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Introduction: Corticotroph pituitary neuroendocrine tumors (PitNETs) develop from ACTH-producing cells. They commonly cause Cushing's disease (CD), however, some remain clinically silent. Recurrent USP8, USP48, BRAF and TP53 mutations occur in corticotroph PitNETs. The aim of our study was to determine frequency and relevance of these mutations in a possibly large series of corticotroph PitNETs. Methods: Study included 147 patients (100 CD and 47 silent tumors) that were screened for hot-spot mutations in USP8, USP48 and BRAF with Sanger sequencing, while 128 of these patients were screened for TP53 mutations with next generation sequencing and immunohistochemistry. Results: USP8 mutations were found in 41% CD and 8,5% silent tumors, while USP48 mutations were found in 6% CD patients only. Both were more prevalent in women. They were related to higher rate of biochemical remission, noninvasive tumor growth, its smaller size and densely granulated histology, suggesting that these mutation may be favorable clinical features. Multivariate survival analyses did not confirm possible prognostic value of mutation in protein deubiquitinases. No BRAF mutations were found. Four TP53 mutations were identified (2 in CD, 2 in silent tumors) in tumors with size >10mm including 3 invasive ones. They were found in Crooke's cell and sparsely granulated tumors. Tumors with missense TP53 mutations had higher TP53 immunoreactivity score than wild-type tumors. Tumor with frameshift TP53 variant had low protein expression. TP53 mutation was a poor prognostic factor in CD according to uniand multivariate survival analyses in spite of low mutations frequency. Conclusions: We confirmed high prevalence of USP8 mutations and low incidence of USP48 and TP53 mutations. Changes in protein deubiquitinases genes appear to be favorable prognostic factors in CD. TP53 mutations are rare, occur in both functioning and silent tumors and are related to poor clinical outcome in CD. [ABSTRACT FROM AUTHOR]

Objectives: Chronic rhinosinusitis (CRS) is a disease that represents a challenging therapeutic problem. Vitamin D and its receptors (VDR) are involved in the regulation of the immune system and may play role in CRS. Objectives of this study were to assess the relationships between the total concentration of vitamin D (25VD3) in sera, vitamin D receptor (VDR) expression, 1α-hydroxylase expression, and clinical data, including age, gender, Sino-Nasal Outcome Test (SNOT-22), computerized tomography (CT) scan, allergy status, and vitamin D supplementation in CRS patients with (CRSwNP) and without nasal polyps (CRSsNP), and in a control group.Methods: The studied group comprised 52 patients with CRS without nasal polyps (sNP), 55 with CRS with nasal polyps (wNP), and 59 in the control group. The endpoints were determined by appropriate methods. We conducted immunohistochemical staining of gathered tissue from the ostiomeatal complex for determination of VDR and 1α-hydroxylase. Analytical results were compared with clinical data as already noted.Results: A decrease in VDR nuclear staining occurred in CRS patients as compared to controls. Insignificant differences were observed in 1α-hydroxylase, expression in all studied groups, while VDR and cytochrome CYP27B1 protein expression (1α-hydroxylase) correlated with clinical data.Conclusions: The data provide evidence that indicates that vitamin D and its receptor and enzymes may play a role in CRS. [ABSTRACT FROM AUTHOR]

Simple Summary: Growing tumors induce an immune response. For proper immune response, both CD8+ and CD4+ effector T cells are required. Tumors avoid attacks from tumor-infiltrating lymphocytes (TILs) via induction of several inhibitory signals, such as PD-L1/2, which bind to the PD-1 receptor, consequently leading to T cell dysfunction, exhaustion, and apoptosis. The mechanism of T cell exhaustion has been studied mostly in CD8+ T cells, although some results suggest that CD4+ effector T cells also undergo exhaustion. In this study, we analyze global transcript profiling, PD-1 and PD-L1 expression, and chromatin status on the PD-L1 locus. We find that in exhausted CD4+ T cells, the levels of PD-L1 are increased at both the transcript and protein levels, while PD-L1 expression depends on SWI/SNF chromatin remodeling and PRC2-repressive complexes. The expression of PD-L1 in exhausted CD4+ T cells can be reversible. Growing tumors avoid recognition and destruction by the immune system. During continuous stimulation of tumor-infiltrating lymphocytes (TILs) by tumors, TILs become functionally exhausted; thus, they become unable to kill tumor cells and to produce certain cytokines and lose their ability to proliferate. This collectively results in the immune escape of cancer cells. Here, we show that breast cancer cells expressing PD-L1 can accelerate exhaustion of persistently activated human effector CD4+ T cells, manifesting in high PD-1 and PD-L1 expression level son T cell surfaces, decreased glucose metabolism genes, strong downregulation of SWI/SNF chromatin remodeling complex subunits, and p21 cell cycle inhibitor upregulation. This results in inhibition of T cell proliferation and reduction of T cell numbers. The RNAseq analysis on exhausted CD4+ T cells indicated strong overexpression of IDO1 and genes encoding pro-inflammatory cytokines and chemokines. Some interleukins were also detected in media from CD4+ T cells co-cultured with cancer cells. The PD-L1 overexpression was also observed in CD4+ T cells after co-cultivation with other cell lines overexpressing PD-L1, which suggested the existence of a general mechanism of CD4+ T cell exhaustion induced by cancer cells. The ChIP analysis on the PD-L1 promoter region indicated that the BRM recruitment in control CD4+ T cells was replaced by BRG1 and EZH2 in CD4+ T cells strongly exhausted by cancer cells. These findings suggest that epi-drugs such as EZH2 inhibitors may be used as immunomodulators in cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Our study aimed to advance the understanding of vulvar squamous cell carcinoma (VSCC) biology by recognizing biological pathways that drive the progression of this disease. We applied the experimental path from global proteomic analysis of vulvar tumors to the targeted and quantitative assessment of specific proteins both in the tumors and blood of VSCC patients. The proteomic analysis has advanced the knowledge on VSCC biology by pointing at inflammation as a driver of progression and by providing grounds for the hypothesis of vulvovaginal microflora disturbances as a trigger for the inflammatory response. The study results indicate prognostic protein markers and potential therapeutic targets for improved and personalized management of VSCC. Current knowledge on the biology of squamous cell vulvar carcinoma (VSCC) is limited. We aimed to identify protein markers of VSCC tumors that would permit to stratify patients by progression risk. Early-stage tumors from patients who progressed (progVSCC) and from those who were disease-free (d-fVSCC) during follow-up, along with normal vulvar tissues were examined by mass spectrometry-based proteomics. Differentially expressed proteins (DEPs) were then verified in solid tissues and blood samples of patients with VSCC tumors and vulvar premalignant lesions. In progVSCC vs. d-fVSCC tumors, the immune response was the most over-represented Gene Ontology category for the identified DEPs. Pathway profiling suggested bacterial infections to be linked to aggressive VSCC phenotypes. High Mobility Group AT-Hook 2 (HMGA2) and Proteinase 3 (PRTN3) were revealed as proteins predicting VSCC progression. HMGA2 and PRTN3 abundances are associated with an aggressive phenotype, and hold promise as markers for VSCC patient stratification. It appears that vulvovaginal microflora disturbances trigger an inflammatory response contributing to cancer progression, suggesting that bacterial rather than viral infection status should be considered in the development of targeted therapies in VSCC. [ABSTRACT FROM AUTHOR]

Introduction. Chronic rhinosinusitis (CRS) is a common inflammatory disorder that is a challenging therapeutic problem. One of the theories behind the CRS pathophysiology is the idea that deficiency of vitamin D3 influences innate immune functions in the paranasal sinuses. Aim. 1. Assessment of total and active amount of vitamin D3 in sera of CRS patients with (CRSwNP) and without nasal polyps (CRSsNP) and in healthy controls (HC). 2. Correlation of results with clinical data, i.e. SNOT-20 questionnaire, CT scan, presence of asthma, vitamin D3 supplemantation. Material and methods. The research comprised 114 patients. The sera level of 25(OH)D3 and 1.25(OH)2D3 was estimated in 48 HC, 32 patients with CRSsNP, 34 patients with CRSsNP with the average age 43 years. All patients were evaluated clinically according to the Lund-Mackay CT score, SNOT-20. Results. There is suboptimal status of 25(OH)D3 level and target concentration of 1,25(OH)2D3 in all studied groups, without statistically significant differences between the groups (p>0.05) and seasons of the year (p>0.05). The sera level of 25(OH)D3 and 1.25(OH)2D3 does not correlate with Lund-Mackay CT score, SNOT-20 and vitamin D3 supplementation. Conclusions. Our data provided the evidence that there is suboptimal status of 25(OH)D3 level in all studied groups. There is a need for further research on D3-reliant molecular mechanisms in paranasal sinuses mucosa. [ABSTRACT FROM AUTHOR]

Introduction. Over the last two decades, progress of science in the fields of immunology and molecular biology has brought understanding, at cellular level, of different pathophysiological processes involved in CRS. Nevertheless, the pathomechanisms of CRS remains unclear. SWI/SNF is a human ATP-dependent chromatin remodeling complex which plays an important role in several distinct cellular processes. SWI/SNF complex enables glucocorticoid receptor (GR) to function correctly and plays a role in regulation of inflammation. It has been hypothesized that SWI/SNF complex contributes to the pathogenesis of CRS. Aim. Assessment of the protein expression level of the SWI/ SNF complex subunits (BAF155, BRM and BRG1) in the group of patients with CRS. Materials. The study population consisted of 30 subjects, aged 19-81 (12 women and 18 men), including 10 patients with CRS without polyps, 10 patients with CRS and polyps and 10 subjects without CRS constituting the control group. Results. Results of the observation revealed lower expression of the SWI\SNF complex in both CRS groups in comparison to the control group. Conclusions. SWI/SNF complex may play an important role in pathogenesis of CRS, probably through the influence on steroid hormone signaling and GR function. Further analysis of this issue is needed. [ABSTRACT FROM AUTHOR]

About 40% of clear cell renal cell carcinoma (ccRCC) cases carry the pbrm1 mutation inactivating BAF180 subunit of the SWI/SNF chromatin remodeling complex (CRC). Here we show that the majority of transcriptomic changes appear at the stage I of ccRCC development. By contrast, the stage II ccRCC exhibits hyperactivation of DNA replication demonstrated by the overexpression of several genes, e.g., RRM1 and RRM2 genes encoding subunits of ribonucleotide reductase (RNR) complex. We found that the degree of RRM1 and RRM2 upregulation in ccRCC patients depends on pbrm1 mutation. We show that the BAF180 protein product of the PBRM1 gene directly binds to RRM1 and RRM2 loci . The BAF180 binding regions are targeted by regulatory proteins previously reported as SWI/SNF CRC interacting partners. BAF180 binding to RRMs loci correlates with enrichment of H3K27me3 in case of RRM1 and H3K14Ac on RRM2 , indicating the existence of differential regulatory mechanism controlling expression of these genes. We found that the strong overexpression of RRM2 in ccRCC patient samples correlates with T cell infiltration. Surprisingly, the majority of tumor infiltrating lymphocytes (TILs) consisted of CD4 + T cells. Furthermore, we show that exhausted CD4 + T cells induced the expression of the RRM2 gene in the primary ccRCC cell line. Collectively, our results provide the link between PBRM1 loss, RRM2 expression and T cell infiltration, which may lead to the establishment of new treatment of this disease., Competing Interests: None., (AJCR Copyright © 2021.)