Conservation of the unusual dimeric JmjC fold of JMJD7 from Drosophila melanogaster to humans

The JmjC family of 2-oxoglutarate dependent oxygenases catalyse a range of hydroxylation and demethylation reactions in humans and other animals. Jumonji domain-containing 7 (JMJD7) is a JmjC (3S)-lysyl-hydroxylase that catalyses the modification of Developmentally Regulated GTP Binding Proteins 1 and 2 (DRG1 and 2); JMJD7 has also been reported to have histone endopeptidase activity. Here we report biophysical and biochemical studies on JMJD7 from Drosophila melanogaster (dmJMJD7). Notably, crystallographic analyses reveal that the unusual dimerization mode of JMJD7, which involves interactions between both the N- and C-terminal regions of both dmJMJD7 monomers and disulfide formation, is conserved in human JMJD7 (hsJMJD7). The results further support the assignment of JMJD7 as a lysyl hydroxylase and will help enable the development of selective inhibitors for it and other JmjC oxygenases

The refinement of the haemagglutinin membrane glycoprotein of influenza virus

The crystal structure of the haemagglutinin glycoprotein, a trimer from the membrane of influenza virus, has been refined at 3.0 Å resolution to an R factor of 20.4%. The first 23 cycles were carried out on coordinates of an averaged monomer determined from a non-crystallographically threefold-symmetry-averaged electron density map. The contribution of structure factors to the least-squares equations were determined from non-crystallographically averaged gradient difference and curvature Fourier maps. The refinement was restrained using the Hendrickson & Konnert algorithm. These initial cycles were followed by 25 cycles of refinement with trigonometric evaluation of the derivatives on the complete trimer (208 422 daltons) on a Cray 1/S. Forty-eight water molecules and portions of five N-linked oligosaccharides were identified

Dantrolene for the Prevention and Treatment of Cerebral Vasospasm after Subarachnoid Hemorrhage – a Randomized Placebo-Controlled Trial to assess Safety, Tolerability and Feasibility

Introduction: Dantrolene is neuroprotective in animal models and may attenuate cerebral vasospasm (cVSP) after aneurysmal subarachnoid hemorrhage (aSAH) in humans. We evaluated safety/tolerability and feasibility of intravenous dantrolene (IV-D) after aSAH. Methods: In this single-center, randomized, double blind, placebo-controlled trial, 31 patients with acute aSAH were randomized to IV-D 1.25 mg IV every 6 hours x 7 days (n=16) or placebo (n=15). Primary endpoint was incidence of hyponatremia (sNa ≤ 134 mmol/L) and liver toxicity (% patients with ALT, AST and AlkPhos \u3e5x upper limit of normal). Secondary safety endpoints included tolerability, systemic hypotension and intracranial hypertension. Efficacy was explored by clinical, transcranial Doppler (TCD) or angiographic cVSP occurrence, delayed cerebral ischemia (DCI) and 3-month modified-Rankin-Scale, Glasgow Outcome Scale and Barthel Index. Statistical analysis was performed using non-parametric tests, generalized estimating equations and mixed models. Results: Between IV-D vs. placebo, no differences were observed in the primary outcome (hyponatremia: 44% vs. 67% [p=0.29]; liver toxicity 6% vs. 0% [p=1.0]). Numerically more AEs and SAEs were seen in the IV-D group, but did not reach statistical significance (16 vs. 5 AEs, of which 5 vs. 2 were severe; RR 2.2; 95% CI 0.7-6.7; p=0.16). Three IV-D vs. two placebo patients reached stop criteria: one IV-D patient developed liver toxicity; two patients in each group developed brain edema requiring osmotherapy. No differences in angiographic, TCD, clinical cVSP, DCI, or 3-month functional outcomes were seen. Quantitative angiogram analysis revealed a trend towards increased vessel diameters in the IV-D group after the 7-day infusion-period (p=0.05). Conclusions: In this small trial, IV-Dantrolene after aSAH was feasible, tolerable and safe, but was underpowered to show efficacy or outcome differences

An anemia of Alzheimer\u27s disease

Lower hemoglobin is associated with cognitive impairment and Alzheimer\u27s disease (AD). Since brain iron homeostasis is perturbed in AD, we investigated whether this is peripherally reflected in the hematological and related blood chemistry values from the Australian Imaging Biomarker and Lifestyle (AIBL) study (a community-based, cross-sectional cohort comprising 768 healthy controls (HC), 133 participants with mild cognitive impairment (MCI) and 211 participants with AD). We found that individuals with AD had significantly lower hemoglobin, mean cell hemoglobin concentrations, packed cell volume and higher erythrocyte sedimentation rates (adjusted for age, gender, APOE-ε4 and site). In AD, plasma iron, transferrin, transferrin saturation and red cell folate levels exhibited a significant distortion of their customary relationship to hemoglobin levels. There was a strong association between anemia and AD (adjusted odds ratio (OR)=2.43, confidence interval (CI) (1.31, 4.54)). Moreover, AD emerged as a strong risk factor for anemia on step-down regression, even when controlling for all other available explanations for anemia (adjusted OR=3.41, 95% CI (1.68, 6.92)). These data indicated that AD is complicated by anemia, which may itself contribute to cognitive decline

Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs\u27 therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy

Electrical-thermal analytical modeling of monopolar RF thermal ablation of biological tissues: determining the circumstances under which tissue temperature reaches a steady state

This is a pre-copy-editing, author-produced PDF of an article accepted for publication in MATHEMATICAL BIOSCIENCES doi:10.3934/mbe.2015003 AND ENGINEERING following peer review. The definitive publisher-authenticated version Mathematical Biosciences and Engineering (MBE) Pages: 281 - 301, Volume 13, Issue 2, April 2016 is available online at http://www.aimsciences.org/journals/displayArticlesnew.jsp?paperID=11998[EN] It has been suggested that during RF thermal ablation of biological tissue the thermal lesion could reach an equilibrium size after 1-2 minutes. Our objective was to determine under which circumstances of electrode geometry (needle-like vs. ball-tip), electrode type (dry vs. cooled) and blood perfusion the temperature will reach a steady state at any point in the tissue. We solved the bioheat equation analytically both in cylindrical and spherical coordinates and the resultant limit temperatures were compared. Our results demonstrate mathematically that tissue temperature reaches a steady value in all cases except for cylindrical coordinates without the blood perfusion term, both for dry and cooled electrodes, where temperature increases infinitely. This result is only true when the boundary condition far from the active electrode is considered to be at infinitum. In contrast, when a finite and sufficiently large domain is considered, temperature reaches always a steady state.This work received financial support from the Spanish "Plan Estatal de Investigacion, Desarrollo e Innovacion Orientada a los Retos de la Sociedad" under Grant TEC2014-52383-C3-R (TEC2014-52383-C3-1-R).López Molina, JA.; Rivera Ortun, MJ.; Berjano, E. (2016). Electrical-thermal analytical modeling of monopolar RF thermal ablation of biological tissues: determining the circumstances under which tissue temperature reaches a steady state. Mathematical Biosciences and Engineering. 13(2):281-301. https://doi.org/10.3934/mbe.2015003S28130113

Environmental drivers of distribution and reef development of the Mediterranean coral Cladocora caespitosa

Cladocora caespitosa is the only Mediterranean scleractinian similar to tropical reef-building corals. While this species is part of the recent fossil history of the Mediterranean Sea, it is currently considered endangered due to its decline during the last decades. Environmental factors affecting the distribution and persistence of extensive bank reefs of this endemic species across its whole geographic range are poorly understood. In this study, we examined the environmental response of C. caespitosa and its main types of assemblages using ecological niche modeling and ordination analysis. We also predicted other suitable areas for the occurrence of the species and assessed the conservation effectiveness of Mediterranean marine protected areas (MPAs) for this coral. We found that phosphate concentration and wave height were factors affecting both the occurrence of this versatile species and the distribution of its extensive bioconstructions in the Mediterranean Sea. A set of factors (diffuse attenuation coefficient, calcite and nitrate concentrations, mean wave height, sea surface temperature, and shape of the coast) likely act as environmental barriers preventing the species from expansion to the Atlantic Ocean and the Black Sea. Uncertainties in our large-scale statistical results and departures from previous physiological and ecological studies are also discussed under an integrative perspective. This study reveals that Mediterranean MPAs encompass eight of the ten banks and 16 of the 21 beds of C. caespitosa. Preservation of water clarity by avoiding phosphate discharges may improve the protection of this emblematic species.Spanish Ministry of Economy and Competitiveness [CTM2014-57949-R]info:eu-repo/semantics/publishedVersio

The Lingering Environmental Impact of Repressive Governance: The Environmental Legacy of the Apartheid Era for the New South Africa

This article aims to explore the historical link between contemporary environmental problems and the environmental, economic and political policies of the apartheid government. The analysis draws on an examination of the detrimental environmental impacts of the apartheid era and how international isolation impacted on governmental environmental management in the country, before turning attention to the way in which the ANC government has managed the South African natural and human environments in the period after 1994. The article shows that despite many important new developments since 1994, that there are high levels of continuity between the environmental management practices of the old and the new regimes. This state of affairs negatively impacts on the ability of the ANC government to provide every South African citizen with the clean and safe environment guaranteed to all within the 1996 Bill of Rights.This article also appeared unchanged as a chapter in the following edited collection: Jan Oosthoek and Barry K. Gills (eds), _The Globalization of Environmental Crisis_ (Abingdon: Routledge, 2008), pp. 109-120

Crizotinib-Resistant Mutants of EML4-ALK Identified Through an Accelerated Mutagenesis Screen

Activating gene rearrangements of anaplastic lymphoma kinase (ALK) have been identified as driver mutations in non-small-cell lung cancer, inflammatory myofibroblastic tumors, and other cancers. Crizotinib, a dual MET/ALK inhibitor, has demonstrated promising clinical activity in patients with non-small-cell lung cancer and inflammatory myofibroblastic tumors harboring ALK translocations. Inhibitors of driver kinases often elicit kinase domain mutations that confer resistance, and such mutations have been successfully predicted using in vitro mutagenesis screens. Here, this approach was used to discover an extensive set of ALK mutations that can confer resistance to crizotinib. Mutations at 16 residues were identified, structurally clustered into five regions around the kinase active site, which conferred varying degrees of resistance. The screen successfully predicted the L1196M, C1156Y, and F1174L mutations, recently identified in crizotinib-resistant patients. In separate studies, we demonstrated that crizotinib has relatively modest potency in ALK-positive non-small-cell lung cancer cell lines. A more potent ALK inhibitor, TAE684, maintained substantial activity against mutations that conferred resistance to crizotinib. Our study identifies multiple novel mutations in ALK that may confer clinical resistance to crizotinib, suggests that crizotinib's narrow selectivity window may underlie its susceptibility to such resistance and demonstrates that a more potent ALK inhibitor may be effective at overcoming resistance