MTOR cross-talk in cancer and potential for combination therapy

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy

Fouling of European freshwater bivalves (Unionidae) by the invasive zebra mussel (Dreissena polymorpha)

1. The zebra mussel (Dreissena polymorpha) is well known for its invasive success and its ecological and economic impacts. Of particular concern has been the regional extinction of North American freshwater mussels (Order Unionoida) on whose exposed shells the zebra mussels settle. Surprisingly, relatively little attention has been given to the fouling of European unionoids. 2. We investigated interspecific patterns in fouling at six United Kingdom localities between 1998 and 2008. To quantify the effect on two pan-European unionoids (Anodonta anatina and Unio pictorum), we used two measures of physiological status: tissue mass : shell mass and tissue glycogen content. 3. The proportion of fouled mussels increased between 1998 and 2008, reflecting the recent, rapid increase in zebra mussels in the U.K. Anodonta anatina was consistently more heavily fouled than U. pictorum and had a greater surface area of shell exposed in the water column. 4. Fouled mussels had a lower physiological condition than unfouled mussels. Unlike tissue mass : shell mass ratio, tissue glycogen content was independent of mussel size, making it a particularly useful measure of condition. Unio pictorum showed a stronger decline in glycogen with increasing zebra mussel load, but had a broadly higher condition than A. anatina at the time of study (July). 5. Given the high conservation status and important ecological roles of unionoids, the increased spatial distribution and fouling rates by D. polymorpha in Europe should receive more attention.Malacological Society of London Research Grant was provided to FP to support this study. Howard Baylis and Barrie Fuller (Zoology Department, University of Cambridge) facilitated the glycogen assays. Many thanks to Philine zu Ermgassen, Rebecca Mant, Anna McIvor, Nicole Spann and Alexandra Zieritz for field and lab assistance. Special thanks to David Strayer, Alan Hildrew and an anonymous referee for helpful suggestions on the manuscript

Connectivity for the frisbee architecture

In this paper we investigate the kconnectivity threshold of distributed dense ad hoc heterogeneous wireless sensor network architecture. We consider the situation when sensors are deployed in the surveillance area according to a uniform distribution perturbed by a Gaussian noise. We derive analytically the minimum detection range which guarantees an emerging structure in the network, namely the connectivity, which becomes larger and larger as the number of sensors in the network increase. This allows the target track to be propagated almost surely throughout the network using the minimum possible amount ofprime energy. We report the results of some simulation experiments which further support the theoretical results

Algorithms for the selection of the active sensors in distributed tracking: Comparison between Frisbee and GNS methods

This paper compares two different approaches for sensor selection for distributed tracking: 1) The Frisbee method, and 2) Global Node Selection (GNS). The Frisbee method is based on the proximity of the nodes to the predicted location of the target; GNS is based on minimizing the unbiased Cramer Rao lower bound (CRLB). Both theoretical and experimental results indicate that the Frisbee method is as effective as GNS. Furthermore, the Frisbee method is attractive due to its very light computational load

Seizure characteristics and the use of anti-epileptic drugs in children and young people with brain tumours and epileptic seizures: analysis of regional paediatric cancer service population

PURPOSE: Epileptic seizures complicate the management of childhood brain tumours. There are no published standards for clinical practice concerning risk factors, treatment selection or strategies to withdraw treatment with antiepileptic drugs (AED). METHOD: We undertook a case note review of 120 patients with newly diagnosed brain tumours, referred to a regional paediatric cancer service. RESULTS: Data was available on 117/120 (98%) children <18 years: median age at tumour presentation was 8.1 years (IQR 25°-75°: 3.6-12.7), median follow up was 33 months (IQR 25°-75°: 24-56), and 35/117 (29%) experienced seizures. A cortical tumour location was associated with the highest risk of seizures (OR: 7.1; CI 95% 2.9-17.3). At a median follow up of 24 months (IQR25°-75°: 15-48), 22/35 (63%) with seizures, had a single seizure episode, 15/35 (43%) were seizure free (SF) on AEDs, 13/35 (37%) were SF off AEDs, and 7/35 (20%) experienced continuing epileptic seizures. Overall 34/35 (97%) were treated with AEDs after a seizure, of whom 12/35 (35%) withdrew from AED medication, and although 4/35 (12%) had seizure relapse, all were after further acute events. The median duration of AED before withdrawal was 11 months (IQR25°-75° 5-14 months), and the median follow up after withdrawal was 15 months (IQR25°-75° 5-34 months). CONCLUSIONS: Seizures affect about 1/3rd of children and young people presenting with and being treated for brain tumours particularly when the tumour is in the cerebral cortex. The low risk of recurrent seizures after AED treatment justifies consideration of early withdrawal of AED after seizure control

Multidimensional prognostic index and mortality in intermediate care facilities: A retrospective study

Multidimensional prognostic index (MPI) is a frailty assessment tool used for stratifying prognosis in older hospitalized people, but data regarding older people admitted to intermediate care facilities (ICFs) are missing. The aim of this study is to evaluate whether MPI can predict mortality in older patients admitted to the ICFs. MPI was calculated using different domains explored by a standard comprehensive geriatric assessment and categorized into tertiles (MPI-1 ≤ 0.20, MPI 2 0.20–0.34, MPI 3 &gt; 0.34). A Cox’s regression analysis, taking mortality as the outcome, was used, reporting the results as hazard ratios (HRs) with 95% confidence intervals (CIs). In total, 653 older patients were enrolled (mean age: 82 years, 59.1% females). Patients in MPI-2 (HR = 3.66; 95%CI: 2.45–5.47) and MPI-3 (HR = 6.22; 95%CI: 4.22–9.16) experienced a higher risk of mortality, compared to MPI-1. The accuracy of MPI in predicting mortality was good (area under the curve (AUC) = 0.74, 95%CI: 0.70–0.78). In conclusion, our study showed that prognostic stratification, as assessed by the MPI, was associated with a significantly different risk of mortality in older patients admitted to the ICFs, indicating the necessity of using a CGA-based tool for better managing older people in this setting as well. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Role of inflammation in diabetic macular edema and neovascular age-related macular degeneration

Diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) are multifactorial disorders that affect the macula and cause significant vision loss. Although inflammation and neoangiogenesis are hallmarks of DME and nAMD, respectively, they share some biochemical mediators. While inflammation is a trigger for the processes that lead to the development of DME, in nAMD inflammation seems to be the consequence of retinal pigment epithelium and Bruch membrane alterations. These pathophysiologic differences may be the key issue that justifies the difference in treatment strategies. Vascular endothelial growth factor inhibitors have changed the treatment of both diseases, however, many patients with DME fail to achieve the established therapeutic goals. From a clinical perspective, targeting inflammatory pathways with intravitreal corticosteroids has been proven to be effective in patients with DME. On the contrary, the clinical relevance of addressing inflammation in patients with nAMD has not been proven yet. We explore the role and implication of inflammation in the development of nAMD and DME and its therapeutical relevance

The European palaeoecological record of Swedish red-listed beetles

Recent global changes have triggered a biodiversity crisis. However, climate fluctuations have always influenced biodiversity and humans have affected species distributions since prehistoric times. Conservation palaeobiology is a developing field that aims to understand the long-term dynamics of such interactions by studying the geohistorical records in a conservation perspective. Case studies exist for vertebrates and plants, but insects have largely been overlooked so far. Here, we analysed the current red-listed beetle species (Coleoptera) in Sweden and investigated their occurrence and representation in the European Quaternary fossil record. Fossil data currently exist for one third of the Swedish red-listed beetle species. All the red-list conservation classes are represented in the fossil record, which may allow for comparative studies. We found significantly different representations in the fossil records among taxonomic groups and ecological traits, which may depend on the fossil depositional and sampling environments and variation in how difficult species are to identify. Species that are today associated with modern urban environments were mostly found in Quaternary sites with archaeological human settlements, reflecting early human-driven environmental change. Combining modern and fossil insect species data for biodiversity conservation needs to be undertaken with care, and attention paid to biases in both modern and palaeo-data. Nevertheless, this approach opens new opportunities for conservation biology by providing a millennial-scale perspective on biodiversity change, including consideration of the long-term dynamics of species range shifts, species invasions and regional extinctions under changing climates

PSS21 The Cost-Effectiveness of Intravitreal Aflibercept (IVT-AFL) in Treating Neovascular Age-Related Macular Degeneration in an Italian Setting

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The Left Ventricular Dysfunction Questionnaire: Italian translation and validation.

Patients affected by heart failure have a compromised quality of life (QOL) and in the last few years "health related quality of life" has become an important outcome indicator for the evaluation of heart failure treatment. Methods: Translation into Italian of the Left Ventricular Dysfunction Questionnaire (LVD-36), a new, 36-item, disease-specific health status instrument for patients with congestive heart failure, and its subsequent validation by administration to 50 consecutive patients in our heart failure outpatient clinic. The Italian LVD-36 was compared to the "The Minnesota Living with Heart Failure Questionnaire" (MLHF). Results: The Italian version of the LVD-36 correlates well with MLHF for ejection fraction (EF), NYHA class I and II, etiology and therapy. Since, however, the LVD-36 has only one domain, it may be able to offer more synthetic information than MLHF about patients' status. Conclusions: The Italian version of the LVD-36 appears to be a reliable instrument for assessing patients' QOL and the degree of limitations imposed on them by the disease. It is short, clear and easy to complete. In patients with heart failure the LVD-36 correlates well with the MLHF and may be considered a new disease- specific instrument to estimate changes in health status, and an useful support in optimizing therapeutic options