STAT6 and phosphorylated STAT6 are differentially expressed in lymphomas.

BACKGROUND: The STAT6 pathway is implicated in the pathogenesis of various lymphomas; however, its immunohistochemical expression has not been fully investigated. Thus, the aim of this study was to investigate the immunohistochemical expression of the two forms of STAT6, phosphorylated or not, in a series of systemic lymphomas. MATERIALS AND METHODS: Immunohistochemical expression of two antibodies, STAT6 (clone YE361) and pSTAT6 (clone Y641), which recognise the phosphorylated form of the molecule was studied in 60 lymphomas. RESULTS: STAT6YE361 expression was cytoplasmic, with 23.3% of the cases showing high expression. pSTAT6Y641 expression was mostly nuclear and found in 45% of the cases. pSTAT6Y641 nuclear expression was associated with the lymphoma type (p < 0.0001), as it was seen mostly in follicular, Hodgkin and angioimmunoblastic T cell lymphomas. STAT6YE361 cytoplasmic expression was also associated with lymphoma type (p = 0.001), as it was mostly found in diffuse large B cell and marginal B cell lymphomas. No association with PD-L1 expression, other clinicopathological data or prognosis was found. CONCLUSION: The two STAT6 clones are differentially expressed between lymphoma types.

Primary solitary fibrous tumour of the prostate: A case report and literature review.

INTRODUCTION: Solitary fibrous tumour (SFT) is a rare mesenchymal tumour with intermediate malignant potential. Although this tumour arises in several sites, prostatic SFT is an extremely rare neoplasm and may prove confusing owing to the lack of clinical experience because of tumour rarity. The diagnosis may be further difficult because SFTs can manifest positive immunoreactivity for CD34 and progesterone receptor, which are known markers of prostatic stromal tumours. Herein, we describe a case of prostatic SFT that was difficult to differentiate from a prostatic stromal tumour of uncertain malignant potential because of positive immunoreactivity to CD34 and progesterone receptor. CASE REPORT: A 40-year-old Japanese man presented with lower abdominal pain. Computed tomography revealed a prostatic mass; furthermore, prostate core needle biopsy revealed proliferating bland spindle cells, without necrosis or prominent mitoses. Tumour cells were positive for CD34 and progesterone receptor on immunohistochemical analysis; thus, a prostatic stromal tumour of uncertain malignant potential was initially suspected. However, as the tumour cells showed positive immunoreactivity for STAT6, the final diagnosis was an SFT of the prostate. The patient underwent tumour resection, and at the 6-month postoperative follow-up, neither local recurrence nor distant metastasis occurred. CONCLUSION: For an accurate diagnosis of an SFT of the prostate, STAT6 immunohistochemistry should be conducted for all mesenchymal tumours of the prostate. When STAT6 immunohistochemical analysis is unfeasible, pathologists should be aware that the morphological and immunohistochemical characteristics of SFT variable from case to case and diagnose with combined analysis of several immunohistochemical markers.

[Solitary fibrous tumor of pleura (symptoms, diagnosis, treatment)]. / Solitarnaya fibroznaya opukhol' plevry (klinika, diagnostika, lechenie).

OBJECTIVE: Optimization of diagnosis and treatment of patients with solitary fibrous tumor of pleura, analysis of overall survival and disease-free survival, predictors of recurrence. MATERIAL AND METHODS: There were 66 patients with solitary fibrous tumor of pleura (26 men and 40 women) aged 57.6 years (range 26-80 years). Asymptomatic course was found in 29 (44%) patients, various symptoms - in 37 (56%) patients. Thoracotomy was applied in 36 patients, thoracoscopy - in 30 patients. Immunohistochemical examination included analysis of definition of Stat6 expression. RESULTS: Benign variant of SFT was diagnosed in 50 (75.7%) patients, malignant variant - in 16 (24.3%) patients. STAT6 expression was observed in all cases. Postoperative morbidity was 9%, mortality - 1.6%. Recurrence was diagnosed in 2 (4%) patients with benign variant of disease and in 5 (31.2%) patients with malignant variant (2 of them died from progression of disease). Progression-free survival was 89.4%, overall survival - 95.4%. Predictors of recurrence are tumor dimension over 10 cm, necrosis and/or hemorrhagic component of tumor, mitotic count of at least four per 10 high-power fields. CONCLUSION. S: Olitary fibrous tumor of pleura is a rare mesenchymal fibroblastic neoplasm growing from submesothelial layer. Differential and preoperative morphological diagnosis of SFT is difficult and demands a special immunohistochemical examination with analysis of Stat 6 expression. Surgery is preferred for tumor de novo and recurrent neoplasm.

The Importance of STAT6 in a Schwannoma-like Grade III Solitary Fibrous Tumor/Hemangiopericytoma Located in the Cerebellopontine Angle and Meckel's Cave.

BACKGROUND: Hemangiopericytoma (HPC) is a rare mesenchymal tumor of the brain that occurs in the central nervous system as a solitary fibrous tumor. Surgical treatment of HPC is known to be beneficial, but results on the role of complete resection and adjuvant radiation are conflicting. However, it is often difficult to detect a central nervous system solitary fibrous tumor/HPC before surgery. We describe a presumed left trigeminal schwannoma that was histopathologically shown to be an HPC. CASE DESCRIPTION: A 65-year-old man presented with paresthesia of the second and third branches of the left trigeminal nerve. Magnetic resonance imaging showed a tumoral lesion in the left cerebellopontine angle and Meckel's cave. We suspected a schwannoma and performed surgery, which resulted in only a partial resection because of tumor bleeding and unexpected intraoperative histologic findings. We could not achieve a definitive diagnosis. However, we observed local recurrence and disseminated lesions 5 and 6.5 years later, respectively. We performed a second surgery and were able to definitively diagnose the lesion as a grade III HPC based on the positive expression of STAT6 during immunostaining. CONCLUSIONS: As solitary fibrous tumor/HPC requires gross total resection for effective resolution, it is imperative to consider it in the differential diagnoses of similar tumors. If an unusual pathologic image is found, we recommend rapid immunostaining for STAT6 to reach a definitive conclusion regarding the tumor type. This case highlights the importance of considering HPC when screening or diagnosing central nervous system lesions, especially in this rare location.

Combined p53- and PTEN-deficiency activates expression of mesenchyme homeobox 1 (MEOX1) required for growth of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive cancer subtype for which effective therapies are unavailable. TNBC has a high frequency of tumor protein p53 (Tp53/p53)- and phosphatase and tensin homolog (PTEN) deficiencies, and combined p53- and PTEN-deficiency is associated with poor prognosis and poor response to anticancer therapies. In this study, we discovered that combined p53- and PTEN-deficiency in TNBC activates expression of the transcription factor mesenchyme homeobox 1 (MEOX1). We found that MEOX1 is expressed only in TNBC cells with frequent deficiencies in p53 and PTEN, and that its expression is undetectable in luminal A, luminal B, and HER2+ subtypes, as well as in normal breast cells with wild-type (WT) p53 and PTEN. Notably, siRNA knockdown of both p53 and PTEN activated MEOX1 expression in breast cancer cells, whereas individual knockdowns of either p53 or PTEN had only minimal effects on MEOX1 expression. MEOX1 knockdown abolished cell proliferation of p53- and PTEN-deficient TNBC in vitro and inhibited tumor growth in vivo, but had no effect on the proliferation of luminal and HER2+ cancer cells and normal breast cells. RNA-Seq and immunoblotting analyses showed that MEOX1 knockdown decreased expression of tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 5B (STAT5B), and STAT6 in p53- and PTEN-deficient TNBC cells. These results reveal the effects of combined p53- and PTEN-deficiency on MEOX1 expression and TNBC cell proliferation, suggesting that MEOX1 may serve as a potential therapeutic target for managing p53- and PTEN-deficient TNBC.

STAT6 Expression in Solitary Fibrous Tumor and Histologic Mimics: a Single Institution Experience.

STAT6 stain has proved to be a good surrogate marker for the genetic alteration (NAB2-STAT6 gene fusion) in solitary fibrous tumor (SFT). This study aims to validate the use of STAT6 rabbit monoclonal antibody in differentiating SFT from its histologic mimics. Forty-five cases of SFT and 110 cases from 9 other spindle cell tumors were collected for STAT6 immunostaining. Positive nuclear STAT6 staining was present in all 45 SFT cases (100% sensitivity). No nuclear staining was identified in other spindle cell neoplasms (0/13, dedifferentiated liposarcoma; 0/17, synovial sarcoma; 0/16, malignant peripheral nerve sheath tumors; 0/25, undifferentiated pleomorphic sarcoma; 0/10, dermatofibrosarcoma protuberans; 0/9, low-grade fibromyxoid sarcoma; 0/6, angiofibroma; 0/5, deep fibromatosis; 0/9, gastrointestinal tumor). The STAT6 staining in SFT was usually diffuse (5+ in 19 cases; 4+ in 17 cases) and strong (40 cases). Monoclonal STAT6 stain is highly sensitive and specific for SFTs and particularly useful in the diagnosis of difficult SFT cases.

Diagnostic utility of STAT6YE361 expression in classical Hodgkin lymphoma and related entities.

Although the distinction of classical Hodgkin lymphoma from nodular lymphocyte predominant Hodgkin lymphoma using morphology and immunostains is straightforward in most instances, occasional cases pose diagnostic challenge. We sought to determine the utility of the novel YE361 STAT6 rabbit monoclonal antibody in Hodgkin lymphoma and diagnostically challenging B- and T-cell non-Hodgkin lymphoma entities with Hodgkin-like features. Cases from seven institutions included: 57 classical Hodgkin lymphomas (31% EBV+), 34 nodular lymphocyte predominant Hodgkin lymphomas, 34 mimicking B- and T-cell non-Hodgkin lymphomas, and 7 reactive lymphoproliferations. After review of histology, STAT6YE361 immunostaining was performed. The intensity and spatial localization of immunopositivity was assessed in neoplastic cells. Additional FISH for programmed death ligand-1 (PD-L1) was performed in one patient in paired treatment-naive and relapse biopsy tissues. Two STAT6YE361 immunopositive cases were examined by whole-exome sequencing after flow sorting to assess mutations in STAT6 pathway genes. Most classical Hodgkin lymphomas showed nuclear staining for STAT6YE361 [46/57 cases (80%)] on Hodgkin cells. Staining was exclusively nuclear in a minority [12/46 (26%)], while dual nuclear and cytoplasmic localization was more common [34/46 (74%)]. In contrast, all nodular lymphocyte predominant Hodgkin lymphomas [0/34 (0%)] were negative for nuclear STAT6YE361 staining on the lymphocyte predominant cells. Within B- and T-cell non-Hodgkin lymphomas, nuclear STAT6YE361 was seen in: B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and in primary mediastinal large B-cell lymphoma. Strong PD-L1 gene amplification was noted in the paired cHL and relapse B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, although STAT6YE361 was negative in both biopsies. Whole-exome sequencing identified mutations in B2M, XPO1, and ITPKB as well CISHP213L (in the STAT pathway) in one classical Hodgkin lymphoma patient positive for nuclear STAT6YE361 although no underlying STAT6 mutations were observed in either sample examined. STAT6YE361 nuclear staining has 100% positive predictive value and 85.7% negative predictive value in confirming or excluding classical Hodgkin lymphoma diagnosis in the distinction from nodular lymphocyte predominant Hodgkin lymphoma and other benign and malignant entities.

Role of microRNA in CB1 antagonist-mediated regulation of adipose tissue macrophage polarization and chemotaxis during diet-induced obesity.

Although cannabinoid receptor 1 (CB1) antagonists have been shown to attenuate diet-induced obesity (DIO) and associated inflammation, the precise molecular mechanisms involved are not clear. In the current study, we investigated the role of microRNA (miR) in the regulation of adipose tissue macrophage (ATM) phenotype following treatment of DIO mice with the CB1 antagonist SR141716A. DIO mice were fed high-fat diet (HFD) for 12 weeks and then treated daily with SR141716A (10 mg/kg) for 4 weeks while continuing HFD. Treated mice experienced weight loss, persistent reduction in fat mass, improvements in metabolic profile, and decreased adipose inflammation. CB1 blockade resulted in down-regulation of several miRs in ATMs, including the miR-466 family and miR-762. Reduced expression of the miR-466 family led to induction of anti-inflammatory M2 transcription factors KLF4 and STAT6, whereas down-regulation of miR-762 promoted induction of AGAP-2, a negative regulator of the neuroimmune retention cues, Netrin-1 and its coreceptor UNC5B. Furthermore, treatment of primary macrophages with SR141716A up-regulated KLF4 and STAT6, reduced secretion of Netrin-1, and increased migration toward the lymph node chemoattractant CCL19. These studies demonstrate for the first time that CB1 receptor blockade attenuates DIO-associated inflammation through alterations in ATM miR expression that promote M2 ATM polarization and macrophage egress from adipose tissue. The current study also identifies additional novel therapeutic targets for diet-induced obesity and metabolic disorder.

Intracranial Solitary Fibrous Tumors: A Heterogeneous Entity with an Uncertain Clinical Behavior.

BACKGROUND: Intracranial solitary fibrous tumors (ISFTs) are rare mesenchymal neoplasms originating in the meninges and characterized by very different biologic and clinical behaviors. Benign histotypes, such as hemangiopericytomas, are now considered a cellular phenotypic variant of this heterogeneous group of rare spindle-cell tumors. Owing to their rarity and resemblance to other, more common brain tumors, ISFTs are often poorly recognized and remain a diagnostic challenge. METHODS: We describe a surgical series of 29 patients treated for ISFTs confirmed histologically and through immunohistochemistry. We attempt to provide a focus on the natural history of these pathologies and the need for tailored management. RESULTS: This was a retrospective consecutive series of 29 patients with either solitary fibrous tumor (n = 14) or hemangiopericytoma (n = 15) over a 10-year period. Mean follow-up time was 37.71 months. Recurrence rate was 42.9% for solitary fibrous tumors versus 26.7% for hemangiopericytomas. STAT6 expression was 66.7% in hemangiopericytomas versus 42.9% in SFTs. CONCLUSIONS: Histopathology and immunohistochemical staining (characterized by positive expression of mainly STAT6 but also CD34, Bcl-2 protein, and vimentin) are key in diagnosis and management of ISFTs. Although ISFTs are still considered benign lesions with very rare aggressive evolution, their clinical behavior is largely unpredictable. This study highlights the importance of relying on immunohistochemistry for a thorough definition of the management strategy.

STAT6 expression in spindle cell lesions of the breast: An immunohistochemical study of 48 cases.

The diagnosis of spindle cell lesions of the breast parenchyma is challenging. Some of these lesions share the expression of CD34, posing differential diagnostic problems, especially in core biopsies. Recently, antibodies against the STAT6 C-terminal, are being used in paraffin-embedded tissues as a surrogate for identifying the NAB2-STA6 fusion gene which is considered a specific molecular marker for solitary fibrous tumor. Accordingly, we investigated the expression of STAT6 in a large series of uncommon spindle cell tumor-like and tumor lesions occurring primarily in the breast parenchyma. We collected 10 classic-type myofibroblastomas, 9 desmoid-type fibromatosis, 6 spindle cell metaplastic carcinoma, 5 benign fibroblastic spindle cell tumors, 3 solitary fibrous tumors, 7 pseudoangiomatous stromal hyperplasias, 2 reactive spindle cell nodules, 1 leiomyoma, 1 spindle cell lipoma, 1 case of inflammatory pseudotumor, 1 nodular fasciitis, 1 myxoma and 1 dermatofibrosarcoma protuberans. A diffuse and strong nuclear STAT6 expression was restricted only to solitary fibrous tumors, while the other lesions were negative or showed only weak cytoplasmic expression. The present study confirms that the demonstration of a diffuse and strong STAT6 nuclear staining is very helpful in distinguishing solitary fibrous tumor from other spindle cell mimics arising in the breast.

Synergistic action of dual IGF1/R and MEK inhibition sensitizes childhood acute lymphoblastic leukemia (ALL) cells to cytotoxic agents and involves downregulation of STAT6 and PDAP1.

Heterogeneous upregulation of multiple prosurvival pathways underlies resistance to damage-induced apoptosis in acute lymphoblastic leukemia (ALL) cells despite normal p53 responses. Here, we show that the dual combination of insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1/R) and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition using AG1024 + U0126 can sensitize apoptosis-resistant ALL cells to ionizing radiation-induced DNA damage irrespective of effect of single pathway inhibition in vitro. This AG1024 + U0126 combination also significantly potentiates the ability of the core chemotherapy compounds vincristine, dexamethasone, and daunorubicin to kill ALL cells in vitro. Evidence of the synergistic action of AG1024 + U0126 in samples with variable basal levels of phosphorylated IGF1/Rß and ERK1/2 suggested additional targets of this drug combination. Consistent with this, gene expression profiling identified 32 "synergy genes" differentially targeted by IGF1/R + MEK inhibition and, among these, Signal transducer and activator of transcription 6 (STAT6) and platelet-derived growth factor-associated protein 1 (PDAP1) were the most differentially downregulated cluster. Pearson correlation analysesrevealed that STAT6 and PDAP1 display significant expression codependency and a common expression pattern linked with other key "synergy" genes, supporting their predicted role in an STAT6-ERK-nuclear factor kappa beta (NF-κB) network. Knockdown studies revealed that loss of STAT6, but not PDAP1, impinges on the cell cycle, causing reduced numbers of viable cells. In combination with daunorubicin, STAT6 loss has an additive effect on cell killing, whereas PDAP1 loss is synergistic, indicating an important role of PDAP1 in the cellular response to this anthracycline. Inhibition of STAT6 or PDAP1 may therefore represent a potential novel therapeutic strategy for resistant ALL by enhancing sensitivity to chemotherapy.

Inhibition of STAT6/Anoctamin-1 Activation Suppresses Proliferation and Invasion of Gastric Cancer Cells.

BACKGROUND: Gastric carcinoma is the most popular cancer worldwide. Anoctamin-1 is a calcium-activated channel and highly expressed in various tumors. A previous study indicated that suppressed Anoctamin-1 expression decreased cancer cell proliferation or migration. As a signal transduction and transcription activator, STAT6 is a novel agonist for Anoctamin-1 promoter. However, its role in tumor cell proliferation or migration remains unclear. Therefore, this study aimed to suppress STAT6 and Anoctamin-1 protein expression in gastric cancer cells to test the inhibitory effects on gastric cancer cell migration or invasion. MATERIALS AND METHODS: MTT colorimetry was used to test cell proliferation. Western blot was used to measure STAT6 and Anoctamin-1 expression before and after small interfering RNA (siRNA) treatment. A scratch assay was performed to measure cell migration, followed by Transwell chamber assay analysis of cell invasion. RESULTS: After STAT6 siRNA interference, the expression of STAT6 and Anoctamin-1 was significantly decreased in the gastric carcinoma cell line. Anoctamin-1 siRNA interference only decreased its protein expression, but not STAT6 protein expression. Interference of STAT6 or Anoctamin-1 reduced their protein expression and inhibited proliferation, migration, or invasion of gastric cancer cells. CONCLUSIONS: Inhibition of STAT6/Anoctamin-1 activation decreased proliferation, migration, or invasion of gastric cancer cells, suggesting that the STAT6/Anoctamin-1 pathway might be a novel target for treating gastric cancer.

Sulfur dioxide exposure enhances Th2 inflammatory responses via activating STAT6 pathway in asthmatic mice.

Sulfur dioxide (SO2) is one of potential risk factors for induction and/or exacerbation of asthma, but the underlying mechanisms are not well understood. In this study, we investigate the role of SO2 in asthma using a classical asthmatic model with allergic airway inflammation by treating C57BL/6 mice with ovalbumin (OVA) and/or 10 mg/m3 SO2. Our results showed that SO2 exposure alone induced slight pathological changes but did not significantly increase inflammatory cell counts, pro-inflammatory cytokine expression, and mucus production in the airway of mice, whereas SO2 exposure in OVA-induced asthmatic mice caused marked pulmonary pathological changes and significantly increased the counts of eosinophil-rich leukocytes compared with OVA alone asthmatic mice. The expression of MUC5AC, TNF-α, Th2 cytokines (IL-4, IL-5, and IL-13) and STAT6 was further up-regulated in OVA plus SO2 treated mice compared with OVA alone treated mice. In addition, exposure to SO2 alone markedly elevated STAT6 mRNA levels and hydrogen peroxide (H2O2) content in the lung. These findings suggest that SO2 amplifies Th2 inflammatory responses in OVA-induced asthmatic mice by activating STAT6, which can further induce Th2 cytokine expression. Induction of STAT6 expression might be an important mechanism underlying the increased risk for asthma after environmental exposure.

STAT6 Reliably Distinguishes Solitary Fibrous Tumors from Myofibromas.

Solitary fibrous tumors (SFT) and myofibromas (MF) historically have belonged to the same morphologic spectrum and have been lumped together under the nonspecific umbrella term, "hemangiopericytoma" along with other pericytic/myoid tumors. While current evidence shows clear distinction between the two entities, they frequently remain in the same histopathologic differential diagnosis. This diagnostic dilemma especially is common for smaller incisional biopsies from the oral cavity. STAT6 immunohistochemistry (IHC) recently was established as a reliable method to detect solitary fibrous tumor; however, the literature is sparse regarding STAT6 reactivity in MFs. The authors report ten new cases of oral solitary fibrous tumor, discuss histopathologic similarities and differences between the two tumors, and list respective STAT6 IHC expressivity. After IRB approval, 10 cases diagnosed as SFT and 24 cases of MF were collected from the University of Florida Oral and Maxillofacial Pathology Biopsy Service between the years 1994 and 2016. The original hematoxylin and eosin slides and related IHC were reviewed. IHC with STAT6 antibody was performed on all 34 samples, and the findings were analyzed. All cases were from the oral cavity or perioral regions. 10/10 SFTs expressed STAT6 nuclear reactivity, while no cases of MF showed nuclear expression of STAT6. STAT6 is a dependable marker to differentiate SFTs from MFs.

Downregulation of miR-214-3p May Contribute to Pathogenesis of Ulcerative Colitis via Targeting STAT6.

MicroRNAs (miRs) are small noncoding RNA molecules and recently have demonstrated that altered expression and functions are their tight association with ulcerative colitis (UC). Previous microarray study reported that miR-214 was downregulated in the sigmoid colon of patients with active UC, but the roles of miR-214 in the pathogenesis of UC remain to be elucidated. In this study, significant lower level of miR-214-3p and higher level of STAT6 in the intestinal mucosa of active UC patients compared with the health controls were confirmed by quantitative real-time PCR. Results of luciferase reporter assays and western blot demonstrated that miR-214-3p directly targets STAT6 and negatively regulates the expression of STAT6 at the posttranscriptional level. Furthermore, the expression of miR-214-3p was decreased in TNF-α treated HT29 cells and STAT6 protein level was increased in a time-dependent manner. Silenced STAT6 and upregulation of miR-214-3p could decrease the level of INF-γ in TNF-α treated HT29 cells. Additionally, the results of the present study indicate that miR-214-3p and STAT6 axis may be a novel therapeutic target for intestinal inflammation of patients with active UC.

Validation of nuclear STAT6 immunostaining as a diagnostic marker of meningeal solitary fibrous tumor (SFT)/hemangiopericytoma.

INTRODUCTION: NAB2-STAT6 gene fusion is a molecular characteristic of solitary fibrous tumors (SFT) and hemangiopericytoma, underscoring their definition as one diagnostic entity. NAB2-STAT6 fusion is associated with nuclear relocation of STAT6 protein that can be detected by immunohistochemistry. We evaluated the diagnostic value of STAT6 expression in meningeal tumors. METHODS: 77 meningeal tumors (17/77 (22.0%) SFT/hemangiopericytoma, 11/77 meningothelial meningioma, 10/77 atypical meningioma 8/77 chordoid meningioma, 9/77 fibroblastic meningioma, 10/77 transitional meningioma, 3/77 rhabdoid meningioma and 9/77 anaplastic meningioma) were included. STAT6 immunohistochemistry was performed on FFPE specimens using a fully automated slide-staining system and anti-STAT6 antibody SC-20:sc621. Two independent observers analyzed all specimens blinded to histological diagnoses, and a third observer was consulted in case of discordancy. RESULTS: STAT6 immunohistochemistry yielded an exclusively nuclear immunostaining signal. 16/17 (94%) SFT/hemangiopericytoma specimens presented with clear-cut, wide-spread, and moderate to strong staining in tumor cell nuclei and were rated as STAT6-positive. In only 1 SFT case with weak and focal nuclear STAT6 immunostaining signal, STAT6 expression was rated discordant (observer 1: STAT6-negative, observers 2 and 3: STAT6-positive). All non-SFT/hemangiopericytoma cases were unanimously rated as STAT6-negative. In 76/77 (98.7%) cases the evaluation of STAT6 immunostaining results was in agreement among observers. CONCLUSION: STAT6 immunohistochemistry is a robust method to verify diagnosis of SFT/hemangiopericytoma and should therefore be included in the diagnostic work-up of meningeal tumors. In singular cases, weak and focal STAT6 expression may lead to false-negative evaluation and may prompt further molecular work-up.
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Exploring the mechanism of non-small-cell lung cancer cell lines resistant to epidermal growth factor receptor tyrosine kinase inhibitor.

PURPOSE: Here we aimed to explore the possible mechanism and potential regulatory relationships in which the non.small.cell lung cancer. (NSCLC)-resisted epidermal growth factor receptor. (EGFR) tyrosine kinase inhibitor erlotinib. MATERIALS AND METHODS: GSE38310, the gene expression profiles of NSCLC cell lines treated with dimethylsulfoxide or erlotinib, including HCC827, ER3, and T15-2, were downloaded from Gene Expression Omnibus database and preprocessed by normalization. Basing on the regulatory relationships of transcriptional factors obtained from University of California Santa Cruz. (UCSC) database, the differentially expressed genes. (DEGs) were screened using limma package in R with. |logFC| >1 and P < 0.05, and regulatory networks of these DEGs were built with supervised inference of regulatory networks (SIRENE). Subsequently, differentially regulatory networks were compared basing on Limit Fold Change. (LFC) method. RESULTS: Totally 24,380 genes were obtained, 1,531 DEGs were identified in HCC827 cell lines, 37 DEGs in ER3 cell lines, 156 DEGs in T15-2 cell lines. After removing the redundancy genes, 1,575 differentially expressed genes were got at last. Basing on three regulatory networks of HCC827 cell lines, ER3 cell lines and T15-2 cell lies, sex-determining region Y (SRY).related high mobility group-box gene 9. (SOX9) and Suppressor of cytokine signaling 3 (STAT3) were identified by comparing with HCC827 and ER3 networks. And suppressor of cytokine signaling 5 B (STAT5B), early growth response-1 (EGR1) and STAT6 were obtained in comparison of HCC827 and T15-2 networks. CONCLUSIONS: The regulatory edges with remarkable changes between HCC827 and ER3, HCC827 and T15.2 included some transcription factors and genes. (e. g., STAT3 and SOX9). STAT3, SOX9, STAT5B, EGR1, and STAT6 might affect the resistance of NSCLC to erlotinib.

Intracranial solitary fibrous tumor/ hemangiopericytoma with osteoclast-like multinucleated giant cells: comparison with giant cell-rich solitary fibrous tumor.

AIMS: Intracranial solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a mesenchymal neoplasm that typically presents in adults as a dural-based lesion. The presence of giant cells in these tumors is a rare occurrence. MATERIALS AND METHODS: We studied a case of intracranial SFT/HPC with unusual multinucleated, osteoclast-like giant cells and compared it to the so-called giant cell angiofibroma (i.e., giant cell-rich solitary fibrous tumor) withattention to STAT6 immunohistochemistry. RESULTS: A 73-year-old man developed a right frontoparietal dural mass that was completely resected. Histology demonstrated a hypercellular neoplasm consisting of spindle to oval cells and scattered osteoclast-like multinucleated giant cells (MGCs), with distinctive "staghorn" blood vessels. Necrosis and brisk mitotic activity were present. The spindle cell component showed strong focal CD34 and nuclear STAT6 immunohistochemical labeling, while CD68 and CD163 were positive in MGCs. No nuclear STAT6 reactivity was detected in MGCs. By contrast, nuclear STAT6 staining was present in three cases of giant cell angiofibroma (i.e., giant-cell rich solitary fibrous tumor), both in the spindle cell component and MGCs. CONCLUSION: Intracranial SFT/HPC is characterized by nuclear STAT6 immunoreactivity as its soft tissue counterparts. The presence of osteoclast-like MGCs is an unusual finding in this neoplasm, which is distinct from giant cell-rich solitary fibrous tumor.

Inhibition of MDM2 expression by rosmarinic acid in TSLP-stimulated mast cell.

Rosmarinic acid (RA) has an anti-inflammatory property while thymic stromal lymphopoietin (TSLP) has an important role in mast cell-mediated inflammatory responses. Thus, the aim of this study was to determine the regulatory effect of RA in TSLP-stimulated human mast cell line, HMC-1 cells, and short ragweed pollen-induced allergic conjunctivitis mouse model. As a result, we found that RA significantly decreased the TSLP-induced mast cell proliferation and murine double minute (MDM) 2 expression. RA significantly decreased the levels of interleukin (IL)-13 and phosphorylated the signal transducer and activation of transcription 6 in the TSLP-stimulated HMC-1 cells. RA induced the increment of p53 levels, caspase-3 activation, and poly-ADP-ribose polymerase cleavage and the reduction of the procaspase-3 and Bcl2. RA significantly reduced the production of tumor necrosis factor-α, IL-1ß, and IL-6 on the TSLP-stimulated HMC-1 cells. In addition, RA significantly reduced the levels of IgE, IL-4, and TSLP in the short ragweed pollen-induced allergic conjunctivitis mouse model. In conclusion, the results of the study suggest that RA has a significant anti-inflammatory effect on TSLP-induced inflammatory reactions. These effects of RA are likely to be mediated through inhibiting the MDM2 increased by TSLP.