Superficial CD34+ fibroblastic tumor with focal atypical presentation: A case report.

Superficial CD34+ fibroblastic tumors (SCPFTs) are rare mesenchymal tumors with distinct morphological features. Although several cases of SCPFT have been reported, a comprehensive understanding of its clinical and biological features necessitates the inclusion of additional cases. The current study presents a case of SCPFT, where morphological observations, immunohistochemical staining and fluorescence in situ hybridization (FISH) were performed. Immunohistochemistry revealed diffuse CD34 expression and integrase interactor 1 expression, whilst FISH indicated rearrangement of the PR/SET domain 10 gene. Microscopic assessment demonstrated typical SCPFT pathology, with a focal nodular region showing a high Ki-67 index, suggesting heterogeneity and the potential for local recurrence. The present study also briefly reviews the differential diagnosis of tumors with morphological similarities. It was found that the precise diagnosis of SCPFT relies on the distinctive pathological features, the use of immunohistochemical markers, including CD34 staining, and the differentiation from similar histological lesions.

[Prolyl Isomerase Pin1 Impacts on Metabolism in Muscle and Adipocytes].

Prolyl isomerase Pin1 is associated with various substrates and controls their functions through the isomerization of proline. Interestingly, a high fat diet increases Pin1 levels in adipose tissues. Accordingly, we investigated how Pin1 regulates energy metabolism in adipose tissues. Currently, adipocytes are divided into three types with distinct features. White adipocytes (WATs) store energy as triglycerides under fed conditions and release non-esterified fatty acids and glycerol through lipolysis while fasting. Brown and beige adipocytes, which exist in subcutaneous fat (scWAT), promote energy consumption through thermogenesis. We found that Pin1 impacts both thermogenesis and lipolysis upon interaction with distinct substrates. When mice were exposed to cold stress, both brown adipose tissues (BAT) and scWAT from adipocyte-specific Pin1 knockout (KO) mice showed higher expression levels of thermogenic genes in comparison to those from wild-type mice. Furthermore, we observed that Pin1 binds to the PRDM16 transcriptional cofactor, a major contributor to thermogenic programs, and promotes its degradation. Therefore, Pin1 suppresses thermogenesis. Meanwhile, in white adipocytes, Pin1 is involved in lipolysis. Pin1 deficiency enhanced lipolysis activity in epididymal WAT (epiWAT), but not in scWAT and BAT. In epiWAT, Pin1 interacts with adipose triglyceride lipase (ATGL) which is a rate-limiting enzyme for lipolysis, and downregulates ATGL levels. Finally, adipocyte-specific Pin1 KO mice have less body weight and better glucose metabolism under high fat diet conditions. These observations indicate that Pin1 is involved in the function of adipocytes through its association with PRDM16 and ATGL. Pin1 inhibitors could have therapeutic applications in the treatment of obesity.

Differential effects of two catalytic mutations on full-length PRDM9 and its isolated PR/SET domain reveal a case of pseudomodularity.

PRDM9 is a DNA-binding histone methyltransferase that designates and activates recombination hotspots in mammals by locally trimethylating lysines 4 and 36 of histone H3. In mice, we recently reported two independently produced point mutations at the same residue, Glu360Pro (Prdm9EP) and Glu360Lys (Prdm9EK), which severely reduce its H3K4 and H3K36 methyltransferase activities in vivo. Prdm9EP is slightly less hypomorphic than Prdm9EK, but both mutations reduce both the number and amplitude of PRDM9-dependent H3K4me3 and H3K36me3 peaks in spermatocytes. While both mutations cause infertility with complete meiotic arrest in males, Prdm9EP, but not Prdm9EK, is compatible with some female fertility. When we tested the effects of these mutations in vitro, both Prdm9EP and Prdm9EK abolished H3K4 and H3K36 methyltransferase activity in full-length PRDM9. However, in the isolated PRDM9 PR/SET domain, these mutations selectively compromised H3K36 methyltransferase activity, while leaving H3K4 methyltransferase activity intact. The difference in these effects on the PR/SET domain vs the full-length protein shows that PRDM9 is not an intrinsically modular enzyme; its catalytic domain is influenced by its tertiary structure and possibly by its interactions with DNA and other proteins in vivo. These two informative mutations illuminate the enzymatic chemistry of PRDM9, and potentially of PR/SET domains in general, reveal the minimal threshold of PRDM9-dependent catalytic activity for female fertility, and potentially have some practical utility for genetic mapping and genomics.

Down-regulation of PR/SET domain 10 underlies natural killer cell dysfunction in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the world's leading cause of tumor-related mortalities. Natural killer (NK) cells play a critical role at the first immunological defense line against HCC initiation and progression. NK cell dysfunction is therefore an important mechanism for immune evasion of HCC cells. In the present study using a murine HCC model, we revealed the down-regulation of PR/SET Domain 10 (PRDM10) in hepatic NK cells that were phenotypically and functionally exhausted. PRDM10 silencing diminished the expression of natural killer group 2 member D (NKG2D) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), augmented T cell immunoglobulin and ITIM domain (TIGIT) expression, and decreased the expression of interferon (IFN)-γ, perforin and granzyme B in normal hepatic NK cells in vitro. Consistently, PRDM10-deficient NK cells exhibited impaired cytotoxicity on target cells. In contrast, PRDM10 over-expression promoted NKG2D and Fas ligand (FasL) expression, reduced CD96 expression and enhanced transcripts of IFN-γ, perforin and granzyme B in NK cells in vivo. Moreover, PRDM10 silencing and PRDM10 over-expression down-regulated and up-regulated Eomesodermin (Eomes) expression, respectively. In summary, this study reveals PRDM10 down-regulation as a novel mechanism underlying NK cell dysfunction and identifies PRDM10 as a supporting factor of NK cell function.

Structural and functional annotation of PR/SET Domain (PRDM) protein family: In-silico study elaborating role of PRDM12 mutation in congenital insensitivity to pain.

Congenital insensitivity to pain (CIP), classified as a type of hereditary sensory and autonomic neuropathies, is a rare disease in which the affected individuals fail to perceive sensation of pain. One of the PR/SET Domain Proteins, PRDM12, has been identified in recent past as a candidate gene for congenital insensitivity to pain. In the present study, we performed whole exome sequencing in a Pakistani family with CIP phenotype to ascertain the causative mutation. We identified a previously described alanine repeat duplication in PRDM12 (Ala353_Ala359dup) in this family. After this, we performed structural annotations for PR/SET Domain (PRDM) containing protein family to prognosticate the potential hypothetical structure of PRDM proteins with physical and chemical parameters. Out of nineteen members of this family, four members (PRDM5, PRDM8, PRDM12 and PRDM13) were specially focused because of their role in neurological disorders. Predictions about structure and interactions of these proteins revealed novel interacting molecules and pathways. Detailed in silico analysis of PRDM12 was performed to elaborate importance of its domain structure in interaction with other proteins and its role in pain insensitivity phenotype. These results have substantially enhanced our understanding regarding the etiology of congenital pain insensitivity and would stimulate further research on therapy and prevention.

Extranodal NK/T-cell lymphoma, nasal type without evidence of EBV infection.

Extranodal natural killer/T cell lymphoma-nasal type (EN-NK/T-NT) is extremely rare in Western countries; however, it is the most common subtype of peripheral T cell lymphoma in China. Despite this, there are a limited number of clinicopathological research studies on Epstein-Barr virus (EBV)-negative EN-NK/T-NTs. EBV-negative EN-NK/T-NT is a rare disease type, which has not been fully investigated. If other diagnostic criteria are met, such as the lesions being located predominantly in the upper aerodigestive tract, the presence of angiocentricity or angioinvasion, necrosis and expression of NK/T-cell phenotype, EN-NK/T-NT may be diagnosed, even if EBV is negative. In the present study, 99 cases of EN-NK/T-NTs were analyzed retrospectively, among which seven cases were EBV-negative EN-NK/T-NTs and selected for further investigation. In addition, the present study reviewed previously published research into EN-NK/T-NT, highlighting that EBV-negative EN-NK/T-NT is rare and that its geographical distribution is mainly in countries in Asia, Central America and South America. Patients with EBV-negative EN-NK/T-NT were all of Chinese ethnicity, with a median age of 32 years and primarily female. Furthermore, these patients shared similar clinicopathological characteristics (such as the tumor occurring mainly in the upper aerodigestive tract, the presence of vascular destruction, necrosis and cytotoxic phenotypes) to patients with EBV-positive EN-NK/T-NT. Immunohistochemistry and molecular analysis results indicated that tumor cells were primarily of NK or cytotoxic T origin; however, EBV-encoded small RNAs were not detected in any of these cases. Among the immunochemistry markers, T-bet was statistical significantly different between EBV-positive and -negative cases. Fluorescence in situ hybridization was also performed in two EBV-negative cases, including one case with a co-deletion of 6q21 and PR/SET domain 1 genes. There was only available follow-up data in 3/5 patients who survived for 37-113 months (median, 40 months). As EN-NK/T-NT can be diagnosed, even when EBV is negative, awareness of this subtype may prevent misdiagnosis or delayed diagnosis.