Obesity and Breast Cancer: Interaction or Interference with the Response to Therapy?

Background: Aromatase inhibitors (AI) are widely used for treating hormone-sensitive breast cancer (BC). Obesity, however, due to aromatase-mediated androgen conversion into estradiol in the peripheral adipose tissue, might impair AI inhibitory capacity. We aimed at identifying a cut-off of body mass index (BMI) with significant prognostic impact, in a cohort of stage I-II BC patients on systemic adjuvant therapy with AI. Methods: we retrospectively evaluated routinely collected baseline parameters. The optimal BMI cut-off affecting disease-free survival (DFS) in AI-treated BC patients was identified through maximally selected rank statistics; non-linear association between BMI and DFS in the AI cohort was assessed by hazard-ratio-smoothed curve analysis using BMI as continuous variable. The impact of the BMI cut-off on survival outcomes was estimated through Kaplan-Meier plots, with log-rank test and hazard ratio estimation comparing patient subgroups. Results: A total of 319 BC patients under adjuvant endocrine therapy and/or adjuvant chemotherapy were included. Curve-fitting analysis showed that for a BMI cut-off >29 in AI-treated BC patients (n = 172), DFS was increasingly deteriorating and that the impact of BMI on 2-year DFS identified a cut-off specific only for the cohort of postmenopausal BC patients under adjuvant therapy with AI. Conclusion: in radically resected hormone-sensitive BC patients undergoing neoadjuvant or adjuvant chemotherapy and treated with AI, obesity represents a risk factor for recurrence, with a significantly reduced 2-year DFS

PCSK6 and Survival in Idiopathic Pulmonary Fibrosis

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. Objectives: To identify and validate molecular determinants of IPF survival. Methods: A staged genome-wide association study was performed using paired genomic and survival data. Stage I cases were drawn from centers across the United States and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplantation-free survival (TFS). Stage I variants with nominal significance (P < 5 x 10(-5)) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (P < 5 x 10(-8)). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance. Measurements and Main Results: After quality controls, 1,481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of PCSK6 (proprotein convertase subtilisin/kexin type 6) reaching genome-wide significance (hazard ratio, 4.11 [95% confidence interval, 2.54-6.67]; P = 9.45 x 10(-9)). PCSK6 protein was highly expressed in IPF lung parenchyma. PCSK6 lung staining intensity, peripheral blood gene expression, and plasma concentration were associated with reduced TFS. Conclusions: We identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein plays a potentially important role in IPF progression

3D finite element analysis of anchorage zones in post-tensioned concrete girder

The anchorage zone of post-tensioned concrete structures is a discontinuity region, where a redistribution of stress occurs behind the anchor device, as the concentrated prestressing force spreads out over the full concrete section. This disturbed zone is subjected to a very complex three-dimensional state of stress, with transverse tensile forces that cause longitudinal cracks which can extend throughout the beam span, thus causing failure. To prevent excessive cracking, therefore, concrete must be adequately reinforced with supplementary or ‘’bursting'' reinforcement. The problem of the stress distribution in the anchorage zone has been well studied in the past decades using various methods such as linear elastic theory [1-5], experimental investigations [6-7], strut and tie models [7] and finite element analyses [8-10]. Most efforts in the previous analyses have focused on evaluating the ultimate strength of post-tensioned beams tested to anchorage failure and only few works have considered the effects of support reaction. Although ultimate limite states are the most important considerations in the design of prestressed structures, more in depth study is required at serviceability limit states in order to evaluate the effectiveness of bursting reinforcement to control maximum crack width. Prediction of this behavior requires advanced analytical techniques with the ability to simulate the highly nonlinear behaviour of the concrete. To date, most of the nonlinear finite element analyses have consisted of two-dimensional models of the anchorage zones, although it is a three-dimensional one even in a rectangular beam. The main reason for this choice is generally attributed to a lack of a proper description of material properties of concrete. In this study, three-dimensional non-linear finite element analyses have been carried out using the program Atena to simulate the behaviour of end zones of rectangular section post-tensioned girders, with the presence of the support reaction. This program includes an advanced three-dimensional material model which allows employing it as an effective tool for the investigation of reinforced and prestressed concrete elements. The validity of the finite element model has been verified through comparisons with tests reported in literature and it was found good agreement between the experimental and numerical results. The validated model has been used to investigate the influence of the arrangement of bursting reinforcement on stirrups strains and crack development at serviceability and ultimate limit state

Molecular parasitism in the Escherichia coli-Bdellovibrio bacteriovorus system: translocation of the matrix protein from the host to the parasite outer membrane.

During the intracellular maturation in Escherichia coli of the parasite Bdellovibrio bacteriovorus the outer membrane, major protein I of E. coli (i.e., the matrix protein) becomes associated with the outer membrane of the emerging parasite cells. The binding properties of this protein with the outer membrane of the host and of the parasite are identical. An analogous phenomenon also occurs during Bdellovibrio parasitism on Klebsiella pneumoniae and on Salmonella typhimurium. Possible roles for this scavenging action of Bdellovibrio, and similar phenomena in other parasitic systems, are discussed