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.

Inhibitors of NAD+ Production in Cancer Treatment: State of the Art and Perspectives.

The addiction of tumors to elevated nicotinamide adenine dinucleotide (NAD+) levels is a hallmark of cancer metabolism. Obstructing NAD+ biosynthesis in tumors is a new and promising antineoplastic strategy. Inhibitors developed against nicotinamide phosphoribosyltransferase (NAMPT), the main enzyme in NAD+ production from nicotinamide, elicited robust anticancer activity in preclinical models but not in patients, implying that other NAD+-biosynthetic pathways are also active in tumors and provide sufficient NAD+ amounts despite NAMPT obstruction. Recent studies show that NAD+ biosynthesis through the so-called "Preiss-Handler (PH) pathway", which utilizes nicotinate as a precursor, actively operates in many tumors and accounts for tumor resistance to NAMPT inhibitors. The PH pathway consists of three sequential enzymatic steps that are catalyzed by nicotinate phosphoribosyltransferase (NAPRT), nicotinamide mononucleotide adenylyltransferases (NMNATs), and NAD+ synthetase (NADSYN1). Here, we focus on these enzymes as emerging targets in cancer drug discovery, summarizing their reported inhibitors and describing their current or potential exploitation as anticancer agents. Finally, we also focus on additional NAD+-producing enzymes acting in alternative NAD+-producing routes that could also be relevant in tumors and thus become viable targets for drug discovery.

Frailty, psychological well-being, and social isolation in older adults with cognitive impairment during the SARS-CoV-2 pandemic: data from the GeroCovid initiative.

BACKGROUND: The containment measures linked to the COVID-19 pandemic negatively affected the phyco-physical well-being of the population, especially older adults with neurocognitive disorders (NCDs). This study aims to evaluate whether the frailty of NCD patients was associated with different changes in multiple health domains, in particular in relation to loneliness and social isolation, pre- and post-lockdown. MATERIALS AND METHODS: Patients were recruited from 10 Italian Centers for Cognitive Disorders and Dementia. Data were collected in the pre-pandemic period (T0), during the pandemic lockdown (T1), and 6-9 months post-lockdown (T2). The UCLA Loneliness Scale-3, Activities of Daily Living (ADL), Instrumental ADL (IADL), Mini-Mental State Examination, and Neuropsychiatric Inventory (NPI) were administered. Caregivers' burden was also tested. Patients were categorized as non-frail, pre-frail, and frail according to the Fatigue, Resistance, Ambulation, Illness, and Loss of Weight scale. RESULTS: The sample included 165 subjects (61.9% women, mean age 79.5 ± 4.9 years). In the whole sample, the ADL, IADL, and NPI scores significantly declined between T0 and T2. There were no significative variations in functional and cognitive domains between the frail groups. During lockdown we recorded higher Depression Anxiety Stress Scales and Perceived Stress Scale scores in frail people. In multivariable logistic regression, frailty was associated with an increase in social isolation, and a loss of IADL. CONCLUSIONS: We observed a global deterioration in functional and neuro-psychiatric domains irrespective of the degree of frailty. Frailty was associated with the worsening of social isolation during lockdown. Frail patients and their caregivers seemed to experience more anxiety and stress disorders during SARS-CoV-2 pandemic.

Frailty assessment, hip fracture and long-term clinical outcomes in older adults.

BACKGROUND: The primary aim of the study was determining the validation of the modified 19-item Frailty Index (mFI-19), based on the standard procedure for creating a frailty index scoring in the accumulation deficit theory of Rockwood and comparing it with the gold standard comprehensive geriatric assessment (CGA) in old age patients with hip fracture. As a secondary aim, we compared prognostic accuracies of mFI-19 and CGA in predicting long-term mortality after surgery. MATERIALS AND METHODS: A total of 364 older patients with hip fractures, each a candidate for surgery, were consecutively enrolled. All were subjected to CGA and mFI-19 at baseline and time to death (years from hip surgery) were collected prospectively. RESULTS: Mean patient age was 86.5 (SD: 5.65) years. The most common clinical phenotype (77%) was frail. Both CGA and mFI-19 performed similarly in predicting long-term mortality (Harrell's C-index: 0.66 and 0.68, respectively). CONCLUSIONS: The mFI-19 was validated, compared to the gold standard CGA, based on a systematic process for creating a frailty index in relation to the accumulation deficit. This is one of few prospective studies addressing long-term mortality in older adults with hip fractures, invoking a methodologically robust frailty screening assessment.

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.

The new small tyrosine kinase inhibitor ARQ531 targets acute myeloid leukemia cells by disrupting multiple tumor-addicted programs.

Tyrosine kinases have been implicated in promoting tumorigenesis of several human cancers. Exploiting these vulnerabilities has been shown to be an effective anti-tumor strategy as demonstrated for example by the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, for treatment of various blood cancers. Here, we characterize a new multiple kinase inhibitor, ARQ531, and evaluate its mechanism of action in preclinical models of acute myeloid leukemia. Treatment with ARQ531, by producing global signaling pathway deregulation, resulted in impaired cell cycle progression and survival in a large panel of leukemia cell lines and patient-derived tumor cells, regardless of the specific genetic background and/or the presence of bone marrow stromal cells. RNA-seq analysis revealed that ARQ531 constrained tumor cell proliferation and survival through Bruton's tyrosine kinase and transcriptional program dysregulation, with proteasome-mediated MYB degradation and depletion of short-lived proteins that are crucial for tumor growth and survival, including ERK, MYC and MCL1. Finally, ARQ531 treatment was effective in a patient-derived leukemia mouse model with significant impairment of tumor progression and survival, at tolerated doses. These data justify the clinical development of ARQ531 as a promising targeted agent for the treatment of patients with acute myeloid leukemia.

Three-year National report from the Gruppo Italiano di Ortogeriatria (GIOG) in the management of hip-fractured patients.

BACKGROUND: Hip fractures (HF) are a major issue worldwide. We aimed at evaluating the practices in delivering care to patients with HF among several Italian Orthogeriatric centers. METHODS: The study took place from February 2016 to July 2018. Seven performance indicators (pre-surgical cognitive assessment, surgery performed ≤ 48 h from fracture, removal of urinary catheter/absence of delirium/start of physiotherapy on the first post-operative day, prescription of bone protection at discharge, and discharge toward rehabilitation) were collected. RESULTS: The 14 participating hospitals totally recruited 3.017 patients. Patients were old (median age 86 years; Inter Quartile Range [IQR] 80-90), mostly females (77%). Nearly 55% of them were already impaired in mobility and about 10% were nursing home residents. Median time-to-surgery was 41 h (IQR 23-62). Models of care greatly varied among centers, only 49.3% of patients being co-managed by geriatricians and orthopedics. There was high variability across centers in four indicators ("pre-surgical cognitive assessment", "bone protection prescription", "use of urinary catheter" and "start of physiotherapy"), moderate in two indicators ("surgery performed ≤ 48 h from fracture" and "discharge toward rehabilitation" and low in one ("absence of delirium on day following surgery"). Comparison with international studies suggests very different ways of providing care to HF Italian patients. CONCLUSIONS: The study results suggest high inter-center variability in the key-performance indicators, and different approaches in providing care to our HF patients in comparison to other countries. A National debate on the topic is required in Italy to harmonize practices of orthogeriatric care.

A two-step surgery and a multidisciplinary approach in a centenarian patient with an acute presentation of right colon cancer.

BACKGROUND: As surgery remains the cornerstone of colorectal cancer (CRC) treatment, the number of older patients presented for colorectal resection is rapidly increasing. Nevertheless, the choice to operate an oldest-old patient still remain challenging and requires a careful assessment of risk to benefit ratio in order to guarantee appropriate surgical strategies and perioperative management. CASE PRESENTATION: A centenarian patient, acutely admitted to the emergency department, was diagnosed with an ileus caused by stenosing ascending colon cancer with abnormal distension of the right colon at high risk of perforation. Facing with this complex clinical scenario, a lateral decompressive cecostomy as alternative surgical procedure, was performed in local anesthesia in order to avoid the stressful event of an emergency surgery. Thereafter, the patient was admitted to the surgical ward and followed by a geriatrician who performed a comprehensive geriatric assessment (CGA) and daily clinical evaluations. This integrated plan of care was mainly focused on rehabilitation, nutritional interventions and therapeutic reconciliation, maximizing patient's clinical conditions and performance status. Then, the second surgical step, the radical colon surgery with curative intent and bowel continuity reestablishment was performed, demonstrating to be feasible and safety also in a very advanced age patient in term of prolonged survival and preservation of an adequate quality of life. CONCLUSIONS: This is the first case-report that illustrates a successful two step surgery for CRC in a centenarian patient thanks to a multidisciplinary based approach, overwhelming the mere concept of chronological age.

Predictors of cardiovascular outcome and rehospitalization in elderly patients with heart failure.

BACKGROUND: Heart failure (HF) is a major public health problem and represents the only cardiac disease continuing to increase in prevalence, in particular among elderly patients. The frequent rehospitalizations have a negative impact on quality of life of patients with HF, constituting a substantial cost for patients and the health system. The aim of this review was to look into biochemical, echocardiographic and socioeconomical parameters as predictors of clinical outcomes and rehospitalizations. METHODS: This narrative review is based on the material searched for and obtained via PubMed from January 2000 up to March 2018. The search terms we used were as follows: "elderly, heart failure, cardiovascular" in combination with "biomarker, echocardiography and hospitalization." RESULTS: This review analyses the potential predictive role of biochemical and echocardiographic and socioeconomical parameters on clinical outcomes (particularly cardiovascular) and hospital readmissions in patients with chronic HF. We focused on risk stratification of elderly patients with HF, who constitute a category of frail subjects at higher risk for readmission to hospital. CONCLUSIONS: In elderly subjects with chronic HF, the risk stratification could benefit of a multiparametric approach combining biochemical, echocardiographic, demographic and socioeconomical parameters, thus ensuring a better quality of life and at the same time a better allocation of financial resources.

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.

Aripiprazole-induced persistent hiccup: a case report and review of the literature.

Aripiprazole is an interesting psychoactive compound acting as a dopamine D2 partial agonist, serotonin 5-HT(1A) partial agonist and serotonin 5-HT(2A) antagonist. Aripiprazole possesses a well-documented efficacy in the treatment of both positive and negative psychotic symptoms. However, this medication may be rarely associated with the onset of hiccup. Here, we present the case of aripiprazole-induced hiccup in a young inpatient at his first psychiatric admission together with a review of the current literature about this topic. The possible etiology underlying the emergence of hiccups together with the clinical implications of this adverse event are discussed.

Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells.

Multiple myeloma (MM) is characterized by a highly unstable genome, with aneuploidy observed in nearly all patients. The mechanism causing this karyotypic instability is largely unknown, but recent observations have correlated these abnormalities with dysfunctional DNA damage response. Here, we show that the NAD(+)-dependent deacetylase SIRT6 is highly expressed in MM cells, as an adaptive response to genomic stability, and that high SIRT6 levels are associated with adverse prognosis. Mechanistically, SIRT6 interacts with the transcription factor ELK1 and with the ERK signaling-related gene. By binding to their promoters and deacetylating H3K9 at these sites, SIRT6 downregulates the expression of mitogen-activated protein kinase (MAPK) pathway genes, MAPK signaling, and proliferation. In addition, inactivation of ERK2/p90RSK signaling triggered by high SIRT6 levels increases DNA repair via Chk1 and confers resistance to DNA damage. Using genetic and biochemical studies in vitro and in human MM xenograft models, we show that SIRT6 depletion both enhances proliferation and confers sensitization to DNA-damaging agents. Our findings therefore provide insights into the functional interplay between SIRT6 and DNA repair mechanisms, with implications for both tumorigenesis and the treatment of MM.

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.

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.

Rethinking Dementia Risk Prediction: A Critical Evaluation of a Multimodal Machine Learning Predictive Model.

A recent study by Ding et al. explores the integration of artificial intelligence (AI) in predicting dementia risk over a 10-year period using a multimodal approach. While revealing the potential of machine learning models in identifying high-risk individuals through neuropsychological testing, MRI imaging, and clinical risk factors, the imperative of dynamic frailty assessment emerges for accurate late-life dementia prediction. The commentary highlights challenges associated with AI models, including dimensionality and data standardization, emphasizing the critical need for a dynamic, comprehensive approach to reflect the evolving nature of dementia and improve predictive accuracy.