The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+ and CD8+ memory T-cells.

Tyrosine kinase 2 (TYK2) belongs to the Janus kinase (JAK) family of tyrosine kinases, which transmit signals from activated cytokine receptors. GWAS have consistently implicated TYK2 in psoriasis susceptibility. We performed an in-depth association analysis of TYK2 using GWAS and resequencing data. Strong genetic association of three nonsynonymous variants in the exonic regions of the TYK2 gene (rs34536443, rs12720356, and rs2304256) were found. rs12720356 encoding I684S is predicted to be deleterious based on its location in the pseudokinase domain. We analyzed PBMCs from 29 individuals representing the haplotypes containing each of the significantly associated signals. STAT4 phosphorylation was evaluated by phospho-flow cytometry after CD3/CD28 activation of cells followed by IL-12 stimulation. Individuals carrying the protective I684S variant manifested significantly reduced p-STAT4 levels in CD4 + CD25 + CD45RO+ (mean Stimulation Index (S.I.) 48.08, n = 10) and CD8 + CD25 + CD45RO + cells (S.I. 55.71, n = 10), compared to controls homozygous for the ancestral haplotype (S.I. 68.19, n = 10 (p = 0.002) and 76.76 n = 10 (p = 0.0008) respectively). Reduced p-STAT4 levels were also observed in skin-homing, cutaneous lymphocyte associated antigen (CLA)-positive CD4 and CD8 cells from I684S carriers. No significant changes in p-STAT4 for the psoriasis-associated variant rs34536443 was found. These data establish the functional significance of the TYK2 I684S variant in psoriasis susceptibility.

IgA- and SIgA anti-PR3 antibodies in serum versus organ involvement and disease activity in PR3-ANCA-associated vasculitis.

Circulating immunoglobulin (Ig)A class anti-neutrophil cytoplasm antibodies (ANCA) directed against proteinase 3 (PR3) have been reported in ANCA-associated vasculitis (AAV) with mucosal involvement. However, secretory IgA (SIgA) PR3-ANCA has not been reported previously. In this study we compared serum levels of SIgA PR3-ANCA and IgA PR3-ANCA with IgG PR3-ANCA in relation to disease characteristics. Among 73 patients with AAV and PR3-ANCA at diagnosis, 84% tested positive for IgG PR3-ANCA, 47% for IgA-ANCA and 36% for SIgA PR3-ANCA at the time of sampling for the present study. IgA and IgG PR3-ANCA were represented similarly among patients with different organ manifestations, i.e. upper airway, lung or kidney at time of sampling. However, SIgA PR3-ANCA was significantly less represented among patients with upper airway involvement. During active disease, the proportions of IgA PR3-ANCA and SIgA PR3-ANCA-positive patients were significantly higher compared to inactive disease. Eight patients were sampled prospectively during 24 months from onset of active disease. In these patients, IgA PR3-ANCA and SIgA PR3-ANCA turned negative more often after remission induction compared to IgG PR3-ANCA. Our findings suggest that serum IgA PR3-ANCA and SIgA PR3-ANCA are related more closely to disease activity in AAV compared to IgG PR3-ANCA. Further studies are required to reveal if this has implications for disease activity monitoring. The mean number of PR3-ANCA isotypes increased along with disease activity, suggesting a global B cell activation during active disease.

Commissioning the neutron production of a Linac: development of a simple tool for second cancer risk estimation.

PURPOSE: Knowing the contribution of neutron to collateral effects in treatments is both a complex and a mandatory task. This work aims to present an operative procedure for neutron estimates in any facility using a neutron digital detector. METHODS: The authors' previous work established a linear relationship between the total second cancer risk due to neutrons (TR(n)) and the number of MU of the treatment. Given that the digital detector also presents linearity with MU, its response can be used to determine the TR(n) per unit MU, denoted as m, normally associated to a generic Linac model and radiotherapy facility. Thus, from the number of MU of each patient treatment, the associated risk can be estimated. The feasibility of the procedure was tested by applying it in eight facilities; patients were evaluated as well. RESULTS: From the reading of the detector under selected irradiation conditions, m values were obtained for different machines, ranging from 0.25 × 10(-4)% per MU for an Elekta Axesse at 10 MV to 6.5 × 10(-4)% per MU for a Varian Clinac at 18 MV. Using these values, TR(n) of patients was estimated in each facility and compared to that from the individual evaluation. Differences were within the range of uncertainty of the authors' methodology of equivalent dose and risk estimations. CONCLUSIONS: The procedure presented here allows an easy estimation of the second cancer risk due to neutrons for any patient, given the number of MU of the treatment. It will enable the consideration of this information when selecting the optimal treatment for a patient by its implementation in the treatment planning system.

Malnutrition and food intake in relation to quality of life in head and neck cancer patients.

BACKGROUND: The quality of life (QL) of cancer patients has attracted an increasing interest in recent years. Patients with head and neck cancer often have troublesome symptoms due to the disease and to treatment side effects, which will have an impact on the patient's QL. The aim of this study was to evaluate the possibility of studying QL in relation to well-known clinical parameters. METHODS: Patient's QL was evaluated according to the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) combined with a diagnosis-specific questionnaire. Quality of life was measured in a cross section of head and neck cancer patients (n = 48) and related to nutritional status, energy intake, severity of disease, and 2-year survival. RESULTS: Fifty-one percent of the patients (mean age, 67 years) fulfilled the criteria proposed for malnutrition, and 55% had a negative energy balance. We did not find any correlation between the severity of the cancer disease and the patient's self-rated QL. However, we found significantly better QL ratings among the 2-year survivors (mean, 63; range 52-76 versus mean, 42; range, 31-54; p < .05). There were few correlations between the QL items and malnutrition. CONCLUSIONS: Quality of life measurements offer objective information on well-being, sometimes quite opposite that of other clinical parameters, such as tumor stage. Furthermore, QL measurements may be of prognostic value concerning the survival of head and neck cancer patients.

Bromocriptina e tumor hipofisario produtor de prolactina. / Bromocriptine and prolactin-producing pituitary tumor

Uma paciente com um tumor hipofisario produtor de prolactina e infertilidade foi tratada com bromocriptina. A terapia resultou em gravidez. Por causa de um aumento inicial do volume do tumor, a bromocriptina foi mantida durante todo o periodo de gestacao. O feto nasceu prematuramente por decisao medica, mas desenvolveu-se normalmente no periodo pos-natal. A paciente esta bem. Uma revisao da literatura e incluida