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Remes, Satu Maria; Leijon, Helena; Vesterinen, Tiina; Louhimo, Johanna; Pulkkinen, Ville; Ezer, Sini; Kere, Juha; Haglund, Caj; Arola, Johanna
doi: 10.1111/apm.13071pmid: 32794589
Neuroendocrine tumors (NETs) are often diagnosed from the metastases of an unknown primary tumor. Specific immunohistochemical (IHC) markers indicating the location of a primary tumor are needed. The proprotein convertase subtilisin/kexin type 2 (PCSK2) is found in normal neural and neuroendocrine cells, and known to express in NETs. We investigated the tissue microarray (TMA) of 86 primary tumors from 13 different organs and 9 metastatic NETs, including primary tumor‐metastasis pairs, for PCSK2 expression with polymer‐based IHC. PCSK2 was strongly positive in all small intestine and appendiceal NETs, the so‐called midgut NETs, in most pheochromocytomas and paragangliomas, and in some of the typical and atypical pulmonary carcinoid tumors. NETs showing strong positivity were re‐evaluated in larger tumor cohorts confirming the primary observation. In the metastases, the expression of PCSK2 mirrored that of the corresponding primary tumors. We found negative or weak staining in NETs from the thymus, gastric mucosa, pancreas, rectum, thyroid, and parathyroid. PCSK2 expression did not correlate with Ki‐67 in well‐differentiated NETs. Our data suggest that PCSK2 positivity can indicate the location of the primary tumor. Thus, PCSK2 could function in the IHC panel determined from screening metastatic NET biopsies of unknown primary origins.
Jensen, Steffen Grann; Thomas, Peter Engel; Christensen, Ib Jarle; Balslev, Eva; Hansen, Alastair; Høgdall, Estrid
doi: 10.1111/apm.13076pmid: 32860265
Human epidermal growth factor receptor 2 (HER2) gene status and overexpression, occurring in ~ 13.6% of primary breast cancers, is essential for identifying patients likely to benefit from biological treatment. In this method of evaluation study, we tested and compared the HER2 gene–protein assay (GPA) with routine HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The GPA was evaluated using 67 formalin‐fixed paraffin‐embedded (FFPE) HER2 equivoval IHC (2+) breast cancer tissue samples. Overall, agreement between GPA silver in situ hybridization (SISH) and FISH was 91.9% (57/62). Regression analysis revealed slightly higher, but non‐significant difference in HER2/chromosome enumeration probe 17 (CEP17) ratio for GPA as compared to FISH (p = 0.074). Intraclass correlation coefficients (ICCs) of 0.94 and Spearman´s rank correlation coefficients of 0.93 (p < 0.0001) for FISH and GPA SISH suggested strong inter‐observer association for methods with one observer counting on average 0.23 significant higher for GPA SISH (p = 0.014). Intra‐observer IHC method reproducibility was 52.6% (κ = 0.3122, p = 0.004) and 79.7% (κ = 0.6428, p = 0.9197), suggesting fair significant and substantial non‐significant difference between tests for reviewers. Inter‐observer reproducibility for IHC methods was 53%. While inter‐observer reproducibility for experienced IHC interpretation suggested significant differences (κ = 0.3636, p = 0.0332), unexperienced interpretation of IHC GPA suggested fair non‐significant difference between reviewers (κ = 0.3101, p = 0.0747). Using FISH as reference, the diagnostic indices for GPA SISH were as follows: sensitivity 100%, specificity 95% and accuracy 92%. Inaccuracy between tests was in 80% of cases due to ISH categorization as equivocal by one of the methods. IHC results highlight that it may be beneficial with a method for simultaneously visualization of HER2 gene and protein status.
Parastouei, Karim; Solaymani‐Mohammadi, Farid; Shiri‐Shahsavar, Mohammad Reza; Chahardoli, Reza; Nasl‐Khameneh, Ateke Mousavi; Zarandi, Mehdi Borhani; Ghotloo, Somayeh; Saboor‐Yaraghi, Ali Akbar
doi: 10.1111/apm.13073pmid: 32865844
Mohammadzadeh, Sara; Roohvand, Farzin; Ehsani, Parastoo; Salmanian, Ali Hatef; Ajdary, Soheila
doi: 10.1111/apm.13074pmid: 32870528
Induction of broad Th1 cellular immune responses and cytokines is crucial characteristics for vaccines against intracellular infections such as hepatitis C virus (HCV). Plants (especially oilseed tissues) and plant‐immunomodulators (like oil bodies) offer cost‐effective and scalable possibilities for the production of immunologically relevant and safe vaccine antigens and adjuvants, respectively. Herein, we provide data of the murine immunization by transgenic canola oilseed‐derived HCV core protein (HCVcp) soluble extract (TSE) and Escherichia coli‐ derived rHCVcp in combination with Canola oil bodies (oil) compared to that of the Freund’s (FA) adjuvant. Mice immunized by TSE+ oil developed both strong humeral (IgG) and Th1‐biased cellular responses, manifested by high levels of IFN‐γ and lower IgG1/IgG2a ratio and IL‐4 secretion. Results of the intracellular cytokine staining indicated that TSE+ oil immunization in mice triggered both CD4+ and CD8+ T cells to release IFN‐γ, while CD4+ cells were mostly triggered when FA was used. Analyses by qRT‐PCR indicated that a combination of rHCVcp/TSE with oil body induced high levels of IL‐10 cytokines compared to that of the FA adjuvant. These characteristics are important properties for the design of an HCV vaccine candidate and indicate the potential of Canola‐derived antigen and oil bodies in addressing these concerns.
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Multiple sclerosis (MS) is an immune‐mediated inflammatory disease which affects the central nervous system (CNS). In the present study, the in vivo effects of ATRA, calcitriol, and their combinations on the expression of murine CD4+ T cell cytokines and their specific transcription factors in experimental autoimmune encephalomyelitis (EAE)‐induced mice were explored. Thirty‐two EAE induced inbred C57BL/6 female mice with an age ranged from 8 to 10 weeks were divided into four categories in a random manner. The first, second, and third groups received ATRA, calcitriol, ATRA+ calcitriol, respectively, and the fourth group received vehicle. The treatment started on the day prior to immunization and through the IP injections every other days for 21 days. The dosages of administration for calcitriol, ATRA, and calcitriol+ ATRA were 100 ng, 250 μg, and 50ng + 125 μg, respectively per mouse. An equal volume of excipient was administered for the vehicle group. T‐bet, IFN‐γ, GATA‐3, and IL‐4 genes expression were assessed in the splenocytes of EAE ‐induced mice. The expression of T‐bet and IFN‐γ genes in the splenocytes of ATRA, calcitriol and combination‐ treated mice were significantly reduced compared to vehicle group (p < 0.05). A significant decrease in T‐bet expression was observed in the combination‐treated group compared to the ATRA‐treated group (p < 0.05). The expression of GATA3 and IL‐4 genes was significantly increased in the ATRA‐, calcitriol‐, and combination‐treated mice when compared with the control group (p < 0.05). Furthermore, the effect of calcitriol alone and in combination with ATRA was more considerable than that of ATRA alone. The nutraceutical approaches may be promising in the prevention and/or treatment of MS.