Validation of the area under the Watts factor curve during the voiding cycle as a novel parameter for diagnosing detrusor underactivity in females.

OBJECTIVE: Detrusor underactivity (DU) is a common cause of lower urinary tract symptoms (LUTS). To date, no consensus has been reached on the urodynamic criteria for defining DU. We previously proposed the area under the curve of the Watts factor (WF-AUC) as a new parameter for diagnosing DU. By comparing previously reported five criteria for DU and WF-AUC, we analyzed whether the WF-AUC could assess detrusor contraction in women with LUTS. METHODS: Using urodynamic data of consecutive 77 women with LUTS, first, we classified DU based on previously reported five criteria. Second, we assessed the potential correlation between multiple parameters and WF-AUC. Third, receiver operating characteristic curve analysis was performed to determine the cutoff value of WF-AUC for diagnosing DU based on previously reported five criteria. Fourth, a linear regression analysis was conducted and compared using multiple criteria and female bladder outlet obstruction index (BOOIf). RESULTS: WF-AUC was positively correlated with the maximum values of WF, bladder contractility index (BCI), and projected isovolumetric pressure 1 (PIP1) with correlation coefficients of 0.63, 0.57, and 0.34, respectively. AUC for diagnosing DU based on previously reported five criteria ranging from 0.773 to 0.896 with different cutoff values of AUC-WF. The Spearman's correlation test revealed that BOOIf was significantly correlated with BCI, but not Wmax, PIP1 and WF-AUC. CONCLUSIONS: This study demonstrated the non-inferiority of the WF-AUC compared to previously reported criteria for defining DU. Depending on the cutoff value, the WF-AUC could appropriately evaluate women with DU, regardless of the presence of BOO.

Ischemic priapism caused by self intracavernous injection of tadalafil.

Introduction: We present a case of ischemic priapism caused by self intracavernous injection of tadalafil. Case presentation: A 77-year-old man developed priapism due to self-injection of tadalafil into the corpus cavernosum. He presented to our hospital 2 days after the development of priapism and severe penile pain. The blood gas analysis of the corpus cavernosum revealed ischemic priapism. At first, we performed percutaneous distal shunt (T-shunt) and cavernosal irrigation, resulting in slight improvement of penile tumescence. Several hours later, penile tumescence and severe pain reappeared. Bilateral proximal (corpora-spongiosal) shunt was performed under anesthesia again. Penile tumescence was slowly and gradually relieved. His erectile function was declined. Conclusion: We experienced a case of priapism due to self intracavernous administration of tadalafil who needed a proximal shunt to relieve the severe penile pain. This case report may serve as a warning for physicians and patients not to use phosphodiesterase 5 inhibitor inappropriately.

An Autopsy Case of Fulminant Myocarditis with Massive Left Ventricular Calcification.

Myocardial calcification in myocarditis is rare and may be linked to poor outcomes. We herein report a case of fulminant myocarditis with massive myocardial calcification and its pathological outcomes at autopsy. A 49-year-old man experienced chest pain and was diagnosed with acute myocarditis. His cardiac function did not recover despite mechanical circulatory support in combination with V-A extracorporeal membrane oxygenation and IMPELLA CP®. He eventually developed sepsis and gastrointestinal bleeding and died on day 27. Diffuse myocardial calcification was observed on computed tomography at autopsy. The pathological autopsy depicted that calcification filled every myocardial cell in the left ventricle.

Downregulation of lipolysis-stimulated lipoprotein receptor promotes cell invasion via claudin-1-mediated matrix metalloproteinases in human endometrial cancer.

Lipolysis-stimulated lipoprotein receptor (LSR) is a novel molecule present at tricellular contacts which recruits tricellulin (TRIC), a molecular component of tricellular tight junctions (tTJs). LSR and TRIC are colocalized with the bicellular tight junction (bTJ) protein claudin (CLDN)-1-based tight junction strands at tricellular corners. Knockdown of LSR in normal epithelial cells affects tTJ formation and the epithelial barrier function. In cancer cells knockdown of LSR has been demonstrated to increase cell invasion. However, the detailed mechanisms of how the downregulation of LSR enhances cell invasion in cancer remain unclear. In the present study, knockdown of LSR by small interfering RNA (siRNA) in Sawano human endometrial adenocarcinoma cells induced cell invasion. In LSR-knockdown Sawano cells, upregulation of CLDN-1 protein, which contributes to the cell invasion via matrix metalloproteinases (MMPs), was observed compared with the control group by western blotting and immunostaining. Knockdown of LSR significantly induced Sp1 transcription factor activity in the CLDN-1 promoter region. In LSR-knockdown Sawano cells, DNA microarray analysis demonstrated that MMP-1, MMP-2 and MMP-10 mRNA levels were increased, and the protein levels of membrane-type 1-MMP, MMP-2, MMP-9 and MMP-10 were shown to be increased on western blots. Knockdown of CLDN-1 with siRNA prevented the upregulation of cell invasion induced by the knockdown of LSR in Sawano cells. On the invasive front of human endometrial carcinoma tissue samples, a decrease in LSR and increase in CLDN-1 protein levels were observed using immunohistochemical methods. In conclusion, the results indicate that the downregulation of LSR promotes cell invasion of human endometrial cancer via CLDN-1 mediation of MMPs. This mechanism is important for studying the association of tTJs with the cellular invasion of cancer.

Loss of tricellular tight junction protein LSR promotes cell invasion and migration via upregulation of TEAD1/AREG in human endometrial cancer.

Lipolysis-stimulated lipoprotein receptor (LSR) is a unique molecule of tricellular contacts of normal and cancer cells. We investigated how the loss of LSR induced cell migration, invasion and proliferation in endometrial cancer cell line Sawano. mRNAs of amphiregulin (AREG) and TEA domain family member 1 (TEAD1) were markedly upregulated by siRNA-LSR. In endometrial cancer tissues, downregulation of LSR and upregulation of AREG were observed together with malignancy, and Yes-associated protein (YAP) was present in the nuclei. siRNA-AREG prevented the cell migration and invasion induced by siRNA-LSR, whereas treatment with AREG induced cell migration and invasion. LSR was colocalized with TRIC, angiomotin (AMOT), Merlin and phosphorylated YAP (pYAP). siRNA-LSR increased expression of pYAP and decreased that of AMOT and Merlin. siRNA-YAP prevented expression of the mRNAs of AREG and TEAD1, and the cell migration and invasion induced by siRNA-LSR. Treatment with dobutamine and 2-deoxy-D-glucose and glucose starvation induced the pYAP expression and prevented the cell migration and invasion induced by siRNA-LSR. siRNA-AMOT decreased the Merlin expression and prevented the cell migration and invasion induced by siRNA-LSR. The loss of LSR promoted cell invasion and migration via upregulation of TEAD1/AREG dependent on YAP/pYAP and AMOT/Merlin in human endometrial cancer cells.

The roles of tricellular tight junction protein lipolysis-stimulated lipoprotein receptor in malignancy of human endometrial cancer cells.

Lipolysis-stimulated lipoprotein receptor (LSR) has been identified as a novel molecular constituent of tricellular contacts that have a barrier function for the cellular sheet. LSR recruits tricellulin (TRIC), which is the first molecular component of tricellular tight junctions. Knockdown of LSR increases cell motility and invasion of certain cancer cells. However, the behavior and the roles of LSR in endometrial cancer remain unknown. In the present study, we investigated the behavior and roles of LSR in normal and endometrial cancer cells in vivo and in vitro. In endometriosis and endometrial cancer, LSR was observed not only in the subapical region but also throughout the lateral region as well as in normal endometrial epithelial cells in the secretory phase, and LSR in the cancer was reduced in correlation with the malignancy. Knockdown of LSR by the siRNA in cells of the endometrial cancer cell line Sawano, induced cell migration, invasion and proliferation, while TRIC relocalized from the tricellular region to the bicellular region at the membrane. In Sawano cells and normal HEEs, a decrease of LSR induced by leptin and an increase of LSR induced by adiponectin and the drugs for type 2 diabetes metformin and berberine were observed via distinct signaling pathways including JAK2/STAT. In Sawano cells, metformin and berberine prevented cell migration and invasion induced by downregulation of LSR by the siRNA and leptin treatment. The dissection of the mechanism in the downregulation of endometrial LSR during obesity is important in developing new diagnostic and therapy for endometrial cancer.

Dysregulation of junctional adhesion molecule-A via p63/GATA-3 in head and neck squamous cell carcinoma.

Junctional adhesion molecule-A (JAM-A), which belongs to the IgG superfamily, is a tight junction molecule associated with epithelial and endothelial barrier function. Overexpression of JAM-A is also closely associated with invasion and metastasis of cancers such as breast cancer, lung cancer and pancreatic cancer. However, little is known about the mechanism in overexpression of JAM-A in head and neck squamous cell carcinoma (HNSCC). In the present study, we found high expression of JAM-A at the protein and mRNA levels in HNSCC tissues, including those of the oropharynx, larynx, and hypopharynx, together with high protein expression of ß-catenin, p63, ΔNp63 and GATA-3. Furthermore, in ELISA, a significant increase of soluble JAM-A in the sera of HNSCC patients was observed compared to healthy subjects. Knockdown of JAM-A by siRNA inhibited cell proliferation, invasion and migration in the HNSCC cell line Detroit562 in vitro. JAM-A expression in Detroit562 was increased via a distinct signal transduction pathway including NF-κB. Expression of JAM-A, ß-catenin, p63 and ΔNp63 in Detroit562 was decreased under hypoxia. Knockdown of p63, ΔNp63 or GATA-3 by siRNAs reduced JAM-A expression in Detroit562. In primary cultured HNSCC cells in which CK7, p63, ΔNp63 and GATA-3 were detected, JAM-A expression was decreased by knockdown of p63 or ΔNp63. These results indicate that JAM-A is a biomarker of malignancy in HNSCC and that plasma soluble JAM-A may contribute to serum-based diagnosis of HNSCC. The mechanism of dysregulation of JAM-A via p63/GATA-3 is important in possible molecular targeted therapy for HNSCC.