New mutation causing androgen insensitivity syndrome – a case report and review of literature

Androgen insensitivity syndrome (AIS) is a congenital disorder in which a defect in the androgen receptor (AR) gene leads to cellular resistance to androgens. Defects in the AR gene, located on the X chromosome, result in the development of a feminine phenotype in chromosomally male (46, XY) individuals. In this case report, we present a 44?years old patient with complete androgen insensitivity syndrome (CAIS) initially presenting with primary amenorrhea. The patient underwent a full clinical evaluation, revealing hypoplastic vagina and a lack of uterus and ovaries. Hormonal evaluation revealed markedly elevated testosterone, FSH, and LH serum concentrations. Diagnostic imaging, including pelvic MRI, confirmed the presence of two solid masses in the inguinal canals (right 26?×?13?mm, left 25?×?15?mm). The patient underwent genetic testing, revealing a 46 XY karyotype and an as of yet unprecedented androgen receptor mutation. The type of the mutation was a single-base exchange – the substitution from cytosine to thymine in chromosome X:66942710 position (referred to human reference genome GRCh37), which has resulted in an amino acid changes from leucine (CTT) to phenyloalanine (TTT) in ligand-binding domain.     

Autoimmunity through cytokine-induced dendritic cell activation

We propose a model where autoimmunity can be viewed as a dynamic system driven by opposite vectors IFN-alpha/beta and TNF. These cytokines drive differentiation of distinct types of DCs, TNF-DCs, or IFN-DCs, which present different antigens leading to distinct autoimmune responses. When balanced, both cytokines synergize in protective immunity. When one of the cytokines prevails, autoimmunity occurs, Type I interferons (IFN-alpha/beta) playing a major role in systemic lupus erythematosus (SLE) and TNF playing a major role in rheumatoid arthritis. This model complements the Type 1/Type 2 paradigm. Therefore, immunity can be viewed as a dynamic system driven by two sets of opposite vectors: IFN-alpha/beta/TNF and IFN-gamma/IL-4.     

Influence of polymorphisms in xenobiotic-metabolizing genes and DNA-repair genes on diepoxybutane-induced SCE frequency

Analysis of the combined effects of polymorphisms in genes encoding xenobiotic metabolizing enzymes (XMEs) and DNA repair proteins may be a key to understanding the role of these genes in the susceptibility of individuals to mutagens. In the present study, we performed an in vitro experiment on lymphocytes from 118 healthy donors that measured the frequency of diepoxybutane (DEB) induced sister chromatid exchanges (SCEs) in relation to genetic polymorphisms in genes coding for XMEs (CYP1A1, CYP2E1, GSTT1, EPHX, and NAT2), as well as DNA repair proteins (XRCC1, XRCC2, XRCC3, XPD, XPA, XPC, XPG, XPF, ERCC1, BRCA1, NBS1, and RAD51). We found that GSTT1(-) and CYP2E1 c1/c2 polymorphisms were associated with higher DEB-induced SCE frequencies, and that NAT2 G(590)A was associated with lower SCE induction by DEB. Analysis of the effect of pairs of genes showed that for a fixed GSTT1 genotype, the SCE level increased with an increasing number of Tyr alleles in EPHX codon 113. We found that among GSTT1(+) individuals the DEB-induced SCE level was significantly lower when the EPHX 139 codon was His/Arg rather than His/His. An interaction between polymorphisms in CYP2E1 and at EPHX codon 113 was also observed. The results of our study confirm observations in cancer patients and in people exposed to xenobiotics indicating that sensitivity to mutagens depends upon a combined effect of a variety of "minor impact" genes. Moreover, our results indicate that polymorphisms in genes coding for XMEs have a greater influence on the genotoxic activity of DEB, measured by DEB-induced SCE frequency, than polymorphisms in genes encoding DNA repair proteins.     

Analysis of MDR genes expression and cross-resistance in eight drug resistant ovarian cancer cell lines

Ovarian endometriomas affect a substantial proportion of women of reproductive age who may have a potential risk of diminished ovarian reserve (DOR) after ovarian cystectomy. Here, we investigated the risk factors for pre-surgical DOR in patients with ovarian endometriomas and for DOR after laparoscopic ovarian cystectomy for endometriomas and evaluated the feasibility of the pre-surgical prediction of post-surgical DOR based on the Bologna criteria. A total of 143 patients with ovarian endometriomas who underwent laparoscopic cystectomy from January 2009 to May 2015 at our hospital were prospectively enrolled and evaluated. Serum anti-Müllerian hormone (AMH) concentrations were measured pre-surgically and at 3 and 6 months after surgery. In accordance with the Bologna criteria, the patients whose AMH concentrations were <1.1 ng/mL before surgery and 3 or 6 months after surgery were classified into pre- and post-surgical adverse DOR (aDOR) groups, respectively. Thirty-one (21.7 %) of 143 patients were classified as pre-surgical aDOR. Patient age and serum follicle-stimulating hormone level were significantly positively correlated with pre-surgical aDOR [odds ratios (ORs), 1.26 and 1.16; p < 0.001 and p = 0.003, respectively]. Among the remaining 112 patients, 38 patients (33.9 %) had post-surgical aDOR 3 and 6 months after surgery. Bilateral cystectomy was positively correlated with post-surgical aDOR (at 3 months: OR, 4.7; p = 0.001; at 6 months: OR, 3.71; p = 0.006); conversely, pre-surgical serum AMH concentrations were negatively correlated with post-surgical aDOR (at 3 months: OR, 0.65; p = 0.005; at 6 months: OR, 0.43; p < 0.001). The optimal cut-off point of pre-surgical AMH concentrations for predicting aDOR at 3 and 6 months in the patients undergoing unilateral cystectomy was 2.1 ng/mL. In contrast, the optimal cut-off points at 3 and 6 months in the patients undergoing bilateral cystectomy were 3.0 and 3.5 ng/mL, respectively. Our data suggest that the pre-surgical serum AMH concentrations and bilateral cystectomy are significant factors for the risk of aDOR following surgery and that predicting post-surgical aDOR according to the Bologna criteria could be feasible using pre-operative measurements of serum AMH concentrations.     

Lower proportion of CD19+IL-10+ and CD19+CD24+CD27+ but not CD1d+CD5+CD19+CD24+CD27+ IL-10+ B cells in children with autoimmune thyroid diseases

Abstract

Introduction: As it is generally known, regulatory B cells (Bregs) control inflammation and autoimmunity. The significance of Bregs in the population of children with autoimmune thyroid diseases (AITD) still offers plenty of potential to explore. The aim of this study was to estimate the expression of Bregs (phenotype CD19⁺CD24⁺CD27⁺IL-10⁺, CD19⁺IL-10⁺, CD1d⁺CD5⁺CD19⁺IL-10⁺ and CD1d⁺CD5⁺CD19⁺CD24⁺CD27⁺) in a paediatric cohort with AITD and in health controls.

Materials and methods: A total of 100 blood samples were obtained from 53 paediatric patients with Graves’ disease (GD) (N?=?12 newly diagnosed, mean age 12.5?±?3.5 and N?=?17 during methimazole therapy, mean age 12.7?±?4.4), Hashimoto’s thyroiditis (HT) (N?=?10 newly diagnosed, mean age 13.3?±?2.9 and N?=?10 during L-thyroxine therapy, mean age 13.7?±?3.4) and compared with healthy controls (C) (N?=?15, mean age 13.1?±?3.1). The expressions of the immune cell populations were analysed by four-color flow cytometry using a FASC Canto II cytometer (BD Biosciences).

Results: There was a decreasing tendency in the number of lymphocytes B producing IL-10 (B10) cells among all B lymphocytes and more widely, also among all lymphocytes, in each study group, as compared to C. We reported a reduction in IL-10 production in Bregs with the expression of CD19⁺CD24⁺CD27⁺IL-10 and CD1d⁺CD5⁺CD19⁺IL-10⁺ in both untreated and treated AITD.

Conclusions: Our data demonstrate that the reduction in the number of Bregs with CD19⁺CD24⁺CD27⁺IL-10⁺ and CD19⁺IL-10⁺ expression could be responsible for breaking immune tolerance and for AITD development in children.     

Analysis of cytogenetic alterations in stage III serous ovarian adenocarcinoma reveals a heterogeneous group regarding survival, surgical outcome, and substage

Ovarian cancer is the leading cause of death among patients with gynecological cancers, but the biology of these tumors is still among the least understood of all major human malignancies. In this study, comparative genomic hybridization was used to determine chromosomal alterations in 98 stage III serous papillary adenocarcinomas. The tumors were grouped according to survival and the main prognostic factors stage and surgical outcome. There were chromosomal imbalances that were significantly more common in tumors from patients who died than in tumors from patients who survived: gains of 1q24-qter and losses of 4p, 4q31.1-qter, 5q12-q22, 8p, 16q, and X. Furthermore, we observed that gains of 8q23-8q24.2 and losses of 4p, 4q13-4q26, 4q31.1-qter, 5q12-q22, 8p, and 16q were significantly more common in tumors from patients with macroscopic residual tumor after primary surgery, compared to tumors from those who had undergone radical surgery. Gains of 3q13.3-qter, 6p, 7q21-q31, and 11q13-q23 and losses of 4q31.1-qter and 16q were more common in stage IIIc tumors than in stage IIIa+b tumors. On the basis of our results, we suggest that there are biological differences among the groups mentioned above and that absence of chromosomal aberrations in specific regions predicts a good clinical outcome for individual patients.     

Consistent mutation status within histologically heterogeneous lung cancer lesions

Mattsson J S M, Imgenberg‐Kreuz J, Edlund K, Botling J & Micke P
(2012) Histopathology  61, 744–748 Consistent mutation status within histologically heterogeneous lung cancer lesions Aims: Activating epidermal growth factor receptor (EGFR) and KRAS mutations characterize molecular subgroups of non‐small‐cell lung cancer (NSCLC) with a strong predictive value for response to EGFR inhibitor therapy. However, the temporal occurrence and clonal stability of these mutations during the course of cancer progression are debated. The aim of this study was to characterize the presence of EGFR and KRAS mutations in histologically different areas of primary NSCLC lesions. Methods and results: Formalin‐fixed paraffin‐embedded cancer specimens from six cases with EGFR mutations and five cases with KRAS mutations were selected from a pool of primary resected NSCLC patients. From each tumour, three morphologically distinct areas were manually microdissected and analysed for the presence of mutations. The results demonstrated consistent EGFR and KRAS mutation status in the different histological areas of all primary tumours. Conclusions: The results support the concept that activating EGFR and KRAS mutations are oncogenic events that are consistently present throughout the primary tumour independently of histological heterogeneity. Thus, for molecular diagnostics, any part of the tumour is likely to be representative for EGFR and KRAS mutation testing.     

Preparations of intravenous immunoglobulins diminish the number and proinflammatory response of CD14+CD16++ monocytes in common variable immunodeficiency (CVID) patients

We have studied the effect of intravenous immunoglobulins (IVIG) on monocyte subpopulations and cytokine production in patients with CVID. The absolute number of CD14(+)CD16(++) monocytes decreased on average 2.5-fold 4h after IVIG and after 20h returned to the baseline. The cytokine level in the supernatants of peripheral blood mononuclear cells (PBMC) after ex vivo LPS stimulation demonstrated the >2-fold decrease in TNF production 4h after IVIG. The TNF expression, which is higher in the CD14(+)CD16(++) monocytes, was decreased in these cells by IVIG in 4/7 CVID cases. In vitro exposure of the healthy individuals' monocytes to the IVIG preparation resulted in reduced TNF production, which was overcome by blockade of the FcγRIIB in the CD14(+)CD16(++) CD32B(high) monocytes. Our data suggest that reduction in the number of CD14(+)CD16(++) monocytes and the blockade of their cytokine production via triggering CD32B can contribute to the anti-inflammatory action of IVIG.