Vitamin D receptor genotype influences risk of upper respiratory infection.

SNP in the vitamin D receptor (VDR) gene is associated with risk of lower respiratory infections. The influence of genetic variation in the vitamin D pathway resulting in susceptibility to upper respiratory infections (URI) has not been investigated. We evaluated the influence of thirty-three SNP in eleven vitamin D pathway genes (DBP, DHCR7, RXRA, CYP2R1, CYP27B1, CYP24A1, CYP3A4, CYP27A1, LRP2, CUBN and VDR) resulting in URI risk in 725 adults in London, UK, using an additive model with adjustment for potential confounders and correction for multiple comparisons. Significant associations in this cohort were investigated in a validation cohort of 737 children in Manchester, UK. In all, three SNP in VDR (rs4334089, rs11568820 and rs7970314) and one SNP in CYP3A4 (rs2740574) were associated with risk of URI in the discovery cohort after adjusting for potential confounders and correcting for multiple comparisons (adjusted incidence rate ratio per additional minor allele ≥1·15, P for trend ≤0·030). This association was replicated for rs4334089 in the validation cohort (P for trend=0·048) but not for rs11568820, rs7970314 or rs2740574. Carriage of the minor allele of the rs4334089 SNP in VDR was associated with increased susceptibility to URI in children and adult cohorts in the United Kingdom.National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Ref. no. RP-PG-0407-10398). Chair from Asthma UK (no. CH11SJ) and Medical Research Council Centre (grant no. G1000758)

Enhanced T-cell maturation and monocyte aggregation are features of cellular inflammation in human T-lymphotropic virus type-1-associated myelopathy

Background Human T-lymphotropic virus type-1 (HTLV-1) associated myelopathy (HAM), is an inflammatory condition characterised by severe disability and high levels of infected white blood cells. The circulating cellular inflammatory changes that distinguish this condition from asymptomatic infection are not well understood. Methods To investigate the immune characteristics of individuals with low or high HTLV-1 proviral load (pVL), symptomatic disease and the impact of immunosuppressive therapy, thirty-eight women living with HTLV-1 infection, with a median age 59 (52-68) years were studied. Nineteen were asymptomatic carriers, with low or high pVL, and nineteen were diagnosed with HAM, with ten receiving anti-inflammatory therapy. Peripheral blood mononuclear cells were stained and analysed for frequency distribution and activation of innate and adaptive immune cell subsets using multi-parameter flow cytometry. Results Inflation of the CD4:CD8 ratio (>2) was observed amongst all groups irrespective of pVL. The frequency of naïve CD4+ T-cells correlated inversely with HTLV-1 pVL (rs=-0.344, p=0.026). Mature TEM CD4+ T-cells were expanded in patients with untreated HAM compared with asymptomatic carriers (p<0.001), but less so in those on therapy. High levels of exhausted (PD-1+) and senescent (CD28null) CD4+ and CD8+ T-cells were observed in all individuals particularly in those with HAM, whilst monocytes showed increased aggregation, and CD14+CD56- monocytes were less frequent. Conclusions CD4:CD8 ratio inflation is a feature of HTLV-1 infection, whereas enhanced CD4+ T-cell maturation and monocyte aggregation are features of HAM reflecting widespread inflammatory change, which may be detectable pre-symptomatically, and be amenable to anti-inflammatory treatment

Revisiting binary sequence length requirements for the accurate emulation of highly dispersive transmission systems

For accurate emulation, pseudo-random sequence lengths need not exceed requirements of Monte- Carlo theory, scaling like the inverse of the expected bit error rate, even with strong inter-symbol correlations

Quantification of T cell clonality in Human T cell leukaemia virus type-1 carriers can detect the development of Adult T cell Leukaemia early

Adult T cell leukaemia/lymphoma (ATL) arises from clonally expanded T cells which are infected with Human T cell leukaemia virus type-1 (HTLV-1). Here, we show that ATL could be detected early in HTLV-1-carriers through quantification of T-cell receptor (TCR)Vβ subunit diversity on T-cells infected with HTLV-1 (CD3+CCR4+CD26-T-cells) using an ‘oligoclonality index’ (OCI-flow). We established a reference range for OCI-flow by analysing peripheral blood mononuclear cells (PBMCs) from HTLV-1-carriers who had not developed ATL in a median of 10.5 years follow up (n=38) and patients with ATL (n=30). In a third cohort of HTLV-1-carriers with no history or clinical evidence of ATL (n=106), 19% of high proviral load (PVL, ≥4 copies of HTLV-1/100 PBMCs) carriers had an OCI-flow in the ATL range, >0.770. Carriers with an OCI-flow >0.770 (n=14) had higher lymphocyte counts and PVLs, and were more likely to have a family history of ATL than carriers with OCI-flow ≤0.770. ATL subsequently developed in two of these 14 carriers but no carriers with OCI-flow ≤0.770 (p=0.03, cumulative follow-up 129 person-years). This method can be used to identify a subset of high-PVL HTLV-1-carriers at increased risk of developing ATL who may benefit from intervention therapy, prior to the detection of disease

Long-term clinical remission maintained after cessation of zidovudine and interferon-α therapy in chronic adult T-cell leukemia/lymphoma

Globally, > 5–10 million people are estimated to be infected with Human T-lymphotropic virus type 1 (HTLV-1), of whom ~ 5% develop adult T-cell leukemia/lymphoma (ATL). Despite advances in chemotherapy, overall survival (OS) has not improved in the 35 years since HTLV-1 was first described. In Europe/USA, combination treatment with zidovudine and interferon-α (ZDV/IFN-α) has substantially changed the management of patients with the leukemic subtypes of ATL (acute or unfavorable chronic ATL) and is under clinical trial evaluation in Japan. However, there is only a single published report of long-term clinical remission on discontinuing ZDV/IFN-α therapy and the optimal duration of treatment is unknown. Anecdotal cases where therapy is discontinued due to side effects or compliance have been associated with rapid disease relapse, and it has been widely accepted that the majority of patients will require life-long therapy. The development of molecular methods to quantify minimal residual disease is essential to potentially guide therapy for individual patients. Here, for the first time, we report molecular evidence that supports long-term clinical remission in a patient who was previously treated with ZDV/IFN-α for 5 years, and who has now been off all therapy for over 6 years

Explore-ALK : étude de cohorte prospectif non interventionnelle, nationale et multicentrique de patients atteints de cancer bronchopulmonaire non à petites cellules caractérisés par un réarrangement ALK. Caractéristiques cliniques et biologiques des 100 premiers patients de la cohorte

National audienceLes cancers broncho-pulmonaire non à petites cellules (CBNPC) avec réarrangement ALK représente environ 5 % des adénocarcinomes bronchique [1]. Il s’agit d’un sous-groupe de patients particularités cliniques et radiologiques. De fait la prévalence du réarrangement, les données ne sont pas exhaustives. objectifs l’étude explore-ALK mieux caractériser ces sur le plan clinique, d’évaluer séquences thérapeutiques, l’efficacité tolérance différentes lignes traitement pratique courante en termes recherche mécanisme résistance. L’étude Explore GFPC 03-2019 (ID RCB 2020-A00771-38) est une cohorte multicentrique prospective interventionnelle atteints CBPNC ALK. inclus manière consécutive sans restriction d’état général ni modalités thérapeutiques. Ils suivis selon pratiques chaque centre. L’évaluation réponse, progression locales. La survie globale calculée partir date diagnostic. Nous présentons l’inclusion 100 premiers Au total, 101 ont été 22/07/2020 dans 30/06/2022 par 22 centres, 57 étaient femmes, 50 non-fumeurs. diagnostic, 84 16 un ECOG-PS 0/1 &amp;gt; 2 respectivement. répartition stades au diagnostic était %, 5,1 15,3 77,7 pour I, II, III IV stade métastatique, 25 pts atteinte cérébrale. Le a obtenu IHC 60 40 d’autres techniques. En 1re ligne métastatiques, 66 Alectinib, 31 brigatinib, lorlatinib. Après suivi médian 8 (IC95 : 7–9,4) mois médianes PFS atteintes sous alectinib (NR, IC95 :15,8–NR), brigatinib NR–NR). toujours ouvert prévue d’inclure 250 ans après dernière inclusio