Hybrid materials for molecular sieves

Hybrid microporous organosilica membranes for molecular separations made by acid-catalyzed solgel synthesis from bridged silsesquioxane precursors have demonstrated good performance in terms of flux and selectivity and remarkable hydrothermal stability in various pervaporation and gas separation processes. The availability of wide range of α,ω-bis(trialkoxysilyl)alkane and 1,4-bis (triethoxysilyl)benzene precursors allows tuning of membrane properties such as pore size and chemistry. This chapter presents an overview of the synthesis and application of hybrid organosilica microporous membranes in liquid and gas separation processes. After a concise discussion of the history of solgel-derived microporous ceramic membranes for molecular separations, the solgel chemistry of bridged silsesquioxanes and all relevant processing steps needed to obtain a supported microporous films suitable for molecular separations are discussed. The performance of these membranes is correlated with the membrane compositional properties, such as nature, stiffness and length of the bridging group, and details of the solgel process

Summary of cerebrospinal fluid routine parameters in neurodegenerative diseases

In neurodegenerative diseases, cerebrospinal fluid analysis (CSF) is predominantly performed to exclude inflammatory diseases and to perform a risk assessment in dementive disorders by measurement of tau proteins and amyloid beta peptides. However, large scale data on basic findings of CSF routine parameters are generally lacking. The objective of the study was to define a normal reference spectrum of routine CSF parameters in neurodegenerative diseases. Routine CSF parameters (white cell count, lactate and albumin concentrations, CSF/serum quotients of albumin (Qalb), IgG, IgA, IgM, and oligoclonal IgG bands (OCB)) were retrospectively analyzed in an academic research setting. A total of 765 patients (Alzheimer’s disease (AD), Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), vascular dementia (VD), frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), multisystem atrophy (MSA), motor neuron diseases (MND), spinocerebellar ataxia (SCA), Huntington’s disease (HD)) and non-demented control groups including a group of patients with muscular disorders (MD). The main outcome measures included statistical analyses of routine CSF parameters. Mildly elevated Qalb were found in a small percentage of nearly all subgroups and in a higher proportion of patients with PSP, MSA, VD, PDD, and MND. With the exception of 1 MND patient, no intrathecal Ig synthesis was observed. Isolated OCBs in CSF were sometimes found in patients with neurodegenerative diseases without elevated cell counts; lactate levels were always normal. A slightly elevated Qalb was observed in a subgroup of patients with neurodegenerative diseases and does not exclude the diagnosis. Extensive elevation of routine parameters is not characteristic and should encourage a re-evaluation of the clinical diagnosis

Immune Responses Elicited in Tertiary Lymphoid Tissues Display Distinctive Features

During chronic inflammation, immune effectors progressively organize themselves into a functional tertiary lymphoid tissue (TLT) within the targeted organ. TLT has been observed in a wide range of chronic inflammatory conditions but its pathophysiological significance remains unknown. We used the rat aortic interposition model in which a TLT has been evidenced in the adventitia of chronically rejected allografts one month after transplantation. The immune responses elicited in adventitial TLT and those taking place in spleen and draining lymph nodes (LN) were compared in terms of antibody production, T cell activation and repertoire perturbations. The anti-MHC humoral response was more intense and more diverse in TLT. This difference was associated with an increased percentage of activated CD4+ T cells and a symmetric reduction of regulatory T cell subsets. Moreover, TCR repertoire perturbations in TLT were not only increased and different from the common pattern observed in spleen and LN but also “stochastic,” since each recipient displayed a specific pattern. We propose that the abnormal activation of CD4+ T cells promotes the development of an exaggerated pathogenic immune humoral response in TLT. Preliminary findings suggest that this phenomenon i) is due to a defective immune regulation in this non-professional inflammatory-induced lymphoid tissue, and ii) also occurs in human chronically rejected grafts

The BET inhibitor JQ1 selectively impairs tumour response to hypoxia and downregulates CA9 and angiogenesis in triple negative breast cancer

The availability of bromodomain and extra-terminal inhibitors (BETi) has enabled translational epigenetic studies in cancer. BET proteins regulate transcription by selectively recognizing acetylated lysine residues on chromatin. BETi compete with this process leading to both downregulation and upregulation of gene expression. Hypoxia enables progression of triple negative breast cancer (TNBC), the most aggressive form of breast cancer, partly by driving metabolic adaptation, angiogenesis and metastasis through upregulation of hypoxia-regulated genes (for example, carbonic anhydrase 9 (CA9) and vascular endothelial growth factor A (VEGF-A). Responses to hypoxia can be mediated epigenetically, thus we investigated whether BETi JQ1 could impair the TNBC response induced by hypoxia and exert anti-tumour effects. JQ1 significantly modulated 44% of hypoxia-induced genes, of which two-thirds were downregulated including CA9 and VEGF-A. JQ1 prevented HIF binding to the hypoxia response element in CA9 promoter, but did not alter HIF expression or activity, suggesting some HIF targets are BET-dependent. JQ1 reduced TNBC growth in vitro and in vivo and inhibited xenograft vascularization. These findings identify that BETi dually targets angiogenesis and the hypoxic response, an effective combination at reducing tumour growth in preclinical studies

Targeting Angiogenesis-Dependent Calcified Neoplasms Using Combined Polymer Therapeutics

There is an immense clinical need for novel therapeutics for the treatment of angiogenesis-dependent calcified neoplasms such as osteosarcomas and bone metastases. We developed a new therapeutic strategy to target bone metastases and calcified neoplasms using combined polymer-bound angiogenesis inhibitors. Using an advanced "living polymerization" technique, the reversible addition-fragmentation chain transfer (RAFT), we conjugated the aminobisphosphonate alendronate (ALN), and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer through a Glycine-Glycine-Proline-Norleucine linker, cleaved by cathepsin K, a cysteine protease overexpressed at resorption sites in bone tissues. In this approach, dual targeting is achieved. Passive accumulation is possible due to the increase in molecular weight following polymer conjugation of the drugs, thus extravasating from the tumor leaky vessels and not from normal healthy vessels. Active targeting to the calcified tissues is achieved by ALN's affinity to bone mineral.The anti-angiogenic and antitumor potency of HPMA copolymer-ALN-TNP-470 conjugate was evaluated both in vitro and in vivo. We show that free and conjugated ALN-TNP-470 have synergistic anti-angiogenic and antitumor activity by inhibiting proliferation, migration and capillary-like tube formation of endothelial and human osteosarcoma cells in vitro. Evaluation of anti-angiogenic, antitumor activity and body distribution of HPMA copolymer-ALN-TNP-470 conjugate was performed on severe combined immunodeficiency (SCID) male mice inoculated with mCherry-labeled MG-63-Ras human osteosarcoma and by modified Miles permeability assay. Our targeted bi-specific conjugate reduced VEGF-induced vascular hyperpermeability by 92% and remarkably inhibited osteosarcoma growth in mice by 96%.This is the first report to describe a new concept of a narrowly-dispersed combined polymer therapeutic designed to target both tumor and endothelial compartments of bone metastases and calcified neoplasms at a single administration. This new approach of co-delivery of two synergistic drugs may have clinical utility as a potential therapy for angiogenesis-dependent cancers such as osteosarcoma and bone metastases

The emerging dental workforce: why dentistry? A quantitative study of final year dental students' views on their professional career

<p>Abstract</p> <p>Background</p> <p>Dental graduates are joining a profession experiencing changes in systems of care, funding and skill mix. Research into the motivation and expectations of the emerging workforce is vital to inform professional and policy decisions. The objective of this research was to investigate final year dental students' perceived motivation for their choice of career in relation to sex, ethnicity and mode of entry.</p> <p>Methods</p> <p>Self-administered questionnaire survey of all final year dental students at King's College London. Data were entered into SPSS; statistical analysis included Chi Squared tests for linear association, multiple regression, factor analysis and logistic regression.</p> <p>Results</p> <p>A response of 90% (n = 126) was achieved. The majority were aged 23 years (59%), female (58%) and Asian (70%). One in 10 were mature students. Eighty per cent identified 11 or more 'important' or 'very important' influences, the most common of which were related to features of the job: 'regular working hours' (91%), 'degree leading to recognised job' (90%) and 'job security' (90%). There were significant differences in important influences by sex (males > females: 'able to run own business'; females > males: 'a desire to work with people'), ethnic group (Asians > white: 'wish to provide public service', 'influence of friends', 'desire to work in healthcare', having 'tried an alternative career/course' and 'work experience') and mode of entry (mature > early entry: 'a desire to work with people'). Multivariate analysis suggested 61% of the variation in influences is explained by five factors: the 'professional job' (31%), 'healthcare-people' (11%), 'academic-scientific' (8%), 'careers-advising' (6%), and 'family/friends' (6%). The single major influence on choice of career was a 'desire to work with people'; Indian students were twice as likely to report this as white or other ethnic groups.</p> <p>Conclusion</p> <p>Final year dental students report a wide range of important influences on their choice of dentistry, with variation by sex, ethnicity and mode of entry in relation to individual influences. Features of the 'professional job', followed by 'healthcare and people' were the most important underlying factors influencing choice of career.</p

Injectable Materials for the Treatment of Myocardial Infarction and Heart Failure: The Promise of Decellularized Matrices

Cardiovascular disease continues to be the leading cause of death, suggesting that new therapies are needed to treat the progression of heart failure post-myocardial infarction. As cardiac tissue has a limited ability to regenerate itself, experimental biomaterial therapies have focused on the replacement of necrotic cardiomyocytes and repair of the damaged extracellular matrix. While acellular and cellular cardiac patches are applied surgically to the epicardial surface of the heart, injectable materials offer the prospective advantage of minimally invasive delivery directly into the myocardium to either replace the damaged extracellular matrix or to act as a scaffold for cell delivery. Cardiac-specific decellularized matrices offer the further advantage of being biomimetic of the native biochemical and structural matrix composition, as well as the potential to be autologous therapies. This review will focus on the requirements of an ideal scaffold for catheter-based delivery as well as highlight the promise of decellularized matrices as injectable materials for cardiac repair

HIV-1 Residual Viremia Correlates with Persistent T-Cell Activation in Poor Immunological Responders to Combination Antiretroviral Therapy

BACKGROUND:The clinical significance and cellular sources of residual human immunodeficiency virus type 1 (HIV-1) production despite suppressive combination antiretroviral therapy (cART) remain unclear and the effect of low-level viremia on T-cell homeostasis is still debated. METHODOLOGY/PRINCIPAL FINDINGS:We characterized the recently produced residual viruses in the plasma and short-lived blood monocytes of 23 patients with various immunological responses to sustained suppressive cART. We quantified the residual HIV-1 in the plasma below 50 copies/ml, and in the CD14(high) CD16(-) and CD16+ monocyte subsets sorted by flow cytometry, and predicted coreceptor usage by genotyping V3 env sequences. We detected residual viremia in the plasma of 8 of 10 patients with poor CD4+ T-cell reconstitution in response to cART and in only 5 of 13 patients with good CD4+ T-cell reconstitution. CXCR4-using viruses were frequent among the recently produced viruses in the plasma and in the main CD14(high) CD16(-) monocyte subset. Finally, the residual viremia was correlated with persistent CD4+ and CD8+ T-cell activation in patients with poor immune reconstitution. CONCLUSIONS:Low-level viremia could result from the release of archived viruses from cellular reservoirs and/or from ongoing virus replication in some patients. The compartmentalization of the viruses between the plasma and the blood monocytes suggests at least two origins of residual virus production during effective cART. CXCR4-using viruses might be produced preferentially in patients on cART. Our results also suggest that low-level HIV-1 production in some patients may contribute to persistent immune dysfunction despite cART

A Functional Description of Adult Picky Eating Using Latent Profile Analysis

Abstract Objective Research has indicated that adult picky eating (PE) is associated with elevated psychosocial impairment and limited dietary variety and fruit and vegetable intake; however, research operationalizing PE behaviors is limited. Previous research identified a PE profile in children, marked by high food avoidance (satiety responsiveness, fussiness, and slow eating) and low food approach (food enjoyment and responsiveness) appetitive traits. The present study aimed to replicate a similar latent eating behavior profile in an adult sample. Methods A sample of 1339 US adults recruited through Amazon’s MTurk completed an online survey that included a modified self-report version of the Child Eating Behavior Questionnaire (CEBQ-A). Latent profile analysis was employed to identify eating profiles using the CEBQ-A subscales, ANCOVAs were employed to examine profile differences on various self-report measures, and eating profiles were compared across BMI classifications. Results Analyses converged on a four-profile solution, and a picky eater profile that closely resembled the past child profile emerged. Participants in the picky eater profile (18.1%) scored higher on measures of adult PE and social eating anxiety compared to all other profiles, scored higher on eating-related impairment and depression than moderate eating profiles, and were more likely to be of normal weight. Discussion A distinct adult PE profile was observed, indicating childhood PE and appetitive behaviors may carry over into adulthood. Research identifying meaningful groups of picky eaters will help to shed light on the conditions under which picky eating is a risk factor for significant psychosocial impairment or distress, or weight-related problems