Increased tissue expression of IL-31 in patients with psoriasis.

Psoriasis is a chronic inflammatory skin disease, and its pathogenesis remains unclear. Although many studies have demonstrated the role of serum interleukin-31 (IL-31) in psoriasis, only one study has examined histopathological expression in lesional skin. This study aimed to investigate the expression of IL-31 in skin biopsy specimens of psoriasis patients compared to healthy subjects and identify its possible correlation to disease severity and itch intensity. Psoriasis patients and healthy volunteers were recruited. Four-millimeter punch biopsy was performed at the lesional skin of psoriasis patients and normal skin of healthy subjects. Expression of IL-31 was measured by immunohistochemistry. Baseline characteristics, disease activity, itch intensity, and related laboratory results were collected. Twenty-six biopsy specimens of psoriasis patients and 10 tissue samples of healthy subjects were evaluated. Epidermal and dermal psoriasis lesions had significantly higher IL-31 expression compared to the healthy skin (P < 0.001). However, there was no significant difference in lesional expression of IL-31 by disease severity or itch intensity. Increased IL-31 expression in the lesions of psoriasis patients suggests the involvement of IL-31 in the pathogenesis of psoriasis.

Case Report: Melioidosis-Related Severe Cutaneous Features of Erythema Nodosum in a Thai Child.

Erythema nodosum (EN) is characterized by rapidly developing, painful, erythematous subcutaneous nodules, most of which are located in the pretibial areas. This cutaneous finding can be caused by a variety of conditions, however Burkholderia pseudomallei is rarely the cause. This particular patient presented with a high-grade fever with characteristic EN on both pretibial areas. All of the typical EN causes were investigated, but the findings were all negative. The lesions progressed to severe hemorrhagic bleb features, and because the patient resided in Northeast Thailand, a melioidosis-endemic region, testing for B. pseudomallei was performed. Because a high level of melioidosis serology of more than 1:10,240 was detected, melioidosis therapy was started. At the 12-week follow-up after melioidosis therapy, the titer had declined to 1:1,280, indicating that melioidosis-related severe, cutaneous EN symptoms were the most likely diagnosis in this patient. We discovered a case of EN with severe hemorrhagic bleb features as a unique clinical manifestation of melioidosis. When a patient resides in an endemic area, B. pseudomallei should always be considered as a possible causative organism.

High XB130 expression in renal cell carcinoma is strongly associated with poor prognosis.

The aim of this study was to assess the prognostic value of XB130 expression in three major RCC subtypes, and its association with clinical outcomes and adverse clinicopathologic features. A total of 101 nephrectomy samples at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Thailand, from 2007 to 2017 were included in the study. XB130 immunohistochemistry was performed on slides from a tissue microarray comprised of 71 clear cell RCCs, 23 papillary RCCs, and 7 chromophobe RCCs, and were scored using a Histoscore system on a 0-300 scale. High XB130 expression in clear cell RCC and papillary RCC patients was associated with poor prognosis (log-rank test, P = 0.013, and P = 0.001, respectively). WHO/ISUP grade (P = 0.001) and XB130 high expression (P = 0.019) were found to be independent risk factors for mortality in clear cell RCC using multivariate analysis. The high expression of XB130 in clear cell RCC patients was also associated with high WHO/ISUP grade (P = 0.011), distant metastasis (P = 0.036), TNM stage (P = 0.007), sarcomatoid/rhabdoid differentiation (P = 0.061), and urinary collecting system invasion (P = 0.002). Similarly, high XB130 expression (P = 0.038) was associated with poor prognosis among papillary RCC patients as well as with lymphovascular invasion (P = 0.022), TNM stage (P = 0.030), and sarcomatoid/rhabdoid differentiation (P = 0.044). Overall, our findings showed that high XB130 expression in clear cell RCC and papillary RCC patients are associated with a worse prognosis.

Inflammatory Myo-Fibroblastic Tumor of the Gallbladder with Multivisceral Involvement: Successful Treatment with Radical Surgery.

Inflammatory myo-fibroblastic tumor (IMT) of the gallbladder is an extremely rare condition. Only seven cases have been reported. All of these were presented either with polyp/mass inside the gallbladder or gallbladder wall thickening, involving just one adjacent organ. We herein present a case of IMT of gallbladder presenting with a huge mass replacing the gallbladder with multiple organ involvement, successfully treated by en bloc multivisceral resection. Moreover, we have compared it with the characteristics of all reported cases of IMT of the gallbladder.

Overexpression of Insulin Receptor Substrate 1 (IRS1) Relates to Poor Prognosis and Promotes Proliferation, Stemness, Migration, and Oxidative Stress Resistance in Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is one of the oxidative stress-driven carcinogenesis through chronic inflammation. Insulin receptor substrate 1 (IRS1), an adaptor protein of insulin signaling pathways, is associated with the progression of many inflammation-related cancers. This study hypothesized that oxidative stress regulates IRS1 expression and that up-regulation of IRS1 induces CCA progression. The localizations of IRS1 and an oxidative stress marker (8-oxodG) were detected in CCA tissues using immunohistochemistry (IHC). The presence of IRS1 in CCA tissues was confirmed using immortal cholangiocyte cells (MMNK1), a long-term oxidative-stress-induced cell line (ox-MMNK1-L), and five CCA cell lines as cell culture models. IRS1 was overexpressed in tumor cells and this was associated with a shorter patient survival time and an increase in 8-oxodG. IRS1 expression was higher in ox-MMNK1-L cells than in MMNK1 cells. Knockdown of IRS1 by siRNA in two CCA cell lines led to inhibition of proliferation, cell cycle progression, migration, invasion, stemness, and oxidative stress resistance properties. Moreover, a transcriptomics study demonstrated that suppressing IRS1 in the KKU-213B CCA cell line reduced the expression levels of several genes and pathways involved in the cellular functions. The findings indicate that IRS1 is a key molecule in the connection between oxidative stress and CCA progression. Therefore, IRS1 and its related genes can be used as prognostic markers and therapeutic targets for CCA therapy.

Increased IL-31 expression in serum and tissue protein in prurigo nodularis.

Background: Prurigo nodularis (PN) is a chronic pruritic skin disease which can greatly impact patients' quality of life. Moreover, the pathogenesis remains unclear, making it a difficult-to-treat condition. Aims: To investigate the expression of interleukin-31 (IL-31) in serum and skin biopsy specimens of PN patients and healthy subjects and identify its possible correlation to disease severity and itch intensity. Methods: Patients with PN and healthy volunteers were recruited for the study. Expression levels of IL-31 were measured by enzyme-linked immunosorbent assay and immunohistochemistry. Baseline characteristics, disease activity, itch intensity, and related laboratory results were collected. Results: Forty-three PN patients and 31 healthy subjects participated in our study. The PN patients had significantly higher mean serum IL-31 levels than the healthy subjects (52.9 ± 18.2 versus 36.3 ± 10.7 pg/ml, p < 0.001). Epidermal and dermal PN lesions also exhibited significantly higher IL-31 expression compared with the healthy skin (p < 0.001 and p = 0.01, respectively). However, there was no significant difference in serum or lesional expression of IL-31 by disease severity or itch intensity. Conclusion: Increased IL-31 expression in serum and PN lesions suggests that IL-31 has a potential role in the pathogenesis of PN.

Adaptor protein XB130 regulates the aggressiveness of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a group of heterogenous malignancies arising from bile duct epithelium with distinct pathological features. Adaptor proteins have implicated in cell proliferation, migration, and invasion of different cancer cells. The objective of this study was to assess whether the adaptor protein XB130 (AFAP1L2) is a critical biological determinant of CCA outcome. XB130 expression levels were investigated in four CCA cell lines compared to an immortalized cholangiocyte cell line by Western blotting. Small interfering (si) RNA-mediated XB130 gene silencing was conducted to evaluate the effects of reduced XB130 expression on cell proliferation, migration, and invasion by MTT, transwell migration and cell invasion assay. The immunohistochemical quantification of XB130 levels were performed in surgically resected formalin-fixed, paraffin-embedded specimens obtained from 151 CCA patients. The relationship between XB130 expression and the clinicopathological parameters of CCA patients were analyzed. Our results showed that XB130 was highly expressed in KKU-213A cell line. Knockdown of XB130 using siRNA significantly decreased the proliferation, migration, and invasion properties of KKU-213A cells through the inhibition of PI3K/Akt pathway, suggesting that XB130 plays an important role in CCA progression. Moreover, elevated XB130 expression levels were positive relationship with lymphovascular space invasion (LVSI), intrahepatic type of CCA, high TNM staging (stage III, IV), high T classification (T3, T4), and lymph node metastasis. We provide the first evidence that the overexpression of XB130 is associated with tumorigenic properties of CCA cells, leading to CCA progression with aggressive clinical outcomes.

Establishment and genetic characterization of cell lines derived from proliferating nasal polyps and sinonasal inverted papillomas.

To better understand the pathogenesis of nasal polyps (NPs) and sinonasal inverted papillomas (SIPs), we aimed to establish cell lines from fresh tissues of NPs and SIPs and characterize them. Primary cell cultures were obtained from two NP tissues (NP2 and NP3) and one SIP tissue (IP4). All the cells were polygonal in shape, expressed cytokeratin 14, and had normal diploid chromosome status. HPV58 DNA was detected in NP3. To obtain immortal primary cells, NP2 and IP4 cells were transduced with a combination of mutant CDK4, cyclinD1 and TERT. These cells were thereafter named NP2/K4DT and IP4/K4DT, respectively. HPV58-positive NP3 cells were transduced with TERT alone, the resulting cells named NP3/T. Phenotypic and genotypic identity of original tissues and derived cells was investigated. All the cell cultures with transgenes were confirmed to be derived from their parental cells and primary tumor tissues by analysis of short tandem repeats (STR) and maintained in vitro growth, genetic profiles and gene expression characteristics of the primary cells. These virtually immortalized cells, as well as the primary cells, have potential as in vitro models for studying the pathogenesis of NPs and SIPs and for preclinical study to develop new therapeutic agents.

Promoter hypermethylation of early B cell factor 1 (EBF1) is associated with cholangiocarcinoma progression.

DNA hypermethylation in a promoter region causes gene silencing via epigenetic changes. We have previously reported that early B cell factor 1 (EBF1) was down-regulated in cholangiocarcinoma (CCA) tissues and related to tumor progression. Thus, we hypothesized that the DNA hypermethylation of EBF1 promoter would suppress EBF1 expression in CCA and induce its progression. In this study, the DNA methylation status of EBF1 and mRNA expression levels were analyzed in CCA and normal bile duct (NBD) tissues using a publicly available database of genome-wide association data. The results showed that the DNA methylation of EBF1 promoter region was significantly increased in CCA tissues compared with those of NBD. The degree of methylation was negatively correlated with EBF1 mRNA expression levels. Using methylation-specific PCR technique, the DNA methylation rates of EBF1 promoter region were investigated in CCA tissues (n=72). CCA patients with high methylation rates of EBF1 promoter region in the tumor tissues (54/72) had a poor prognosis. Higher methylation rates of EBF1 promoter region have shown in all CCA cell lines than that of an immortal cholangiocyte cell line (MMNK1). Upon treatment with the DNA methyltransferase inhibitor 5-Aza-dC, increased EBF1 expression levels and reduced DNA methylation rates were observed in CCA cells. Moreover, restoration of EBF1 expression in CCA cells led to inhibition of cell growth, migration and invasion. In addition, RNA sequencing analysis suggested that EBF1 is involved in suppression of numerous pathways in cancer. Taken together, DNA hypermethylation in the EBF1 promoter region suppresses EBF1 expression and induces CCA progression with aggressive clinical outcomes.

Total en bloc spondylectomy is worth doing in complete paralysis spinal giant cell tumor, a minimum 1-year follow-up.

OBJECTIVE: To investigate the neurological recovery of Frankel A spinal giant cell tumor (GCT) patients after they had received a Total En Bloc Spondylectomy (TES). MATERIALS AND METHODS: We retrospectively recorded data of three patients (two females) with mobile spine GCT (T6, T10, and L2) Enneking stage III with complete paralysis before surgery, who had undergone TES in our institute from January 2018 to September 2020. The duration of neurologic recovery to Frankel E was the primary outcome. The intra-operative blood loss, operative time, operative-related complications, and the local recurrence were the secondary outcomes. RESULTS: The duration of suffering from Frankel A to TES surgery was 2 months for the T6 patient, 3 weeks for the T10 patient, and 1 month for the L2 patient. Three patients had achieved full neurological recovery to Frankel E within 6 months after TES (T6 for 5 months, T10 for 3 months, and L2 for 3 months). The average blood loss was 2833.33 ml and the mean operative time was 400 min. Up until the last follow-up (13-25 months), no evidence of local recurrences had been found in any of the three patients. CONCLUSION: Frankel A spinal GCT patients can achieve full neurological recovery after TES, if the procedure is performed within 3 months after complete paraplegia. TES can effectively control any local recurrences.

Imaging of a glomus tumor of the liver in a child.

Glomus tumors occur preferentially in the subcutaneous tissue of the fingers and toes, but are extremely rare in visceral organs. Although, there have been several reports of glomus tumors in the liver in adult patients, there have yet been no publications reporting glomus tumors of the liver in children. Here, we report a case of an 11-year-old girl who was admitted with a 2-week history of progressive dyspnea on exertion and vomiting. Upon physical examination, she was found to have hypertension and a palpated smooth, firm mass at the epigastrium. Abdominal MRI revealed a well-defined exophytic hypervascular mass with intratumoral hemorrhage at segment 3/4b of the liver. Ultrasound-guided biopsy revealed it to be a glomus tumor. An ultrasound conducted at a 1-month follow-up after preoperative embolization revealed that the mass had decreased in size. A subsequent exploratory laparotomy with left hepatectomy was performed and the histologic results confirmed the diagnosis.

Roles of Zinc Finger Protein 423 in Proliferation and Invasion of Cholangiocarcinoma through Oxidative Stress.

Zinc finger protein 423 (ZNF423) is a transcriptional factor involved in the development and progression of cancers but has not yet been examined in cholangiocarcinoma (CCA), an oxidative stress-driven cancer of biliary epithelium. In this study, we hypothesized that oxidative stress mediated ZNF423 expression regulates its downstream genes resulting in CCA genesis. ZNF423 protein expression patterns and 8-oxodG (an oxidative stress marker) formation in CCA tissues were investigated using immunohistochemical analysis. The results showed that ZNF423 was overexpressed in CCA cells compared to normal bile duct cells adjacent of the tumor. Notably, ZNF423 expression was positively correlated with 8-oxodG formation. Moreover, ZNF423 expression in an immortalized cholangiocyte cell line (MMNK1) was increased by hydrogen peroxide-treatment, suggesting that oxidative stress induces ZNF423 expression. To investigate the roles of ZNF423 in CCA progression, ZNF423 mRNA was silenced using specific siRNA in CCA cell lines, KKU-100 and KKU-213. Silencing of ZNF423 significantly inhibits cell proliferation and invasion of both CCA cell lines. Taking all these results together, the present study denoted that ZNF423 is an oxidative stress-responsive gene with an oncogenic property contributing to the regulation of CCA genesis.

Subcutaneous calcification as a supportive radiologic finding for diagnosis of rhinofacial entomophthoromycosis.

Rhinofacial entomophthoromycosis is an uncommon chronic fungal infection of the head and neck. The diagnosis is usually based on clinical manifestations; however, diagnosis of this infection based on early manifestations is difficult and occasionally rhinofacial entomophthoromycosis is mistaken for other diseases. Therefore, computed tomography is introduced to support the diagnosis. Radiologic findings were nonspecific with swelling of the sinonasal mucosa and perinasal region. However, subcutaneous calcification, that was observed in all our cases, may be a supportive radiologic evidence for diagnosis. The diagnosis should be confirmed definitively using histopathology or fungal culture. Early diagnosis allows prompt and appropriate treatment that will achieve excellent outcomes. We suggest that subcutaneous calcification radiologic finding may guide the aware physician to an early diagnosis of rhinofacial entomophthoromycosis.

Overexpression of CD44 Variant 9: A Novel Cancer Stem Cell Marker in Human Cholangiocarcinoma in Relation to Inflammation.

Various CD44 isoforms are expressed in several cancer stem cells during tumor progression and metastasis. In particular, CD44 variant 9 (CD44v9) is highly expressed in chronic inflammation-induced cancer. We investigated the expression of CD44v9 and assessed whether CD44v9 is a selective biomarker of human cholangiocarcinoma (CCA). The expression profile of CD44v9 was evaluated in human liver fluke Opisthorchis viverrini-related CCA (OV-CCA) tissues, human CCA (independent of OV infection, non-OV-CCA) tissues, and normal liver tissues. CD44v9 overexpression was detected by immunohistochemistry (IHC) in CCA tissues. There was a higher level of CD44v9 expression and IHC score in OV-CCA tissues than in non-OV-CCA tissues, and there was no CD44v9 staining in the bile duct cells of normal liver tissues. In addition, we observed significantly higher expression of inflammation-related markers, such as S100P and COX-2, in OV-CCA tissues compared to that in non-OV and normal liver tissues. Thus, these findings suggest that CD44v9 may be a novel candidate CCA stem cell marker and may be related to inflammation-associated cancer development.

The Importance of CYP19A1 in Estrogen Receptor-Positive Cholangiocarcinoma.

CYP19A1, also called aromatase, is a key enzyme for converting androgens to estrogens of estrogen synthesis. Elevated serum estrogen and high expression levels of estrogen-related proteins are found in cholangiocarcinoma (CCA; bile duct cancer). However, the expression of CYP19A1 in relation to estrogen-related proteins, including estrogen receptors (ERα, ERß, and GPR30) and an estrogen response protein (TFF1), has never been explored in CCA. In this study, we investigated the expressions of CYP19A1 and estrogen-related proteins in CCA tissues (n = 74; 51 males and 23 females) using immunohistochemistry. The results showed that CYP19A1 was overexpressed in CCA cells compared with that in normal bile duct cells in the adjacent tissues. High expression of CYP19A1 was correlated with the metastatic status of the patients. High CYP19A1 expression was also positively correlated with GPR30 expression. Correlation between high CYP19A1 expression in the tumor tissues and shorter survival time was more prominent in male than in female CCA patients. To elucidate further, the effect of CYP19A1 knockdown on a CCA cell line was examined using a specific siRNA. When CYP19A1 gene expression was suppressed, migration and proliferation activities of CCA cells were significantly reduced. Moreover, the cell proliferation of high CYP19A1-expressing KKU-213 cells was more profoundly suppressed by CYP19A1 inhibitors (exemestane and letrozole) than low CYP19A1-expressing KKU-100 cells. Thus, CYP19A1 promotes CCA progression with aggressive clinical outcomes via increased migration and proliferation activities of cancer cells. CYP19A1 can be a potential chemotherapeutic target for CCA, especially in male patients.

Potential role of HIF-1-responsive microRNA210/HIF3 axis on gemcitabine resistance in cholangiocarcinoma cells.

MicroRNA-210 (miR-210) is a robust target for hypoxia-inducible factor, and its overexpression has been detected in a variety of solid tumors. However, the role of miR-210 in the development, progression and response to therapy in cholangiocarcinoma (CCA) remains undefined. We report here that high miR-210 expression was significantly correlated with the shorter survival of CCA patients. Overexpression of miR-210 inhibited CCA cell proliferation at the G2/M phase and reduced the gemcitabine sensitivity in CCA cells under CoCl2-induced pseudohypoxia. Concomitantly, inhibition of endogenous miR-210 activity using miRNA sponges increased cell proliferation under CoCl2-induced pseudohypoxia, resulting in an increase in gemcitabine sensitivity in CCA cells. We showed that HIF-3α, a negative controller of HIF-1α, was a target of miR-210 constituting a feed-forward hypoxic regulatory loop. Our data suggest an important role of miR-210 in sustaining HIF-1α activity via the suppression of HIF-3α, regulating cell growth and chemotherapeutic drug resistance in CCA.

Inhibition of endothelial nitric oxide synthase in cholangiocarcinoma cell lines - a new strategy for therapy.

The isoform of nitric oxide synthase (NOS) found in endothelial cells (eNOS) plays a crucial role in vasodilation. We recently reported the activation of eNOS in cholangiocarcinoma (CCA) tissues and cell lines. Moreover, we also reported that the abundance of eNOS and phosphorylated eNOS (p-eNOS), as well as its upstream regulator proteins, is significantly associated with the metastatic status of CCA patients. However, the function of eNOS in CCA progression has not been addressed. Therefore, the present study aimed to investigate the function of eNOS involved in the migration and invasion ability of CCA cell lines. The results reveal that eNOS activation significantly increases migration and invasion ability of CCA cells via the up-regulation of phosphorylated vasodilator-stimulated protein (p-VASP). A combination treatment with recombinant human vascular endothelial growth factor C and eNOS inhibitor (Nω-nitro-l-arginine methyl ester hydrochloride) resulted in the down-regulation of p-VASP, as well as a decreased migration and invasion ability of the CCA cell line. Thus, this work suggests that eNOS can serve as an attractive target to inhibit the progression of CCA.

Potential of Selenium Compounds as New Anticancer Agents for Cholangiocarcinoma.

We examined the in vitro effects of the selenium compounds sodium selenite (Se) and selenomethionine (SeMet) on cholangiocarcima (CCA) cell growth and migration to determine their potential usefulness as anticancer agents. The effect of both compounds on the selenoprotein M level was investigated, as well as the association between the expression level of selenoprotein M and the patients' clinicopathological data. Se and SeMet inhibited CCA cell growth with half-maximal inhibitory concentration values of 1.7-2.1 µM and 18.8-37.9 µM, respectively. Both compounds increased the ratio of B-cell lymphoma 2 (BCL2) to BCL2-associated X (BAX), triggering apoptotic cell death, and inhibited cell migration by reducing the ratio of N-cadherin to E-cadherin, an epithelial-mesenchymal transition marker. In addition, Se and SeMet increased selenoprotein M protein in CCA cells. Low expression of selenoprotein M in CCA tissues was significantly associated with shorter patient survival. In conclusion, selenium may potentially be an alternative anticancer agent that might lead to a better prognosis in patients with CCA.