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

Role of mTOR signaling in tumor microenvironment. An overview

The mammalian target of rapamycin (mTOR) pathway regulates major processes by integrating a variety of exogenous cues, including diverse environmental inputs in the tumor microenvironment (TME). In recent years, it has been well recognized that cancer cells co-exist and co-evolve with their TME, which is often involved in drug resistance. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both the tumor immunity and angiogenesis. The activation of mTOR signaling is associated with these pro-oncogenic cellular processes, making mTOR a promising target for new combination therapies. This review highlights the role of mTOR signaling in the characterization and the activity of the TME’s elements and their implications in cancer immunotherapy

Combined stable-isotope and fatty-acid analyses demonstrate that large wood increases the autochthonous trophic base of a macroinvertebrate assemblage

This research was carried out within the Erasmus Mundus Doctorate Program SMART (http://www.riverscience.eu) funded by the Education, Audiovisual and Culture Executive Agency (EACEA) of the European commission

Central serous chorioretinopathy: Pathogenesis and management

Central serous chorioretinopathy (CSC) is a common retina disease and has a relative high recurrence rate, etiology, and pathogenesis of which remains largely ambiguous. The effects on the retina are usually self-limited, although some people are left with permanent vision loss due to progressive and irreversible photoreceptor damage or retinal pigment epithelium atrophy. There have been a number of interventions used in CSC, including, but not limited to, laser treatment, photodynamic therapy (PDT), intravitreal injection of anti-vascular endothelial growth factor agents, and subthreshold lasers. It is not clear whether there is a clinically important benefit to treating acute CSC, which often resolves spontaneously as part of its natural history. Of the interventions studied to date, PDT and micropulse laser treatment appear the most promising

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 > 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

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

28073 DYNAMIC RESPONSE OF SHALLOW WATER MONOPOD PLATFORMS

ABSTRACT This paper describes a systematic desktop study of the non-linear dynamic behavior of monopod platforms. The aim of this work is to highlight some important factors in the dynamics of minimum structures in shallow water. The analysis is performed in the time domain with regular wave loading. The non-linearities are due to the wave theory (Stream function of 8 th order), to the shallow water environment and to the dragdominated situation. Idealizations of two braced monopod configurations are compared with the simpler and more commonly studied unbraced monopod. Aspects highlighted for each configuration include the effect of wave period and top mass on the dynamic amplification factor. In particular, the analysis focuses on the highly non-linear behavior in the wave zone. The results show that braced monopods are dynamically more sensitive than unbraced monopods. In particular, braced monopods exhibit more energy at higher harmonics in the quasi-static response. This yields a consistently stronger dynamic response even if the wave period and the natural period of the structure are very different. The importance of the mass at the top of the structure in the dynamic response and in particular its role in increasing the dynamic amplification factor up the water column are highlighted

WISER Deliverable D3.3-2: The importance of invertebrate spatial and temporal variation for ecological status classification for European lakes

European lakes are affected by many human induced disturbances. In principle, ecological theories predict that the structure and functioning of benthic invertebrate assemblage (one of the Biological Quality Elements following the Water Framework Directive, WFD terminology) change in response to the level of disturbances, making this biological element suitable for assessing the status and management of lake ecosystems. In practice, to set up assessment systems based on invertebrates, we need to distiguish community changes that are related to human pressures from those that are inherent natural variability. This task is complicated by the fact that invertebrate communities inhabiting the littoral and the profundal zones of lakes are constrained by different factors and respond unevenly to distinct human disturbances. For example it is not clear yet how the invertebrates assemblages respond to watershed and shoreline alterations, nor the relative importance of spatial and temporal factors on assemblage dynamics and relative bioindicator values of taxa, the habitat constraints on species traits and other taxonomic and methodological limitations. The current lack of knowledge of basic features of invertebrate temporal and spatial variations is limiting the fulfillment of the EU-wide intercalibration of lake ecological quality assessment systems in Europe, and thus compromising the basis for setting the environmental objectives as required by the WFD. The aim of this deliverable is to provide a contribution towards the understanding of basic sources of spatial and temporal variation of lake invertebrate assemblages. The report is structured around selected case studies, manly involving the analysis of existing datasets collated within WISER. The case studies come from different European lake types in the Northern, Central, Alpine and Mediterranean regions. All chapters have an obvious applied objective and our aim is to provide to those dealing with WFD implementation at various levels useful information to consider when designing monitoring programs and / or invertebrate-based classification systems

Comparing the Prognostic Accuracy for All-Cause Mortality of Frailty Instruments: A Multicentre 1-Year Follow-Up in Hospitalized Older Patients

Frailty is a dynamic age-related condition of increased vulnerability characterized by declines across multiple physiologic systems and associated with an increased risk of death. We compared the predictive accuracy for one-month and one-year all-cause mortality of four frailty instruments in a large population of hospitalized older patients in a prospective multicentre cohort study

Mortality attributable to COVID-19 in nursing home residents: a retrospective study

Aim: Coronavirus-19 disease (COVID-19) is a widespread condition in nursing home (NH). It is not known whether COVID-19 is associated with a higher risk of death than residents without COVID-19. Therefore, the aim of this study was to assess whether COVID-19 is associated with a higher mortality rate in NH residents, considering frailty status assessed with the Multidimensional Prognostic Index (MPI). Methods: In this retrospective study, made in 31 NHs in Venice, Italy, the presence of COVID-19 was ascertained with a nasopharyngeal swab. Frailty was evaluated using the MPI, modified according to the tools commonly used in our NHs. A Cox’s regression analysis was used reporting the results as hazard ratios (HRs) with 95% confidence intervals (CIs), using COVID-19 as exposure and mortality as outcome and stratified by MPI tertiles. Similar analyses were run using MPI tertiles as exposure. Results: Overall, 3946 NH residents (median age = 87 years, females: 73.9%) were eligible, with 1136 COVID-19 +. During a median follow-up of 275 days, higher values of MPI, indicating frailer people, were associated with an increased risk of mortality. The incidence of mortality in COVID-19 + was more than doubled than COVID-19- either in MPI-1, MPI-2 and MPI-3 groups. The presence of COVID-19 increased the risk of death (HR = 1.85; 95% CI 1.59–2.15), also in the propensity score model using MPI as confounder (HR = 2.48; 95% CI 2.10–2.93). Conclusion: In this retrospective study of NH residents, COVID-19 was associated with a higher risk of all-cause mortality than those not affected by COVID-19 also considering the different grades of frailty. © 2021, The Author(s)