ALBERT

Description: 〈span〉〈div〉Abstract〈/div〉Three species of 〈span〉Habrostroma〈/span〉 dominate stromatoporoid faunas in the Lower Devonian (Lochkovian) of five areas in North America: New York, Virginia, Maine, Bathurst Island, and Ellesmere Island. In addition, they occur in what could be the upper Silurian (uppermost Pridoli) of Virginia, and possibly New York. Measurements of nine morphologies from 127 specimens of 〈span〉Habrostroma〈/span〉 were subjected to an average linkage cluster analysis. Using average linkage between groups, three distinct clusters were revealed. Group assignments made from the cluster analysis were saved, and entered into a canonical discriminant analysis with the nine morphological variables. An overall Wilks’ lambda was calculated, and is statistically significant at alpha 〈0.001. The hit rate for classifying group 1 is 98%, that for group 2 is 100%, and that for group 3 is 97.9%; the total hit rate is 100%. The morphological variables contributing most to group membership are: (1) percent cystlike microlaminae, (2) microlaminae per mm, (3) gallery height, (4) laminae per mm, and (5) laminar thickness. The statistics confirm that there are three species: 〈span〉H〈/span〉. 〈span〉centrotum〈/span〉, 〈span〉H〈/span〉. 〈span〉microporum〈/span〉, and 〈span〉H〈/span〉. 〈span〉consimile〈/span〉.〈span〉Habrostroma centrotum〈/span〉 occurs in all five areas. This is unusual because Virginia, New York, and Maine are part of the Eastern Americas Realm, and the arctic islands are part of the Old World Realm. Separation of the realms is based on a high percentage of unique genera in each. A breach in the inter-realm barrier is proposed to have existed across the Canadian Shield during the Lochkovian. The nature of the breach is determined to be a shallow-water filter, allowing the passage of a limited number of taxa.〈/span〉

Description: Two new genera of Upper Silurian stromatoporoids in order Actinostromatida are described. Genus Bicolumnostratum Stock, with type species B. micum (Bogoyavlenskaya), is characterized by two kinds of pillars and nonaligned colliculi, and is assigned to family Actinostromatidae. Genus Acosmostroma Stock, with type species A. ataxium Stock new species, contains irregular micropillars and microcolliculi, and is assigned to family Densastromatidae. Two additional new species are Acosmostroma glascoense Stock and A.? cobleskillense Stock. A fourth species is A. tenuissimum (Parks). Bicolumnostratum is known from Ludlow- and Pridoli-age strata, whereas the occurrences of Acosmostroma are strictly Pridoli in age.

Description: Three species of Habrostroma dominate stromatoporoid faunas in the Lower Devonian (Lochkovian) of five areas in North America: New York, Virginia, Maine, Bathurst Island, and Ellesmere Island. In addition, they occur in what could be the upper Silurian (uppermost Pridoli) of Virginia, and possibly New York. Measurements of nine morphologies from 127 specimens of Habrostroma were subjected to an average linkage cluster analysis. Using average linkage between groups, three distinct clusters were revealed. Group assignments made from the cluster analysis were saved, and entered into a canonical discriminant analysis with the nine morphological variables. An overall Wilks’ lambda was calculated, and is statistically significant at alpha 〈0.001. The hit rate for classifying group 1 is 98%, that for group 2 is 100%, and that for group 3 is 97.9%; the total hit rate is 100%. The morphological variables contributing most to group membership are: (1) percent cystlike microlaminae, (2) microlaminae per mm, (3) gallery height, (4) laminae per mm, and (5) laminar thickness. The statistics confirm that there are three species: H. centrotum, H. microporum, and H. consimile.Habrostroma centrotum occurs in all five areas. This is unusual because Virginia, New York, and Maine are part of the Eastern Americas Realm, and the arctic islands are part of the Old World Realm. Separation of the realms is based on a high percentage of unique genera in each. A breach in the inter-realm barrier is proposed to have existed across the Canadian Shield during the Lochkovian. The nature of the breach is determined to be a shallow-water filter, allowing the passage of a limited number of taxa.

Description: Journal of Climate, Ahead of Print. 〈br/〉

Description: A bstract A large and abundant columnar stromatoporoid, Quasiaulacera n. gen., from the Ellis Bay Formation, up to 3 m long and 40 cm in diameter, marks the Hirnantian (latest Ordovician) of Anticosti Island. Two species are present: Quasiaulacera stellata n. sp. from the basal Ellis Bay Formation (basal Prinsta Member, lower Hirnantian) along the northeastern coast of the island, and the type species Q. occidua n. sp. from the upper Ellis Bay Formation (Lousy Cove Member, upper Hirnantian) in the western carbonate facies of the island. Quasiaulacera is rare or absent in the reefal Laframboise Member (uppermost Hirnantian) of the formation. The new genus differs from Aulacera in the underlying Vaureal Formation (upper Katian) in having a large central axial zone marked by a single stack of large, convex-up cyst-plates, that is surrounded by a middle layer of small, concentric microcyst-plates, in places denticulate, and an outer layer composed of concentric laminae with dense pillars, in which microcyst-plates are either absent or rare. The outer two layers are defined by longitudinal fluting; there are no branching forms. Both species demonstrate a ball-like holdfast system, some with diameters of 30 to 70 cm, microbially cemented into the substrate. Quasiaulacera "gigantism" in the paleotropical Anticosti Basin evolved at a time of global cooling associated with the Hirnantian glaciation in south polar Gondwana, but terminated in mass extinction of the aulaceratids at the O/S boundary in Laurentia. This supports other evidence that the Hirnantian featured not only generic loss, but also innovation and migration in tropical latitudes.

Description: Anthropogenic climate change is projected to lead to ocean warming, acidification, deoxygenation, reductions in near-surface nutrients, and changes to primary production, all of which are expected to affect marine ecosystems. Here we assess projections of these drivers of environmental change over the twenty-first century from Earth system models (ESMs) participating in the Coupled Model Intercomparison Project Phase 6 (CMIP6) that were forced under the CMIP6 Shared Socioeconomic Pathways (SSPs). Projections are compared to those from the previous generation (CMIP5) forced under the Representative Concentration Pathways (RCPs). A total of 10 CMIP5 and 13 CMIP6 models are used in the two multi-model ensembles. Under the high-emission scenario SSP5-8.5, the multi-model global mean change (2080–2099 mean values relative to 1870–1899) ± the inter-model SD in sea surface temperature, surface pH, subsurface (100–600 m) oxygen concentration, euphotic (0–100 m) nitrate concentration, and depth-integrated primary production is +3.47±0.78 ∘C, -0.44±0.005, -13.27±5.28, -1.06±0.45 mmol m−3 and -2.99±9.11 %, respectively. Under the low-emission, high-mitigation scenario SSP1-2.6, the corresponding global changes are +1.42±0.32 ∘C, -0.16±0.002, -6.36±2.92, -0.52±0.23 mmol m−3, and -0.56±4.12 %. Projected exposure of the marine ecosystem to these drivers of ocean change depends largely on the extent of future emissions, consistent with previous studies. The ESMs in CMIP6 generally project greater warming, acidification, deoxygenation, and nitrate reductions but lesser primary production declines than those from CMIP5 under comparable radiative forcing. The increased projected ocean warming results from a general increase in the climate sensitivity of CMIP6 models relative to those of CMIP5. This enhanced warming increases upper-ocean stratification in CMIP6 projections, which contributes to greater reductions in upper-ocean nitrate and subsurface oxygen ventilation. The greater surface acidification in CMIP6 is primarily a consequence of the SSPs having higher associated atmospheric CO2 concentrations than their RCP analogues for the same radiative forcing. We find no consistent reduction in inter-model uncertainties, and even an increase in net primary production inter-model uncertainties in CMIP6, as compared to CMIP5.

Description: The coastal ecosystem of the Gulf of Alaska (GOA) is especially vulnerable to the effects of ocean acidification and climate change. Detection of these long-term trends requires a good understanding of the system’s natural state. The GOA is a highly dynamic system that exhibits large inorganic carbon variability on subseasonal to interannual timescales. This variability is poorly understood due to the lack of observations in this expansive and remote region. We developed a new model setup for the GOA that couples the three-dimensional Regional Oceanic Model System (ROMS) and the Carbon, Ocean Biogeochemistry and Lower Trophic (COBALT) ecosystem model. To improve our conceptual understanding of the system, we conducted a hindcast simulation from 1980 to 2013. The model was explicitly forced with temporally and spatially varying coastal freshwater discharges from a high-resolution terrestrial hydrological model, thereby affecting salinity, alkalinity, dissolved inorganic carbon, and nutrient concentrations. This represents a substantial improvement over previous GOA modeling attempts. Here, we evaluate the model on seasonal to interannual timescales using the best available inorganic carbon observations. The model was particularly successful in reproducing observed aragonite oversaturation and undersaturation of near-bottom water in May and September, respectively. The largest deficiency in the model is its inability to adequately simulate springtime surface inorganic carbon chemistry, as it overestimates surface dissolved inorganic carbon, which translates into an underestimation of the surface aragonite saturation state at this time. We also use the model to describe the seasonal cycle and drivers of inorganic carbon parameters along the Seward Line transect in under-sampled months. Model output suggests that the majority of the near-bottom water along the Seward Line is seasonally undersaturated with respect to aragonite between June and January, as a result of upwelling and remineralization. Such an extensive period of reoccurring aragonite undersaturation may be harmful to ocean acidification-sensitive organisms. Furthermore, the influence of freshwater not only decreases the aragonite saturation state in coastal surface waters in summer and fall, but it simultaneously decreases the surface partial pressure of carbon dioxide (pCO2), thereby decoupling the aragonite saturation state from pCO2. The full seasonal cycle and geographic extent of the GOA region is under-sampled, and our model results give new and important insights for months of the year and areas that lack in situ inorganic carbon observations.

Description: Eradication of minimal residual disease (MRD) during the first months of treatment for patients (pts) with ALL is associated with improved disease-free survival (DFS). We hypothesized that Alemtuzumab, a humanized monoclonal antibody directed against CD52, might be an effective, novel agent for eradication of MRD in ALL based on data demonstrating strong CD52 expression in other lymphoid malignancies and in several ALL cell lines, and from case reports of clinical activity in advanced ALL. In CALGB 10102, to define the percentage of CD52+ cases and to demonstrate feasibility, we tested dose escalation of Alemtuzumab in sequential cohorts to a target dose of 30 mg administered sc 3X/week for 4 weeks (12 doses) during post-remission therapy. Pts are eligible to receive Alemtuzumab if lymphoblast CD52 expression at diagnosis is ≥ 10% as determined in a CALGB reference laboratory. The 10102 therapy is composed of monthly treatment modules outlined below: Treatment module sequence is: A,B,C, D, A, B, C followed by maintenance therapy for a total of 2 years. Antimicrobial prophylaxis for cytomegalovirus (CMV) (e.g. acyclovir 800 mg qid) and pneumocystis carinii is mandated. Weekly quantitative monitoring for CMV viremia is performed. 150 pts with untreated ALL have enrolled: Median age is 48 yrs. 124 (83%) pts have precursor-B; 19(13%) have precursor T-ALL and 7 (4%) have biphenotypic or bilineal ALL. Of 139 evaluable pts, 95 (68%) had CD52 ≥ 10%. By immunophenotype, 72% of precursor B and 61% of precursor T pts were eligible to receive Alemtuzumab. Phase I dose escalation was recently completed. Dose limiting toxicity (DLT) for Phase I was defined as the inability to proceed with protocol treatment within 6 weeks of the last dose of Alemtuzumab. Non-heme toxicities have been mild and sc Alemtuzumab administration was well tolerated. Hematologic and infectious toxicities are summarized below: Myelosuppression was transient and use of G-CSF was permitted during Module D. 2 pts were treated for CMV viremia due to rising CMV titers in 2 sequential assays. 6 other pts had transient CMV elevations during or immediately following completion of Alemtuzumab that did not require treatment. 22/24 phase I pts received all 12 doses of Alemtuzumab. There were 2 DLTs reported: 1 pt in cohort 2 due to CMV viremia requiring gancyclovir following completion of Alemtuzumab; and 1 pt in cohort 3 due to ANC 〈 1500 six weeks after Alemtuzumab (pt was not given G-CSF). Based on these Phase I data, the targeted dose of 30 mg Alemtuzumab was recommended for further study in the ongoing Phase II study. In summary, we report for the first time that CD52 is expressed in the majority of ALL cases and demonstrate the feasibility of employing Alemtuzumab in front-line therapy. Ongoing accrual to the phase II study will evaluate the efficacy of Alemtuzumab in eradication of MRD in adult ALL. Module A Module B Module C Module D (Alemtuzumab) Maintenance Cytoxan Cytoxan Methotrexate (IV, PO, IT) 10 mg* cohort 1 Vincristine Daunorubicin Cytarabine Vincristine 20 mg* cohort 2 Dexamethasone Vincristine Vincrisitne 6-MP 30 mg* cohort 3 6-MP Dexamethasone L-asparaginase *Phase I dose escalation Methotrexate L-asparaginase IT-Methotrexate Alemtuzumab cohorts N Myelosuppression (grades 3 or 4) Lymphopenia CMV viremia 10 mg 6 2 1 2 20 mg 10 1 1 4 30 mg 8 1 0 2

Description: Abstract 44 CALGB (now part of the Alliance for Clinical Trials in Oncology) performed a non-randomized phase II study testing one year (yr) of investigational maintenance therapy with decitabine for newly diagnosed adult AML patients (pts) 1 × 109/L, platelets 〉75 × 109/L, and be within 90 days after day 1 of the final consolidation. Decitabine 20mg/m2 was given IV over 1 hour for 4–5 days, every 6 weeks, for 8 cycles. 546 pts enrolled with a median age of 48 yrs (range, 17–60) and median presenting white blood count (WBC) of 12.6 × 109/L (range, 0.3–380 × 109/L). 75% achieved CR (412/546). Reasons for CR pts not receiving maintenance were mainly early relapse, alloHCT in 1st CR, inadequate count recovery, and patient refusal (Blum et al. ASH 2011). 33% of CR pts (134/412) received investigational maintenance. Of these, 46 (34%) were favorable risk; among the remaining 88 pts, 73 were consolidated with autoHCT, and 15 received HiDAC-based consolidation. The median time from initial study registration to initiation of maintenance therapy was 6.3 months. Pts receiving decitabine had a median age of 45 yrs (range, 18–60) and presenting WBC of 13.5 × 109/L (range, 0.4–221 × 109/L). Treatment with decitabine maintenance was feasible and reasonably well tolerated; the primary toxicity was myelosuppression. Preplanned dose reduction criteria for neutropenia were met after the first 20 pts had been treated. After this early timepoint, all subsequent pts who had been consolidated with autoHCT received only 4 days of decitabine per cycle (HiDAC consolidated pts continued to receive 5 days per cycle). The median number of cycles of decitabine received was 7 (range, 1–8); 46% of pts (62/134) received all 8 cycles, and 75% completed at least 4 cycles. Reasons for discontinuation of decitabine before completing 8 cycles included relapse (28%, 38/134), pt refusal (13%), adverse events (4%), and others. In this selected cohort of pts who received post-CR maintenance with decitabine, 1-yr and 3-yr overall survival (OS) were 96% and 66%; 1-yr and 3-yr disease-free survival (DFS) were 80% and 53%. 1-yr “failure-free survival” calculated from the time of registration to decitabine was 68% (70% for favorable risk, 68% for others). These results are similar to the outcomes for comparable pts enrolled on our prior CALGB study 19808 who received identical chemotherapy for induction and consolidation and then were randomized to observation or maintenance with interleukin-2 (3-yr OS 61% and 68%, 3-yr DFS 45% and 56%, for observation and IL-2 respectively). Post-consolidation maintenance with decitabine appears to provide only modest, if any, benefit overall. Correlative studies for CALGB 10503 are ongoing, including investigations into the impact of decitabine in unique molecular and cytogenetic subsets of disease, the prognostic/predictive value of aberrant methylation and other molecular markers, and assessment of minimal residual disease. Supported by CA33601 and CA128377. Disclosures: No relevant conflicts of interest to declare.

Description: Rationale: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the most effective therapy for patients with acute myeloid leukemia (AML). The graft-versus-leukemia effect (GVL), mediated by the engrafted T lymphocytes targeting leukemic cells, is thought to play an important role in affecting the overall outcome of patients with AML. Umbilical cord blood (UCB) has emerged as an alternative and effective source of hematopoietic stem cells in high risk patients. We previously reported the hematopoietic reconstitution and clinical outcomes in 45 patients undergoing haplo-cord transplant, a novel approach which combines haploidentical and cord blood grafts to avoid delayed hematopoietic recovery after cord blood transplant (Liu H,et al. Blood. 2011;118(24):6438-45). However, very little is known about immune reconstitution of cord blood cells and whether the emerging immune repertoire correlates with clinical outcome. The great majority of T cell receptors in T lymphocytes are heterodimers of alpha (TCRA) and beta (TCRB) subunits. Somatic recombination combining the VJ (alpha) and VDJ (beta) segments results in an astronomical functional diversity and complexity of TCR receptors, and makes the characterization of their functions a tremendously complex process. To obtain insights into the T-cell repertoire, we have utilized next-generation sequencing (NGS) technology to comprehensively characterize T-cell kinetics and diversity following haplo-cord transplantation. Methods: We evaluated the emerging T-cell repertoire in 10 patients (pts) with high-risk AML enrolled on a clinical trial of haplo-cord transplantation at the University of Chicago. The median age of the pts was 57 years old (range: 26-67) and 3 pts had active disease at the time of transplant. The median UCB dose was 1.6x107 TNC/kg with HLA cord matching of 4/6 in 3 pts and 5/6 or 6/6 in 7 pts. The median overall and disease free survival were 2.4 and 2.2 years, respectively. cDNA was generated from mRNA isolated from peripheral blood mononuclear cells prior to and at sequential time points 30, 100, 180 and 365 days post haplo-cord transplant were sequenced the samples with Ion Personal Genome Machine (PGM) Sequencer and a 400-bp reading kit. We analyzed the sequences by applying a recently developed algorithm in order to determine the VJ and VDJ combinations and CDR3 sequences. Chimerism was determined by microsatellite sequences of DNA of donor and recipient cells. Diversity was calculated for each of TCRA and TCRB using the inverse Simpson’s index. Results: Several clones found in pre-treatment samples obtained from recipients before transplant persisted at low frequency on days 100 and 365 post-transplant suggesting that these clones have evaded the immuno-suppressive conditioning regimens. In order to correlate the diversity of TCRs with the percentage of cord cells in patients’ blood at different time points, we dichotomized patients into cord present (〉5%) and cord absent (≤5%) groups, based on the cord blood percentage in blood on day 30 post haplo-cord transplant and correlated it with diversity on day 100. We found that TCRs of pts with 〉5% cord cells on day 30 post haplo-cord transplant were significantly more diverse (TCRA; P=0.008) and (TCRB; P=0.01) (Fig.1) on day 100 compared to TCRs in patients with 90% cord cells on day 100 post-transplant. Therefore, we examined the correlation between diversity calculated on day 100 and percentage of persisting haplo-identical cells on the same day. We found,, the diversity of TCRB of pts with persistence of 〉10% haplo-identical cells were 15.05 compared with 72.95 for those with 10% and