Integrin Signaling Shaping BTK-Inhibitor Resistance.

Integrins are adhesion molecules that function as anchors in retaining tumor cells in supportive tissues and facilitating metastasis. Beta1 integrins are known to contribute to cell adhesion-mediated drug resistance in cancer. Very late antigen-4 (VLA-4), a CD49d/CD29 heterodimer, is a beta1 integrin implicated in therapy resistance in both solid tumors and haematological malignancies such as chronic lymphocytic leukemia (CLL). A complex inside-out signaling mechanism activates VLA-4, which might include several therapeutic targets for CLL. Treatment regimens for this disease have recently shifted towards novel agents targeting BCR signaling. Bruton's tyrosine kinase (BTK) is a component of B cell receptor signaling and BTK inhibitors such as ibrutinib are highly successful; however, their limitations include indefinite drug administration, the development of therapy resistance, and toxicities. VLA-4 might be activated independently of BTK, resulting in an ongoing interaction of CD49d-expressing leukemic cells with their surrounding tissue, which may reduce the success of therapy with BTK inhibitors and increases the need for alternative therapies. In this context, we discuss the inside-out signaling cascade culminating in VLA-4 activation, consider the advantages and disadvantages of BTK inhibitors in CLL and elucidate the mechanisms behind cell adhesion-mediated drug resistance.

Dietary total antioxidant capacity in relation to endometrial cancer risk: a case-control study in Italy.

PURPOSE: To investigate the role of the overall antioxidant activity of diet, we estimated the relation between three dietary indices of total antioxidant capacity (TAC) and endometrial cancer risk METHODS: We analyzed data from an Italian case-control study including 454 women with incident, histologically confirmed endometrial cancer, and 908 frequency-matched controls admitted to the same hospitals as cases for acute non-neoplastic conditions. A reproducible and valid food frequency questionnaire was used to assess subjects' habitual diet. TAC was measured using Italian food composition tables in terms of Ferric-reducing antioxidant power (FRAP), Trolox equivalent antioxidant capacity (TEAC), and total radical-trapping antioxidant parameter (TRAP). We computed odds ratios (OR) and corresponding 95 % confidence intervals (CIs) using conditional multiple logistic regression models, including terms for recognized endometrial cancer risk factors and total energy intake. RESULTS: TAC was inversely related to endometrial cancer risk with ORs for the highest versus the lowest quartile of 0.69 (95 % CI 0.47-1.00) for FRAP, 0.68 (95 % CI 0.46-0.99) for TEAC, and 0.68 (95 % CI 0.47-0.98) for TRAP. The relations appeared consistent in strata of selected risk factors and decreased when considering TAC without the contribution of coffee. CONCLUSIONS: Our findings suggest a favorable role of a diet high in TAC on endometrial cancer risk, which can be partially driven by coffee consumption.

Coffee, Tea, Cola, and Bladder Cancer Risk: Dose and Time Relationships.

OBJECTIVE: To further analyze the relation between coffee, tea, and energy drinks and bladder cancer risk, considering dose, duration, and other time-related factors. METHODS AND RESULTS: A multicentric case-control study on 690 bladder cancer cases and 665 hospital controls was conducted in Italy between 2003 and 2014. Odds ratios (ORs) for bladder cancer were estimated using multiple logistic regression models. Sex-, age-, and tobacco-adjusted ORs were 1.27 (95% confidence interval [CI] 0.84-1.94) for current drinkers and 1.69 (95% CI 1.05-2.72) for lifetime drinkers of ≥4 cups/day, compared with non- or occasional coffee drinkers. The corresponding ORs for an increment of 1 cup/day were 1.03 (95% CI 0.96-1.11) and 1.07 (95% CI 0.99-1.15). No association was found between bladder cancer risk and duration or age at starting, and no significant heterogeneity was found according to age and sex, although a slight increased risk emerged in never smokers. Decaffeinated coffee, tea, cola, and energy drinks were not related with bladder cancer risk. CONCLUSION: Our study found no significant relation between coffee and bladder cancer risk after accounting for smoking, although the OR was above unity for high lifetime habit. The lack of dose and duration relationships, however, suggests the absence of a causal relation.

Dietary vitamins E and C and prostate cancer risk.

BACKGROUND: The epidemiologic evidence on dietary vitamins E and C and prostate cancer is controversial. Therefore, a case-control study was carried out to investigate the role of dietary intake of vitamins E and C in the etiology of prostate cancer. MATERIAL AND METHODS: Cases were 1 294 men with incident, histologically confirmed prostate cancer, admitted to the major teaching and general hospitals of five Italian areas between 1991 and 2002. Controls were 1 451 men admitted for acute, non-neoplastic conditions to the same hospitals. Information on dietary habits and nutrient intake was elicited using a validated food frequency questionnaire including 78 food groups and recipes. Odds ratios (OR) and 95% confidence intervals (CI) for increasing levels of vitamin intake were estimated after allowance for total energy intake and other confounding factors. RESULTS: Vitamin E showed a significant inverse association with prostate cancer (OR = 0.78 for the highest versus the lowest tertile of intake, 95% CI: 0.58-0.96; p-value for trend = 0.02), whereas for vitamin C the inverse association was of borderline statistical significance (OR = 0.86; 95% CI: 0.65-1.08). Results were consistent in strata of age, body mass index, and family history of prostate cancer. DISCUSSION: The present study shows an inverse association between dietary intake of vitamins E and prostate cancer incidence. This finding is likely to reflect the influence of diet itself since supplementation or food fortification with vitamins is rare in the Italian population.

Allium vegetables intake and endometrial cancer risk.

OBJECTIVE: The potential role of allium vegetables on endometrial cancer risk has been scarcely investigated and the results of previous Chinese studies are not easily applicable to Western populations. Therefore, we evaluated the relationship between onion and garlic intake and endometrial cancer, using data from an Italian case-control study. SETTING: We analysed data from a multi-centre case-control study of 454 endometrial cancer cases and 908 controls, admitted to the same hospitals for a wide spectrum of acute, non-neoplastic conditions. Information was collected by trained interviewers using a validated and reproducible FFQ. Multivariate odds ratios and 95% confidence intervals were obtained after allowance for recognized confounding factors. RESULTS: Compared with non-users, the OR of endometrial cancer for successive categories of onion intake were 0.94 (95% CI 0.72, 1.21) for <2 portions/week and 0.40 (95% CI 0.22, 0.72) for > or =2 portions/week, with a significant inverse trend in risk (P = 0.01). The OR for an increment of one portion (i.e. 80 g) of onions per week was 0.81 (95% CI 0.70, 0.95). For garlic, the OR for successive categories of intake were 0.89 (95% CI 0.68, 1.15) for intermediate use and 0.62 (95% CI 0.42, 0.92) for high use, with a significant inverse trend in risk (P = 0.02). CONCLUSIONS: Our study found a moderate protective role of allium vegetables on the risk of endometrial cancer.

Food groups and endometrial cancer risk: a case-control study from Italy.

OBJECTIVE: Although several studies have been conducted on the relation between dietary habits and endometrial cancer risk, the evidence for specific food groups is still controversial. STUDY DESIGN: We analyzed data from an Italian case-control study including 454 women with histologically confirmed endometrial cancer and 908 controls admitted to the same hospitals for acute, nonneoplastic conditions. Multivariate odds ratios (ORs) were obtained after allowance for major potential confounding factors. RESULTS: A significant increase in risk was observed for red meat, with an OR of 2.07 for an increment of 1 serving per day. Inverse associations were observed for coffee (OR, 0.83), cereals (OR, 0.92), and vegetables (OR, 0.83). CONCLUSION: Our results support the existence of a relation between dietary habits and endometrial cancer risk and in particular suggest that a diet rich in red meat and poor in vegetables may have an unfavorable effect.

Macronutrients, fatty acids, cholesterol and renal cell cancer risk.

The role of selected macronutrients, fatty acids and cholesterol in the etiology of renal cell carcinoma (RCC) was analyzed using data from a case-control study conducted in 4 Italian areas between 1992 and 2004. Cases were 767 patients with incident, histologically confirmed RCC, admitted to major teaching and general hospitals of the study areas. Controls were 1,534 subjects admitted for acute, nonneoplastic conditions to the same hospitals. Information on dietary habits and nutrient intake was elicited using a validated food frequency questionnaire including 78 food groups and recipes. Odds ratios (OR) and 95% confidence intervals (CI) for increasing levels of nutrient intake were estimated after allowance for total energy intake and other potential confounding factors. A direct association with RCC was found for starch intake (OR = 1.9 for highest versus lowest quintile of intake; 95% CI: 1.4-2.6, p-value for trend = 0.001), while an inverse association was found for fats from vegetable sources (OR = 0.6; 95% CI: 0.5-0.8; p-value for trend = 0.002), unsaturated fatty acids (OR = 0.5; 95% CI: 0.4-0.7; p-value for trend = 0.0002), and polyunsaturated fatty acids (OR = 0.5; 95% CI: 0.4-0.7; p-value for trend = 0.001). Among polyunsaturated fatty acids, linoleic acid (OR = 0.5; 95% CI: 0.4-0.7; p-value for trend = 0.0001) and linolenic acid (OR = 0.7; 95% CI: 0.5-1.0; p-value for trend = 0.01) were inversely related to RCC. When 6 major macronutrients were included in the same model, the adverse effect of high intake of starch remained statistically significant, together with the protective effect of polyunsaturated fatty acids. Results were consistent in strata of age, body mass index, treated hypertension, energy intake, stage and family history of RCC.