Body composition in anorexia nervosa: Meta-analysis and meta-regression of cross-sectional and longitudinal studies

Objective: Clinically, anorexia nervosa (AN) presents with altered body composition. We quantified these alterations and evaluated their relationships with metabolites and hormones in patients with AN longitudinally. Method: In accordance with PRISMA guidelines, we conducted 94 meta-analyses on 62 samples published during 1996–2019, comparing up to 2,319 pretreatment, posttreatment, and weight-recovered female patients with AN with up to 1,879 controls. Primary outcomes were fat mass, fat-free mass, body fat percentage, and their regional distribution. Secondary outcomes were bone mineral density, metabolites, and hormones. Meta-regressions examined relationships among those measures and moderators. Results: Pretreatment female patients with AN evidenced 50% lower fat mass (mean difference [MD]: −8.80 kg, 95% CI: −9.81, −7.79, Q = 1.01 × 10−63) and 4.98 kg (95% CI: −5.85, −4.12, Q = 1.99 × 10−28) lower fat-free mass, with fat mass preferentially stored in the trunk region during early weight restoration (4.2%, 95% CI: −2.1, −6.2, Q = 2.30 × 10−4). While the majority of traits returned to levels seen in healthy controls after weight restoration, fat-free mass (MD: −1.27 kg, 95% CI: −1.79, −0.75, Q = 5.49 × 10−6) and bone mineral density (MD: −0.10 kg, 95% CI: −0.18, −0.03, Q = 0.01) remained significantly altered. Discussion: Body composition is markedly altered in AN, warranting research into these phenotypes as clinical risk or relapse predictors. Notably, the long-term altered levels of fat-free mass and bone mineral density suggest that these parameters should be investigated as potential AN trait markers

Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer

Background Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. Methods A panel of ER+ BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1wt or ESR1Y537S, modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Results Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Conclusions Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER

The effect of solvent on the catalytic properties of microperoxidase-11

peer-reviewedThe effect of a range of solvents on the catalytic oxidation of methyl phenyl sulfide to methyl phenyl sulfoxide by MP-11 and by a cyclodextrin derivative of MP-11 was examined. The addition of low concentrations of alcohols enhanced the initial rate of sulfoxidation, most likely due to dispersion of MP-11 aggregates. Higher alcohol concentrations resulted in a decrease in activity arising from solvation of the hydrophobic sulfide, disrupting binding to the catalyst. In alcohols, the yield of product was decreased due to increased rates of MP-11 deactivation via the formation of aldehydes (for primary alcohols) or by peroxide-based deactivation. The catalytic activity of the cyclodextrin modified MP-11 was similar to that of MP-11 itself, demonstrating that it is the N-terminal side of MP-11 which is the determinant of catalytic activity.ACCEPTEDpeer-reviewe

Angiostatin anti-angiogenesis requires IL-12: The innate immune system as a key target

© 2009 Albini et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

METH-2 silencing and promoter hypermethylation in NSCLC

The antiangiogenic factor METH-2 (ADAMTS-8) was identified in a previous dual-channel cDNA microarray analysis to be at least two-fold under-represented in 85% (28 out of 33) of primary non-small-cell lung carcinomas (NSCLCs). This observation has been validated in an independent series of NSCLCs and adjacent normal tissues by comparative multiplex RT—PCR, and METH-2 mRNA expression was dramatically reduced in all 23 tumour samples analysed. Immunohistochemical analysis of the same sample set demonstrated that METH-2 was strongly expressed in 14 out of 19 normal epithelial sites examined but only one out of 20 NSCLCs. DNA methylation analysis of the proximal promoter region of this gene revealed abnormal hypermethylation in 67% of the adenocarcinomas and 50% of squamous cell carcinomas, indicating that epigenetic mechanisms are involved in silencing this gene in NSCLC. No homozygous deletions of METH-2 were found in lung cancer cell lines. Allelic imbalance in METH-2 was assessed by an intronic single nucleotide polymorphism (SNP) assay and observed in 44% of informative primary samples. In conclusion, the downregulation of METH-2 expression in primary NSCLC, often associated with promoter hypermethylation, is a frequent event, which may be related to the development of the disease

Environmental Factors Controlling the Distribution of Symbiodinium Harboured by the Coral Acropora millepora on the Great Barrier Reef

Background: The Symbiodinium community associated with scleractinian corals is widely considered to be shaped by seawater temperature, as the coral's upper temperature tolerance is largely contingent on the Symbiodinium types harboured. Few studies have challenged this paradigm as knowledge of other environmental drivers on the distribution of Symbiodinium is limited. Here, we examine the influence of a range of environmental variables on the distribution of Symbiodinium associated with Acropora millepora collected from 47 coral reefs spanning 1,400 km on the Great Barrier Reef (GBR), Australia

Inhibition of Chondrosarcoma Growth by mTOR Inhibitor in an In Vivo Syngeneic Rat Model

BACKGROUND: Chondrosarcomas are the second most frequent primary malignant type of bone tumor. No effective systemic treatment has been identified in advanced or adjuvant phases for chondrosarcoma. The aim of the present study was to determine the antitumor effects of doxorubicin and everolimus, an mTOR inhibitor on chondrosarcoma progression. METHODS AND FINDINGS: Doxorubin and/or everolimus were tested in vivo as single agent or in combination in the rat orthotopic Schwarm chondrosarcoma model, in macroscopic phase, as well as with microscopic residual disease. Response to everolimus and/or doxorubicin was evaluated using chondrosarcoma volume evolution (MRI). Histological response was evaluated with % of tumor necrosis, tumor proliferation index, metabolism quantification analysis between the treated and control groups. Statistical analyses were performed using chi square, Fishers exact test. Doxorubicin single agent has no effect of tumor growth as compared to no treatment; conversely, everolimus single agent significantly inhibited tumor progression in macroscopic tumors with no synergistic additive effect with doxorubicin. Everolimus inhibited chondrosarcoma proliferation as evaluated by Ki67 expression did not induce the apoptosis of tumor cells; everolimus reduced Glut1 and 4EBP1 expression. Importantly when given in rats with microscopic residual diseases, in a pseudo neoadjuvant setting, following R1 resection of the implanted tumor, everolimus significantly delayed or prevented tumor recurrence. CONCLUSIONS: MTOR inhibitor everolimus blocks cell proliferation, Glut1 expression and HIF1a expression, and prevents in vivo chondrosarcoma tumor progression in both macroscopic and in adjuvant phase post R1 resection. Taken together, our preclinical data indicate that mTOR inhibitor may be effective as a single agent in treating chondrosarcoma patients. A clinical trial evaluating mTOr inhibitor as neo-adjuvant and adjuvant therapy in chondrosarcoma patients is being constructed

Additive Anti-Tumor Effects of Lovastatin and Everolimus In Vitro through Simultaneous Inhibition of Signaling Pathways

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThis work was supported by a research grant from the Ludwig-Maximilians University of Munich (Förderprogramm für Forschung und Lehre [FöFoLe], grant number 865/829)

The Expected Impacts of Climate Change on the Ocean Economy

The ocean is critically important to our global economy. Collectively, it is estimated that ocean-based industries and activities contribute hundreds of millions of jobs and approximately US $2.5 trillion to the global economy each year, making it the world’s seventh-largest economy when compared with national gross domestic products. In addition, the nonmarket services and benefts provided by the global ocean are signifcant and may in fact far exceed the value added by market-based goods and services. • Climate change is altering ocean climate, chemistry, circulation, sea level and ice distribution. Collectively, these system changes have critical impacts on the habitats, biological productivities and species assemblages that underpin many of the economic benefts of the sea. • Swift efforts to reduce anthropogenic greenhouse gas emissions are needed to maintain a robust ocean economy. The recent Intergovernmental Panel on Climate Change report estimates that climate-induced declines in ocean health will cost the global economy$428 billion/year by 2050 and $1.98 trillion/year by 2100. • Climate change is reducing the productivities and changing the spatial distributions of economically important marine species and their habitats. All countries stand to gain signifcant benefts relative to a business-as-usual trajectory by implementing climate-adaptive fsheries management reforms that address both changes in species’ distributions and productivities due to climate change. Many countries could maintain or improve profts and catches into the future with effective adaptation. • The potential of marine aquaculture (mariculture) is likely to remain high under climate change and, with careful planning, mariculture could offset losses in food and income from capture fsheries in those countries that will experience losses in that sector. Expanding the potential for marine aquaculture will require enhancing technical capac�ities, defning best practices, easing undue regulatory bur�dens, increasing access to credit and insurance, breeding stocks for faster growth and improving feed technology. • The combined effects of ocean warming and acidifcation result in predictions of negative impacts on coral reef cover and tourism values for all countries, with magnitudes dependent on the strength of climate change. For a high emissions scenario (Representative Concentration Pathway 8.5), coral cover is expected to decline by 72–87%, causing on-reef tourism values to decrease by over 90% in 2100. • Climate change impacts will differ by country and sector and solutions must be context-specifc. By exploring climate change impacts at the country level for fsheries, aquaculture and reef tourism, countries can assess what they stand to gain or lose due to climate change and understand how they might capitalise on these predictions to inform their investments and actions. • Implementing certain key strategies will help build socio�ecological resilience to climate change and ensure the continued, or improved, provision of functions and ser�vices from the ocean, especially for the most vulnerable coastal nations. These strategies include the following: – A focus on equity. Climate change is likely to cause and exacerbate global inequities, reducing resilience and thereby likely worsening outcomes under all climate change scenarios. It will thus be profoundly important to examine the equity implications of all new and existing management decisions across all three sectors. Looking forward. The future of the ocean economy is expected to drastically change given climate change, and the nature and magnitude of these changes can be highly variable. Each of these three sectors will need to work to understand risks and anticipate changes, and build precautionary and adaptive strategies into their management decisions. – Co-operating across boundaries. As suitable habitats shift and change, marine species will move across jurisdictional boundaries and regional, national and international cooperative agreements will be necessary to ensure that these species are well-managed, and that the benefts are fairly distributed during and after the transitions