Harm-to-Benefit Ratio of Fecal Immunochemical Test-Based Screening for Colorectal Cancer Given Prior Fecal Hemoglobin Concentrations.

Background And Aims: This study aimed to provide evidence on the harm-to-benefit ratio of fecal immunochemical test (FIT)-based colorectal cancer (CRC) screening by previous fecal hemoglobin (f-Hb) concentrations, as reflected in the number needed to screen (NNS) and number needed to scope (NNSc).

Methods: Participants in up to 4 FIT screening rounds of the Dutch CRC screening program were included. The main outcomes of this study were the NNS and NNSc to detect 1 CRC and/or advanced neoplasia (AN) in screening rounds 2, 3, or 4, conditional on previous f-Hb concentrations.

Development and evaluations of the ancestry informative markers of the VISAGE Enhanced Tool for Appearance and Ancestry.

The VISAGE Enhanced Tool for Appearance and Ancestry (ET) has been designed to combine markers for the prediction of bio-geographical ancestry plus a range of externally visible characteristics into a single massively parallel sequencing (MPS) assay. We describe the development of the ancestry panel markers used in ET, and the enhanced analyses they provide compared to previous MPS-based forensic ancestry assays. As well as established autosomal single nucleotide polymorphisms (SNPs) that differentiate sub-Saharan African, European, East Asian, South Asian, Native American, and Oceanian populations, ET includes autosomal SNPs able to efficiently differentiate populations from Middle East regions.

Imputation-powered whole-exome analysis identifies genes associated with kidney function and disease in the UK Biobank.

Genome-wide association studies have discovered hundreds of associations between common genotypes and kidney function but cannot comprehensively investigate rare coding variants. Here, we apply a genotype imputation approach to whole exome sequencing data from the UK Biobank to increase sample size from 166,891 to 408,511. We detect 158 rare variants and 105 genes significantly associated with one or more of five kidney function traits, including genes not previously linked to kidney disease in humans.

Evaluation of supervised machine-learning methods for predicting appearance traits from DNA.

The prediction of human externally visible characteristics (EVCs) based solely on DNA information has become an established approach in forensic and anthropological genetics in recent years. While for a large set of EVCs, predictive models have already been established using multinomial logistic regression (MLR), the prediction performances of other possible classification methods have not been thoroughly investigated thus far. Motivated by the question to identify a potential classifier that outperforms these specific trait models, we conducted a systematic comparison between the widely used MLR and three popular machine learning (ML) classifiers, namely support vector machines (SVM), random forest (RF) and artificial neural networks (ANN), that have shown good performance outside EVC prediction.

Testing the impact of trait prevalence priors in Bayesian-based genetic prediction modeling of human appearance traits.

The prediction of appearance traits by use of solely genetic information has become an established approach and a number of statistical prediction models have already been developed for this purpose. However, given limited knowledge on appearance genetics, currently available models are incomplete and do not include all causal genetic variants as predictors. Therefore such prediction models may benefit from the inclusion of additional information that acts as a proxy for this unknown genetic background.

Anti-CD20 Agents for Multiple Sclerosis: Spotlight on Ocrelizumab and Ofatumumab.

Until recently, in the pathogenesis of Multiple Sclerosis (MS), the contribution of B cells has been largely underestimated, and the disease was considered a T-cell-mediated disorder. However, newer evidence shows that B cells play a crucial role in the pathogenesis of MS via antigen-driven autoantibody responses and through the cross regulation of T-helper cells. As B cells express the surface molecule CD20 at all points of differentiation, it provides a specific target for monoclonal antibodies, and the development and clinical testing of anti-CD20 antibody treatments for MS have been successful.

True colors: A literature review on the spatial distribution of eye and hair pigmentation.

DNA-based prediction of externally visible characteristics has become an established approach in forensic genetics, with the aim of tracing individuals who are potentially unknown to the investigating authorities but without using this prediction as evidence in court. While a number of prediction models have been proposed, use of prior probabilities in those models has largely been absent. Here, we aim at compiling information on the spatial distribution of eye and hair coloration in order to use this as prior knowledge to improve prediction accuracy.

Cyclization of PLP peptide reduces its encephalitogenic potential in experimental autoimmune encephalomyelitis.

We report the novel synthesis of cyclic PLP (cPLP) and its application in SJL/J mice to study its encephalitogenic effects. Our results indicate that the cPLP analog is minimally encephalitogenic when administered to induce experimental autoimmune encephalomyelitis (low disease burden, minimal inflammatory, demyelinating and axonopathic pathology compared to its linear counterpart). Proliferation assays confirmed the low stimulatory potential of the cPLP compared to linPLP (2.

Multiple Sclerosis: Immunopathology and Treatment Update.

The treatment of multiple sclerosis (MS) has changed over the last 20 years. All immunotherapeutic drugs target relapsing remitting MS (RRMS) and it still remains a medical challenge in MS to develop a treatment for progressive forms. The most common injectable disease-modifying therapies in RRMS include β-interferons 1a or 1b and glatiramer acetate.

Immune responses of linear and cyclic PLP139-151 mutant peptides in SJL/J mice: peptides in their free state versus mannan conjugation.

Background: The predominant proteins of the CNS are myelin basic protein, proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein. PLP139-151 is one of the major encephalitogenic epitopes of PLP. The epitope PLP139-151 binds to MHC class II (I-A(s)) of SJL/J mice and induces Th1 responses.

Conformational studies of immunodominant myelin basic protein 1-11 analogues using NMR and molecular modeling.

Τwo dimensional nuclear magnetic resonance studies complimented by molecular dynamics simulations were conducted to investigate the conformation of the immunodominant epitope of acetylated myelin basic protein residues 1-11 (Ac-MBP(1-11)) and its altered peptide ligands, mutated at position 4 to an alanine (Ac-MBP(1-11)[4A]) or a tyrosine residue (Ac-MBP(1-11)[4Y]). Conformational analysis of the three analogues indicated that they adopt an extended conformation in DMSO solution as no long distance NOE connectivities were observed and seem to have a similar conformation when bound to the active site of the major histocompatibility complex (MHC II). The interaction of each peptide with MHC class II I-A(u) was further investigated in order to explore the molecular mechanism of experimental autoimmune encephalomyelitis induction/inhibition in mice.

A complementary role for the tetraspanins CD37 and Tssc6 in cellular immunity.

The cooperative nature of tetraspanin-tetraspanin interactions in membrane organization suggests functional overlap is likely to be important in tetraspanin biology. Previous functional studies of the tetraspanins CD37 and Tssc6 in the immune system found that both CD37 and Tssc6 regulate T cell proliferative responses in vitro. CD37(-/-) mice also displayed a hyper-stimulatory dendritic cell phenotype and dysregulated humoral responses.

Methods to measure T-cell responses.

A successful vaccine for immunotherapy, particularly for solid tumors or viral infections, requires a suitable target antigen and the production of a cytotoxic T-cell response. In addition, CD4 T cells play an important role in cellular immunity. Here, we briefly discuss methods by which T cells are measured in vitro after vaccination.

Structural elucidation of Leuprolide and its analogues in solution: insight into their bioactive conformation.

Leuprolide [DLeu6, NHEt10]GnRH, a potent gonadotropin-releasing hormone (GnRH) agonist, is used in a wide variety of hormone-related diseases like cancer and endometriosis. In this report, the conformational behaviour of Leuprolide and its linear synthetic analogues, namely [Tyr5(OMe), DLeu6, Aze9, NHEt10]GnRH (1) and [Tyr5(OMe), DLeu6, NHEt10]GnRH (2) have been studied in DMSO and H2O solutions by means of 2D nuclear magnetic resonance (NMR) experiments and detailed molecular dynamics (MD) simulations. The aim was to identify the conformational requirements of GnRH analogues for agonistic activity.

Acute respiratory admissions in Thessaloniki, Greece: 14-year follow-up.

Background: Acute exacerbations of respiratory diseases are a common cause of hospitalization among infants and children.

Aim: To assess the epidemiological characteristics of asthma, bronchiolitis and croup among hospitalized children in Thessaloniki, from 1990 to 2003 included.

Methods: Data from the patient registry with discharge diagnosis "asthma", "bronchiolitis" and "croup" were analyzed retrospectively, in five Paediatric Departments of Thessaloniki.

Altered peptide ligands of myelin basic protein ( MBP87-99 ) conjugated to reduced mannan modulate immune responses in mice.

Mutations of peptides to generate altered peptide ligands, capable of switching immune responses from T helper 1 (Th1) to T helper 2 (Th2), are promising candidates for the immunotherapy of autoimmune diseases such as multiple sclerosis (MS). We synthesized two mutant peptides from myelin basic protein 87-99 (MBP(87-99)), an immunodominant peptide epitope identified in MS. Mutations of residues K(91) and P(96), known to be critical T-cell receptor (TCR) contact sites, resulted in the mutant peptides [R(91), A(96)]MBP(87-99) and [A(91), A(96)]MBP(87-99).

Design and synthesis of a cyclic double mutant peptide (cyclo(87-99)[A91,A96]MBP87-99) induces altered responses in mice after conjugation to mannan: implications in the immunotherapy of multiple sclerosis.

Altered peptide ligands that alter immune responses are a promising approach to the immunotherapy of multiple sclerosis. Cyclic peptides are of interest because the limited stability of linear peptides restricts their use in vivo. We designed and synthesized a cyclic double mutant peptide from MBP(87-99)-[cyclo(87-99)[A(91),A(96)]MBP(87-99)].

Citrullination of linear and cyclic altered peptide ligands from myelin basic protein (MBP(87-99)) epitope elicits a Th1 polarized response by T cells isolated from multiple sclerosis patients: implications in triggering disease.

Derangement of cellular immunity is central in the pathophysiology of multiple sclerosis (MS) and is often manifested by abnormal cytokine production. We investigated cytokine secretion in peripheral blood mononuclear cells (PBMC) of 18 MS patients and 15 controls and correlated cytokine polarization with the nature of antigenic stimulus. We synthesized two novel citrullinated peptides, linear [Cit(91), Ala(96), Cit(97)]MBP(87-99) and cyclo(87-99)[Cit(91), Ala(96), Cit(97)]MBP(87-99) that resulted from citrullination of 91,97 Arg residues in antagonists, linear [Arg(91), Ala(96)]MBP(87-99) and cyclo(87-99)[Arg(91), Ala(96)]MBP(87-99) peptides.

The good, the bad and the ugly: how altered peptide ligands modulate immunity.

Background: The basis of T cell immune responses is the specific recognition of an immunogenic peptide epitope by a T cell receptor. Peptide alterations of such T cell epitopes with single or few amino acid variations can have drastic effects on the outcome of this recognition. These altered peptide ligands can act as modulators of immune responses as they are capable of downregulating or upregulating responses.

Strategies used for MUC1 immunotherapy: human clinical studies.

MUC1 is a high-molecular-weight glycoprotein that is overexpressed in adenocarcinomas and hematological cancers. Numerous preclinical studies in mice have demonstrated that MUC1 is immunogenic, and that cellular and humoral immune responses could be induced depending on the MUC1 vaccine formulation. MUC1-based vaccines have quickly entered into human clinical trials, and immune responses and some clinical responses have been reported.

A double mutation of MBP(83-99) peptide induces IL-4 responses and antagonizes IFN-gamma responses.

A number of treatment options are available to multiple sclerosis patients, however this needs to be improved. Herein, we designed and synthesized a number of peptides by mutating principal TCR contact residues based on MBP(83-99) peptide epitope. Immunization of SJL/J mice with MBP(83-99) and mutant [A(91)]MBP(83-99), [E(91)]MBP(83-99), [F(91)]MBP(83-99), [Y(91)]MBP(83-99), and [R(91), A(96)]MBP(83-99) peptides, induced IFN-gamma, and only [R(91), A(96)]MBP(83-99) mutant peptide was able to induce IL-4 secretion by T cells.

Towards immunotherapeutic drugs and vaccines against multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. Numerous treatment options are available to MS patients; however, these options need to be improved. Herein, we review the current drugs and therapeutic approaches available to MS patients, preclinical trial interventions and recent animal model studies for the potential therapy of MS.

Design of novel cyclic altered peptide ligands of myelin basic protein MBP83-99 that modulate immune responses in SJL/J mice.

The use of antagonist peptides derived from the myelin sheath constitutes a promising therapeutic approach for multiple sclerosis (MS). Cyclization of peptide analogues is of great interest, since the limited stability of linear peptides restricts their potential as therapeutic agents. Herein, we designed and synthesized a number of cyclic peptides by mutating TCR contact sites of the MBP 83-99 epitope.

Mannosylation of mutated MBP83-99 peptides diverts immune responses from Th1 to Th2.

Multiple sclerosis (MS) is an autoimmune demyelinating disease mediated primarily by CD4+ T cells. The design of peptide mutants of disease-associated myelin epitopes to alter immune responses offers a promising avenue for the treatment of MS. We designed and synthesized a number of peptide analogs by mutating the principal TCR contact residue based on MBP83-99 epitope and these peptides were conjugated to reduced mannan.