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 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

Development and Validation of a New Questionnaire for the Evaluation of Upper Gastrointestinal Symptoms in the Elderly Population: A Multicenter Study

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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

Association between the multidimensional prognostic index and mortality during 15 Years of Follow-up in the InCHIANTI Study

Background: Multidimensional Prognostic Index (MPI) is recognized as a prognostic tool in hospitalized patients, but data on the value of MPI in community-dwelling older persons are limited. Using data from a representative cohort of community-dwelling persons, we tested the hypothesis that MPI explains mortality during 15 years of follow-up. Methods: A standardized comprehensive geriatric assessment was used to calculate the MPI and to categorize participants in low-, moderate-, and high-risk classes. The results were reported as hazard ratios (HRs) and the accuracy was evaluated with the area under the curve (AUC), with 95% confidence intervals (CIs) and the C-index. We also reported the median survival time by standard age groups. Results: All 1453 participants (mean age 68.9 years, women = 55.8%) enrolled in the InCHIANTI study at baseline were included. Compared to low-risk group, participants in moderate (HR = 2.10; 95% CI: 1.73-2.55) and high-risk MPI group (HR = 4.94; 95% CI: 3.91-6.24) had significantly higher mortality risk. The C-index of the model containing age, sex, and MPI was 82.1, indicating a very good accuracy of this model in explaining mortality. Additionally, the time-dependent AUC indicated that the accuracy of the model incorporating MPI to age and sex was excellent (>85.0) during the whole follow-up period. Compared to participants in the low-risk MPI group across different age groups, those in moderate- and high-risk groups survived 2.9-7.0 years less and 4.3-8.9 years less, respectively. Conclusions: In community-dwelling individuals, higher MPI values are associated with higher risk of all-cause mortality with a dose-response effect. © 2020 The Author(s) 2020

Accuracy of screening tools for Pap smears in general practice

Background: Data extraction tools (DETs) are increasingly being used for research and audit of general practice, despite their limitations. Objective: This study explores the accuracy of Pap smear rates obtained with a DET compared to that of the Pap smear rate obtained with a manual file audit. Method: A widely available DET was used to establish the rate of Pap smears in a large multi-general practice (multi-GP) in regional New South Wales followed by a manual audit of patient files. The main outcome measure was identification of possible discrepancies between the rates established. Results: The DET used significantly underestimated the level of cervical screening compared to the manual audit. In some instances, the patient file contained phone/specialist record of Pap smear conducted elsewhere, which accounted for the failure of the DET to detect some smears. Those patients who had Pap smears whose pathology codes differed between time intervals, i.e. from different pathology providers or from within the same provider but using a different code, were less likely to have had their most recent Pap smear detected by the DET (p \u3c 0.001). Conclusion: Data obtained from DETs should be used with caution as they may not accurately reflect the rate of Pap smears from electronic medical records

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

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

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