Backbone NMR resonance assignment of the Abelson kinase domain in complex with imatinib

Imatinib (Glivec or Gleevec) potently inhibits the tyrosine kinase activity of BCR-ABL, a constitutively activated kinase, which causes chronic myelogenous leukemia (CML). Here we report the first almost complete backbone assignment of c-ABL kinase domain in complex with imatini

Poor physical function in elderly women in low-level aged care is related to muscle strength rather than to measures of sarcopenia

Julie L Woods1, Sandra Iuliano-Burns2, Susannah J King1, Boyd J Strauss1, Karen Z Walker11Nutrition and Dietetics Department, Monash University, Victoria, Australia; 2Endocrine Centre of Excellence, Department of Medicine, Austin Health, University of Melbourne, West Heidelberg, AustraliaPurpose: To determine the prevalence of sarcopenia and investigate relationships among body composition, muscle strength, and physical function in elderly women in low-level aged care.Subjects and methods: Sixty-three ambulatory women (mean age 86 years) participated in this cross-sectional study where body composition was determined by dual energy X-ray absorptiometry (DXA); ankle, knee, and hip strength by the Nicholas Manual Muscle Tester; and physical function by ‘timed up and go’ (TUG) and walking speed (WS) over 6 meters. Body composition data from a female reference group (n = 62, mean age 29 years) provided cut-off values for defining sarcopenia.Results: Elderly women had higher body mass index (P < 0.001), lower lean mass (P < 0.001), and higher fat mass (P < 0.01) than the young reference group. Only a small proportion (3.2%) had absolute sarcopenia (defined by appendicular skeletal muscle mass/height squared) whereas 37% had relative sarcopenia class II (defined by percentage skeletal muscle mass). Scores for TUG and WS indicated relatively poor physical function, yet these measures were not associated with muscle mass or indices of sarcopenia. In multivariate analysis, only hip abductor strength predicted both TUG and WS (both P = 0.01).Conclusion: Hip strength is a more important indicator of physical functioning than lean mass. Measurement of hip strength may therefore be a useful screening tool to detect those at risk of functional decline and requirement for additional care. Further longitudinal studies with a range of other strength measures are warranted.Keywords: aged care, body composition, muscle strength, sarcopenia&nbsp

Organic carbon in subsea permafrost: a globally significant but inert carbon pool Frederieke Miesner

Subsea permafrost underlays 2.4 million km2 of the Arctic Shelf, an area equaling ~18% of the terrestrial permafrost region. Most of it was inundated at some point after the last glacial maximum and is in an advanced state of warming. How much organic carbon (OC) accumulated, how this carbon pool was affected by permafrost presence and degradation over time, how much carbon still remains today and how much of it may be mobilized are major unknowns in the global carbon cycle. Recent estimates of OC decomposition from thawing submarine permafrost were as high as 8 Tg OC per year in methane alone. Here, we combine a numerical model of sedimentation and permafrost evolution with simplified carbon turnover to estimate accumulation and microbial decomposition of organic matter on the pan-Arctic shelf over the past four glacial cycles (450 kyr). Organic carbon decomposition is modeled with a reactivity continuum model using inversely determined parameters from incubation experiments and liquid water content within the permafrost as the limiting factor rather than temperature alone. We find that Arctic shelf permafrost is a long-term carbon sink storing 2822 (1518 - 4982) Pg OC, two to four times the amount stored in lowland permafrost. Although subsea permafrost is currently thawing, prior microbial decomposition and organic matter aging would limit decomposition rates to less than 48 Tg OC per year even if all frozen sediment deposited in the past 450 kyr thawed immediately. Since actual thaw rates are orders of magnitude lower, true emissions due to subsea permafrost thaw are also orders of magnitude lower than this. The OC pool in shelf permafrost is therefore largely immobilized. Compared to the organic matter in thawing permafrost large emissions are more likely derived from older and deeper sources as shelf’s frozen lid, the permafrost, becomes more permeable

Osteosarcoma

Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While there have been significant improvements in the outcome of patients with localized disease, with event-free survival outcomes exceeding 60%, in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%. The suspicion of osteosarcoma based on radiographs still requires pathological evaluation of a bone biopsy specimen for definitive diagnosis and CT imaging of the chest should be performed to identify lung nodules. So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers. Current screening focuses only on groups at high risk such as patients with genetic cancer predisposition syndromes. Management of osteosarcoma requires a multidisciplinary team of paediatric and medical oncologists, orthopaedic and general surgeons, pathologists, radiologists and specialist nurses. Survivors of osteosarcoma require specialized medical follow-up, as curative treatment consisting of chemotherapy and surgery has long-term adverse effects, which also affect the quality of life of patients. The development of osteosarcoma model systems and related research as well as the evaluation of new treatment approaches are ongoing to improve disease outcomes, especially for patients with metastases

Submarine Permafrost as a Long-term Late Quaternary Carbon Sink

Organic carbon (OC) stored in Arctic continental shelf sediment is a climate-sensitive but poorly quantified component of the global carbon cycle. The current interglacial period means that most shelf permafrost, along with its OC, is currently warmer than -2 °C, and therefore susceptible to small additional warming in the near future. Estimating how much OC is potentially stored in subsea permafrost is thus key to a quantitative understanding of potential impacts of permafrost thaw on carbon mobilization in a warming Arctic. We developed a process-based model of permafrost distribution and organic matter (OM) sedimentation and decomposition to estimate the contribution of submarine permafrost to Arctic shelf organic carbon stocks. Driven by Earth System Model forcing, our model calculates 1D heat flow below the earth surface, ice caps and sea bed, and uses a reactivity continuum model of OM decomposition. We restrict our modeling to sediment that was buried within the last four glacial cycles (450 kyr), and therefore neglect OC stocks deeper than about 100 m, including any gas hydrates. Restricting OM decomposition to the liquid habitat for microbial activity in the sediment, we estimated that permafrost below the Arctic Shelf stores at least as much OC as the terrestrial counterpart at pre-industrial time, and probably in the range of twice to three times as much OC. We compared the effect of varying the OC sedimentation rates and OC reactivity. Higher reactivity in marine sediments combined with lower ice contents to increase the rate of OM decomposition, relative to sediment deposited in terrestrial settings. As a result, permafrost in our model preserved a greater proportion of marine OM from decomposition while having little effect (< 5%) on the amount of recalcitrant terrestrial OC. These differences in sedimentation rate and reactivity influence the distribution of OC preservation on the Arctic shelf. Our modeling shows that subsea permafrost is a relevant OC stock and that more research is needed to understand microbial OM decomposition in cold but not necessarily frozen sediments. Given that deeper deposits and gas hydrates are not included, we provide conservative estimates of Arctic shelf OC stocks and suggest that the shelves have acted as long-term carbon sinks over multiple glacial--interglacial cycles

Understanding the Astrophysics of Galaxy Evolution: the role of spectroscopic surveys in the next decade

Over the last decade optical spectroscopic surveys have characterized the low redshift galaxy population and uncovered populations of star-forming galaxies back to z ~ 7. This work has shown that the primary epoch of galaxy building and black hole growth occurs at redshifts of 2 to 3. The establishment of the concordance LCDM cosmology shifted the focus of galaxy population studies from constraining cosmological parameters to characterizing the processes which regulate the formation and evolution of galaxies.In the next decade, high redshift observers will attempt to formulate a coherent evolutionary picture connecting galaxies in the high redshift Universe to galaxies today. In order to link galaxy populations at different redshifts, we must not only characterize their evolution in a systematic way, we must establish which physical processes are responsible for it. Considerable progress has already been made in understanding how galaxies evolved from z ~ 1 to the present day. Large spectroscopic surveys in the near infrared are required to push these studies back towards the main epoch of galaxy building. Only then will we understand the full story of the formation of L* galaxies like our own Milky Way. A large near-IR spectroscopic survey will also provide the calibration needed to avoid systematics in the large photometric programs proposed to study the nature of dark matter and dark energy. We provide an outline design for a multi-object 0.4 to 1.8 micron spectrograph, which could be placed on an existing telescope, and which would allow a full characterization of the galaxy population out to z ~ 2. We strongly recommend a serious further study to design a real instrument, which will be required for galaxy formation studies to advance to the next frontier.Comment: White paper, primary author J.E. Gunn, submitted to Astro2010 Decadal Survey, see http://www7.nationalacademies.org/bpa/Astro2010_SWP_byTitle.htm

The Release of Tissue Factor Pathway Inhibitor and Platelet Factor 4 After Heparin Injection in Patients with Thrombocytosis.

Platelet factor 4 (PF4) and tissue factor pathway inhibitor (TFPI) are two proteins with high affinity for heparin. They are each stored in platelets, as well as on endothelial cell surfaces, from where both are displaced or released following an injection of heparin with a rapid and marked increase in serum levels. Prior work has demonstrated that the platelet count is one of the factors affecting the levels of heparin-releasable PF4. We therefore characterized the response to a dose of intravenous heparin previously demonstrated to completely displace PF4 from the non-platelet pool in subjects with normal or increased platelet counts. Seventeen patients with essential thrombocytosis (ET), 10 patients with polycythemia vera and high platelet counts (PV-H), 7 patients with polycythemia vera and normal platelet counts (PV-N) and 10 controls received an initial bolus of 40 I.U./kg of unfractionated heparin, followed 2 hours later by a 2nd bolus of a fixed dose of 1000 I.U. TFPI activity did not show any variation among the different groups, either before (TFPI) or after (HR-TFPI) the first bolus of heparin: ET, TFPI 92.6 ± 21.5%, HR-TFPI 298.3 ± 165.8; PV-H, TFPI 91.5 ± 32.0, HR-TFPI 210 ± 1.0; PV-N, TFPI 69.4 ± 24.0, HR-TFPI 203.0 ± 79.0; C, TFPI 109.5 ± 33.5, HR-TFPI 234.0 ± 60.4. TFPI activity returned to basal values prior to the 2nd injection of heparin, which again elicited a rise in TFPI, albeit smaller due to the lower level of heparin injected. In contrast to the lack of any difference between groups with respect to TFPI, the level of heparin-releasable PF4 (HR-PF4) was significantly higher in ET and PV-H patients compared to PV-N patients or controls. However when normalized for platelet count, both PV-H and PV-N had HR-PF4 levels after the 1st heparin injection that were significantly higher than observed in ET patients (PV-H 1.163 + 0.108, PV-N 1.411 + 0.019, ET 0.737 + 0.086 ng/10/3 platelets) supporting an increased platelet activation in PV. Thus, although platelets contain approximately 5-10% of the total amount of TFPI in plasma, they do not affect the major intravascular pool of TFPI mobilizable by heparin. However, since the concentration at the site of vessel wall injury is enhanced several-fold, TFPI could play a role in competing with PF4 to limit thrombus formation in patients with high platelet count

Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy

INTRODUCTION: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy. OBJECTIVE: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data. METHODS: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated. RESULTS: The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients. CONCLUSIONS: Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity

Clinical trial and postmarketing safety of onasemnogene abeparvovec therapy

INTRODUCTION: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy. OBJECTIVE: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data. METHODS: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated. RESULTS: The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients. CONCLUSIONS: Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity