Are Wnt/β-Catenin and PI3K/AKT/mTORC1 Distinct Pathways in Colorectal Cancer?

Wnt/β-catenin and phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin complex 1 (PI3K/AKT/mTORC1) pathways both are critically involved in colorectal cancer (CRC) development, although they are implicated in the modulation of distinct oncogenic mechanisms. In homeostatic and pathologic conditions, these pathways show a fine regulation based mainly on feedback mechanisms, and are connected at multiple levels involving both upstream and downstream common effectors. The ability of the Wnt/β-catenin and PI3K/AKT/mTORC1 pathways to reciprocally control themselves represents one of the main resistance mechanisms to selective inhibitors in CRC, leading to the hypothesis that in specific settings, particularly in cancer driven by genetic alterations in Wnt/β-catenin signaling, the relationship between Wnt/β-catenin and PI3K/AKT/mTORC1 pathways could be so close that they should be considered as a unique therapeutic target. This review provides an update on the Wnt/β-catenin and PI3K/AKT/mTORC1 pathway interconnections in CRC, describing the main molecular players and the potential implications of combined inhibitors as an approach for CRC chemoprevention and treatment

Chemopreventive effects of eicosapentaenoic acid free fatty acid in a murine model of colitis-associated colorectal cancer

Inflammatory bowel diseases are associated with increased risk of developing colitis-associated colorectal cancer (CAC). Epidemiological data show that the consumption of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) decreases the risk of sporadic colorectal cancer (CRC). Importantly, recent data have shown that eicosapentaenoic acid-free fatty acid (EPA-FFA) reduces polyps formation and growth in models of familial adenomatous polyposis. However, the effects of dietary EPA-FFA are unknown in CAC. We tested the effectiveness of substituting EPA-FFA, for other dietary fats, in preventing inflammation and cancer in the AOM-DSS model of CAC. The AOM-DSS protocols were designed to evaluate the effect of EPA-FFA on both initiation and promotion of carcinogenesis. We found that EPA-FFA diet strongly decreased tumor multiplicity, incidence and maximum tumor size in the promotion and initiation arms. Moreover EPA-FFA, in particular in the initiation arm, led to reduced cell proliferation and nuclear β-catenin expression, whilst it increased apoptosis. In both arms, EPA-FFA treatment led to increased membrane switch from ω-6 to ω-3 PUFAs and a concomitant reduction in PGE2 production. We observed no significant changes in intestinal inflammation between EPA-FFA treated arms and AOM-DSS controls. Importantly, we found that EPA-FFA treatment restored the loss of Notch signaling found in the AOM-DSS control, resulted in the enrichment of Lactobacillus species in the gut microbiota and led to tumor suppressor miR34-a induction. In conclusion, our data suggest that EPA-FFA is an effective chemopreventive agent in CAC

Very-Low-Calorie Ketogenic Diets with Whey, Vegetable or Animal Protein in Patients with Obesity: A Randomized Pilot Study

Context We compared the efficacy, safety and effect of 45-day isocaloric very-low-calorie ketogenic diets (VLCKDs) incorporating whey, vegetable or animal protein on the microbiota in patients with obesity and insulin resistance to test the hypothesis that protein source may modulate the response to VLCKD interventions. Subjects and Methods Forty-eight patients with obesity [19 males and 29 females, HOMA index ≥ 2.5, age 56.2±6.1 years, body mass index (BMI) 35.9±4.1 kg/m2] were randomly assigned to three 45-day isocaloric VLCKD regimens (≤800 kcal/day) containing whey, plant or animal protein. Anthropometric indexes; blood and urine chemistry, including parameters of kidney, liver, glucose and lipid metabolism; body composition; muscle strength; and taxonomic composition of the gut microbiome were assessed. Adverse events were also recorded. Results Body weight, BMI, blood pressure, waist circumference, HOMA index, insulin, and total and LDL cholesterol decreased in all patients. Patients who consumed whey protein had a more pronounced improvement in muscle strength. The markers of renal function worsened slightly in the animal protein group. A decrease in the relative abundance of Firmicutes and an increase in Bacteroidetes were observed after the consumption of VLCKDs. This pattern was less pronounced in patients consuming animal protein. Conclusions VLCKDs led to significant weight loss and a striking improvement in metabolic parameters over a 45-day period. VLCKDs based on whey or vegetable protein have a safer profile and result in a healthier microbiota composition than those containing animal proteins. VLCKDs incorporating whey protein are more effective in maintaining muscle performance

A Mediterranean Diet Mix Has Chemopreventive Effects in a Murine Model of Colorectal Cancer Modulating Apoptosis and the Gut Microbiota

Objectives: Unhealthy dietary patterns have been associated with colorectal cancer (CRC) onset while Mediterranean Diet (MD) has been proposed for CRC prevention. This study evaluated the effect of a Mediterranean Diet Mix (MD-MIX) on colonic tumors development in A/J mice fed a low-fat (LFD) or a high-fat western diet (HFWD), and injected with the procarcinogen azoxymethane (AOM).Materials and Methods: Forty A/J male mice were randomly assigned into four feeding arms (10 mice/arm; LFD, LFD-MD-MIX, HFWD, HFWD-MD-MIX) to be treated with AOM. Ten mice were exposed to the diets alone (Healthy LFD and Healthy HFWD) to be used as control. Tumor incidence and multiplicity were evaluated at sacrifice. Mucosal fatty acid content and urinary phenolic compounds were assayed by mass spectrometry. Apoptosis was evaluated by TUNEL assay and gene expression markers. Cell proliferation was evaluated by Ki67 immunohistochemistry. Microbiota composition was assessed at different time points by 16S RNA sequencing.Results: A tumor incidence of 100% was obtained in AOM-treated mice. The MD-MIX supplementation was able to reduce the number of colonic lesions in both LFD and HFWD-fed mice and to induce apoptosis, in particular in the LFD-MD-MIX arm. Moreover, a preventive effect on low-grade dysplasia and macroscopical lesions (>1 mm) development was found in HFWD-fed mice together with a regulation of the AOM-driven intestinal dysbiosis.Conclusions: MD-MIX was able to counteract CRC development in mice under different dietary backgrounds through the regulation of apoptosis and gut microbiota

Long-term treatment with deferiprone enhances left ventricular ejection function when compared to deferoxamine in patients with thalassemia major

Transfusion and iron chelation treatment have significantly reduced morbidity and improved survival of patients with thalassemia major. However, cardiac disease continues to be the most common cause of death. We report the left-ventricular ejection fraction, determined by echocardiography, in one hundred sixtyeight patients with thalassemia major followed for at least 5 years who received continuous monotherapy with deferoxamine (N = 108) or deferiprone (N = 60). The statistical analysis, using the generalized estimating equations model, indicated that the group treated with deferiprone had a significantly better left-ventricular ejection fraction than did those treated with deferoxamine (coefficient 0.97; 95% CI 0.37; 1.6, p = 0.002). The heart may be particularly sensitive to iron-induced mitochondrial damage because of the large number of mitochondria and its low level of antioxidants. Deferiprone, because of its lower molecular weight, might cross into heart mitochondria more efficiently, improving their activity and, thereby, myocardial cell function. Our findings indicate that the long-term administration of deferiprone significantly enhances left-ventricular function over time in comparison with deferoxamine treatment. However, because of limitations related to the design of this study, these findings should be confirmed in a prospective, randomized clinical trial

Serial echocardiographic left ventricular ejection fraction measurements: a tool for detecting thalassemia major patients at risk of cardiac death

Cardiac damage remains a major cause of mortality among patients with thalassemia major. The detection of a lower cardiac magnetic resonance T2* (CMR-T2*) signal has been suggested as a powerful predictor of the subsequent development of heart failure. However, the lack of worldwide availability of CMR-T2* facilities prevents its widespread use for follow-up evaluations of cardiac function in thalassemia major patients, warranting the need to assess the utility of other possible procedures.In this setting,the determination of left ventricular ejection fraction (LVEF)offers an accurate and reproducible method for heart function evaluation. These findings suggest a reduction in LVEF≥7%, over time, determined by 2-D echocardiography, may be considered a strong predictive tool for the detection of thalassemia major patients with increased risk of cardiac death. The reduction of LVEF≥7% had higher (84.76%) predictive value. Finally, Kaplan–Meier survival curves of thalassemia major patients with LVEF≥7% showed a statistically significant decreased probability of survival for heart disease (p=0.0022). However, because of limitations related to the study design, such findings should be confirmed in a large long-term prospective clinical trial

A: Deferasirox, deferiprone and desferrioxamine treatment in thalassemia major patients: cardiac iron and function comparison determined by quantitative magnetic resonance imaging. Haematologica 2011; 96

Background Oral deferiprone was suggested to be more effective than subcutaneous desferrioxamine for removing heart iron. Oral once-daily chelator deferasirox has recently been made commercially available but its long-term efficacy on cardiac iron and function has not yet been established. Our study aimed to compare the effectiveness of deferasirox, deferiprone and desferrioxamine on myocardial and liver iron concentrations and bi-ventricular function in thalassemia major patients by means of quantitative magnetic resonance imaging. Design and Methods From the first 550 thalassemia subjects enrolled in the Myocardial Iron Overload in Thalassemia network, we retrospectively selected thalassemia major patients who had been receiving one chelator alone for longer than one year. We identified three groups of patients: 24 treated with deferasirox, 42 treated with deferiprone and 89 treated with desferrioxamine. Myocardial iron concentrations were measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Liver iron concentrations were measured by T2* multiecho technique. Results The global heart T2* value was significantly higher in the deferiprone (34±11ms) than in the deferasirox (21±12 ms) and the desferrioxamine groups (27±11 ms) (P=0.0001). We found higher left ventricular ejection fractions in the deferiprone and the desferrioxamine versus the deferasirox group (P=0.010). Liver iron concentration, measured as T2* signal, was significantly lower in the desferrioxamine versus the deferiprone and the deferasirox group (P=0.004). Conclusions The cohort of patients treated with oral deferiprone showed less myocardial iron burden and better global systolic ventricular function compared to the patients treated with oral deferasirox or subcutaneous desferrioxamine. Key words: thalassemia, iron chelation therapy, cardiac magnetic resonance imaging. Citation: Pepe A, Meloni A, Capra M, Cianciulli P, Prossomariti L, Malaventura C, Putti MC, Lippi A, Romeo MA, Bisconte MG, Filosa A, Caruso V, Quarta A, Pitrolo L, Missere M, Midiri M, Rossi G, Positano V, Lombardi M, and Maggio A. Deferasirox, deferipron

How to adapt to fast-changing environments : the case of Ceridian HCM Inc

The present thesis investigates the major factors that can help firms to more effectively cope with fast-changing environments, through the analysis of a case study. More precisely, Ceridian Inc ’s transformation and evolution in the HCM market over the last years is being analyzed because it allows to connect academic material with real world scenarios. As a foundation of the present study, several theoretical perspectives and concepts have been discussed, including Strategic Change, Organizational Agility and Dynamic Capabilities. Data and information concerning the organization were collected through multiple sources, including the company’s website, press releases and articles and a personal interview. The case explores the importance of developing DCs and an innovative organizational culture in fast-paced environments. It also stresses the key role played by constant efforts on R&D and a strong focus on both customer and employee experience. This case study adds to the body of research providing a real-life example of a firm whose approach has “challenged” the traditional perspectives towards change, which generally lie on assumptions mainly based on stability and routine. Instead, Ceridian HCM Inc. kept being updated, proactive and agile over time, developing a culture of innovation, considering the overall ecosystem characterized by “ongoing, evolving, and cumulative” change, as a demonstration that, approaching change, both on a micro and macro level, can allow firms to better cope with the current business environmentA presente tese investiga os principais fatores que podem ajudar as empresas a lidar de maneira mais eficaz com ambientes em rápida mudança, através da análise de um caso de estudo. Em concreto, a transformação e a evolução da Ceridian Inc no mercado de Gestão de Capital Humano nos últimos anos são analisadas, como um exemplo da aplicação das teorias e conceitos académicos a um caso real. Como base para o presente estudo, várias perspetivas e conceitos teóricos foram analisados, incluindo a Mudança Estratégica, a Agilidade Organizacional e as Capacidades Dinâmicas. Os dados e as informações referentes à organização foram recolhidos através de várias fontes, incluindo o site da empresa, comunicados de imprensa, artigos e uma entrevista pessoal. O caso explora a importância do desenvolvimento de Capacidades Dinâmicas e de uma cultura organizacional inovadora em ambientes em rápida mudança. Além disso, enfatiza o papel fundamental desempenhado pelos esforços constantes em investigação e desenvolvimento e pelo foco na experiência do cliente e dos colaboradores. O presente caso de estudo contribui para a literatura existente ao fornecer um exemplo real de uma Empresa cuja abordagem desafiou as perspetivas tradicionais de mudança, que geralmente se baseiam em pressupostos de estabilidade e rotina. A Ceridian HCM Inc. soube manter-se atualizada, proactiva e ágil ao longo do tempo, desenvolvendo uma cultura de inovação. Considerando o ecossistema global caracterizado por mudanças contínuas e evoluções cumulativas, a Empresa demonstrou que abordar a questão da mudança, ao nível micro e macro, pode permitir às empresas lidarem melhor com o ambiente de negócios atual