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

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

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

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

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

Italian cardiovascular mortality charts of the CUORE Project: are they comparable with the SCORE charts?

Background The aim of this study was to build risk charts for the assessment of cardiovascular mortality of the CUORE project, an Italian longitudinal study, and to compare them with the systematic coronary risk evaluation (SCORE) project charts for low risk European countries. Design Random population samples enrolled in the 1980s and 1990s in Italy were included in the analysis: 7520 men and 13 127 women aged 35-69 years without previous cardiovascular events and with a mean follow-up period of 10 years for cardiovascular disease. ICD-9 codes of death certificates similar to those of the SCORE project were considered when they appear as first cause of death. Methods Sex-stratified Cox proportional hazard model including age, systolic blood pressure, ratio between total and HDL cholesterol, and smoking habit as risk factors was used to assess cardiovascular mortality. Results Analysis showed that all risk factors included in the model were statistically significant. The corresponding area under the receiver operating characteristic curve was 0.825 (95% confidence interval: 0.803-0.846) for men and 0.850 (0.823-0.877) for women. The CUORE project charts yielded similar results to the corresponding charts of the SCORE project: Lin's coefficient was 0.929 for men and 0.935 for women. Conclusion The comparison between CUORE and SCORE mortality risk charts shows that SCORE charts reflect quite well the Italian cardiovascular mortality and, correspondingly, Italian cohorts of the CUORE project are quite representative of European countries at low risk for cardiovascular mortality

Body composition as a modulator of response to immunotherapy in lung cancer: time to deal with it

[no abstract available

Exercise levels and preferences in cancer patients: A cross-sectional study

Background: Despite the benefits related to physical exercise, large numbers of cancer patients are not sufficiently active. Methods: To investigate exercise levels and preferences in cancer patients, a cross-sectional study was conducted on a random sample of 392 cancer outpatients who anonymously completed a questionnaire investigating general and medical characteristics, and expressed willingness to participate in exercise programs. Current exercise levels were estimated with the Leisure Score Index (LSI). Results: Most patients (93%) were insufficiently active but 80% declared an interest in exercise programs. Patients preferred oncologist-instructed programs and specified particular exercise needs. Multivariate logistic regression showed that willingness to exercise was associated with education (OR: 1.87; 95% CI: 1.15–3.04 beyond age 14 years vs. up to 14 years) and current physical activity (OR: 1.92; 95% CI: 1.92–3.63 for sweat-inducing activity >2 times/week vs. <1 time/week). Patients given chemotherapy were less inclined to exercise (OR: 0.45; 95% CI: 0.23–0.86) than those who did not. LSI was lower if cancer stage was advanced (β:-0.36; 95% CI: −0.75 to −0.02) than if it was in remission. High LSI was also associated with longer education, lower BMI, and longer time after diagnosis. Conclusion: Cancer patients are insufficiently active but are willing to participate in personalized exercise programs. Information from this survey may help in designing personalized interventions so these patients will achieve sufficient exercise

A qualitative study exploring the experiences and perspectives of patients with cancer attending a 12-week exercise program

Purpose: Physical activity is associated with a reduction in mortality and recurrence risks in patients with cancer. Despite the well-recognized benefits of exercise, patients’ adherence to an exercise program remains a challenge. The present study aimed to assess the experiences of patients with cancer participating in a 12-week exercise program. Methods: A total of 21 survivors participated in focus group discussions after the conclusion of the exercise intervention. Semi-structured interview questions were developed according to the theory of the Health Belief Model. Data were analyzed using thematic analysis and categorized into perceived benefits, barriers, and cues to action. Results: Patients described a series of benefits achieved during the exercise program, from physical to psychological domains. Treatment-related side effects and logistic factors, including distance from the gym facility, were the most commonly reported barriers to adherence. Concerning cues to action, expected benefits from exercise were the most important reason to participate, while a patient-center program, supervised by skilled experts, highly stimulated patients to complete the program. Conclusion: Overall, patients with cancer reported a positive experience participating in a supervised exercise program. A variety of factors influencing participation and adherence were individuated. This study may help design and develop effective and sustainable programs addressing individuals’ needs