Tamoxifen nel trattamento del carcinoma mammario: studio dei fattori predittivi di risposta

Breast cancer is the tumor with highest incidence in women and the first leading cause of mortality in Western countries. The estrogen receptor positive breast cancer subtype is the most frequent (60-80%) and for its treatment the selective estrogen receptor modulator tamoxifen can be used. Tamoxifen efficacy is widely recognized in the adjuvant setting (post-surgical) of early stages tumors, however, in a significant percentage of patients disease recurs. The aim of our study was to investigate possible factors contributing to the therapeutic failure of tamoxifen treatment in invasive non-metastatic estrogen receptor positive breast cancer patients. Tamoxifen is a pro-drug extensively metabolized by the hepatic cytochrome P450 CYP2D6 into more active and powerful metabolites compared to the parental drug. Among these it has been recently taken into special account the active metabolite endoxifen, which is considered the main responsible for the therapeutic response because of its high affinity for the molecular target, the estrogen receptor alpha (Erα) and because it shows higher plasma levels compared to the similarly active metabolite 4-idrossitamoxifen. Several studies have demonstrated that the gene of CYP2D6 enzyme is highly polymorphic in the population, due to variations in the gene sequence which result in functional alterations, with partial reduction or total elimination of the enzymatic activity. However, the inter-individual differences in endoxifen exposure, clinically observed, are not only explained by CYP2D6 gene polymorphisms, as its activity is significantly influenced also by environmental causes (such as drugs that inhibit the enzyme). Hence the need to identify new ways to predict individual ability of patients to activate tamoxifen, keeping endoxifen plasma levels as a reference parameter. The latter cannot be directly used to estimate the metabolic capacity of CYP2D6 when mostly needed, thas is before or in the early phases of drug treatment, because, due to the prolonged half-life of the drug and its derivatives, the achievement of steady state plasma levels (indicative of concentrations to which patients are exposed for five years of therapy) takes an average of four months. Finally, in addition to the exposure to the active metabolite, another predictive factor of response may include the molecular target of the drug, the estrogen receptor. It has been confirmed by numerous studies that in tumor and healthy mammary tissue estrogen receptor splicing isoforms of Erα and Erβ are coexpressed with the full-length proteins. Recently, an in vitro study revealed that the wild-type Erβ enhanced the antiestrogenic action of endoxifen. For the evaluation of the individual capacity in tamoxifen activation, to overcome genotyping limitations, two strategies were used: the phenotyping test of CYP2D6 by the probe drug dextromethorphan and the determination of endoxifen plasma levels at the first month (previous to the steady state). We have shown that the results of phenotyping test and levels of endoxifen at the first month are significantly associated with endoxifen steady state levels and both can be considered as informative tools to know the metabolic status of the individual patient. The influence of polymorphisms on endoxifen plasma levels was confirmed by genetic analysis of the CYP2D6 in our population; the genotyping results were also significantly associated with those of phenotyping test. The possible role of an estrogen receptor isoform, Erβ2, on the activity of endoxifen was evaluated, in vitro, by monitoring the transcription of two estrogens sensitive genes. Through analysis of expression of IL20 and ADORA1 it was found that, in the presence of concentrations of endoxifen of 40nM for prolonged time (24h), the isoform Erβ2, co-expressed with Erα, reduced the inhibitory action of endoxifen compared to the presence of only Erα

plasma matrix metalloprotease 9 correlates with blood lymphocytosis leukemic cell invasiveness and prognosis in b cell chronic lymphocytic leukemia

The complex biology underlying chronic lymphocytic leukemia cell migration and tissue invasiveness is not yet completely understood and might provide novel predictive markers and therapeutic targets. A total of 36 patients out of treatment from at least 3 months were enrolled and followed up for a median period of 44.2 months (range: 4.4-99.2). Matrix metalloprotease 9 and tissue inhibitor of metalloproteases 1 plasma levels and production/release from lymphoid cells were measured by zymography and enzyme-linked immunosorbent assay (ELISA) analysis. Malignant and normal lymphocyte mobility and matrix-degradation capability were studied using a Boyden chamber system, with and without autologous plasma. Free matrix metalloprotease 9 plasma levels were related with blood lymphocytosis, especially in more advanced stages (p = 0.003), and higher concentrations were associated with an increased disease progression risk (hazard ratio = 9.0, 95% confidence interval = 1.5-13.8). Leukemic cells expressed and secreted very little matrix metalloprotease 9. On the contrary, normal lymphocytes derived from the same leukemic patients showed matrix metalloprotease 9 intracellular levels that were lower in subjects with higher blood lymphocytosis (p = 0.024) and more advanced stages (p = 0.03); the released quantities were inversely associated with matrix metalloprotease 9 plasma concentrations (p = 0.035). Leukemic cells had a reduced spontaneous mobility and matrix-degradation capability that were stimulated by autologous plasma (p = 0.001) and normal lymphocytes (p = 0.005), respectively. Matrix metalloprotease 9 affected cell invasiveness depending on concentration and disease stage. In conclusion, chronic lymphocytic leukemia cells have a reduced mobility, matrix-degradation capability, and matrix metalloprotease 9 production compared to their own autologous normal lymphocytes. They are exposed to matrix metalloprotease 9 of prevalently systemic origin whose higher levels are associated with both leukemic and normal lymphocyte accumulation in the peripheral blood and have a negative prognostic value

Tamoxifen nel trattamento del carcinoma mammario: studio dei fattori predittivi di risposta

Breast cancer is the tumor with highest incidence in women and the first leading cause of mortality in Western countries. The estrogen receptor positive breast cancer subtype is the most frequent (60-80%) and for its treatment the selective estrogen receptor modulator tamoxifen can be used. Tamoxifen efficacy is widely recognized in the adjuvant setting (post-surgical) of early stages tumors, however, in a significant percentage of patients disease recurs. The aim of our study was to investigate possible factors contributing to the therapeutic failure of tamoxifen treatment in invasive non-metastatic estrogen receptor positive breast cancer patients. Tamoxifen is a pro-drug extensively metabolized by the hepatic cytochrome P450 CYP2D6 into more active and powerful metabolites compared to the parental drug. Among these it has been recently taken into special account the active metabolite endoxifen, which is considered the main responsible for the therapeutic response because of its high affinity for the molecular target, the estrogen receptor alpha (Erα) and because it shows higher plasma levels compared to the similarly active metabolite 4-idrossitamoxifen. Several studies have demonstrated that the gene of CYP2D6 enzyme is highly polymorphic in the population, due to variations in the gene sequence which result in functional alterations, with partial reduction or total elimination of the enzymatic activity. However, the inter-individual differences in endoxifen exposure, clinically observed, are not only explained by CYP2D6 gene polymorphisms, as its activity is significantly influenced also by environmental causes (such as drugs that inhibit the enzyme). Hence the need to identify new ways to predict individual ability of patients to activate tamoxifen, keeping endoxifen plasma levels as a reference parameter. The latter cannot be directly used to estimate the metabolic capacity of CYP2D6 when mostly needed, thas is before or in the early phases of drug treatment, because, due to the prolonged half-life of the drug and its derivatives, the achievement of steady state plasma levels (indicative of concentrations to which patients are exposed for five years of therapy) takes an average of four months. Finally, in addition to the exposure to the active metabolite, another predictive factor of response may include the molecular target of the drug, the estrogen receptor. It has been confirmed by numerous studies that in tumor and healthy mammary tissue estrogen receptor splicing isoforms of Erα and Erβ are coexpressed with the full-length proteins. Recently, an in vitro study revealed that the wild-type Erβ enhanced the antiestrogenic action of endoxifen. For the evaluation of the individual capacity in tamoxifen activation, to overcome genotyping limitations, two strategies were used: the phenotyping test of CYP2D6 by the probe drug dextromethorphan and the determination of endoxifen plasma levels at the first month (previous to the steady state). We have shown that the results of phenotyping test and levels of endoxifen at the first month are significantly associated with endoxifen steady state levels and both can be considered as informative tools to know the metabolic status of the individual patient. The influence of polymorphisms on endoxifen plasma levels was confirmed by genetic analysis of the CYP2D6 in our population; the genotyping results were also significantly associated with those of phenotyping test. The possible role of an estrogen receptor isoform, Erβ2, on the activity of endoxifen was evaluated, in vitro, by monitoring the transcription of two estrogens sensitive genes. Through analysis of expression of IL20 and ADORA1 it was found that, in the presence of concentrations of endoxifen of 40nM for prolonged time (24h), the isoform Erβ2, co-expressed with Erα, reduced the inhibitory action of endoxifen compared to the presence of only Erα.La malattia tumorale maligna della mammella rappresenta ad oggi la neoplasia a più alta incidenza nel sesso femminile e la principale causa di mortalità nei paesi occidentali. Il tumore mammario positivo per gli estrogeni rappresenta il sottotipo più frequente (60-80%) per il cui trattamento è previsto l’impiego del modulatore estrogenico selettivo tamoxifen. Tamoxifen ha una efficacia largamente riconosciuta nella fase adiuvante (post-chirurgica) dei tumori in stadio iniziale, tuttavia in una percentuale rilevante di pazienti la malattia si ripresenta. Il nostro studio si pone l'obiettivo di indagare i possibili fattori implicati nel fallimento terapeutico del trattamento con tamoxifen nelle pazienti affette da tumore mammario infiltrante, positivo agli estrogeni, non metastatico. Tamoxifen è un pro-farmaco ampiamente metabolizzato dal citocromo epatico P450 CYP2D6 in metaboliti più attivi e potenti rispetto al farmaco parentale. Tra questi ha recentemente assunto particolare rilievo il metabolita attivo endoxifen, ritenuto il principale responsabile della risposta terapeutica poiché, oltre a possedere un'elevata affinità per il suo target molecolare, il recettore per gli estrogeni alpha (Erα), presenta livelli plasmatici più elevati in confronto al metabolita similmente attivo 4-idrossitamoxifen. Numerosi studi hanno dimostrato che il gene dell'enzima CYP2D6 è altamente polimorfico nella popolazione, a causa di variazioni nella sequenza genica che determinano alterazioni funzionali, con riduzione parziale o azzeramento della attività enzimatica. Tuttavia le differenze inter-individuali nella esposizione ad endoxifen, riscontrate clinicamente, non risultano essere spiegate unicamente dai polimorfismi del gene CYP2D6, poichè la sua attività risulta significativamente influenzata anche da cause cosiddette ambientali (ad esempio farmaci inibitori dell’enzima). Ne deriva la necessità di individuare altri strumenti per la determinazione della capacità delle singole pazienti di attivare il tamoxifen, mantenendo come parametro di riferimento i livelli plasmatici del metabolita attivo endoxifen. Quest’ultimo non può essere usato direttamente per predire la capacità metabolica del CYP2D6 quando maggiormente necessario, cioè prima o nelle prime fasi del trattamento farmacologico, perché, a causa dei prolungati tempi di emivita del farmaco e dei suoi derivati, il raggiungimento dei livelli plasmatici di stato stazionario (indicativi delle concentrazioni a cui sono esposte le pazienti per i cinque anni di terapia) richiede mediamente quattro mesi. Infine, oltre alla esposizione al metabolita attivo, un altro fattore predittivo di risposta potrebbe includere il bersaglio molecolare del farmaco, il recettore per gli estrogeni. Numerosi studi hanno confermato la co-espressione nei tessuti tumorali e sani mammari di isoforme di splicing alternativo alle due forme complete dei recettori estrogenici, Erα ed Erβ. Più recententemente, uno studio in vitro ha rivelato come la forma completa Erβ sia in grado di sensibilizzare le cellule all'azione di endoxifen. Per la valutazione della capacità individuale di attivazione del tamoxifen, superando i limiti della genotipizzazione, abbiamo utilizzato due modalità, il test di fenotipizzazone del CYP2D6 mediante il farmaco sonda destrometorfano e la determinazione dei livelli di endoxifen al primo mese, in fase pre-stazionaria, e li abbiamo correlati ai livelli di endoxifen allo stato stazionario. Abbiamo dimostrato che i risultati del test di fenotipizzazione e i livelli di endoxifen al primo mese sono molto significativamente associati ai livelli di esposizione al metabolita attivo endoxifen allo stato stazionario e possono essere considerati informativi dello status metabolico del singolo paziente. L'analisi genetica del CYP2D6 condotta sui soggetti arruolati ha confermato l'influenza dei polimorfismi sui livelli plasmatici di endoxifen; la genotipizzazione è anche significativamente associata al test di fenotipizzazione. Il possibile ruolo di una isoforma recettoriale estrogenica, Erβ2, sulla attività di endoxifen è stata valutata, in vitro, utilizzando l’induzione della trascrizione di due geni sensibili agli estrogeni. Mediante analisi dell'espressione di ADORA1 ed IL20 è emerso che, in presenza di concentrazioni di endoxifen di 40nM per intervalli di tempo prolungati (24h), l'isoforma Erβ2 co-espressa con Erα riduce l’azione inibitoria di endoxifen rispetto alla presenza di solo Erα

Il rapporto tra parlamento e governo nell'esercizio dell'attivit\ue0 normativa primaria

Le trasformazioni del sistema politico italiano hanno sollecitato, almeno negli ultimi quindici anni, l\u2019interesse crescente della scienza politica tanto italiana quanto internazionale. Da una parte, si nota come le istituzioni centrali dello Stato vengano \u201csvuotate\u201d di molte delle loro funzioni tradizionali, per effetto di pressioni e processi sia interni alla stessa macchina statale, che legati a dinamiche e spinte sopranazionali. Dall\u2019altra, si rileva come a tale trasferimento di poteri, tanto verso l\u2019alto, che verso il basso e alla conseguente alterazione nello scopo dell\u2019azione statale, si accompagni una necessit\ue0 crescente di coordinamento e di direzione che poi, sul piano istituzionale, si traduce nella ridefinizione dei rapporti tra i centri del processo decisionale e, in particolare, nel rafforzamento degli esecutivi nei confronti delle assemblee rappresentative. Si tratta di tendenze evolutive che risultano particolarmente collegate alla trasformazione che gli ordinamenti giuridici hanno conosciuto, a partire dai primi decenni del XX secolo, in virt\uf9 del diffuso processo di democratizzazione, dell\u2019espansione dei compiti dello Stato e del decisivo interventismo di quest\u2019ultimo nella disciplina delle relazioni economiche e sociali, per di pi\uf9 attraverso canali di normazione di origine governativa, in primis la decretazione d\u2019urgenza e delegata, certamente pi\uf9 rapidi, e perci\uf2 pi\uf9 efficaci, per comporre dall\u2019alto l\u2019incalzante e multiforme richiesta di regolamentazione da parte della societ\ue0...Non Disponibil

Evaluation of agro-industrial by-products associated with Tithonia diversifolia in ruminant feeding on ruminal degradability parameters, fermentative kinetics, and in vitro methane production

O crescimento populacional resulta em uma demanda cada vez maior por alimentos, especialmente carne e leite, o que levanta preocupações sobre a sustentabilidade desse setor a longo prazo, sendo necessário repensar os sistemas de produção agrícola. O uso de coprodutos agroindustriais e forrageiras não convencionais, como a Tithonia diversifolia, é uma estratégia promissora para reduzir os impactos ambientais, melhorar a produtividade dos ruminantes e reduzir as emissões de gases de efeito estufa mantendo um bom desempenho dos animais. O objetivo foi investigar a viabilidade dessas abordagens avaliando a composição nutricional dos coprodutos e seu uso em dietas, parâmetros de degradabilidade ruminal, produção de metano in vitro e impacto ambiental em comparação com as dietas convencionais. Primeiramente, foram caracterizados 25 coprodutos provenientes da agroindústria de acordo com sua composição bromatológica, parâmetros fermentativos in vitro, degradabilidade e produção de CH4, dos quais metade foi selecionado (bagaço de laranja (BL), bagaço de mandioca (BM), bagaço de uva tinta (BUT), canola moída (CM), farelo de algodão (FA), farelo de girassol (FG), farelo de soja (FS), palhada de milho (PM), palhada de feijão (PF), resíduo de feijão (RF), rolão de milho (RM), resíduo de cervejaria bagaço (RCB), resíduo de cervejaria - levedura (RCL), resíduo de cervejaria TRUB (RCT), torta de macaúba (TM), e torta de nabo forrageiro (TN)) para constituírem 10 dietas experimentais formuladas para serem compostas por coprodutos e Tithonia diversifolia como forrageira não convencional. As dietas foram avaliadas por análises bromatológicas, ensaios in vitro de degradabilidade e produção de gases e comparadas estatisticamente contra uma dieta controle (DC) contendo ingredientes convencionais (milho, soja e capim xaraés). Foram selecionadas três dietas com alto valor nutricional, degradabilidade e potencial de redução de CH4 entérico em comparação com a DC, sendo elas: Dieta 2 (composta por 25% de Urochloa brizantha, 25% de TD, 22% de bagaço de mandioca e 28% de farelo de girassol), Dieta 3 (25% de Urochloa brizantha, 25% de TD, 3% de bagaço de laranja, 26% de bagaço de mandioca e 21% de farelo de algodão) e Dieta5 (25% de Urochloa brizantha, 25% de TD, 16% de bagaço de laranja, 12% de palhada de feijão e 22% de resíduo de cervejaria levedura); sendo possível concluir a viabilidade de formular dietas utilizando coprodutos agroindustriais selecionados, sem comprometer a produtividade dos animais e a qualidade nutricional da dieta fornecida.Population growth leads to an increasing demand for food, especially meat and milk, raising concerns about the long-term sustainability of this sector. It becomes necessary to rethink agricultural production systems. One promising strategy involves the use of agro-industrial by-products and unconventional forages, such as Tithonia diversifolia, to reduce environmental impacts, improve ruminant productivity, and decrease greenhouse gas emissions while maintaining good animal performance. This study aims to investigate the viability of these approaches by evaluating the nutritional composition of the by-products and their use in diets, ruminal degradability parameters, in vitro methane production, and environmental impact compared to conventional diets. Initially, 25 by-products from the agro-industry were characterized based on their bromatological composition, in vitro fermentative parameters, degradability, and methane production. Half of these by-products were selected (orange pulp (BL), cassava bagasse (BM), red grape pomace (BUT), ground canola (CM), cottonseed meal (FA), sunflower meal (FG), soybean meal (FS), corn straw (PM), bean straw (PF), bean waste (RF), corn cob (R), brewery waste - bagasse (RCB), brewery waste - yeast (RCL), brewery waste - TRUB (RCT), macaw palm cake (TM) and forage turnip cake (TN) to compose 10 experimental diets with Tithonia diversifolia as an unconventional forage. The diets were evaluated through bromatological analyses, in vitro degradability, and gas production assays, statistically compared to a control diet (DC) containing conventional ingredients (corn, soybean, and Xaraés grass). Three diets were selected with high nutritional value, degradability, and potential for enteric methane reduction compared to the DC. These diets are: Diet 2 (composed of 25% Urochloa brizantha, 25% TD, 22% cassava bagasse, and 28% sunflower meal), Diet 3 (25% Urochloa brizantha, 25% TD, 3% orange pulp, 26% cassava bagasse, and 21% cottonseed meal), and Diet 5 (25% Urochloa brizantha, 25% TD, 16% orange pulp, 12% bean straw, and 22% brewery waste - yeast). This study concludes the feasibility of formulating diets using selected agro-industrial by-products without compromising animal productivity and the nutritional quality of the provided diet

The bioethical implications of chatbots in the medical field: The ChatGPT case

ChatGPT is a prototype chatbot based on artificial intelligence (AI) and machine learning. The program was developed to be able to converse with a human user in a number of different situations. This AI tool is, experimentally, also being applied to the medical context where it can potentially become an effective tool to support medical decision-making. This highlights a new paradigm of care that is increasingly being mediated by technology, and which leaves open many ethical and bioethical questions in the process. The purpose of this article is to analyze the risks and potential benefits of such a tool, as well as the possible drawbacks

Systems biology reveals biology of systems

In the last decades, genomic and postgenomic technologies obtained a great amount of information on molecular bases of cell physiology and organization. In spite of this, the knowledge of cells and living organisms in their entirety, is far from being achieved. In order to deal with biological complexity, Systems Biology uses a new approach to overcome this inadequacy. Despite different definitions, Systems Biology's view of biological phenomena highlights that a holistic perspective is needed to integrate and understand the huge amount of empirical data which have been collected. This is one of the aspects that makes Systems Biology so interesting, from a theoretical and epistemological point of view, and that renders it a useful tool to help students approach living beings' dynamics within a comprehensive framework of their biological features as well. © 2010 Wiley Periodicals, Inc. Complexity, 2010 © 2011 Wiley Periodicals, Inc

GLOBAL QUALITY AS DETERMINANT OF CONSUMERBEHAVIOUR

In recent years, the analysis of consumer behaviour has become one of the central aspects of marketing strategies for every organisation. What consumption patterns can we expect to emerge in the future? Until recently, freedom of choice was mainly based on a comparison between prices and rewarding the cheaper offer paying growing attention to the functional and qualitative aspects. Yet, in the last 20 years a wide range of movements have become active in the diffusion of concepts that attribute an environmental and ethical potential to consumption. The purpose of this paper is to demonstrate how responsible consumption has become a key factor for the choices of consumers. The dependence between overall quality and purchase intention has been tested using the method of Multiple Linear Regression for paper handkerchiefs “Viviverde” produced and distributed by a leading Italian retailer. The results of the statistical analysis confirm that “Global quality” can now be considered a determinant of the consumers purchasing behaviour

Oral Metronomic Vinorelbine (OMV) in elderly or pretreated patients with advanced non small cell lung cancer: outcome and pharmacokinetics in the real world

Background Oral metronomic therapy (OMV) is particularly suitable for palliative care, and schedules adapted for unfit patients are advisable. This study investigated the effects of oral vinorelbine given every other day without interruption and its pharmacokinetic profile in patients with advanced lung cancer. Materials and Methods Ninety-two patients received OMV at doses of 20, 30 or 50 mg. Toxic events, clinical benefit and overall survival were analysed. Blood pharmacokinetics were evaluated in 82 patients. Results Median treatment duration and overall survival were 15 (range 1.3-144) and 32.3 weeks, respectively; fourty-eight (60%) patients experienced clinical benefit. Outcomes were unrelated to previous therapies, age, histology or comorbidities. Toxicity was associated with higher blood concentrations of the drug. Pharmacokinetics were stable for up to two years, and were not influenced by treatment line or age. Conclusions OMV produced non-negligible survival in patients and also showed stable long-term blood concentrations. The schedule of 20-30 mg every other day without interruption gave good tolerability and clinical benefit