Study of Whey Protein Adsorption under Turbulent Flow

Reducing fouling in heat exchangers during treatment of milk products is one of the great challenges in the dairy industry. One approach to mitigate fouling is to alter the surface characteristics of the heat exchangers making them less prone to protein adsorption. On this background the European project MODSTEEL was established to study the use of new modified stainless steel surfaces to control fouling of milk components. This part of the project focuses on the adsorption of b-lactoglobulin (b-Lg) from a whey protein solution on unmodified and modified 316 2R stainless steel surfaces by in situ ellipsometry under well-defined flow conditions, in the turbulent regime. The effects of temperature, flow rate and surface modification, including SiF3+ and MoS2 ion implantation, DLC (Diamond-Like Carbon) sputtering, and DLC-PlasmaCVD (Chemical Vapour Deposition), were investigated. The amount of protein adsorbed is discussed in relation to the thermal stability of b-Lg, surface properties and hydrodynamic conditions

Lactoferrin and cancer disease prevention

Lactoferrin (LF) is an iron-binding glycoprotein that is composed of the transferrin family and is predominantly found in the products of the exocrine glands located in the gateways of the digestive, respiratory, and reproductive systems, suggesting a role in the non-specific defence against invading pathogens. Additionally, several physiological roles have been attributed to LF, namely regulation of iron homeostasis, host defence against infection and inflammation, regulation of cellular growth, and differentiation and protection against cancer development and metastasis. These findings have suggested LF's great potential therapeutic use in cancer disease prevention and/or treatment, namely as a chemopreventive agent. This review looks at the recent advances in understanding the mechanisms underlying the multifunctional roles of LF and future perspectives on its potential therapeutic applications.Fundação para a Ciência e a Tecnologia (FCT) - SFRH/BPD/26064/2005

The role of osteopontin in tumour progression and metastasis in breast cancer

The use of cancer biomarkers to anticipate the outlines of disease has been an emerging issue, especially as cancer treatment has made such positive steps in the last few years. Progress in the development of consistent malignancy markers is imminent because advances in genomics and bioinformatics have allowed the examination of immense amounts of data. Osteopontin is a phosphorylated glycoprotein secreted by activated macrophages, leukocytes, and activated T lymphocytes, and is present in extracellular fluids, at sites of inflammation, and in the extracellular matrix of mineralized tissues. Several physiologic roles have been attributed to osteopontin, i.e., in inflammation and immune function, in mineralized tissues, in vascular tissue, and in kidney. Osteopontin interacts with a variety of cell surface receptors, including several integrins and CD44. Binding of osteopontin to these cell surface receptors stimulates cell adhesion, migration, and specific signaling functions. Overexpression of osteopontin has been found in a variety of cancers, including breast cancer, lung cancer, colorectal cancer, stomach cancer, ovarian cancer, and melanoma. Moreover, osteopontin is present in elevated levels in the blood and plasma of some patients with metastatic cancers. Therefore, suppression of the action of osteopontin may confer significant therapeutic activity, and several strategies for bringing about this suppression have been identified. This review looks at the recent advances in understanding the possible mechanisms by which osteopontin may contribute functionally to malignancy, particularly in breast cancer. Furthermore, the measurement of osteopontin in the blood or tumors of patients with cancer, as a way of providing valuable prognostic information, will be discussed based on emerging clinical data.Fundação para a Ciência e a Tecnologia (FC

Cost-effectiveness of rosuvastatin in comparison with generic atorvastatin and simvastatin in a Swedish population at high risk of cardiovascular events

Background: To assess the long-term cost-effectiveness of rosuvastatin therapy compared with generic simvastatin and generic atorvastatin in reducing the incidence of cardiovascular events and mortality in a Swedish population with Framingham risk ≥20%. Methods: A probabilistic Monte Carlo simulation model based on data from JUPITER (the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) was used to estimate the long-term cost-effectiveness of rosuvastatin 20 mg daily versus simvastatin or atorvastatin 40 mg for the prevention of cardiovascular death and morbidity. The three-stage model included cardiovascular event prevention simulating the 4 years of JUPITER, initial prevention beyond the trial, and subsequent cardiovascular event prevention. A Swedish health care payer perspective (direct costs only) was modeled for a lifetime horizon, with 2008/2009 as the costing period. Univariate and probabilistic sensitivity analyses were performed. Results: The incremental cost per quality-adjusted life-year (QALY) gained with rosuvastatin 20 mg over simvastatin or atorvastatin 40 mg ranged from SEK88,113 (rosuvastatin 20 mg versus simvastatin 40 mg; Framingham risk ≥30%; net avoidance of 34 events/1000 patients) to SEK497,542 (versus atorvastatin 40 mg: Framingham risk ≥20%; net avoidance of 11 events/1000 patients) over a lifetime horizon. Probabilistic sensitivity analyses indicated that at a willingness-to-pay threshold of SEK500,000/QALY, rosuvastatin 20 mg would be cost-effective for approximately 75%–85% of simulations relative to atorvastatin or simvastatin 40 mg. Sensitivity analyses indicated the findings to be robust. Conclusion: Rosuvastatin 20 mg is cost-effective over a lifetime horizon compared with generic simvastatin or atorvastatin 40 mg in patients at high cardiovascular risk in Sweden

Significance of osteopontin expression in human invasive breast tumour stroma

Osteopontin has been reported to stimulate cell adhesion, migration and specific signalling functions. Its overexpression has been found in melanoma, breast, lung, colorectal, stomach and ovarian cancer. However, its overexpression and role in human breast cancer remains to be elucidated. In this study, invasive breast tumours from 129 patients were examined by immunohistochemistry in order to assess osteopontin association with several molecular tumour markers. Additionally, its relationship with proliferation and angiogenesis was determined. Ultimately, other tumour variables such as histological grade, tumour size and nodal status were also assessed. Results achieved showed that no statistical significant association exists between osteopontin expression and major clinicopathological parameters or angiogenesis, except for the number of lymph nodes involved. However, a correlation with some molecular markers was observed, namely with P-Cadherin, EGFR, cytokeratin 14 and vimentin. Additionally, higher proliferation rates were found for the tumours expressing osteopontin. Although several studies refer osteopontin as a potential breast cancer biomarker, it is still not clear if it can provide important diagnosis information, evaluate treatment effects or assess the potential for metastatic disease in patients.Fundação para a Ciência e a Tecnologia (FCT

A search for modifying genetic factors in CHEK2 : c.1100delC breast cancer patients

The risk of breast cancer associated with CHEK2:c.1100delC is 2-threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.Peer reviewe

In vitro epithelial-to-mesenchymal transformation in human adult epicardial cells is regulated by TGFβ-signaling and WT1

Adult epicardial cells are required for endogenous cardiac repair. After myocardial injury, they are reactivated, undergo epithelial-to-mesenchymal transformation (EMT) and migrate into the injured myocardium where they generate various cell types, including coronary smooth muscle cells and cardiac interstitial fibroblasts, which contribute to cardiac repair. To understand what drives epicardial EMT, we used an in vitro model for human adult epicardial cells. These cells have an epithelium-like morphology and markedly express the cell surface marker vascular cell adhesion marker (VCAM-1). In culture, epicardial cells spontaneously undergo EMT after which the spindle-shaped cells now express endoglin. Both epicardial cells before and after EMT express the epicardial marker, Wilms tumor 1 (WT1). Adding transforming growth factor beta (TGFβ) induces loss of epithelial character and initiates the onset of mesenchymal differentiation in human adult epicardial cells. In this study, we show that TGFβ-induced EMT is dependent on type-1 TGFβ receptor activity and can be inhibited by soluble VCAM-1. We also show that epicardial-specific knockdown of Wilms tumor-1 (WT1) induces the process of EMT in human adult epicardial cells, through transcriptional regulation of platelet-derived growth factor receptor alpha (Pdgfrα), Snai1 and VCAM-1. These data provide new insights into the process of EMT in human adult epicardial cells, which might provide opportunities to develop new strategies for endogenous cell-based cardiac repair

Drug-resilient cancer cell phenotype is acquired via polyploidization associated with early stress response coupled to HIF-2α transcriptional regulation

Therapeutic resistance and recurrence remain core challenges in cancer therapy. How therapy resistance arises is currently not fully understood with tumors surviving via multiple alternative routes. Here, we demonstrate that a subset of cancer cells survives therapeutic stress by entering a transient state characterized by whole genome doubling. At the onset of the polyploidization program, we identified an upregulation of key transcriptional regulators, including the early stress-response protein AP-1 and normoxic stabilization of HIF-2α. We found altered chromatin accessibility, ablated expression of RB1, and enrichment of AP-1 motif accessibility. We demonstrate that AP-1 and HIF-2α regulate a therapy resilient and survivor phenotype in cancer cells. Consistent with this, genetic or pharmacologic targeting of AP-1 and HIF-2α reduced the number of surviving cells following chemotherapy treatment. The role of AP-1 and HIF-2α in stress-response by polyploidy suggest a novel avenue for tackling chemotherapy-induced resistance in cancer

Mesenchymal Transition and PDGFRA Amplification/Mutation Are Key Distinct Oncogenic Events in Pediatric Diffuse Intrinsic Pontine Gliomas

Diffuse intrinsic pontine glioma (DIPG) is one of the most frequent malignant pediatric brain tumor and its prognosis is universaly fatal. No significant improvement has been made in last thirty years over the standard treatment with radiotherapy. To address the paucity of understanding of DIPGs, we have carried out integrated molecular profiling of a large series of samples obtained with stereotactic biopsy at diagnosis. While chromosomal imbalances did not distinguish DIPG and supratentorial tumors on CGHarrays, gene expression profiling revealed clear differences between them, with brainstem gliomas resembling midline/thalamic tumours, indicating a closely-related origin. Two distinct subgroups of DIPG were identified. The first subgroup displayed mesenchymal and pro-angiogenic characteristics, with stem cell markers enrichment consistent with the possibility to grow tumor stem cells from these biopsies. The other subgroup displayed oligodendroglial features, and appeared largely driven by PDGFRA, in particular through amplification and/or novel missense mutations in the extracellular domain. Patients in this later group had a significantly worse outcome with an hazard ratio for early deaths, ie before 10 months, 8 fold greater that the ones in the other subgroup (p = 0.041, Cox regression model). The worse outcome of patients with the oligodendroglial type of tumors was confirmed on a series of 55 paraffin-embedded biopsy samples at diagnosis (median OS of 7.73 versus 12.37 months, p = 0.045, log-rank test). Two distinct transcriptional subclasses of DIPG with specific genomic alterations can be defined at diagnosis by oligodendroglial differentiation or mesenchymal transition, respectively. Classifying these tumors by signal transduction pathway activation and by mutation in pathway member genes may be particularily valuable for the development of targeted therapies