Upregulation of dihydropyrimidinase-like 3 (DPYSL3) protein predicts poor prognosis in urothelial carcinoma.

BACKGROUND: Dihydropyrimidinase-like 3 (DPYSL3) is a cytosolic phosphoprotein expressed in the nervous system and is crucial for neurogenesis. A previous study showed that increased DPYSL3 expression promotes tumour aggressiveness in pancreatic ductal adenocarcinoma, gastric cancer, and colon cancer. However, the role of DPYSL3 in affecting the biological behaviour of urothelial carcinoma (UC) is not yet understood. METHODS: A UC transcriptomic dataset from the Gene Expression Omnibus and the Urothelial Bladder Cancer (BLCA) dataset from The Cancer Genome Atlas were used for the in silico study. We collected 340 upper urinary tract urothelial carcinoma (UTUC) and 295 urinary bladder urothelial carcinoma (UBUC) samples for the immunohistochemical study. Fresh tumour tissue from 50 patients was used to examine the DPYSL3 mRNA level. In addition, urothelial cell lines with and without DPYSL3 knockdown were used for the functional study. RESULTS: The in silico study revealed that DPYSL3 correlated with advanced tumour stage and metastasis development while functioning primarily in the nucleobase-containing compound metabolic process (GO:0006139). DPYSL3 mRNA expression is significantly upregulated in advanced UC. Furthermore, overexpression of the DPYSL3 protein is significantly associated with the aggressive behaviour of UTUC and UBUC. DPYSL3 expression independently predicts disease-specific survival (DSS) and metastatic-free survival (MFS) in patients with UC. In non-muscle-invasive UBUC, DPYSL3 expression predicts local recurrence-free survival. UC cell lines with DPYSL3 knockdown exhibited decreased proliferation, migration, invasion, and human umbilical vein endothelial cells (HUVECs) tube formation but increased apoptosis and G1 arrest. Gene ontology enrichment analysis revealed that the enriched processes related to DPYSL3 overexpression in UC were tissue morphogenesis, cell mesenchyme migration, smooth muscle regulation, metabolic processes, and RNA processing. In vivo study revealed DPYSL3 knockdown in UC tumours significantly suppressed the growth of tumours and decreased MYC and GLUT1 protein expression. CONCLUSIONS: DPYSL3 promotes the aggressiveness of UC cells by changing their biological behaviours and is likely associated with cytoskeletal and metabolic process modifications. Furthermore, DPYSL3 protein overexpression in UC was associated with aggressive clinicopathological characteristics and independently predicted poor clinical outcomes. Therefore, DPYSL3 can be used as a novel therapeutic target for UC.

Elamipretide treatment during pregnancy ameliorates the progression of polycystic kidney disease in maternal and neonatal mice with PKD1 mutations.

Pregnancy is proposed to aggravate cyst progression in autosomal dominant polycystic kidney disease (ADPKD) but Tolvaptan, the only FDA-approved drug for adult ADPKD, is not recommended for pregnant ADPKD patients because of potential fetal harm. Since pregnancy itself may increase the risk for ADPKD progression, we investigated the safety and efficacy of Elamipretide, a mitochondrial-protective tetrapeptide. Elamipretide was found to ameliorate the progression of kidney disease in pregnant Pkd1RC/RC mice, in parallel with attenuation of ERK1/2 phosphorylation and improvement of mitochondrial supercomplex formation. Furthermore, Elamipretide was found to pass through the placenta and breast milk and ameliorate aggressive infantile polycystic kidney disease without any observed teratogenic or harmful effect. Elamipretide has an excellent safety profile and is currently tested in multiple phase II and phase III clinical trials. These preclinical studies support a potential clinical trial of Elamipretide for the treatment of ADPKD, particularly for patients that cannot take Tolvaptan.

Whole-exome sequencing identified mutational profiles of urothelial carcinoma post kidney transplantation.

Kidney transplantation is a lifesaving option for patients with end-stage kidney disease. In Taiwan, urothelial carcinoma (UC) is the most common de novo cancer after kidney transplantation (KT). UC has a greater degree of molecular heterogeneity than do other solid tumors. Few studies have explored genomic alterations in UC after KT. We performed whole-exome sequencing to compare the genetic alterations in UC developed after kidney transplantation (UCKT) and in UC in patients on hemodialysis (UCHD). After mapping and variant calling, 18,733 and 11,093 variants were identified in patients with UCKT and UCHD, respectively. We excluded known single-nucleotide polymorphisms (SNPs) and retained genes that were annotated in the Catalogue of Somatic Mutations in Cancer (COSMIC), in the Integrative Onco Genomic cancer mutations browser (IntOGen), and in the Cancer Genome Atlas (TCGA) database of genes associated with bladder cancer. A total of 14 UCKT-specific genes with SNPs identified in more than two patients were included in further analyses. The single-base substitution (SBS) profile and signatures showed a relative high T > A pattern compared to COMSIC UC mutations. Ingenuity pathway analysis was used to explore the connections among these genes. GNAQ, IKZF1, and NTRK3 were identified as potentially involved in the signaling network of UCKT. The genetic analysis of posttransplant malignancies may elucidate a fundamental aspect of the molecular pathogenesis of UCKT.

MicroRNA-145 suppresses cell migration and invasion in upper tract urothelial carcinoma by targeting ARF6.

ADP-ribosylation factor 6 (ARF6) is a well-studied protein that is involved in multiple biological functions including cell migration and invasion. The mechanism by which ARF6 regulates the migration and invasion of upper tract urothelial carcinoma (UTUC) is still unknown. MiR-145-5p is a tumor suppressor microRNA, which is downregulated in several cancer types. We aimed to elucidate the molecular mechanism underlying the regulation of ARF6 by miR-145-5p in UTUC. ARF6 expression was observed to be higher in UTUC tissues than paired adjacent normal tissues. A reverse correlation between ARF6 and miR-145-5p was found in UTUC tissues. MiR-145-5p inhibited ARF6 expression by directly targeting its 3'-UTR. The functional studies indicated that ARF6 expression reversed the miR-145-5p-reduced tumor cell migration and invasion. Notably, miR-145-5p reduced MMP2, N-cadherin, FAK and MMP7, and elevated E-cadherin protein levels in vitro; however, the above effects were reversed by ARF6. Further, the expression of epithelial-to-mesenchymal transition (EMT) markers and cell invasion was suppressed by knocking down MMP7 in UTUC cells. These findings suggest that miR-145-5p may suppress UTUC cell motility and invasion by targeting ARF6/MMP7 through EMT.

Predominant global glomerulosclerosis in patients of upper urinary tract urothelial carcinoma with pre-existing renal function impairment is a predictor of poor renal outcomes.

BACKGROUND: Incidence of renal dysfunction and risks of progression to end-stage renal disease (ESRD) were reported higher in upper urinary tract urothelial carcinoma (UTUC) than in renal cell carcinoma (RCC) patients after unilateral nephrectomy. METHODS: Totally 193 renal cancer patients, including 132 UTUC and 61 RCC, were studied to clarify whether the pathological changes of the kidney remnant removed from nephrectomy and the clinical factors might predict the risk of ESRD. Renal tubulointerstitial (TI) score and global glomerulosclerosis (GGS) rate were examined by one pathologist and two nephrologists independently under same histopathological criteria. RESULTS: The glomerular filtration rates at the time of surgery were lower in UTUC than RCC groups (p < 0.001). Average GGS score and average TI rate were higher in UTUC than in RCC groups (p < 0.001; p < 0.001). Competitive risk factor analysis revealed that abnormal GGS rate not related to age, predominant in UTUC with pre-existing renal function impairment, was a histopathological predictor of poor renal outcomes (creatinine doubling or ESRD) within 5 years in UTUC patients. CONCLUSION: Pre-existing renal function and pathological change of kidney remnant in both UTUC and RCC have the value for prediction of renal outcomes.

Synthetic Steroid Hormones Regulated Cell Proliferation Through MicroRNA-34a-5p in Human Ovarian Endometrioma.

Endometriosis is the hormone-dependent product of endometrial tissue found outside the uterus. Recently, micro-RNAs (miRNAs) were shown to play a role in endometriotic lesion development. However, the mechanism of steroid hormones responsible for miRNA remains obscure. In the present study, we assayed for the effects of synthetic steroid hormones (danazol, progesterone, and medroxyprogesterone acetate [MPA]) on miRNAs in endometriosis. We used a global miRNA expression profile microarray to evaluate miRNA expression in endometrial mesenchymal stem cells (EN-MSCs) of ovarian endometrioma following treatment with 1 µM danazol, progesterone, or MPA. Furthermore, we selected candidate miRNAs whose expression changed more than fivefold and compared the effects of danazol, progesterone, and MPA treatments and also compared those results with controls in EN-MSCs. Among those with a fivefold change, we found 13 ectopically upregulated miRNAs in EN-MSCs. To understand the function of these 13 miRNAs, we subjected their sequences to Ingenuity Pathway Analysis. According to both the etiology and pathogenesis of endometriosis, we found that miR-199a-5p and miR-34a-5p showed specific association with the disease, including molecular and cellular functions. Steroid hormone treatment elevated the levels of miR-199a-5p and miR-34a-5p. An inhibitor of miR-34a-5p also reduced the synthetic steroid hormones effects on cell proliferation. In vivo data revealed that miRNA levels in endometriotic lesions correlated with findings following in vitro synthetic hormone treatment. Our data show the effects of synthetic steroid hormones on miRNA regulation. These findings contribute to our understanding of the molecular impact of the synthetic steroid hormones and suggest a potential mechanism for endometriosis treatment.

BCAT1 overexpression is an indicator of poor prognosis in patients with urothelial carcinomas of the upper urinary tract and urinary bladder.

AIMS: Amino acid biosynthesis is one of the cardinal events of carcinogenesis that has not been investigated in urothelial carcinoma (UC). By data-mining a published transcriptomic database of UCs of urinary bladder (UBUCs) (GSE31684), we identified branched-chain amino acid transaminase 1 (BCAT1) as the most significantly stepwise up-regulated gene during tumour progression among those associated with the amino acid biosynthetic process (GO:0008652). Accordingly, we analysed BCAT1 transcript and protein expression with their clinicopathological significance. METHODS AND RESULTS: We used real-time reverse transcription-polymerase chain reaction (RT-PCR) to detect BCAT1 transcript levels in 20 UCs of upper tract (UTUCs) and 20 UBUCs, respectively. Immunohistochemical study was performed to determine BCAT1 protein expression in 340 UTUCs and 295 UBUCs. Higher BCAT1 transcript levels were associated with higher pT status in both groups (P < 0.05). BCAT1 protein overexpression was also associated significantly with adverse clinicopathological features, e.g. advanced pT stage, nodal metastasis, high pathological grade, etc. (P < 0.05). BCAT1 overexpression predicted worse disease-specific survival and metastasis-free survival in both univariate and multivariate analyses (P ≤ 0.001). CONCLUSION: BCAT1 overexpression is associated with advanced tumour status, and implies adverse clinical outcomes of UCs, suggesting that its role in tumour progression could serve as a prognostic biomarker and a novel therapeutic target in UC.

Overexpression of PTP4A3 is associated with metastasis and unfavorable prognosis in bladder cancer.

PURPOSE: Bladder cancer (BC) is the most common malignancy in urinary system. The prognosis of metastatic BC is poor, but there remains no reliable marker to early detect metastasis. Dysregulated prenylated protein tyrosine phosphatases (PTPs) are commonly associated with cancer metastasis. From a published BC transcriptome, we identified that PTP IVA3 (PTP4A3) was the most significantly upregulated gene implicated in tumor progression among genes related to prenylated PTPs. We therefore analyzed PTP4A3 expression in our well-characterized cohort of BC. METHODS: By immunohistochemistry, PTP4A3 expression was determined using H-score. PTP4A3 expression of 295 BCs was compared with clinicopathological parameters, and the effect of PTP4A3 on cancer-specific survival (CSS) and metastasis-free survival (MFS) was also examined. Two independent sets of BCs were used to assess PTP4A3 protein and transcript expression in normal urothelium and different stage tumors. RESULTS: PTP4A3 overexpression was significantly associated with higher pT stage (P < 0.001), nodal metastasis (P < 0.001), vascular invasion (P < 0.001), and perineural invasion (P = 0.021). In multivariate analysis, PTP4A3 overexpression was an independent predictor for CSS (P < 0.001) and MFS (P = 0.007). Notably, the difference in CSS and MFS between high and low PTP4A3-expressing tumors was also significant in muscle-invasive BCs. PTP4A3 protein expression showed significant and stepwise increments from normal urothelium to noninvasive BC, invasive BC, and metastatic foci (P < 0.001). PTP4A3 transcript was also obviously upregulated in high-stage BC (P < 0.001). CONCLUSIONS: PTP4A3 may play a role in BC oncogenesis and is a predictive marker of metastasis. PTP4A3 overexpression represents an independent prognosticator for BC, suggesting its potential theranostic value.

Overexpression of JAK2: a predictor of unfavorable prognosis for nasopharyngeal carcinoma.

PURPOSE: Analysis of the nasopharyngeal carcinoma public transcriptome revealed JAK2 was significantly upregulated in tumors, which encouraged us to investigate its prognostic significance and mutational status. MATERIALS & METHODS: We assessed the immune-expression of JAK2 and its relationships with various clinicopathological parameters. JAK2 mutation was detected by PCR followed by sequencing. RESULTS: High expression of JAK2 was significantly associated with advanced tumor staging (p = 0.019). JAK2 overexpression acted as an independent predictor for worse disease-specific survival (p = 0.005), distant metastasis-free survival (p = 0.036), local recurrence-free survival (p = 0.012) and overall survival (p = 0.007). JAK2 mutation was not detected in selected cases with JAK2 protein overexpression. CONCLUSION: JAK2 can serve as a valuable negative prognostic factor and a potential therapeutic target.

Role of glycine N-methyltransferase in the regulation of T-cell responses in experimental autoimmune encephalomyelitis.

Glycine N-methyltransferase (GNMT) is known for its function as a tumor suppressor gene. Since 100% of female Gnmt(-/-) mice developed hepatocellular carcinoma, we hypothesized that Gnmt(-/-) mice may have defective immune surveillance. In this study, we examined the immune modulation of GNMT in T-cell responses using experimental autoimmune encephalomyelitis (EAE). The results showed that EAE severity was reduced significantly in Gnmt(-/-) mice. Pathological examination of the spinal cords revealed that Gnmt(-/-) mice had significantly lower levels of mononuclear cell infiltration and demyelination than the wild-type mice. In addition, quantitative real-time PCR showed that expression levels of proinflammatory cytokines, including interferon (IFN)-γ and interleukin (IL)-17A, were much lower in the spinal cord of Gnmt(-/-) than in that of wild-type mice. Accordingly, myelin oligodendrocyte glycoprotein (MOG)-specific T-cell proliferation and induction of T-helper (Th)1 and Th17 cells were markedly suppressed in MOG(35-55)-induced Gnmt(-/-) mice. Moreover, the number of regulatory T (Treg) cells was increased significantly in these mice. When the T-cell receptor was stimulated, the proliferative capacity and the activation status of mTOR-associated downstream signaling were decreased significantly in Gnmt(-/-) CD4(+) T cells via an IL-2- and CD25-independent manner. Moreover, GNMT deficiency enhanced the differentiation of Treg cells without affecting the differentiation of Th1 and Th17 cells. Furthermore, the severity of EAE in mice adoptive transferred with GNMT-deficient CD4(+) T cells was much milder than in those with wild-type CD4(+) T cells. In summary, our findings suggest that GNMT is involved in the pathogenesis of EAE and plays a crucial role in the regulation of CD4(+) T-cell functions.

PTP4A3 Independently Predicts Metastasis and Survival in Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy.

PURPOSE: Increasing evidence has shown that protein tyrosine phosphatases have dominant roles in setting the levels of tyrosine phosphorylation and promoting oncogenic processes. PTP4A3 has been implicated in cancer metastasis but to our knowledge the role of PTP4A3 in upper tract urothelial carcinoma is unknown. The aim of this study was to investigate the association of PTP4A3 with disease characteristics, distant metastasis and prognosis of upper tract urothelial carcinoma. MATERIALS AND METHODS: The importance of PTP4A3 was initially examined in paired normal urothelium, noninvasive upper tract urothelial carcinoma, invasive upper tract urothelial carcinoma and nodal metastatic tissue. The PTP4A3 transcript level was assessed in another 20 upper tract urothelial carcinoma samples by real-time reverse transcriptase-polymerase chain reaction. PTP4A3 protein expression was determined by immunohistochemistry using the H-score in 340 upper tract urothelial carcinoma samples. It was further correlated with clinicopathological factors, and disease specific and metastasis-free survival. RESULTS: The expression of PTP4A3 significantly increased from normal urothelium, noninvasive upper tract urothelial carcinoma and invasive upper tract urothelial carcinoma to nodal metastatic tissue (p <0.001). The PTP4A3 transcript level was also markedly up-regulated in higher stage upper tract urothelial carcinoma (p = 0.002). Over expression of PTP4A3 protein was significantly associated with advanced pT status, nodal metastasis, lymphovascular invasion and perineural invasion (each p <0.001) as well as with inferior disease specific and metastasis-free survival on multivariate analysis (each p <0.0001). In addition, it predicted metastasis in patients with pTa, pT1 and pT2 upper tract urothelial carcinoma. CONCLUSIONS: Results imply that PTP4A3 has a role in the carcinogenesis of upper tract urothelial carcinoma. PTP4A3 over expression independently predicted the metastasis and outcome of upper tract urothelial carcinoma, which was even more important in organ confined disease.

FGF7 Over Expression is an Independent Prognosticator in Patients with Urothelial Carcinoma of the Upper Urinary Tract and Bladder.

PURPOSE: Urothelial carcinoma of the bladder and upper tract is the most common tumor type in the urinary tract but its molecular pathogenesis and survival determinants remain obscure. By data mining a published transcriptomic database of bladder urothelial carcinoma (GSE31684) we identified FGF7 as the most significant gene up-regulated during urothelial carcinoma progression. We then used our well characterized urothelial carcinoma cohort to analyze FGF7 transcript and protein expression, and its clinicopathological significance. MATERIALS AND METHODS: We performed real-time reverse transcriptase-polymerase chain reaction assay to determine the FGF7 transcript level in 30 fresh samples each of upper tract and bladder urothelial carcinoma. Immunohistochemistry evaluated by H-score was used to determine FGF7 protein expression in 340 upper tract and 295 bladder urothelial carcinomas. Transcript and protein expression were correlated with clinicopathological features. We further evaluated the prognostic significance of FGF7 protein expression for disease specific and metastasis-free survival. RESULTS: An increased FGF7 transcript level was associated with higher pT stage in upper tract and bladder urothelial carcinoma (p = 0.003 and <0.001, respectively). In the upper tract and bladder carcinoma groups FGF7 protein over expression was also significantly associated with advanced pT status (each p <0.001), lymph node metastasis (p = 0.002 and <0.001), high histological grade (p = 0.019 and <0.001), vascular invasion (each p <0.001), perineural invasion (p = 0.002 and 0.021) and frequent mitoses (p = 0.002 and 0.042, respectively). FGF7 over expression predicted dismal disease specific and metastasis-free survival on univariate and multivariate analysis. CONCLUSIONS: Our study shows that FGF7 over expression is associated with advanced clinical features in patients with upper tract and bladder urothelial carcinoma, justifying its potential prognostic value for urothelial carcinoma.

Prognostic significance of lymphovascular invasion in upper urinary tract urothelial carcinoma is influenced by tumor location.

BACKGROUND: To examine the prognostic value of lymphovascular invasion (LVI) in different tumor locations (i.e., renal pelvis and ureter) of upper urinary tract urothelial carcinoma (UTUC). METHODS: Data from a total of 250 patients with nonmetastatic UTUC who received radical nephroureterectomy between 2004 and 2010 at our institution were analyzed retrospectively. The significance of LVI and other relevant factors on cancer-specific survival (CSS), metastasis-free survival (MFS), and intraluminal recurrence-free survival (IRFS) were evaluated. RESULTS: Lymphovascular invasion was present in 60 patients (24 %) and was related to advanced pathological T stage (P < 0.001), higher tumor grade (P < 0.001), lymph node metastasis (P = 0.005), and pyelocaliceal tumor location (P = 0.002). By Kaplan-Meier analysis, LVI was found to be significantly correlated with worse CSS and MFS but not with IRFS. Multivariate analysis showed that high pathological T stage and regional lymph node involvement were significant prognostic factors for CSS and MFS, and LVI was an independent predictor for MFS (hazard ratio 1.71, 95 % confidence interval 1.00-2.93, P = 0.049). In patients with ureteral tumors, LVI represented the only significant prognosticator for both CSS and MFS in multivariate analysis. The prognostic value of LVI was not observed in pyelocaliceal tumors. CONCLUSIONS: The implication of LVI on prognosis, particularly in ureteral tumors but not in pyelocaliceal tumors, may imply diverse disease characteristics between different tumor locations among UTUC. LVI is essential to identify patients at high risk for metastasis/mortality and can facilitate treatment planning and surveillance strategies, especially in patients with ureteral tumors.

HAS3 underexpression as an indicator of poor prognosis in patients with urothelial carcinoma of the upper urinary tract and urinary bladder.

Via data mining a published transcriptomic database of UBUC (GSE31684), we discovered hyaluronan synthase-3 (HAS3) as the most significant gene stepwise downregulated from early tumorigenesis to progression among those associated with hyaluronan synthase activity (GO:0050501). We consequently analyzed HAS3 protein expression and their association with clinicopathological factors and survival in our well-characterized cohort of urothelial carcinoma of upper urinary tract (UTUC) and urinary bladder (UBUC). HAS3 expression was assessed by immunohistochemistry and evaluated by using H score method in 295 UBUCs and 340 UTUCs, respectively. HAS3 protein expression statuses were further correlated with clinicopathological parameters and evaluated the prognostic significance for disease-specific survival (DSS) and metastasis-free survival (MeFS). HAS3 protein underexpression was significantly associated with advanced pT status, nodal metastasis, high histological grade, vascular invasion, and frequent mitoses in both groups of UCs. HAS3 underexpression not only predicted poorer DSS and MeFS with univariate analysis, but also indicated dismal DSS and MeFS in multivariate analysis. HAS3 underexpression is associated with advanced tumor stage and adverse pathological features, as well as implies inferior clinical outcomes for both groups of patients with UTUCs and UBUCs, suggesting its critical role in tumor progression in UCs and may serve as a prospective prognostic biomarker and a novel therapeutic target in UCs.

INHBA overexpression indicates poor prognosis in urothelial carcinoma of urinary bladder and upper tract.

BACKGROUND: Urothelial carcinoma (UC) originating from the bladder (UBUC) and upper urinary tract (UTUC) is the most common type of urinary tract tumor. While its pathogenesis remains obscured. Computerizing a published transcriptomic database of UBUC (GSE31684), we identified Inhibin, Beta A (INHBA) as the most significant upregulated gene associated with tumor progression among those associated with growth factor activity (GO:0008083). We therefore analyzed the clinicopathological significance of INHBA expression in UC. DESIGN: QuantiGene assay was used to detect INHBA transcript level in 36 UTUCs and 30 UBUCs. Immunohistochemistry evaluated by H-score was used to determine INHBA protein expression in 340 UTUCs and 296 UBUCs. INHBA expression was correlated with clinicopathological features and disease-specific survival (DSS) and metastasis-free survival (MeFS). RESULTS: Increments of INHBA transcript level was associated with higher pT status in both UTUC and UBUC. INHBA protein overexpression was significantly associated with advanced clinicopathological features in both groups of UC. INHBA overexpression significantly implied inferior DSS (UTUC, P = 0.002; UBUC, P = 0.005) and MeFS (UTUC and UBUC, both P < 0.001) in multivariate analysis. CONCLUSION: INHBA overexpression implies adverse clinical outcomes for UC, justifying it is a potential prognostic biomarker and a novel therapeutic target in UC.

Obstructive laryngeal schwannoma in a young female.

Laryngeal schwannomas are rare, benign neurogenic tumors. They normally present as a slow-growing, encapsulated, submucosal mass in the supraglottic region. We describe a 20-year-old female presenting with a 2-year history of hoarseness and progressive worsening dyspnea. Fiberoptic laryngoscopy and computed tomography revealed a round, low-density submucosal mass at right false cord and arytenoepiglottic regions with glottic extension. Microlaryngoscopic biopsy and debulking for this solid tumor were performed without tracheostomy. Schwannoma was confirmed by histopathological study. However, rapidly worsening stridor occurred 2 weeks after the surgery. Fiberoptic laryngoscopy showed an exophytic tumor occupying the right hemilarynx with airway compromise. Definite complete excision of the tumor was performed by right vertical hemilaryngectomy. At 5-month follow-up, the laryngeal wound was clear without signs of recurrence. Rapid occurrence of airway obstruction after debulking and biopsy was demonstrated in this case. Vertical hemilaryngectomy was inevitable to cure this potentially life-threatening laryngeal schwannoma in this young female with postoperative serviceable voice.

BCL6 overexpression is associated with decreased p19 ARF expression and confers an independent prognosticator in gallbladder carcinoma.

B cell lymphoma 6 (BCL6) is a protein that is vital for lymphogenesis. Its expression has been well established in lymphoma, especially in diffuse large B-cell lymphoma. Its role in carcinogenesis is less well understood. Previous study shows that BCL6 expression may regulate p19 functions, an important regulator for the p53 pathway. No prior study has attempted to evaluate the significance of BCL6 and p19(ARF) expression in a large cohort of patients with gallbladder carcinomas (GBCs). We selected 164 patients with GBC and performed immunostains for BCL6 and p19(ARF). BCL6 expression and p19(ARF) expression were evaluated using a histochemical score (H-score). We then correlated the results with various clinicopathological factors, disease-specific survival (DSS), and disease-free survival (DFS). BCL6 overexpression was significantly associated with high pT status, high TNM stage, higher histological grade (p = 0.029), vascular invasion, perineurial invasion, high Ki-67 labeling index, and low p19 expression. Importantly, BCL6 overexpression in GBC was strongly associated with worse DSS (p < 0.0001) and DFS (p < 0.0001) in the univariate analysis, and remained independently predictive of adverse outcomes (p = 0.001, hazard ratio (H.R.) = 3.098 for DSS; p = 0.002, H.R. = 2.255 for DFS). Low p19(ARF) expression was correlated with a poor DSS (p = 0.0144) and DFS (p = 0.0032) in the univariate analysis but was not prognosticatory in the multivariate analysis. In GBC, BCL6 overexpression correlated with adverse phenotypes and decreased p19(ARF) expression. BCL6 overexpression also independently predicts worse DSS and DFS, suggesting it has a role in tumorigenesis or carcinogenesis and could be a potential prognostic indicator in GBC.

TGFB1I1 promotes cell proliferation and migration in urothelial carcinoma.

Urothelial carcinoma (UC) is common cancer worldwide with a high prevalence in Taiwan, especially in the upper urinary tract, including the renal pelvis and ureter, also classifying as upper urinary tract urothelial carcinoma. Here, we aim to find a representative prognostic marker that strongly correlates to this type of carcinoma. Transforming growth factor beta-1-induced transcript 1 (TGFB1I1) is a cofactor of cellular TGF-ß1 and interacts with various nuclear receptors. The previous study showed that TGFB1I1 promotes focal adhesion formation, contributing to the epithelial-mesenchymal transition (EMT) with actin cytoskeleton and vimentin through TGFB1I1 regulation. We aim to reveal the role of TGFB1I1 in the tumorigenesis of UC. In silico and clinicopathological data of upper urinary tract urothelial carcinoma (UTUC) and urinary bladder urothelial carcinoma (UBUC) were accessed and analyzed for IHC staining regarding tumor characteristics, including survival outcome. Finally, an in vitro study was performed to demonstrate the biological changes of UC cells. In UTUC, overexpression of TGFB1I1 was significantly correlated with advanced tumor stage, papillary configuration, and frequent mitosis. Meanwhile, overexpression of TGFB1I1 was significantly correlated with advanced tumor stage and histological grade in UBUC. Moreover, the in vitro study shows that TGFB1I1 affects cell proliferation, viability, migration and wound healing. The EMT markers also decreased upon TGFB1I1 knockdown. In this study, we identified that TGFB1I1 regulates UC cell proliferation and viability and induces the EMT to facilitate cell migration in vitro, leading to its essential role in promoting tumor aggressiveness in both UTUC and UBUC.

Clinicopathological significance of HuR expression in gallbladder carcinoma: with special emphasis on the implications of its nuclear and cytoplasmic expression.

Gallbladder carcinoma (GBC) is a relatively rare disease which pathogenesis is less clarified. Human antigen R (HuR), a RNA-binding protein, modulates the expressions of various cancer-related proteins by stabilizing or regulating the transcription of the corresponding messenger RNA. The significance of HuR expression in a large cohort with GBCs is yet to be evaluated. In total, 164 cases of GBC were selected, and immunostaining for HuR was performed. HuR nuclear (HuR-N) expression and HuR cytoplasmic (HuR-C) expression were evaluated by using a histochemical score. The results of HuR expression were correlated with various clinicopathological factors, disease-specific survival (DSS), and disease-free survival (DFS) in 161 patients with follow-up data. HuR-N overexpression was strongly associated with high histological grade (p = 0.001), vascular invasion (p < 0.001), and high Ki-67 labeling index (p < 0.001). HuR-C overexpression was significantly related to higher primary tumor status (p < 0.001), advanced tumor stage (p < 0.001), histological type (p = 0.006), high histological grade (p < 0.001), vascular and perineurial invasion (p < 0.001 and p = 0.002, respectively), tumor necrosis (p = 0.042), and high Ki-67 labeling index (p = 0.002). Besides, HuR-C overexpression also correlates with HuR-N overexpression (p < 0.001) and cyclin A overexpression (p = 0.026). HuR-N overexpression correlated with poor DFS (p = 0.0348) in univariate analysis, but HuR-C overexpression strongly correlated with a worse DSS and DFS in both univariate (both p < 0.0001) and multivariate (DSS, p = 0.006; DFS, p = 0.001) analyses. Subcellular localization of HuR expression correlates with different adverse phenotypes of GBC. Besides, HuR-C overexpression is an independent prognostic factor for dismal DSS and DFS, suggesting its roles in tumorigenesis or carcinogenesis and as a potential prognostic marker of GBC.