73 research outputs found
Fisheries Surveys Are Essential Ocean Observing Programs in a Time of Global Change: A Synthesis of Oceanographic and Ecological Data From U.S. West Coast Fisheries Surveys
As climate change and other anthropogenic impacts on marine ecosystems accelerate in the 21st century, there is an increasing need for sustained ocean time series. A robust and collaborative network of regional monitoring programs can detect early signs of unanticipated changes, provide a more holistic understanding of ecosystem responses, and prompt faster management actions. Fisheries-related surveys that collect fisheries-independent data (hereafter referred to as āfisheries surveysā) are a key pillar of sustainable fisheries management and are ubiquitous in the United States and other countries. From the perspective of ocean observing, fisheries surveys offer three key strengths: (1) they are sustained due to largely consistent funding support from federal and state public sector fisheries agencies, (2) they collect paired physical, chemical, and biological data, and (3) they have large and frequently overlapping spatial footprints that extend into the offshore region. Despite this, information about fisheries survey data collection can remain poorly known to the broader academic and ocean observing communities. During the 2019 CalCOFI Symposium, marking the 70th anniversary of the California Cooperative Oceanic Fisheries Investigations (CalCOFI), representatives from 21 ocean monitoring programs on the North American West Coast came together to share the status of their monitoring programs and examine opportunities to leverage efforts to support regional ecosystem management needs. To increase awareness about collected ocean observing data, we catalog these ongoing ocean time series programs and detail the activities of the nine major federal or state fisheries surveys on the U.S. West Coast. We then present three case studies showing how fisheries survey data contribute to the understanding of emergent ecosystem management challenges: marine heatwaves, ocean acidification, and contaminant spills. Moving forward, increased cross-survey analyses and cooperation can improve regional capacity to address emerging challenges. Fisheries surveys represent a foundational blueprint for ecosystem monitoring. As the international community moves toward a global strategy for ocean observing needs, fisheries survey programs should be included as data contributors.publishedVersio
An experimental investigation of cut mark production and stone tool attrition
Abstract In discussions of Paleolithic hominin behavior it is often assumed that cut marks are an unwanted byproduct of butchery activities, and that their production causes the dulling of stone tool edges. It is also presumed that Paleolithic butchers would have refrained from making cut marks to extend the use life of their tools. We conducted a series of butchery experiments designed to test the hypothesis that cut marks affect the use life of tools. Results suggest cut marks are not associated with edge attrition of simple flake tools, and therefore it is unlikely that Paleolithic butchers would have avoided contact between bone surfaces and tool edges. Edge attrition is, however, significantly greater during skinning and disarticulation than during defleshing. This suggests that skinning and disarticulation activities would require more tool edges relative to butchery events focused purely on defleshing. Differences between the number of cut-marked bones relative to the number of stone artifacts deposited at taphonomically comparable archaeological localities may be explicable in terms of different types of butchery activities conducted there, rather than strictly the timing of carcass access by hominins. Archaeological localities with higher artifact discard rates relative to raw material availability may represent an emphasis on activities associated with higher edge attrition (e.g. skinning or disarticulation)
Zephyr: The Eighth Issue
This is the eighth issue of Zephyr, the University of New England\u27s journal of creative expression. Since 2000, Zephyr has published original drawings, paintings, photography, prose, and verse created by current and former members of the University community. Zephyr\u27s Editorial Board is made up exclusively of matriculating students.https://dune.une.edu/zephyr/1007/thumbnail.jp
lentiglobin gene therapy for transfusion dependent Ī² thalassemia outcomes from the phase 1 2 northstar and phase 3 northstar 2 studies
Introduction Transfusion-dependent Ī²-thalassemia (TDT) is a severe genetic disease characterized by anemia, iron overload and serious comorbidities for which gene therapy may be an effective treatment option. LentiGlobin gene therapy contains autologous CD34+ hematopoietic stem cells (HSCs) transduced ex vivo with the BB305 lentiviral vector (LVV) encoding Ī²-globin with a T87Q substitution. Objective Evaluate the efficacy and safety of LentiGlobin in patients with TDT in the phase 1/2 Northstar (HGB-204; NCT01745120) and phase 3 Northstar-2 (HGB-207; NCT02906202) studies. Methods Patients with TDT (ā„100 mL/kg/yr of red blood cells [RBCs] or ā„8 RBC transfusions/yr) received G-CSF and plerixafor for mobilization and HSCs were transduced with the BB305 LVV. Patients underwent single agent busulfan myeloablative conditioning, were infused with transduced cells, and were followed for engraftment, safety, and efficacy. Statistics are presented as median (min ā max). Results As of March 7, 2018, 18 patients (12 ā 35 yrs) were treated in Northstar (follow-up 32.1 [23.1 ā 41.9] months) and as of May 15, 2018, 11 patients (12 ā 24 yrs) were treated in Northstar-2 (follow-up 8.5 [0.3 ā 16.2] months). Patients received a median cell dose of 8.0 (5.0 ā 19.4) CD34+ cells Ć 106/kg in both studies. The median time to neutrophil and platelet engraftment in both studies was 19 (14 ā 30) days and 44 (19 ā 191) days, respectively; 1 patient in Northstar-2 (0.3 months follow-up) had not engrafted at time of analysis. Of 6 patients with platelet engraftment ā„ Day 60, 4 had non-serious bleeding events prior to engraftment. All 6 had intact spleens and 3/6 received G-CSF between Days 0 ā 21. Both factors appeared associated with time to platelet engraftment. In Northstar, 8/10 patients with non-Ī²0/Ī²0 genotypes and 2/8 patients with Ī²0/Ī²0 genotypes achieved transfusion independence (TI; weighted average hemoglobin [Hb] ā„ 9 g/dL without RBC transfusions for ā„ 12 months). Median Hb during TI was 10.0 (9.3 ā 13.1) g/dL. In Northstar-2, 7/8 patients with non-Ī²0/Ī²0 genotypes and ā„ 6 months follow-up stopped RBC transfusions with Hb of 11.1 ā 13.3 g/dL at last visit; the first patient treated achieved TI. Non-hematologic grade ā„ 3 adverse events post-infusion in ā„ 5/29 (15%) patients were stomatitis, febrile neutropenia, and pharyngeal inflammation. Veno-occlusive liver disease attributed to busulfan occurred in 4/29 patients (Table 1). There was no transplant-related mortality, vector-mediated replication competent lentivirus, or clonal dominance. Conclusion In Northstar, 80% of patients with non-Ī²0/Ī²0 genotypes achieved TI and early Northstar-2 data suggest that patients can achieve near-normal Hb without transfusions. The safety profile of LentiGlobin is consistent with myeloablative busulfan conditioning. Longer time to platelet engraftment was observed in few patients, but no graft failure or deaths were reported
A role for monoubiquitinated FANCD2 at telomeres in ALT cells
Both Fanconi anemia (FA) and telomere dysfunction are associated with chromosome instability and an increased risk of cancer. Because of these similarities, we have investigated whether there is a relationship between the FA protein, FANCD2 and telomeres. We find that FANCD2 nuclear foci colocalize with telomeres and PML bodies in immortalized telomerase-negative cells. These cells maintain telomeres by alternative lengthening of telomeres (ALT). In contrast, FANCD2 does not colocalize with telomeres or PML bodies in cells which express telomerase. Using a siRNA approach we find that FANCA and FANCL, which are components of the FA nuclear core complex, regulate FANCD2 monoubiquitination and the telomeric localization of FANCD2 in ALT cells. Transient depletion of FANCD2, or FANCA, results in a dramatic loss of detectable telomeres in ALT cells but not in telomerase-expressing cells. Furthermore, telomere loss following depletion of these proteins in ALT cells is associated with decreased homologous recombination between telomeres (T-SCE). Thus, the FA pathway has a novel function in ALT telomere maintenance related to DNA repair. ALT telomere maintenance is therefore one mechanism by which monoubiquitinated FANCD2 may promote genetic stability
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Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial
Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5ā20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatmentāresponse phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients
Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling
Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy1,2,3. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes1,3. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-ĪŗB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1)1,3,4. Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.This work was supported by an Alex's Lemonade Stand Young Investigator Award (S.C.M.), The CIHR Banting Fellowship (S.C.M.), The Cancer Prevention Research Institute of Texas (S.C.M., RR170023), Sibylle Assmus Award for Neurooncology (K.W.P.), the DKFZ-MOST (Ministry of Science, Technology & Space, Israel) program in cancer research (H.W.), James S. McDonnell Foundation (J.N.R.) and NIH grants: CA154130 (J.N.R.), R01 CA169117 (J.N.R.), R01 CA171652 (J.N.R.), R01 NS087913 (J.N.R.) and R01 NS089272 (J.N.R.). R.C.G. is supported by NIH grants T32GM00725 and F30CA217065. M.D.T. is supported by The Garron Family Chair in Childhood Cancer Research, and grants from the Pediatric Brain Tumour Foundation, Grand Challenge Award from CureSearch for Childrenās Cancer, the National Institutes of Health (R01CA148699, R01CA159859), The Terry Fox Research Institute and Brainchild. M.D.T. is also supported by a Stand Up To Cancer St. Baldrickās Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113)
Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 r4ra randomized trial
Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5ā20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; nā=ā164), patients with low/absent synovial Bācell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC)ā=ā0.74), tocilizumab (AUCā=ā0.68) and, notably, multidrug resistance (AUCā=ā0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatmentāresponse phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients
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