL, cases were classified into 9 previously described subtypes based on dysregulation of transcription factor genes and gene expression. In 1,659 cases subject to exome sequencing (1259 B-ALL, 405 T-ALL) we identified 18,954 nonsynonymous single nucleotide variants (SNV) and 2,329 insertion-deletion mutations (indels) in 8,985 genes. Overall, 161 potential driver genes were identified by the mutation-significance detection tool MutSigCV or by presence of pathogenic variants in known cancer genes. Integration of sequence mutations and DNA copy number alteration data in B-ALL identified 7 recurrently mutated pathways: transcriptional regulation (40.6%), cell cycle and tumor suppression (38.0%), B-cell development (34.5%), epigenetic regulation (24.7%), Ras signaling (33.0%), JAK-STAT signaling (12.0%) and protein modification (ubiquitination or SUMOylation, 5.0%). The top 10 genes altered by deletion or mutation in B-ALL were CDKN2A/B (30.1%), ETV6 (27.0%), PAX5 (24.6%), CDKN1B (20.3%), IKZF1 (17.6%), KRAS (16.5%), NRAS (14.6%), BTG1 (7.5%) histone genes on chromosome 6 (6.9%) and FLT3 (6.1%), and for T-ALL, CDKN2A/B (74.7%), NOTCH1 (68.2%), FBXW7 (21.3%), PTEN (20.5%) and PHF6 (18.2%) (Figure 1A). We identified 17 putative novel driver genes involved in ubiquitination (UBE2D3, UBE2A, UHRF1, and USP1), SUMOylation (SAE1, UBE2I), transcriptional regulation (ZMYM2, HMGB1), immune function (B2M), migration (CXCR4), epigenetic regulation (DOT1L) and mitochondrial function (LETM1). We also observed variation in the frequency of genes and pathways altered across B-ALL subtypes (Figure 1B). Interestingly, alteration of SAE1 and UBA2, novel genes that form a heterodimeric complex important for SUMOylation, and UHRF1 were enriched in ETV6-RUNX1 cases. Deletions of LETM1, ZMYM2 and CHD4 were associated with near haploid and low hypodiploid cases. Deletion of histone genes on chromosome 6 and alterations of HDAC7 were enriched in Ph+ and Ph-like ALL. Mutations in the RNA-binding protein ZFP36L2 were observed in PAX5alt, DUX4 and MEF2D subgroups. Genomic subtypes were prognostic. ETV6-RUNX1, hyperdiploid, DUX4 and ZNF384 ALL were associated with good outcome (5-yr EFS 91.1%, 87.2%, 91.9% and 85.7%, respectively), ETV6-RUNX1-like, iAMP21, low hyperdiploid, PAX5 P80R and PAX5alt were associated with intermediate outcome (5-yr EFS 68.6%, 72.2%, 70.8%, 77.0% and 70.9%, respectively), whilst KMT2A, MEF2D, Ph-like CRLF2 and Ph-like other conferred a poor prognosis (55.5%, 67.1%, 51.5% and 62.1%, respectively). TCF3-HLF and near haploid had the worst outcome with 5-yr EFS rates of 27.3% and 47.2%, respectively. Conclusions: These findings provide a comprehensive landscape of genomic alterations in childhood ALL. The associations of mutations with ALL subtypes highlights the need for specific patterns of cooperating mutations in the development of leukemia, which may help identify vulnerabilities for therapy intervention. Disclosures Gastier-Foster: Bristol Myers Squibb (BMS): Other: Commercial Research; Incyte Corporation: Other: Commercial Research. Willman:to come: Patents & Royalties; to come: Membership on an entity's Board of Directors or advisory committees; to come: Research Funding. Raetz:Pfizer: Research Funding. Borowitz:Beckman Coulter: Honoraria. Zweidler-McKay:ImmunoGen: Employment. Angiolillo:Servier Pharmaceuticals: Consultancy. Relling:Servier Pharmaceuticals: Research Funding. Hunger:Jazz: Honoraria; Amgen: Consultancy, Equity Ownership; Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees. Mullighan:Amgen: Honoraria, Other: speaker, sponsored travel; Loxo Oncology: Research Funding; AbbVie: Research Funding; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel.

Description: Key Points In a multicenter, randomized phase 3 trial, MPR-R was not superior over MPT-T with respect to response rate, PFS, and OS. Grade 3/4 hematologic toxicity requiring growth factor support occurred with MPR-R vs clinically significant neuropathy with MPT-T.