The correlation between inflammatory biomarkers and polygenic risk score in Alzheimer's Disease

Plasma biomarkers to aid the early diagnosis of Alzheimer’s disease (AD) or to monitor disease progression have long been sought and continue to be widely studied. Biomarkers that correlate with AD polygenic risk score, a measure of the polygenic architecture of the disease and highly predictive of AD status, would be excellent candidates. Therefore, we undertook a preliminary study to assess the association of plasma inflammatory biomarkers with an overall AD polygenic risk score as well as with an inflammation-specific AD polygenic risk score in a sample set of 93 AD cases. We measured five complement biomarkers [complement receptor 1 (CR1), clusterin, complement component 9 (C9), C1 inhibitor (C1inh), terminal complement complex (TCC)] and the benchmark inflammatory marker C-reactive protein (CRP). Plasma clusterin level showed an association with overall AD polygenic risk score, while clusterin, C1inh, and CRP levels each displayed some association with the inflammatory-specific AD polygenic risk score. The results suggest that elevated plasma levels of inflammatory biomarkers, including complement proteins, associate with polygenic risk scores in AD, further strengthening the link between genetic and biomarker disease predictors and indicating a potential role for these markers in disease prediction and patient stratification in AD

Purity of transferred CD8+ T cells is crucial for safety and efficacy of combinatorial tumor immunotherapy in the absence of SHP-1

Adoptive transfer of tumor-specific cytotoxic T cells is a promising advance in cancer therapy. Similarly, checkpoint inhibition has shown striking clinical results in some patients. Here we combine adoptive cell transfer with ablation of the checkpoint protein Src homology 2-domain-containing phosphatase 1 (SHP-1, Ptpn6). Naturally occurring motheaten mice lack SHP-1 and do not survive weaning due to extensive immunopathology. To circumvent this limitation, we created a novel SHP-1(null) mouse that is viable up to 12 weeks of age by knocking out IL1r1. Using this model, we demonstrate that the absence of SHP-1 augments the ability of adoptively transferred CD8(+) T cells to control tumor growth. This therapeutic effect was only observed in situations where T-cell numbers were limited, analogous to clinical settings. However, adoptive transfer of non-CD8(+) SHP-1(null) hematopoietic cells resulted in lethal motheaten-like pathology, indicating that systemic inhibition of SHP-1 could have serious adverse effects. Despite this caveat, our findings support the development of SHP-1 inhibition strategies in human T cells to complement adoptive transfer therapies in the clinic

ADAM17-dependent proteolysis of L-selectin promotes early clonal expansion of cytotoxic T cells

L-selectin on T-cells is best known as an adhesion molecule that supports recruitment of blood-borne naïve and central memory cells into lymph nodes. Proteolytic shedding of the ectodomain is thought to redirect activated T-cells from lymph nodes to sites of infection. However, we have shown that activated T-cells re-express L-selectin before lymph node egress and use L-selectin to locate to virus-infected tissues. Therefore, we considered other roles for L-selectin proteolysis during T cell activation. In this study, we used T cells expressing cleavable or non-cleavable L-selectin and determined the impact of L-selectin proteolysis on T cell activation in virus-infected mice. We confirm an essential and non-redundant role for ADAM17 in TCR-induced proteolysis of L-selectin in mouse and human T cells and show that L-selectin cleavage does not regulate T cell activation measured by CD69 or TCR internalisation. Following virus infection of mice, L-selectin proteolysis promoted early clonal expansion of cytotoxic T cells resulting in an 8-fold increase over T cells unable to cleave L-selectin. T cells unable to cleave L-selectin showed delayed proliferation in vitro which correlated with lower CD25 expression. Based on these results, we propose that ADAM17-dependent proteolysis of L-selectin should be considered a regulator of T-cell activation at sites of immune activity

Association of maternal prenatal copper concentration with gestational duration and preterm birth: a multicountry meta-analysis

Background Copper (Cu), an essential trace mineral regulating multiple actions of inflammation and oxidative stress, has been implicated in risk for preterm birth (PTB). Objectives This study aimed to determine the association of maternal Cu concentration during pregnancy with PTB risk and gestational duration in a large multicohort study including diverse populations. Methods Maternal plasma or serum samples of 10,449 singleton live births were obtained from 18 geographically diverse study cohorts. Maternal Cu concentrations were determined using inductively coupled plasma mass spectrometry. The associations of maternal Cu with PTB and gestational duration were analyzed using logistic and linear regressions for each cohort. The estimates were then combined using meta-analysis. Associations between maternal Cu and acute-phase reactants (APRs) and infection status were analyzed in 1239 samples from the Malawi cohort. Results The maternal prenatal Cu concentration in our study samples followed normal distribution with mean of 1.92 μg/mL and standard deviation of 0.43 μg/mL, and Cu concentrations increased with gestational age up to 20 wk. The random-effect meta-analysis across 18 cohorts revealed that 1 μg/mL increase in maternal Cu concentration was associated with higher risk of PTB with odds ratio of 1.30 (95% confidence interval [CI]: 1.08, 1.57) and shorter gestational duration of 1.64 d (95% CI: 0.56, 2.73). In the Malawi cohort, higher maternal Cu concentration, concentrations of multiple APRs, and infections (malaria and HIV) were correlated and associated with greater risk of PTB and shorter gestational duration. Conclusions Our study supports robust negative association between maternal Cu and gestational duration and positive association with risk for PTB. Cu concentration was strongly correlated with APRs and infection status suggesting its potential role in inflammation, a pathway implicated in the mechanisms of PTB. Therefore, maternal Cu could be used as potential marker of integrated inflammatory pathways during pregnancy and risk for PTB

A novel Alzheimer disease locus located near the gene encoding tau protein

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAPOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ε4+ (10 352 cases and 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted

Bartrum Genealogical Project

Sail y prosiect hwn yw llafur cariad Dr P C Bartrum, gŵr heb unrhyw gysylltiad â Chymru a aned yn Hampstead, Llundain, ac a fu farw yn 2008 yn gan mlwydd oed. Meteorolegydd ydoedd wrth ei alwedigaeth hyd ei ymddeoliad yn 1955, ond serch hynny, ef oedd, yng ngeiriau Dr Michael Siddons, 'pennaf ysgolhaig achyddiaeth Gymreig ganoloesol' (ysgrif goffa yn Studia Celtica 43 (2009) 221-2). Er 1929 bu’n casglu gwybodaeth am achau’r Cymry o weithiau cynnar megis Brut y Tywysogion ac o lawysgrifau fel Harley 3859 (a gedwir yn y Llyfrgell Brydeinig) sy’n dyddio o tua 1100 a llawysgrifau eraill yn dyddio gan mwyaf o’r 15fed ganrif ymlaen, rhai a luniwyd gan yr arwyddfeirdd, sef y beirdd a oedd yn arbenigwyr ar hanes achyddol yr uchelwyr. Yn 1974 cyhoeddodd Dr Bartrum gyfres o 8 gyfrol o dan y teitl Welsh Genealogies AD 330-1400 (WG1) (Gwasg Prifysgol Cymru), ac yn 1983 cyhoeddodd 18 cyfrol fel dilyniant i’r gyfres gyntaf, Welsh Genealogies AD 1400-1500 (WG2) (Llyfrgell Genedlaethol Cymru). Ers eu cyhoeddi bu Dr Bartrum yn ychwanegu atynt yn helaeth ac yn eu cywiro. Trosglwyddodd ei set bersonol ef ei hun o’r cyfrolau i ofal yr Adran Gymraeg lle bu tîm o ymchwilwyr yn sganio’r deunydd yn electronaidd er mwyn ei gyhoeddi ar y we ac ar DVD. Archive Cyff-Cyfl contains the introduction with all abbreviations etc to Welsh Genealogies 300-1400 (WG1) and Welsh Genealogies 1400-1500 (WG2). Archives CyffA to CyffY are colour scans of the entire contents of WG1; and archives WG1Ind1 to WG1Ind11 contain the indices to those volumes. N.B. Plates 32-40 of CyffRh were left blank by Dr. Bartrum. Archives Tab1 to Tab9 are colour scans of the entire contents of WG2; and archives WG2Ind1 to WG2Ind23 contain the indices to those volumes.The Bartrum Project is based on the work of Dr P. C. Bartrum who died in 2008 at the age of 100. A native of Hampstead, London, he had no links with Wales whatsoever, and worked as meteorologist until his retirement in 1955. Nevertheless, in the words of Dr Michael Siddons, he became 'the foremost scholar of medieval Welsh genealogy' (obituary in Studia Celtica 43 (2009) 221-2). Since 1929 he collected information about Welsh ancestry from early works such as Brut y Tywysogion, manuscripts such as Harley 3859 (which is kept at the British Library) which dates from around 1100, and other manuscripts largely from the 15th century onwards, which were compiled by heraldic bards, poets who were experts in the ancestral history of noble families. In 1974 Dr Bartrum published an 8 volume series under the title Welsh Genealogies AD 300-1400 (WG1) (University of Wales Press), and in 1983 he published a further 18 volumes, Welsh Genealogies AD 1400-1500 (WG2) (National Library of Wales). Since their publication Dr Bartrum revised the work adding significant amendments and corrections. He then handed his own emended typescript over to the Welsh Department where a team of researchers started on the work of electronically scanning all the work so that it can be published on-line and as a DVD. Archive Cyff-Cyfl contains the introduction with all abbreviations etc to Welsh Genealogies 300-1400 (WG1) and Welsh Genealogies 1400-1500 (WG2). Archives CyffA to CyffY are colour scans of the entire contents of WG1; and archives WG1Ind1 to WG1Ind11 contain the indices to those volumes. N.B. Plates 32-40 of CyffRh were left blank by Dr. Bartrum. Archives Tab1 to Tab9 are colour scans of the entire contents of WG2; and archives WG2Ind1 to WG2Ind23 contain the indices to those volumes

Profound inhibition of antigen-specific T-cell effector functions by dasatinib

Purpose: The dual BCR-ABL/SRC kinase inhibitor dasatinib entered the clinic for the treatment of chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. Because SRC kinases are known to play an important role in physiologic T-cell activation, we analyzed the immunobiological effects of dasatinib on T-cell function. The effect of dasatinib on multiple T-cell effector functions was examined at clinically relevant doses (1-100 nmol/L); the promiscuous tyrosine kinase inhibitor staurosporine was used as a comparator. Experimental Design: Purified human CD3+ cells and virus-specific CD8+ T cells from healthy blood donors were studied directly ex vivo; antigen-specific effects were confirmed in defined T-cell clones. Functional outcomes included cytokine production (interleukin-2, IFNγ, and tumor necrosis factor α), degranulation (CD107a/b mobilization), activation (CD69 up-regulation), proliferation (carboxyfluorescein diacetate succinimidyl ester dilution), apoptosis/necrosis induction, and signal transduction. Results: Both dasatinib and staurosporine inhibited T-cell activation, proliferation, cytokine production, and degranulation in a dose-dependent manner. Mechanistically, this was mediated by the blockade of early signal transduction events and was not due to loss of T-cell viability. Overall, CD4+ T cells seemed to be more sensitive to these effects than CD8+ T cells, and naïve T cells more sensitive than memory T-cell subsets. The inhibitory effects of dasatinib were so profound that all T-cell effector functions were shut down at therapeutically relevant concentrations. Conclusion: These findings indicate that caution is warranted with use of this drug in the clinical setting and provide a rationale to explore the potential of dasatinib as an immunosuppressant in the fields of transplantation and T-cell–driven autoimmune disease