Fasting-mimicking diet and hormone therapy induce breast cancer regression.

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.

Comprehensive geriatric assessment in older adults with cancer: Recommendations by the Italian Society of Geriatrics and Gerontology (SIGG).

INTRODUCTION: Optimizing the approach to older adults with cancer is now a priority given the increasing frequency of new cancer diagnoses that are made in the older population. The comprehensive geriatric assessment (CGA) represents the gold-standard for (1) defining prognosis and ability to withstand cancer treatments, (2) exploring the multiple aspects that define the complexity of frail older persons, and (3) designing person-tailored interventions. MATERIALS AND METHODS: In this document, based on a comprehensive revision of the literature, the Italian Society for Geriatrics and Gerontology proposes a CGA model (ONCOGER CGA) to be adopted by oncology centers for their routine approach to older patients with cancer. RESULTS AND DISCUSSION: A widespread use of this standardized CGA format will facilitate comparisons across institutions, promote studies based on a multidimensional patient assessment, and foster the inclusion of geriatric endpoints in oncological clinical trials. Furthermore, we predict that the use of a standardized CGA approach will increase the integration of geriatricians into oncology care teams with the final result of improving therapeutic choices and clinical outcomes.

Social vulnerability underlying disability amongst older adults: A systematic review.

BACKGROUND: Older adults face radical changes in their social life during ageing, dealing with several age-related social adaptations. The aim of this review is to systematically explore the literature on social vulnerability (SV) and its association with functional decline activity of daily living (ADL)/instrumental activities of daily living (IADL) as an endpoint in older adults. METHODS: We searched for relevant studies in three different databases: PubMed, Ovid Medline and PsychInfo. Inclusion criteria included: prospective cohort studies assessing SV correlation; studies in English, Italian, French and Spanish to the end of March 2018; a general population aged >65 years living in a community setting and/or studies including younger participants if the mean age was >65 years; and basic ADL and/or IADL by Katz and Lawton, respectively, as functional decline and clinical outcomes. RESULTS: We identified 65 manuscripts that assessed the role of SV in functional decline. Our systematic analysis showed that 26, 36 and 19 studies observed a correlation between Basic Social Needs, Social Resources and Social Behaviour and Activity, respectively, and the onset of ADL/IADL functional decline. Twenty-six studies explored the correlation between General Social Resources and the onset of ADL/IADL functional decline. CONCLUSIONS: When examining a wide set of social variables, the "quality," rather than just structure, and "type" of social relationship represents the core feature of SV that predicts functional decline in older adults. By defining individual SV, its measurement and evaluation, we can plan effective social interventions aimed at preventing or delaying functional decline or death.

Behavioral Disturbances in Dementia and Beyond: Time for a New Conceptual Frame?

Alzheimer's disease and vascular dementia are estimated to be the most common causes of dementia, although mixed dementia could represent the most prevalent form of dementia in older adults aged more than 80 years. Behavioral disturbances are common in the natural history of dementia. However, so far, there is a paucity of studies that investigated the causal association between behavioral psychological symptoms of dementia and dementia sub-types, due to the high heterogeneity of methodology, study design and type of clinical assessment. To understand the scant evidence on such a relevant clinical issue, it could be hypothesized that a new shifting paradigm could result in a better identification of the relationship between behavioral disturbances and dementia. This narrative review provides an update of evidence on the behavioral patterns associated with different dementia sub-types and offers a potential future perspective as common ground for the development of new translational studies in the field of behavioral disturbances in dementia and the appropriateness of psychoactive treatments.

Correlation between bone quality and microvascular damage in systemic sclerosis patients.

Objectives: SSc patients are recognized as presenting an increased risk of altered bone mass. The aim of this study was to assess the bone quality, by trabecular bone score (TBS), in SSc patients in correlation with different levels of microvascular damage, as evaluated by nailfold videocapillaroscopy (NVC), and to compare the results regarding bone quality with RA patients and healthy subjects (CNT). Methods: Eighty-four SSc patients, 98 RA patients and 60 CNT, were studied. BMD (g/cm2) of the lumbar spine (L1-L4) was analysed by DXA scan. Lumbar spine bone quality was derived from each spine DXA examination using the TBS analysis. NVC patterns were analysed. Results: A total of 56/84 SSc patients (66%) as well as 78/98 RA patients (80%) showed bone loss at DXA and BMD was found to be significantly lower than in the CNT (P < 0.001). Similarly, lumbar spine TBS was found to be significantly lower in SSc and RA patients than in CNT (P < 0.001). TBS values were found to be lower in SSc with a late NVC pattern, compared with the active or early pattern (late vs active and early pattern, P < 0.001). There was no statistically significant difference in the mean lumbar spine TBS between SSc and RA patients (P = 0.238). Conclusion: The data obtained showed significantly lower bone quality (lower TBS and BMD) in SSc and RA patients compared with CNT. The bone quality seemed lower in SSc patients with more altered microvasculature (late NVC pattern).

Reliability Study in Five Languages of the Translation of the Pain Observational Scale Algoplus.

Objective: Acute pain is frequent and underestimated in older persons, especially when they suffer from cognitive impairment. Algoplus is an observational scale for acute pain evaluation, validated in French in older persons with communication disorders. We present the validation by an international expert team of the Algoplus scale in five languages: English, Spanish, Italian, Portuguese, and Turkish. Methods: A total of 181 older consecutive patients were included in five countries (Spain, Australia, Italy, Portugal, and Turkey). Test-retest and inter-rater reliabilities were determined by weighted kappa coefficient for each item and internal consistency by Kuder-Richardson-20 (KD). Results: Regarding test-retest reliability, the kappa coefficient for the five items ranged from 0.68 to 0.84. Inter-rater reliability kappa values ranged from 0.64 to 0.82. Internal consistency was indicated at a KD greater than 0.6. Satisfaction was good to excellent for all teams. Results show that reliability tests are good to excellent for all items of Algoplus. Conclusions: This study shows evidence that Algoplus is an acceptable, reproducible, reliable, and easy-to-use tool. It provides a unique opportunity to include the translated Algoplus scale in daily assessment of older persons with communication disorders in many countries.

A Dedicated Nutritional Care Program (NUTRICARE) to reduce malnutrition in institutionalised dysphagic older people: A quasi-experimental study.

AIMS AND OBJECTIVES: To assess the effects of a texture-modified food program for dysphagia on the nutritional, biochemical and functional profile in a cohort of institutionalised older people in Italy. BACKGROUND: Dysphagic institutionalised older people, often also affected by dementia, are frequently exposed to malnutrition. Malnutrition in older people has negative effects on mortality, days of hospitalisation, infection, wound healing and risk of pressure injuries. Therefore, it is very important to prevent malnutrition in this frail population. DESIGN: A pre-post study without a control group. METHODS: The study included 479 dysphagic institutionalised older people from 20 nursing homes. Anthropometrical, biochemical, nutritional and functional parameters were collected retrospectively, 6 months before the study intervention, at time zero and, prospectively for 6 months after implementing the NUTRICARE food programme, for a total of nine evaluations. The NUTRICARE programme includes meals without nutritional supplementation, and personalised levels of density, viscosity, texture and particle size. RESULTS: The total mean body mass index of our sample passed from 17.88-19.00; body weight averagely improved by 7.19%, as well as their nutritional and biochemical profiles. There was a progressive improvement of total protein and serum albumin values. Nutritional parameters (serum transferrin and lymphocytes) displayed similar changes. Plasma lymphocytes reached normal levels in 98.23% of the sample. Plasma creatinine levels remained steady throughout the study and within the normal range. No side effects were reported. CONCLUSION: The NUTRICARE food programme with a adequate proteins, calories, balanced nutritional and bromatological properties, and appropriate texture and palatability significantly improved the nutritional, biochemical and functional profile in a cohort of institutionalised dysphagic older people. RELEVANCE TO CLINICAL PRACTICE: The introduction of a balanced nutritional programme, using high-quality natural ingredients, appropriate texture and palatability can significantly improve health and quality of life in dysphagic older people.

Nicotinamide phosphoribosyltransferase promotes epithelial-to-mesenchymal transition as a soluble factor independent of its enzymatic activity.

Boosting NAD(+) biosynthesis with NAD(+) intermediates has been proposed as a strategy for preventing and treating age-associated diseases, including cancer. However, concerns in this area were raised by observations that nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in mammalian NAD(+) biosynthesis, is frequently up-regulated in human malignancies, including breast cancer, suggesting possible protumorigenic effects for this protein. We addressed this issue by studying NAMPT expression and function in human breast cancer in vivo and in vitro. Our data indicate that high NAMPT levels are associated with aggressive pathological and molecular features, such as estrogen receptor negativity as well as HER2-enriched and basal-like PAM50 phenotypes. Consistent with these findings, we found that NAMPT overexpression in mammary epithelial cells induced epithelial-to-mesenchymal transition, a morphological and functional switch that confers cancer cells an increased metastatic potential. However, importantly, NAMPT-induced epithelial-to-mesenchymal transition was found to be independent of NAMPT enzymatic activity and of the NAMPT product nicotinamide mononucleotide. Instead, it was mediated by secreted NAMPT through its ability to activate the TGFß signaling pathway via increased TGFß1 production. These findings have implications for the design of therapeutic strategies exploiting NAD(+) biosynthesis via NAMPT in aging and cancer and also suggest the potential of anticancer agents designed to specifically neutralize extracellular NAMPT. Notably, because high levels of circulating NAMPT are found in obese and diabetic patients, our data could also explain the increased predisposition to cancer of these subjects.

Changes in oxidative stress in response to different levels of energy restriction in obese ponies.

The present study evaluated the effect of different levels of energy restriction on metabolic parameters in obese ponies. Relative weight changes, markers of lipid metabolism and oxidant/antioxidant balance were monitored. A total of eighteen obese (body condition score ≥ 7/9) Shetland ponies were studied over a 23·5-week trial, which was divided into three periods. The first period involved a 4-week adaptation period in which each animal was fed 100% of their maintenance energy requirements needed to maintain a stable obese body weight (MERob). This was followed by a 16·5-week weight-loss period in which ponies were assigned to receive either 100% (control group, CONTROL), 80% (slow weight-loss (SLOW) group) or 60% (rapid weight-loss (RAPID) group) of their MERob. During the 3-week end-phase period, all ponies were again fed 100% of their MERob. Relative weight loss was higher in the RAPID group (P< 0·001) compared with the SLOW group. No linear relationship was found as a doubling of the percentage of energy restriction was accompanied by a tripling of the percentage of weight loss. Relative weight gain afterwards in the end-phase period was higher in the RAPID group (P< 0·001) compared with the SLOW and CONTROL groups. During the weight-loss period, TAG and NEFA concentrations were highest in the RAPID group, as were α-tocopherol and ferric-reducing ability of plasma concentrations. After 8 weeks of weight loss, the concentrations of advanced oxidation protein products were higher in the RAPID group compared with the SLOW and CONTROL groups (P< 0·001). In conclusion, the level of energy restriction influences the extent of changes in oxidant/antioxidant balance. Practically, more severe energy restriction regimens may be associated with a greater regain of weight after the restriction period.

Pentosidine determination in CSF: a potential biomarker of Alzheimer's disease?

BACKGROUND: The histopathological hallmarks in Alzheimer's disease (AD) include neuronal cell death, formation of amyloid plaques and neurofibrillary tangles. Glycoxidation plays a crucial role in AD pathogenesis, as pentosidine and Nε- carboxymethyl-lysine (CML), were detected in AD hallmarks, and in vivo cerebrospinal fluid (CSF). However, the definitive role of AGEs in the neuropathology of AD is inconclusive. The aim of this preliminary study was to assess the level of pentosidine in CSF of patients affected by neurological disorders, including probable AD, in order to assess the feasibility of AGEs detection in CSF and to explore pentosidine as a potential biomarker in AD. METHODS: Twenty-five patients diagnosed with AD (NINCDS ADRDA criteria) and different neurological disorders were enrolled. Diabetic patients were excluded. Pentosidine, CML, amyloid ß1-42 were assessed by high performance liquid chromatography (HPLC) by Odetti modified method,and by sandwich ELISA respectively. RESULTS: Our data showed the presence of pentosidine in all CSF samples, a significant increase in CSF pentosidine levels with age (p<0.05) and a significant decreased concentration of pentosidine in four AD subjects (p<0.01), after normalization to CSF protein concentration. CONCLUSIONS: The study showed that AGEs concentration in CSF might benefit from age correction, at least for pentosidine, originally addressing a potential systemic age-dependent AGEs accumulation. The significant decrease of CSF pentosidine in AD, even in 4 patients, might conceive that different AGEs inform specific types of neurodegeneration, depending on oxidative stress levels, blood - brain barrier permeability, brain localization and systemic risk factors.

Short exposure of albumin to high concentrations of malondialdehyde does not mimic physiological conditions.

Malondialdehyde (MDA), a major lipid peroxidation product, spontaneously binds to, and modifies proteins. In vivo, proteins are physiologically exposed to micromolar MDA concentrations for long periods. In order to mimic this process in vitro, protein modification is often performed by short exposure to millimolar MDA concentrations, also in order to generate antigenic structures for antibody production. However, in our study, spectrophotometric and fluorimetric characteristics, electrophoretic migration, susceptibility to trypsin digestion and reactivity to antibodies indicated substantial differences between albumin incubated with millimolar MDA concentrations for a short period of time and albumin incubated with micromolar MDA concentrations for a long period of time. Therefore, our study showed that short incubation of albumin with millimolar MDA concentrations does not mimic the consequences of albumin exposure to long incubation with micromolar MDA concentrations. This casts doubts on the real possibility that antibodies, elicited with proteins modified with millimolar MDA concentrations for a short period, could detect all MDA-modified proteins in vivo. Moreover, natural antibodies against albumin, modified with micromolar MDA concentrations, have been detected in the serum of healthy blood donors, which appears to justify the existence of these kinds of modified proteins in vivo.

Structural alterations of human serum albumin caused by glycative and oxidative stressors revealed by circular dichroism analysis.

The aim of this work was to evaluate the ability of oxidative and glycative stressors to modify properties of human serum albumin (HSA) by analyzing markers of glycation (pentosidine) and oxidation (advanced oxidative protein products (AOPPs)) and assessing fluorescence and circular dichroism. HSA was incubated for up to 21 days with ribose, ascorbic acid (AA) and diethylenetriamine pentacetate (DTPA) in various combinations in order to evaluate influences of these substances on the structure of HSA. Ribose was included as a strong glycative molecule, AA as a modulator of oxidative stress, and DTPA as an inhibitor of metal-catalyzed oxidation. Ribose induced a significant increase in pentosidine levels. AA and DTPA prevented the accumulation of pentosidine, especially at later time points. Ribose induced a mild increase in AOPP formation, while AA was a strong inducer of AOPP formation. Ribose, in combination with AA, further increased the formation of AOPP. DTPA prevented the AA-induced generation of AOPP. Ribose was also a potent inducer of fluorescence at 335nm ex/385nm em, which is typical of pentosidine. AA and DTPA prevented this fluorescence. Circular dichroism showed complex results, in which AA and DTPA were strong modifiers of the percentages of the alpha-helical structure of HSA, while ribose affected the structure of HSA only at later time points.

Fasting-mimicking diet cycles reduce neuroinflammation to attenuate cognitive decline in Alzheimer's models.

The effects of fasting-mimicking diet (FMD) cycles in reducing many aging and disease risk factors indicate it could affect Alzheimer's disease (AD). Here, we show that FMD cycles reduce cognitive decline and AD pathology in E4FAD and 3xTg AD mouse models, with effects superior to those caused by protein restriction cycles. In 3xTg mice, long-term FMD cycles reduce hippocampal Aß load and hyperphosphorylated tau, enhance genesis of neural stem cells, decrease microglia number, and reduce expression of neuroinflammatory genes, including superoxide-generating NADPH oxidase (Nox2). 3xTg mice lacking Nox2 or mice treated with the NADPH oxidase inhibitor apocynin also display improved cognition and reduced microglia activation compared with controls. Clinical data indicate that FMD cycles are feasible and generally safe in a small group of AD patients. These results indicate that FMD cycles delay cognitive decline in AD models in part by reducing neuroinflammation and/or superoxide production in the brain.

Biogerontology in Italy.

In this paper experimental gerontology in Italy is reviewed on the basis of research developed in Academic and non Academic Centres. There are several groups across Italy working actively on basic science of aging producing high impact papers with a significant contribution to biogerontology. Some distinguished Italian scientist working abroad is also mentioned. Interesting issues on longevity and interventions on aging (including caloric restriction) and on aging brain are quoted. Relevant studies encompass the (glyco-)oxidative stress as direct damage mechanism and main process of theory of aging, other research lines include IGF-1, mitochondria DNA, obesity/sarcopenia and exercise and also an animal model for aging studies is reported. Notwithstanding financial restrictions and structure deficit the biogerontology research in Italy could be judged as good, but additional resources are necessary to keep this good rank.

Management of Opioid-Induced Constipation and Bowel Dysfunction: Expert Opinion of an Italian Multidisciplinary Panel.

The prescribing and use of opioid analgesics is increasing in Italy owing to a profusion in the number and types of opioid analgesic products available, and the increasing prevalence of conditions associated with severe pain, the latter being related to population aging. Herein we provide the expert opinion of an Italian multidisciplinary panel on the management of opioid-induced constipation (OIC) and bowel dysfunction. OIC and opioid-induced bowel dysfunction are well-recognised unwanted effects of treatment with opioid analgesics that can profoundly affect quality of life. OIC can be due to additional factors such as reduced mobility, a low-fibre diet, comorbidities, and concomitant medications. Fixed-dose combinations of opioids with mu (µ) opioid receptor antagonists, such as oxycodone/naloxone, have become available, but have limited utility in clinical practice because the individual components cannot be independently titrated, creating a risk of breakthrough pain as the dose is increased. A comprehensive prevention and management strategy for OIC should include interventions that aim to improve fibre and fluid intake, increase mobility or exercise, and restore bowel function without compromising pain control. Recommended first-line pharmacological treatment of OIC is with an osmotic laxative (preferably polyethylene glycol [macrogol]), or a stimulant laxative such as an anthraquinone. A second laxative with a complementary mechanism of action should be added in the event of an inadequate response. Second-line treatment with a peripherally acting µ opioid receptor antagonist (PAMORA), such as methylnaltrexone, naloxegol or naldemedine, should be considered in patients with OIC that has not responded to combination laxative treatment. Prokinetics or intestinal secretagogues, such as lubiprostone, may be appropriate in the third-line setting, but their use in OIC is off-label in Italy, and should therefore be restricted to settings such as specialist centres and clinical trials.

The tower of London test: a test for dementia.

OBJECTIVES: The Tower of London (ToL) is a problem-solving task, which is a valuable tool for the neuropsychological examination of a patient with a possible cognitive decline. The aim of the present study was to evaluate the ToL in comparison to the Mini Mental State Examination (MMSE) in a group of older people with or without dementia. METHOD: Seventy outpatients of both sexes, 30 with low-moderate dementia and 40 with apparently normal cognition were evaluated with the MMSE and the ToL task in the same day. The ToL score was calculated according to the Krikorian method and also the execution time was measured. The differences between groups were assessed with the unpaired t-test, and the relationship between two parameters was assessed with the analysis of the coefficient of linear regression. The results were adjusted for age and education. RESULTS: The evaluation of cognitive impairment by MMSE showed a significant difference in the two groups (p < 0.001). The mean scores (p < 0.001) and execution times (p < 0.05) of the ToL, resulted significantly lower in the patients affected by dementia. However, seven participants with dementia had a normal score in the ToL test, indicating that the executive neuropsychological tasks could be preserved notwithstanding the cognitive decline and nine participants with normal MMSE obtained a low ToL score, suggestive of the higher sensibility of the ToL for the executive task that reveals an unknown cognitive deficit. CONCLUSION: The correlation between MMSE and ToL is good, but ToL test provides complementary information to the MMSE and vice versa.

Development of a predictor of one-year mortality in older patients with cancer by geriatric and oncologic parameters.

OBJECTIVES: More than 60% of the new cancer diagnoses are currently made in older adults, a highly heterogeneous population. Reliable and time-saving tools to define older adults' prognosis are needed to inform the oncologist's decisions in routine clinical practice. We sought to define a multi-domain classification tool for the prediction of all-cause one-year mortality in a cohort of older adults with solid tumors. MATERIALS AND METHODS: We conducted a single-centre, prospective study of patients with solid cancer aged 65 or older and with G8 score ≤ 14. All patients underwent a comprehensive geriatric assessment (CGA) before starting their surgical or medical treatment. One-year mortality was recorded. A CGA-based prediction tool of one-year mortality was developed and subsequently validated in two independent training and testing cohorts with a 70/30 split, respectively. RESULTS: 162 patients were enrolled. Mean patient age was 78 ±â€¯5.5 years. Forty-three percent of the patients were men. Colorectal and breast cancer were the most common diagnoses. The clinical variables selected for the development of the new classifier (MetaGENUA®) were: mini-nutritional assessment (MNA), instrumental day life activities (IADL), Cumulative Illness Rating Scale (CIRS), geriatric depression scale (GDS), age, and cancer stage. In our independent validation cohort, MetaGENUA® showed high specificity (0.86) and AUC = 0.71 (95% CI = 0.55-0.87). CONCLUSIONS: MetaGENUA® predicts one-year mortality in older patients with cancer with high specificity. As such, MetaGENUA® is predicted to reveal as a useful tool to guide the oncologist's decisions in clinical practice.

Nutrients in the Prevention of Alzheimer's Disease.

Alzheimer's disease (AD) is a disease caused by the complex interaction of multiple mechanisms, some of which are still not fully understood. To date, pharmacological treatments and supplementation of individual nutrients have been poorly effective in terms of the prevention and treatment of AD, while alternative strategies based on multimodal approaches (diet, exercise, and cognitive training) seem to be more promising. In this context, the focus on dietary patterns rather than on single food components could be more useful in preventing or counteracting the pathological processes typical of AD, thanks to the potential synergistic effects of various nutrients (neuronutrients). The aim of this narrative review is to summarize the currently existing preclinical and clinical evidence regarding the Mediterranean diet (MeDi), the Dietary Approaches to Stop Hypertension (DASH) diet, and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, which are three dietary patterns with well-known anti-inflammatory and antioxidant properties. Recently, they have been related to brain protection and AD prevention, perhaps thanks to their high content of neuroprotective bioactive compounds. Similarly, intermittent fasting (IF) or calorie restriction (CR) is emerging as interesting approaches that seem to promote hippocampal neurogenesis, activate adaptive stress response systems, and enhance neuronal plasticity, thus leading to motor and cognitive improvements in animal models of AD and hopefully also in human beings.