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

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

Increased age and male sex are independently associated with higher frequency of blood–cerebrospinal fluid barrier dysfunction using the albumin quotient

Background: The cerebrospinal fluid (CSF)/serum quotient of albumin (QAlb) is the most used biomarker for the evaluation of blood–cerebrospinal fluid barrier (B-CSF-B) permeability. For years QAlb was considered only as an age-related parameter but recently it has also been associated to sex. The aim of the present study was to explore the impact of sex in the determination of B-CSF-B dysfunction. Methods: The analysis was retrospectively conducted on subjects consecutively admitted to the neurological ward. CSF and serum albumin levels were measured by immunonephelometry and pathological QAlb thresholds were considered: 6.5 under 40 years, 8.0 in the age 40–60 and 9.0 over 60 years. Results: 1209 subjects were included in the study. 718 females and 491 males (age: 15–88 years): 24.6% of patients had a diagnosis of multiple sclerosis, 23.2% suffered from other inflammatory neurological diseases, 24.6% were affected by non-inflammatory neurological diseases, and for 27.6% of patients the final neurological diagnosis could not be traced. Dysfunctional B-CSF-B was detected more frequently (44 vs. 20.1%, p < 0.0001) and median QAlb value were higher (7.18 vs. 4.87, p < 0.0001) in males than in females in the overall study population and in all disease sub- groups. QAlb and age were positively correlated both in female (p < 0.0001) and male (p < 0.0001) patients, however the slopes of the two regression lines were not significantly different (p = 0.7149), while the difference between the elevations was extremely significant (p < 0.0001) with a gap of 2.2 units between the two sexes. Finally, in a multivari- able linear regression analysis increased age and male sex were independently associated with higher QAlb in the overall study population (both p < 0.001) and after stratification by age and disease group. Conclusions: Accordingly, identification and validation of sex-targeted QAlb thresholds should be considered as a novel tool in an effort to achieve more precision in the medical approach

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

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

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)

The Severe Heart Failure Questionnaire: Italian translation and linguistic validation

Introduction. The quality of life (QoL) is an important outcome indicator for heart failure management. As the use of a validate questionnaire in a different cultural context can affect data interpretation our main objective is the Italian translation and linguistic validation of the Severe Heart Failure Questionnaire (SHF) and its comparison with the MLHF (Minnesota Living with Heart Failure) Questionnaire. Methods. The SHF and ?The Minnesota Living with Heart Failure Questionnaire? were translated. A consensus involving parallel back-translations was established among a group of cardiologists, psychologists and biostatisticians. SHF and MLHF were both administrated to a sample of 50 patients Results. The patients? median age was 63 years. Ace inhibitors therapy was administered in 88% of cases and betablockers in 56% of cases. Finally the Italian version of SHF correlates well with MLHF for all domains, except life satisfaction SHF domain. Discussion: The Italian version of the SHF correlates well with MLHF for almost all domains and it represents a valid alterna- tive for quality of life assessment in heart failure patients

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

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