A pulsatile flow system to engineer aneurysm and atherosclerosis mimetic extracellular matrix

Alterations of blood flow patterns strongly correlate with arterial wall diseases such as atherosclerosis and aneurysm. Here, a simple, pumpless, close-loop, easy-to-replicate, and miniaturized flow device is introduced to concurrently expose 3D engineered vascular smooth muscle tissues to high-velocity pulsatile flow versus low-velocity disturbed flow conditions. Two flow regimes are distinguished, one that promotes elastin and impairs collagen I assembly, while the other impairs elastin and promotes collagen assembly. This latter extracellular matrix (ECM) composition shares characteristics with aneurysmal or atherosclerotic tissue phenotypes, thus recapitulating crucial hallmarks of flow-induced tissue morphogenesis in vessel walls. It is shown that the mRNA levels of ECM of collagens and elastin are not affected by the differential flow conditions. Instead, the differential gene expression of matrix metalloproteinase (MMP) and their inhibitors (TIMPs) is flow-dependent, and thus drives the alterations in ECM composition. In further support, treatment with doxycycline, an MMP inhibitor and a clinically used drug to treat vascular diseases, halts the effect of low-velocity flow on the ECM remodeling. This illustrates how the platform can be exploited for drug efficacy studies by providing crucial mechanistic insights into how different therapeutic interventions may affect tissue growth and ECM assembly

Early β-amyloid accumulation in the brain is associated with peripheral T cell alterations

INTRODUCTION Fast and minimally invasive approaches for early diagnosis of Alzheimer's disease (AD) are highly anticipated. Evidence of adaptive immune cells responding to cerebral β-amyloidosis has raised the question of whether immune markers could be used as proxies for β-amyloid accumulation in the brain. METHODS Here, we apply multidimensional mass-cytometry combined with unbiased machine-learning techniques to immunophenotype peripheral blood mononuclear cells from a total of 251 participants in cross-sectional and longitudinal studies. RESULTS We show that increases in antigen-experienced adaptive immune cells in the blood, particularly CD45RA-reactivated T effector memory (TEMRA) cells, are associated with early accumulation of brain β-amyloid and with changes in plasma AD biomarkers in still cognitively healthy subjects. DISCUSSION Our results suggest that preclinical AD pathology is linked to systemic alterations of the adaptive immune system. These immunophenotype changes may help identify and develop novel diagnostic tools for early AD assessment and better understand clinical outcomes

Reduced naïve CD8+T-cell priming efficacy in elderly adults

International audienceAging is associated with impaired vaccine efficacy and increased susceptibility to infectious and malignant diseases. CD8 + T-cells are key players in the immune response against pathogens and tumors. In aged mice, the dwindling na€ ıve CD8 + T-cell compartment is thought to compromise the induction of de novo immune responses, but no experimental evidence is yet available in humans. Here, we used an original in vitro assay based on an accelerated dendritic cell coculture system in unfractioned peripheral blood mononuclear cells to examine CD8 + T-cell priming efficacy in human volunteers. Using this approach, we report that old individuals consistently mount quantitatively and qualitatively impaired de novo CD8 + T-cell responses specific for a model antigen. Reduced CD8 + T-cell priming capacity in vitro was further associated with poor primary immune responsiveness in vivo. This immune deficit likely arises as a consequence of intrinsic cellular defects and a reduction in the size of the na€ ıve CD8 + T-cell pool. Collectively, these findings provide new insights into the cellular immune insufficiencies that accompany human aging

Viral infection prevents diabetes by inducing regulatory T cells through NKT cell–plasmacytoid dendritic cell interplay

iNKT cell and pDC cross talk prevents type 1 diabetes by inducing T reg cells in the pancreatic lymph node during viral infection

Cancer cure for 32 cancer types: results from the EUROCARE-5 study.

BACKGROUND: Few studies have estimated the probability of being cured for cancer patients. This study aims to estimate population-based indicators of cancer cure in Europe by type, sex, age and period. METHODS: 7.2 million cancer patients (42 population-based cancer registries in 17 European countries) diagnosed at ages 15-74 years in 1990-2007 with follow-up to 2008 were selected from the EUROCARE-5 dataset. Mixture-cure models were used to estimate: (i) life expectancy of fatal cases (LEF); (ii) cure fraction (CF) as proportion of patients with same death rates as the general population; (iii) time to cure (TTC) as time to reach 5-year conditional relative survival (CRS) >95%. RESULTS: LEF ranged from 10 years for chronic lymphocytic leukaemia patients to 5 years for women with breast cancer. The CF was 94% for testis, 87% for thyroid cancer in women and 70% in men, 86% for skin melanoma in women and 76% in men, 66% for breast, 63% for prostate and <10% for liver, lung and pancreatic cancers. TTC was <5 years for testis and thyroid cancer patients diagnosed below age 55 years, and <10 years for stomach, colorectal, corpus uteri and melanoma patients of all ages. For breast and prostate cancers, a small excess (CRS < 95%) remained for at least 15 years. CONCLUSIONS: Estimates from this analysis should help to reduce unneeded medicalization and costs. They represent an opportunity to improve patients' quality of life

Cancer cure for 32 cancer types: results from the EUROCARE-5 study.

BACKGROUND: Few studies have estimated the probability of being cured for cancer patients. This study aims to estimate population-based indicators of cancer cure in Europe by type, sex, age and period. METHODS: 7.2 million cancer patients (42 population-based cancer registries in 17 European countries) diagnosed at ages 15-74 years in 1990-2007 with follow-up to 2008 were selected from the EUROCARE-5 dataset. Mixture-cure models were used to estimate: (i) life expectancy of fatal cases (LEF); (ii) cure fraction (CF) as proportion of patients with same death rates as the general population; (iii) time to cure (TTC) as time to reach 5-year conditional relative survival (CRS) >95%. RESULTS: LEF ranged from 10 years for chronic lymphocytic leukaemia patients to 5 years for women with breast cancer. The CF was 94% for testis, 87% for thyroid cancer in women and 70% in men, 86% for skin melanoma in women and 76% in men, 66% for breast, 63% for prostate and <10% for liver, lung and pancreatic cancers. TTC was <5 years for testis and thyroid cancer patients diagnosed below age 55 years, and <10 years for stomach, colorectal, corpus uteri and melanoma patients of all ages. For breast and prostate cancers, a small excess (CRS < 95%) remained for at least 15 years. CONCLUSIONS: Estimates from this analysis should help to reduce unneeded medicalization and costs. They represent an opportunity to improve patients' quality of life

Cardiovascular Regenerative Technologies: Update and Future Outlook

In the effort of improving treatment for cardiovascular disease (CVD), scientists struggle with the lack of the regenerative capacities of finally differentiated cardiovascular tissues. In this context, the advancements in regenerative medicine contributed to the development of cell-based therapies as well as macro- and micro-scale tissue-engineering technologies. The current experimental approaches focus on different regenerative strategies including a broad spectrum of techniques such as paracrine-based stimulation of autologous cardiac stem cells, mesenchymal cell injections, 3D microtissue culture techniques and vascular tissue-engineering methods. These potential next-generation strategies are leading the way to a revolution in addressing CVD, and numerous studies are now undertaken to assess their therapeutic value. With this review, we provide an update on the current research directions, on their major challenges, limitations, and achievements

Biofabricating atherosclerotic plaques: In vitro engineering of a three-dimensional human fibroatheroma model

Atherosclerotic plaques are cholesterol-induced inflammatory niches accumulating in the vascular sub-endothelial space. Cellular and extracellular composition of human plaques is maneuvered by local inflammation that leads to alterations in the original vascular microenvironment and to the recruitment of an invading fibrous layer (fibroatharoma). In the present study we introduce a bioengineered three-dimensional model of human fibroatheroma (ps-plaque) assembled with a tailored hanging-drop protocol. Using vi-SNE based multidimensional flow cytometry data analysis we compared the myeloid cell-populations in ps-plaques to those in plaques isolated from human carotid arteries. We observed that plasmacytoid and activated dendritic cells are the main myeloid components of human carotid plaques and that both cell types are present in the biofabricated model. We found that low-density lipoproteins affect cell viability and contribute to population polarization in ps-plaques. The current work describes the first human bioengineered in vitro model of late atherosclerotic lesion for the investigation of atherosclerosis aetiopathogenesis

Oligomeric Forms of Human Amyloid-Beta(1-42) Inhibit Antigen Presentation.

Genetic, clinical, biochemical and histochemical data indicate a crucial involvement of inflammation in Alzheimer's disease (AD), but harnessing the immune system to cure or prevent AD has so far proven difficult. Clarifying the cellular heterogeneity and signaling pathways associated with the presence of the AD hallmarks beta-amyloid and tau in the brain, would help to identify potential targets for therapy. While much attention has been so far devoted to microglia and their homeostatic phagocytic activity, additional cell types and immune functions might be affected in AD. Beyond microglia localized in the brain parenchyma, additional antigen-presenting cell (APC) types might be affected by beta-amyloid toxicity. Here, we investigated potential immunomodulatory properties of oligomeric species of beta-amyloid-peptide (Aβ) on microglia and putative APCs. We performed a comprehensive characterization of time- and pathology-dependent APC and T-cell alterations in a model of AD-like brain beta-amyloidosis, the APP-PS1-dE9 mouse model. We show that the deposition of first beta-amyloid plaques is accompanied by a significant reduction in MHC class II surface levels on brain APCs. Furthermore, taking advantage of customized in vitro systems and RNAseq, we demonstrate that a preparation containing various forms of oligomeric Aβ1-42 inhibits antigen presentation by altering the transcription of key immune mediators in dendritic cells. These results suggest that, beyond their neurotoxic effects, certain oligomeric Aβ forms can act as immunomodulatory agents on cerebral APCs and interfere with brain antigen presentation. Impaired brain immune surveillance might be one of the factors that facilitate Aβ and tau spreading in AD