Influenza del microbiota intestinale su biomarcatori di efficacia clinica in pazienti in trattamento con farmaci anticoagulanti

La fibrillazione atriale è una patologia frequente e associata ad elevata morbidità se non trattata efficacemente. La principale complicanza della fibrillazione atriale è lo sviluppo di eventi tromboembolici. La terapia preventiva delle complicanze tromboemboliche della fibrillazione atriale è la terapia anticoagulante orale, con farmaci antagonisti della vitamina K (TAO) e farmaci antagonisti diretti (NAO). Ampi studi osservazionali hanno dimostrato un’ampia variabilità dell’efficacia clinica di TAO e NAO. Tra i possibili fattori determinanti la variabilità inter-individuale della terapia anticoagulante orale con TAO e NAO, vanno annoverati il microbiota intestinale e le isoforme dei principali sistemi enzimatici coinvolti nel metabolismo dei farmaci (i.e., CYP450, ABCB1 e di VKORC1). Obbiettivo del presente studio osservazionale, monocentrico e prospettico con follow-up di 12 mesi è stato la ricerca di possibili associazioni tra microbiota intestinale, isoforme enzimatiche, e marcatori surrogati di efficacia/sicurezza clinica della terapia anticoagulante. Pazienti con indicazione alla terapia anticoagulante sono stati arruolati nello studio, e dopo tre mesi di terapia hanno fornito un campione di feci e di sangue. L’analisi del microbiota è stata condotta con metodica 16S rRNA e sono stati misurati i livelli circolanti di metaboliti dello stesso microbiota (LPS e TMAO). Le isoforme enzimatiche sono state misurate con metodica NGS Illumina. L’efficacia clinica è stata misurata calcolando il time in therapeutic range (TTR) nei pazienti TAO, e dosando le concentrazioni del farmaco a picco e a valle nei pazienti NAO. Nel periodo di osservazione, sono stati studiati 103 pazienti, 51 trattati con TAO e 52 con NAO. Nei pazienti TAO, abbiamo osservato un significativo aumento di LPS nei pazienti con peggiore TTR, mentre nei pazienti NAO abbiamo osservato un aumento di TMAO al non raggiungimento delle concentrazioni di farmaco attese. Inoltre, abbiamo osservato uno specifico profilo del microbiota nei pazienti TAO e nei pazienti NAO. Infine, non sono state osservate influenze delle isoforme enzimatiche sui parametri surrogati di efficacia clinica. Il nostro studio suggerisce che il microbiota intestinale può interferire in maniera specifica e distinta sulla efficacia clinica della terapia TAO e NAO, mentre il profilo genetico degli enzimi che metabolizzano i farmaci sembra avere un ruolo minore. Ulteriori studi con più ampia casistica e prolungato periodo di osservazione potranno definire meglio le caratteristiche di queste influenze

Practical Management of Cancer Cachexia

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Osteoporosis and alzheimer pathology: Role of cellular stress response and hormetic redox signaling in aging and bone remodeling

Alzheimer’s disease (AD) and osteoporosis are multifactorial progressive degenerative disorders. Increasing evidence shows that osteoporosis and hip fracture are common complication observed in AD patients, although the mechanisms underlying this association remain poorly understood. Reactive oxygen species (ROS) are emerging as intracellular redox signaling molecules involved in the regulation of bone metabolism, including receptor activator of nuclear factor-κB ligand-dependent osteoclast differentiation, but they also have cytotoxic effects that include lipoperoxidation and oxidative damage to proteins and DNA. ROS generation, which is implicated in the regulation of cellular stress response mechanisms, is an integrated, highly regulated, process under control of redox sensitive genes coding for redox proteins called vitagenes. Vitagenes, encoding for proteins such as heat shock proteins (Hsps) Hsp32, Hsp70, the thioredoxin, and the sirtuin protein, represent a systems controlling a complex network of intracellular signaling pathways relevant to life span and involved in the preservation of cellular homeostasis under stress conditions. Consistently, nutritional anti-oxidants have demonstrated their neuroprotective potential through a hormetic-dependent activation of vitagenes. The biological relevance of dose–response affects those strategies pointing to the optimal dosing to patients in the treatment of numerous diseases. Thus, the heat shock response has become an important hormetic target for novel cytoprotective strategies focusing on the pharmacological development of compounds capable of modulating stress response mechanisms. Here we discuss possible signaling mechanisms involved in the activation of vitagenes which, relevant to bone remodeling and through enhancement of cellular stress resistance provide a rationale to limit the deleterious consequences associated to homeostasis disruption with consequent impact on the aging process

Changing the approach to anticoagulant therapy in older patients with multimorbidity using a precision medicine approach

The ageing of the world population has resulted in an increase in the number of older patients with multimorbid conditions receiving multiple therapies. This emerging clinical scenario poses new challenges, which are mostly related to the increased incidence of adverse effects. This translates into poor clinical care, reduced cost-effectiveness of drug therapies, and social isolation of multimorbid patients due to reduced autonomy. A strategy to address these emerging challenges could involve the personalization of therapies based on the clinical, molecular, and genetic characterization of multimorbid patients. Anticoagulation therapy is a feasible model to implement personalized medicine since it generally involves older multimorbid patients receiving multiple drugs. In this study, in patients with atrial fibrillation, the use of the new generation of anticoagulation therapy, i.e., direct oral anti-coagulants (DOACs), is based on a preliminary assessment of the molecular targets of DOACS and any possible drug–drug interactions. Then, the genetic polymorphism of enzymes metabolizing DOACs is studied. After DOAC prescription, its circulating levels are measured. Clinical data are being collected to assess whether this personalized approach improves the safety and efficacy profiles of anticoagulation therapy using DOACs, thereby reducing the costs of healthcare for ageing multimorbid patients

Nutrition support in the time of SARS-CoV-2 (COVID-19)

No abstract availabl

Nutrition support and clinical outcome in advanced cancer patients

Newly diagnosed cancer patients are frequently found suffering from a metastatic disease, which poses additional challenges to the delivery of effective therapies. Chemotherapy and radiotherapy are associated with side effects which reduce tolerance to treatment and likelihood of tumour response. Identifying preventable factors of reduced response to therapy would translate into better care of cancer patients. Among other factors, malnutrition, as diagnosed by non-volitional weight loss, and cachexia, as revealed by sarcopenia, are universally recognised negative prognostic factors. Less certainty exists on the role of nutrition therapy in improving cancer patients' body composition and clinical outcome. The reasons for the lack of convincing evidence are manifold, mostly related to the poor design of nutritional trials. Metastatic cancer patients should receive a quantitatively and qualitatively adequate diet, and in case of reduced tolerance of food, artificial nutrition is indicated. Most importantly, nutritional care should target the underlying mechanisms of reduced food intake/impaired anabolic response, and aim at minimising the impact of catabolic crisis, to maximise the recovery phase. The combined and early use of supplemental energies and proteins, as well as modulators of inflammatory response has been shown to improve nutritional status and may also benefit clinical outcome. When part of early palliative care, nutrition therapy improves cancer patients' quality of life and may prolong survival at a fraction of the costs of developing new drugs

Does nutrition support have a role in managing cancer cachexia?

Purpose of review: Cachexia is a negative prognostic factor in cancer patients. The pathogenesis is related to a variable combination of reduced food intake and metabolic changes. However, whether nutritional support may contribute to effectively prevent and treat cachexia remains a debated issue. Recent findings: Consistent evidence demonstrates that anabolic windows of opportunity occur during the clinical trajectory of cancer patients. Also, the use of specific nutrients, namely omega-3 fatty acids, may enhance the efficacy of nutritional support when tumor-driven inflammatory response is high. Of greater interest, it is now becoming clearer that the use of nutritional support at key time points in the clinical journey of cancer patients (i.e., perioperative period) may extend its clinical benefits beyond those on nutritional status. Summary: Nutritional support plays a role in managing cancer cachexia, when it is timely delivered, when it provides adequate amounts of calories and proteins, and when it is part of a concurrent palliative care approach. Specific nutrients, that is, omega-3 fatty acids, may help in those cancer patients with high-inflammatory response, and may also contribute to positively influence long-term clinical outcomes