Key signalling nodes in mammary gland development and cancer. The Snail1-Twist1 conspiracy in malignant breast cancer progression

Breast cancer is the most common cancer among women, and despite significant advances in diagnosing and treating it, metastatic spread of cancer cells results in a high mortality rate. Epithelial-to-mesenchymal transition (EMT) is an embryonic program in which epithelial cells lose their characteristics and gain mesenchymal features. Therefore, EMT might play a very important role during malignant tumour progression. In this review we summarise recent advances in breast cancer research with a particular focus on the transcription factors Snail1 and Twist1. Besides discussing the role of EMT in normal mammary gland development, we describe regulatory mechanisms involving newly discovered upstream regulators and microRNAs, the association of EMT with breast cancer stem cells, and the involvement of the tumour microenvironment in breast cancer progression

Subtype analysis and mutations to antiviral drugs in HIV-1-infected patients from Mozambique before initiation of antiretroviral therapy: Results from the DREAM programme

Phylogenetic analysis and evaluation of drug-resistance were carried out upon 59 plasma samples from 58 treatment-naïve HIV-1 infected patients from Mozambique, enrolled in a free antiviral-therapy protocol in the frame of Drug-Resource-Enhancement against AIDS and Malnutrition (DREAM) programme. Sequencing of the first 1,300 bases of the pol-gene shows that all virus strains cluster within clade C, with the exception of a single patient carrying a G-subtype virus. Relevant mutations in the reverse transcriptase (RT) are rare: 118A/I/L/G (four patients), 179E/D/I (three patients), 333E/D (two patients), 101R, and 210F (one patient each). In Protease (PR), V82I (10.3%) is the only relevant mutation, while natural polymorphisms/secondary mutations are found, some at very high frequency: 20R (25.9%), 36I (91.4%), 36L (8.6%), 60E (31.0%), 63P (29.3%), and 93L (96.6%). Among them, mutations with a frequency >25% were further investigated to assess their covariation pattern with PI resistance associated mutations. The pattern of covariation observed for K20R and D60E (but not L63P and M36I) was different between C and B subtype isolates from PR-inhibitor-treated patients. The sequences were also analyzed to calculate the ratio of non-synonymous to synonymous substitution. The ratio for PR and RT was 0.116 and 0.093, respectively, suggesting a greater conservation in RT than PR in both subtypes B and C HIV strains. Taken together, the results demonstrate a consistent clade-homogeneity of viral strains circulating in Mozambique, and the very limited presence, in drug-naïve patients, of mutations associated with resistance to RT-inhibitors. The high frequency of secondary mutations/polymorphisms in HIV-PR deserves further studies to evaluate its relevance in clinical settings. © 2005 Wiley-Liss, Inc

Incidence and predictors of single drug discontinuation according to the presence of HCV coinfection in HIV patients from the ICONA Foundation Cohort Study

To evaluate incidence rates of and predictors for any antiretroviral (ART) drug discontinuation by HCV infection status in a large Italian cohort of HIV infected patients. All patients enrolled in ICONA who started combination antiretroviral therapy (cART) containing abacavir or tenofovir or emtricitabine or lamivudine plus efavirenz or rilpivirine or atazanavir/r or darunavir/r (DRV/r) or lopinavir/r or dolutegravir or elvitegravir or raltegravir were included. Multivariate Poisson regression models were used to determine factors independently associated with single ART drug discontinuation. Inverse probability weighting method to control for potential informative censoring was applied. Data from 10,637 patients were analyzed and 1,030 (9.7%) were HCV-Ab positive. Overall, there were 15,464 ART discontinuations due to any reason in 82,415.9 person-years of follow-up (PYFU) for an incidence rate (IR) of 18.8 (95% confidence interval [95%CI] 18.5-19.1) per 100 PYFU. No difference in IR of ART discontinuation due to any reason between HCV-infected and -uninfected patients was found. In a multivariable Poisson regression model, HCV-infected participants were at higher risk of darunavir/r discontinuation due to any reason (adjusted incidence rate ratio = 1.5, 95%CI 1.01-2.22, p value = 0.045) independently of demographics, HIV-related, ART and life-style factors. Among DRV/r treated patients, we found that HCV-viremic patients had twice the risk of ART discontinuation due to any reason than HCV-aviremic patients. In conclusion, HIV/HCV coinfected patients had a marginal risk increase of DRV/r discontinuation due to any reason compared with those without coinfection

Incidence and predictors of single drug discontinuation according to the presence of HCV coinfection in HIV patients from the ICONA Foundation Cohort Study

To evaluate incidence rates of and predictors for any antiretroviral (ART) drug discontinuation by HCV infection status in a large Italian cohort of HIV infected patients. All patients enrolled in ICONA who started combination antiretroviral therapy (cART) containing abacavir or tenofovir or emtricitabine or lamivudine plus efavirenz or rilpivirine or atazanavir/r or darunavir/r (DRV/r) or lopinavir/r or dolutegravir or elvitegravir or raltegravir were included. Multivariate Poisson regression models were used to determine factors independently associated with single ART drug discontinuation. Inverse probability weighting method to control for potential informative censoring was applied. Data from 10,637 patients were analyzed and 1,030 (9.7%) were HCV-Ab positive. Overall, there were 15,464 ART discontinuations due to any reason in 82,415.9 person-years of follow-up (PYFU) for an incidence rate (IR) of 18.8 (95% confidence interval [95%CI] 18.5\u201319.1) per 100 PYFU. No difference in IR of ART discontinuation due to any reason between HCV-infected and -uninfected patients was found. In a multivariable Poisson regression model, HCV-infected participants were at higher risk of darunavir/r discontinuation due to any reason (adjusted incidence rate ratio = 1.5, 95%CI 1.01\u20132.22, p value = 0.045) independently of demographics, HIV-related, ART and life-style factors. Among DRV/r treated patients, we found that HCV-viremic patients had twice the risk of ART discontinuation due to any reason than HCV-aviremic patients. In conclusion, HIV/HCV coinfected patients had a marginal risk increase of DRV/r discontinuation due to any reason compared with those without coinfection