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Maternal First-Trimester Enterovirus Infection and Future Risk of Type 1 Diabetes in the Exposed Fetus Hanna R. Viskari 1 , Merja Roivainen 2 , Antti Reunanen 2 , Janne Pitkäniemi 2 , Karita Sadeharju 1 , Pentti Koskela 3 , Tapani Hovi 2 , Pauli Leinikki 2 , Pekka Vilja 1 , Jaakko Tuomilehto 2 4 and Heikki Hyöty 1 5 1 Juvenile Diabetes Foundation International Center for the Prevention of type 1 diabetes in Finland and the Department of Virology, University of Tampere, Medical School, Tampere, Finland 2 National Public Health Institute, Helsinki, Finland 3 National Public Health Institute, Oulu, Finland 4 Department of Public Health, University of Helsinki, Helsinki, Finland 5 Department of Clinical Microbiology, Centre for Laboratory Medicine, Tampere University Hospital, Tampere, Finland Abstract Previous studies have suggested that enterovirus infections during pregnancy may increase the risk of type 1 diabetes in the offspring. Our aim was to evaluate the role of first trimester enterovirus infections in a larger cohort of pregnant women. Two series of pregnant women were analyzed as follows: 948 women (series 1) and 680 women (series 2) whose child developed clinical diabetes before the ages of 15 or 7 years, respectively. An equal number of control women with a nondiabetic child was selected. Acute enterovirus infections were diagnosed by measuring IgM class antibodies against coxsackievirus B5 (series 1) and a mixture of coxsackievirus B3, coxsackievirus A16, and echovirus 11 antigens (series 2). In series 2, all sera were also analyzed for IgG class antibodies against an enterovirus peptide antigen. In addition, 152 randomly selected case-control pairs and all IgM-positive mothers’ sera were tested for enterovirus RNA (series 2). In series 1, 3.1% of case women had IgM antibodies against coxsackievirus B5 antigen compared with 4.1% of control women (NS). In series 2, 7.1% of case and 5.3% of control women had IgM against the mixture of enterovirus antigens (NS). IgG class enterovirus antibodies did not differ between the groups. Enterovirus RNA was found only in one case woman (0.3%) of the subgroup of samples and in 5.7% of 70 IgM-positive women. The results suggest that enterovirus infection during the first trimester of pregnancy is not associated with increased risk for type 1 diabetes in the child. Footnotes Address correspondence and reprint requests to Dr. Hanna Viskari, University of Tampere, Medical School/FM3, 5th floor, Department of Virology, Lenkkeilijänkatu 10, 33520 Tampere, Finland. E-mail: hanna.viskari{at}uta.fi . Received for publication 21 February 2002 and accepted in revised form 17 May 2002. CAV, coxsackievirus A; CBV, coxsackievirus B; EIA, enzyme immunoassay; EIU, enzyme immunoassay unit; RIA, radioimmunoassay. DIABETES

OBJECTIVE:Gluten-derived peptides (e.g., amino-acids 31-49 of α-gliadin) have been shown to cause changes typical of celiac disease in the gut. Gluten-derived peptides have mostly been used in in vitro studies. The easiest access to the gastrointestinal system may be the mouth. In the present study we were interested to see whether a synthetic peptide corresponding to amino-acids 31-49 of α-gliadin could induce inflammatory changes in the oral mucosa after a local challenge in celiac disease patients.METHODS:The challenge was made by injecting the peptide solution at a concentration of 10 μg/ml submucosally into the oral mucosa of 10 celiac disease patients after a gluten-free diet (GFD) and 12 healthy control subjects. B and CD45RO+ T cells, mast cells, CD3+, CD4+, CD8+ lymphocytes, and αβ and γδ T-cell receptor-bearing (TcRαβ, TcRγδ) lymphocytes were counted and HLA DR expression was determined. The expression of CD25 and Ki-67 antigen was also examined.RESULTS:The peptide significantly increased the total number of T cells in the lamina propria of the celiac disease patients. The expression of T-cell activation marker CD25 (IL-2 receptor), but not that of cell proliferation marker Ki-67, was also significantly increased in the lamina propria after peptide challenge. Such a reaction was not observed in the controls. The numbers of CD3+ and CD4+ T cells in the lamina propria were also increased in celiac disease patients after the challenge. The count of TcRγδ+ cells was very small in the oral mucosa in celiac disease and showed no increase when the oral mucosa was challenged with the peptide. The expression of HLA DR staining was enhanced after the submucosal peptide challenge in celiac disease; however, the difference was not statistically significant.CONCLUSIONS:The results show that in the celiac disease patients after the peptide challenge the oral mucosal lamina propria responds with a nonproliferative increase of lymphocytes. Thus, submucosal challenge with the peptide 31-49 can be used as an aid in the diagnosis of celiac disease. However, further studies with optimized methodology, including various concentrations of the peptide, adjuvants, other peptides, etc., are warranted, especially because the oral mucosa provides the easiest access to an in vivo peptide challenge in celiac disease.

Heat shock protein 90 (hsp90) is associated with many steroid receptors in tissue homogenates. It is widely accepted that hsp90 regulates the binding of the receptor to the corresponding gene regulatory element. However there is no unequivocal evidence that steroid receptor-hsp90 complexes are present in the intact cells. We demonstrate here the absence of progesterone receptor (PR)-hsp90 complexes in intact target cell nuclei, using immunohistochemical and biochemical methods to determine the location and composition of the nonliganded (aporeceptor) and liganded (holoreceptor) PR complexes. In the chicken oviduct cells, both apo- and holoreceptors were nuclear, while hsp90 was exclusively cytoplasmic. When expressed transiently in HeLa cells, hsp90 was detected in the cytoplasm and PR was detected in the nucleus. Their location or staining intensity was not affected when they were coexpressed in the same cells. To confirm that the sensitivity of the immunohistochemical detection of hsp90 and PR did not differ significantly, a chimeric hsp90-PR was transiently expressed in HeLa cells. Both hsp90 and PR antigens of the chimera were detected in nuclei with the same intensity. In homogenates of the same tissue samples that were used for immunohistochemistry, the PR was complexed with hsp90. Hsp90-PR complexes were formed in vitro when immature bursa of Fabricius, known to contain high levels of hsp90, was homogenized in the presence of hsp90-free aporeceptor, while holoreceptor did not associate with hsp90. Our data show that nuclear PR is not complexed with hsp90 in vivo and suggest that the 8S-PR may be an in vitro artifact generated during tissue processing.

Background Caudal-type homeobox 2 (CDX2) and special AT-rich sequence-binding protein 2 (SATB2) are transcription factors playing important roles in intestinal homeostasis and participating in the regulation of intestinal inflammation. In colorectal cancer (CRC), reduced expression levels of CDX2 and SATB2 have been associated with poor differentiation and worse survival. However, their prognostic significance still needs further clarification, and the associations between CDX2 and SATB2 and immune cell infiltration into the CRC microenvironment are largely unknown. Methods We analyzed CDX2 and SATB2 expression in two large cohorts of stages I–IV CRC patients ( N  = 2302) and analyzed their associations with clinicopathologic parameters, the density of local immune cells (determined with three multiplex immunohistochemistry panels and conventional immunohistochemistry), and survival. Results In mismatch repair-proficient tumors, reduced CDX2 and SATB2 expression were associated with higher densities of immature monocytic cells, macrophages, and M2-like macrophages. Low expression of CDX2 was associated with shorter cancer-specific survival independent of conventional prognostic parameters in both cohorts. In the larger cohort, adjusted hazard ratio (HR) for negative (vs. high) CDX2 expression was 3.62 (95% CI 2.08–6.31, p trend  < 0.0001), and adjusted HR for negative (vs. high) SATB2 level was 1.61 (95% CI 0.97–2.67, p trend  = 0.002). Conclusion This study indicates that reduced CDX2 and SATB2 expression levels are associated with myeloid cell infiltration in the CRC microenvironment and represent markers for poor outcome. These findings highlight the potential of CDX2 and SATB2 as biomarkers for classifying CRC patients and support their role in regulating the tumor microenvironment.

Clear-cell renal cell carcinoma (ccRCC) is the most common origin of pancreatic metastases (PM). Distinct genomic aberrations, favorable prognosis, and clinical observations on high angiogenesis, and succeeding tyrosine kinase inhibitor (TKI) sensitivity have been reported in PM-ccRCC. However, no functional or single-cell studies have been conducted thus far. We recruited five PM-ccRCC patients and investigated the genomic, single-cell transcriptomic, and drug sensitivity profiles of their patient-derived cells (PDCs). The PM depicted both expected and novel genomic alterations. Further, the transcriptomics differed from both primary and metastatic ccRCC, with upregulations of the PI3K/mTOR and – supporting the clinical observations – angiogenesis pathways. Data integration at pathway level showed that transcriptomics explained drug sensitivities the best. Accordingly, PM-ccRCC PDCs shared sensitivity to many PI3K/mTOR inhibitors. Altogether, we show distinct genomic and transcriptomic signatures in PM-ccRCC, highlight the superiority of transcriptomics in interpreting drug sensitivities, and encourage the use of TKIs and PI3K/mTOR inhibitors in PM-ccRCC. Functional precision medicine approach reveals genomic and transcriptomic aberrations that distinguish pancreatic metastases from other types of ccRCC metastases and suggest potential therapeutic targets at the individual level.