The BHLHE40‒PPM1F‒AMPK pathway regulates energy metabolism and is associated with the aggressiveness of endometrial cancer.

BHLHE40 is a basic helix-loop-helix transcription factor that is involved in multiple cell activities including differentiation, cell cycle, and epithelial-to-mesenchymal transition. While there is growing evidence to support the functions of BHLHE40 in energy metabolism, little is known about the mechanism. In this study, we found that BHLHE40 expression was downregulated in cases of endometrial cancer of higher grade and advanced disease. Knockdown of BHLHE40 in endometrial cancer cells resulted in suppressed oxygen consumption and enhanced extracellular acidification. Suppressed pyruvate dehydrogenase (PDH) activity and enhanced lactated dehydrogenase (LDH) activity were observed in the knockdown cells. Knockdown of BHLHE40 also led to dephosphorylation of AMPKα Thr172 and enhanced phosphorylation of pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) Ser293 and lactate dehydrogenase A (LDHA) Tyr10. These results suggested that BHLHE40 modulates PDH and LDH activity by regulating the phosphorylation status of PDHA1 and LDHA. We found that BHLHE40 enhanced AMPKα phosphorylation by directly suppressing the transcription of an AMPKα-specific phosphatase, PPM1F. Our immunohistochemical study showed that the expression of BHLHE40, PPM1F, and phosphorylated AMPKα correlated with the prognosis of endometrial cancer patients. Because AMPK is a central regulator of energy metabolism in cancer cells, targeting the BHLHE40‒PPM1F‒AMPK axis may represent a strategy to control cancer development.

Clinical Significance of Carotid Endarterectomy and Carotid Artery Stenting in Older Patients Over 80.

As the average life expectancy increases, neurosurgeons are likely to encounter patients aged 80 years and above with carotid stenosis; however, whether old age affects clinical post-treatment outcomes of carotid endarterectomy (CEA) or carotid artery stenting (CAS) remains inconclusive. Thus, this study aimed to evaluate the outcomes following CEA or CAS in patients aged 80 years and above. This study included older over 80 years (n = 34) and younger patients (<80 years; n = 222) who underwent CEA or CAS between 2012 and 2022. All of them were followed up for a mean of 55 months. All-cause mortality, the incidence of vascular events, ability to perform daily activities, and nursing home admission rates were assessed. During follow-up periods, 34 patients (13.3%) died due to coronary artery disease, malignancy, and pneumonia, and the incidence was significantly higher in the elderly group than in the younger group (P = 0.03; HR, 3.01; 95% CI, 1.53-5.56). The incidence of vascular events did not differ between the older group (29.5%) and the younger group (26.9%, P = 0.58); however, the incidence was significantly higher in patients with high-intensity plaques than in those without that (P = 0.008; HR, 2.83, 95%CI, 1.27-4.87). The decline in the ability to perform daily activities and increased nursing home admission rates were high in elderly patients (P < 0.01). Although the mortality rate was higher in the elderly group, subsequent vascular events were comparable to that in the younger group. The results suggest that CEA and CAS are safe and useful treatments for carotid stenosis in older patients, especially to prevent ipsilateral ischemic stroke.

Effects of superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis on the cerebrospinal fluid gas tensions and pH in hemodynamically compromised patients.

PURPOSE: This study was aimed to directly measure cerebrospinal fluid (CSF) gas tensions and pH before and after STA-MCA anastomosis for occlusive carotid artery diseases to investigate its direct effects on the ischemic brain. METHODS: This study included 9 patients who underwent STA-MCA anastomosis on the basis of CBF studies. About 1 mL of CSF was collected before and after bypass procedures, and CSF pH, CSF PO2, and CSF PCO2 were measured with a blood gas analyzer. As the controls, the CSF was collected from 6 patients during surgery for unruptured cerebral aneurysm. CSF PO2 and CSF PCO2 were expressed as the ratio to PaO2 and PaCO2, respectively. RESULTS: Before bypass procedure, CSF PO2/PaO2 was 0.88 ± 0.16, being lower than the controls (1.10 ± 0.09; P = 0.005). CSF PCO2/PaCO2 was 0.93 ± 0.13, being higher than the controls (0.84 ± 0.06; P = 0.039). Ipsilateral-to-contralateral CBF ratio had a positive correlation with CSF PO2/PaO2 (P = 0.0028) but a negative correlation with the CSF PCO2/PaCO2 (P = 0.0045). STA-MCA anastomosis increased CSF pH from 7.402 ± 0.133 to 7.504 ± 0.126 (P = 0.0011) and CSF PO2/PaO2 from 0.88 ± 0.16 to 1.05 ± 0.26 (P = 0.018) but decreased CSF PCO2/PaCO2 from 0.93 ± 0.13 to 0.70 ± 0.17 (P = 0.0006). CONCLUSION: The severity of cerebral ischemia before surgery is intensely reflected in the gas tensions and pH of the CSF. STA-MCA anastomosis carries dramatic effects on CSF gas tensions and pH in hemodynamically compromised patients. CSF would be a valuable surrogate biomarker to monitor the severity of cerebral ischemia.

Decision-making for Subsequent Therapy for Patients With Recurrent or Advanced Endometrial Cancer Based on the Platinum-free Interval.

OBJECTIVE: The aim of this study was to evaluate the progression-free survival (PFS) and overall response rate (ORR) of patients with recurrent endometrial cancer (REC) or advanced endometrial cancer (AEC) retreated with platinum-containing chemotherapy (PCC) based on the platinum-free interval (PFI). We compared our results with those reported in the KEYNOTE-775 study (that used pembrolizumab plus lenvatinib). METHODS: A retrospective analysis was conducted of 65 patients with REC or AEC retreated with PCC between 2005 and 2020 at our hospital. Various clinicopathologic variables were analyzed: (1) age, (2) performance status, (3) histology, (4) history of pelvic irradiation in the adjuvant setting, (5) PFI, (6) chemotherapy regimen, (7) PFS and overall survival after retreatment with PCC, and (8) best ORR. Survival analyses were performed using Kaplan-Meier curves and log-rank tests. RESULTS: The best ORR and PFS were 43.3% and 9.5 months, respectively, in patients with REC/AEC with a PFI ≥6 months. These results were comparable with those of patients treated with pembrolizumab and lenvatinib. The best ORR and PFS of patients with a PFI of <6 months appeared to be inferior to those of patients treated with pembrolizumab plus lenvatinib. CONCLUSIONS: Pembrolizumab plus lenvatinib seems to be a better treatment choice for patients with REC or AEC with a PFI of <6 months. For a PFI of ≥6 months, pembrolizumab plus lenvatinib or PCC can be used depending on the degree of residual side -effects associated with cytotoxic agents.

Coil embolization for post-bypass aneurysm of middle meningeal artery for moyamoya disease - preservation of transdural anastomosis.

Background: Middle meningeal artery (MMA) pseudoaneurysm following revascularization surgery for moyamoya disease (MMD) is rare. Case Description: Here, a 29-year-old man presented with an MMA pseudoaneurysm after he underwent revascularization surgery (superficial temporal artery-to-middle cerebral artery bypass and encephalo-duro-myoarterio-pericranial synangiosis) for hemorrhagic MMD. At 3 months post-surgery, digital subtraction angiography showed a pseudoaneurysm in the right MMA. Transdural anastomosis to the parietal and occipital lobes was opacified at the distal MMA of the pseudoaneurysm. Intra-aneurysmal coil embolization was performed for preservation of transdural anastomosis. The postoperative course was uneventful. At 1 month post-embolization, angiography revealed an entirely occluded pseudoaneurysm. Conclusion: An increase in blood flow in the MMA due to bypass surgery may accelerate aneurysm development by increasing the hemodynamic stress. This case suggested that intra-aneurysmal embolization may be a potential treatment.

Endoscopic third ventriculostomy for patients with Blake's pouch cyst with adult-onset hydrocephalus: Importance of improved cerebrospinal fluid flow in the prepontine cistern - A case report.

Background: Blake's pouch cyst (BPC) is a posterior fossa cystic malformation that commonly occurs in children with rare adult onset. Herein, we report a case of adult onsets BPC. Case Description: A 61-year-old man presented with gait and cognitive disturbance. Preoperative magnetic resonance imaging (MRI) revealed scarring in the prepontine cistern, and cine phase-contrast MRI revealed no pulsation. Endoscopic third ventriculostomy (ETV) was performed with opening the scarring in the prepontine cistern. Postoperative cine phase-contrast MRI revealed that cerebrospinal fluid (CSF) flow in the prepontine cistern improved, resolving the patient's symptoms. Conclusion: We report a case of adult-onset BPC. The mechanism by which is becomes symptomatic is still unclear. We opened the scar in prepontine cistern in addition to ETV with good results. In this report, we discussed the importance of the improvement in CSF dynamics in the prepontine cistern.

Tumor-derived ARHGAP35 mutations enhance the Gα13-Rho signaling axis in human endometrial cancer.

Dysregulated G protein-coupled receptor signaling is involved in the formation and progression of human cancers. The heterotrimeric G protein Gα13 is highly expressed in various cancers and regulates diverse cancer-related transcriptional networks and cellular functions by activating Rho. Herein, we demonstrate that increased expression of Gα13 promotes cell proliferation through activation of Rho and the transcription factor AP-1 in human endometrial cancer. Of interest, the RhoGTPase activating protein (RhoGAP), ARHGAP35 is frequently mutated in human endometrial cancers. Among the 509 endometrial cancer samples in The Cancer Genome Atlas database, 108 harbor 152 mutations at 126 different positions within ARHGAP35, representing a somatic mutation frequency of 20.2%. We evaluated the effect of 124 tumor-derived ARHGAP35 mutations on Gα13-mediated Rho and AP-1 activation. The RhoGAP activity of ARHGAP35 was impaired by 55 of 124 tumor-derived mutations, comprised of 23 nonsense, 15 frame-shift, 15 missense mutations, and two in-frame deletions. Considering that ARHGAP35 is mutated in >2% of all tumors, it ranks among the top 30 most significantly mutated genes in human cancer. Our data suggest potential roles of ARHGAP35 as an oncogenic driver gene, providing novel therapeutic opportunities for endometrial cancer.

Prognostic impact of adding bevacizumab to carboplatin and paclitaxel for recurrent, persistent, or metastatic cervical cancer.

OBJECTIVE: Recent randomized phase III trial has shown significant benefit in overall survival (OS) for patients with advanced cervical cancer by adding bevacizumab to conventional chemotherapy. The aim of this study was to evaluate the prognostic impact for Japanese recurrent, persistent, or metastatic cervical cancer patients where bevacizumab was added to paclitaxel plus carboplatin. MATERIALS AND METHODS: A retrospective analysis was performed on 90 patients with recurrent, persistent, or metastatic cervical cancer mainly treated by paclitaxel plus carboplatin between 2005 and 2019 at our hospital. Data for the following clinicopathological variables were analyzed: (1) bevacizumab use; (2) histology; (3) disease presentation; (4) performance status; (5) prior chemotherapy containing platinum agent; (6) pelvic disease; (7) prior pelvic radiotherapy; (8) location of target lesions. Survival analysis was performed using Kaplan-Meier curves, log-rank tests, Wilcoxon tests, and Cox proportional hazards models combined with propensity score matching. RESULTS: Adding bevacizumab to paclitaxel plus carboplatin showed significantly increased complete response to compared with that of non-users. In a Cox regression hazard model, bevacizumab use tended to show better OS though without statistically significance. After propensity score matching, adding bevacizumab to paclitaxel plus carboplatin showed a significant better OS by univariate analysis using Wilcoxon test, not by log-rank test. CONCLUSION: Adding bevacizumab to paclitaxel plus carboplatin showed a limited prognostic impact for recurrent, persistent or advanced cervical cancer patients in the real world. Further effective second-line treatments are needed to prolong OS of patients with recurrent, persistent or advanced cervical cancer.

Thin calcification (< 2 mm) can highly predict intraplaque hemorrhage in carotid plaque: the clinical significance of calcification types.

PURPOSE: Calcification pathogenesis and the relationship between calcification and plaque composition remain unclear. This study explored the calcification characteristics of vulnerable plaques, especially focusing on calcification thickness, using computed tomography angiography and magnetic resonance plaque imaging. METHODS: Demographic, computed tomography angiography, and magnetic resonance plaque imaging data were acquired from 178 patients with 229 lesions diagnosed with carotid stenosis. The calcification types were categorized by calcification thickness. We evaluated their features, including the anatomical location and the plaque composition compared with MR plaque imaging, and clarify the clinical characteristics. Furthermore, an immunohistochemical subgroup analysis was performed on 84 lesions treated with carotid endarterectomy. RESULTS: The result of the ROC analysis suggested the threshold between symptomatic and asymptomatic calcification was 2.04 mm (AUC;0.841, 95%CI; 0.771-0.894). Calcification with ≥ 2 mm thickness was classified as thick calcification and < 2 mm thickness as thin calcification. Multivariate analysis suggested the prevalence of symptomatic patients in the thin calcification group was significantly higher than others (P = 0.01; odds ratio, 4.1; 95% confidence interval 2.8-7.2). Plaques with thin calcification were associated with plaque with intraplaque hemorrhage (P < 0.01). The interobserver reliability (κ) of calcification type was 0.962 (95% confidence interval, 0.941-0.988). Immunohistochemical analysis demonstrated that the numbers of CD68-positive cells and CD31-positive microvessels in shoulder lesions were significantly higher in the thin calcification group than in the non-thin group (both P < 0.01). CONCLUSIONS: Thin calcification was associated with plaques with intraplaque hemorrhage and had different clinical implications than thick calcification.

A Case of Malignant Phyllodes Tumor of the Breast Metastasizing to the Ovary.

Phyllodes tumors of the breast are uncommon, and 6.2% of phyllodes tumors behave in a malignant fashion. The metastatic spread of malignant phyllodes tumor is mainly hematogenous to lung and bone, and malignant phyllodes tumor metastasizing to the ovary is rare, with only 2 cases reported. We report the third case of metastatic malignant phyllodes tumor to the ovary with a focus on the differential diagnosis of ovarian cancer.

Evaluation of Clinical Significance of Lymphovascular Space Invasion in Stage IA Endometrial Cancer.

INTRODUCTION: The prognostic significance of lymphovascular space invasion (LVSI) in stage IA endometrial cancer remains unclear. The aim of this study was to evaluate the clinical significance of LVSI in stage IA endometrial cancer. METHODS: Clinical data of patients with stage IA endometrial cancer who underwent initial surgery at our institution between January 2008 and December 2018 were reviewed retrospectively. Information of patients, surgery, and characteristics of cancer were obtained from medical records and pathological reports. RESULTS: Two hundred ninety-seven patients were enrolled in this study. With a median follow-up of 60 months, 15 patients experienced recurrence (5.1%) and 4 patients died of endometrial cancer (1.3%). The recurrence and mortality rates did not differ significantly between the LVSI-positive and -negative groups (p = 0.07 and p = 0.41, respectively). Recurrence-free survival and endometrial cancer-specific survival also did not differ significantly between these groups (p = 0.11 and p = 0.49, respectively). The 5-year endometrial cancer-specific survival rates for tumors with and without LVSI were 97.0% and 98.9%, respectively. Among patients with low-grade tumors, recurrence-free survival and endometrial cancer-specific survival did not differ significantly between patients with tumors with and without LVSI (p = 0.92 and p = 0.72, respectively). The 5-year endometrial cancer-specific survival rates for low-grade tumors with and without LVSI were 100% and 99.3%, respectively. CONCLUSION: LVSI was not a prognostic factor of not only stage IA endometrial cancer but also stage IA low-grade cancer.

Oro-mandibular dystonia in pediatric moyamoya disease: Two cases report.

BACKGROUND: In this report, we describe rare two pediatric cases that developed oro-mandibular dystonia due to moyamoya disease. CASE DESCRIPTION: A 7-year-old boy presented with oro-mandibular dystonia and transient weakness of the left extremities, and was diagnosed as moyamoya disease. Another 7-year-old boy developed oro-mandibular dystonia alone and was diagnosed as moyamoya disease. In both, cerebral blood flow (CBF) was markedly decreased in the involved hemispheres, including the basal ganglia and cerebral cortex. They successfully underwent combined bypass surgery and experienced no further attacks of oromandibular dystonia during follow-up periods. CBF almost normalized through surgical collaterals through direct and indirect bypass. CONCLUSION: When treating patients with oro-mandibular dystonia, moyamoya disease should be listed as one of the differential diseases. The underlying mechanism of oro-mandibular dystonia in moyamoya disease is still unclear, but persistent cerebral ischemia in the basal ganglia and/or parietal lobe may play a key role to induce this rare symptom.

Prognostic impact of the subclassification of Müllerian cancer stage IV in the FIGO 2014 staging system with a focus of extra-abdominal lymph node metastases.

BACKGROUND: The International Federation of Gynecology and Obstetrics (FIGO) staging system for Müllerian cancer was changed in 2014. Our objective was to evaluate the prognostic impact of stage IV subclassification in this new staging system, especially focusing on extra-abdominal lymph node metastasis. METHODS: Eighty-two patients with stage IV Müllerian cancer treated between 2005 and 2016 at our hospital were retrospectively analyzed. Data for the following clinicopathological variables were analyzed: (1) FIGO stage; (2) tumor stage; (3) lymph node status; (4) histologic type; (5) neoadjuvant chemotherapy; (6) optimal surgery; and (7) bevacizumab use. Survival analysis was performed using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. RESULTS: In accordance with the new classification, 28 and 54 patients were classified as FIGO IVA and IVB, respectively. In the Cox proportional hazards model, early-stage tumors (T1b-3b) and optimal surgery were statistically significant favorable prognostic factors. However, the new FIGO system did not discriminate prognostically between stage IVA and IVB. Median overall survival of stage IVB patients diagnosed with extra-abdominal lymph node metastasis only was better than that of stage IVA and stage IVB patients diagnosed with solid organ metastasis. CONCLUSIONS: In this analysis of the revised FIGO system of patients reclassified as FIGO stage IVA or IVB, no new prognostic information was obtained. There is a possibility that stage IVB patients diagnosed with extra-abdominal lymph node metastasis only can be classified as an earlier stage. Further modification of the FIGO staging system may be needed to improve the prediction of patient prognosis.

Fibronectin mediates activation of stromal fibroblasts by SPARC in endometrial cancer cells.

BACKGROUND: Matricellular glycoprotein, SPARC is a secreted molecule, that mediates the interaction between cells and extracellular matrix. SPARC functions as a regulator of matrix organization and modulates cell behavior. In various kinds of cancer, strong SPARC expression was observed in stromal tissues as well as in cancer epithelial cells. The function of SPARC in cancer cells is somewhat controversial and its impact on peritumoral stromal cells remains to be resolved. METHODS: We investigated the effects of SPARC expression in endometrial cancer cells on the surrounding stromal fibroblasts using in vitro co-culture system. Changes in characteristics of fibroblasts were examined by analysis of fibroblast-specific markers and in vitro contraction assay. RESULTS: SPARC induced AKT phosphorylation and epithelial-to-mesenchymal transition, consistent with previous reports. Cancer-associated fibroblasts of endometrial cancer expressed higher levels of mesenchymal- and fibroblast-associated factors and had a stronger contraction ability. Unexpectedly, cancer-associated fibroblasts expressed comparable levels of SPARC compared with fibroblasts from normal endometrium. However, co-culture of normal fibroblasts with SPARC-expressing Ishikawa cells resulted in activation of the fibroblasts. Immunodepletion of SPARC did not affect the activation of fibroblasts. CONCLUSIONS: Our data indicated that SPARC activated fibroblasts only in the presence of fibronectin, which was abundantly secreted from SPARC-expressing endometrial cancer cells. These results suggested that a SPARC-fibronectin-mediated activation of fibroblasts might be involved in enhanced mobility and invasion of cancer cells.

Prognostic outcomes and risk factors for recurrence after laser vaporization for cervical intraepithelial neoplasia: a single-center retrospective study.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) is a precancerous lesion that may progress to invasive cervical cancer without intervention. We aim to examine the prognostic outcomes and risk factors for recurrence after laser vaporization for CIN 3, CIN 2 with high-risk human papillomavirus (HPV) infection, and CIN 1 persisting for more than 2 years. METHODS: Between 2008 and 2016, a total of 1070 patients underwent cervical laser vaporization using a carbon dioxide laser. We performed a retrospective review of their medical records to assess their clinical characteristics, pathologic factors, and prognostic outcomes. RESULTS: The mean patient age was 34 years (range 18-64 years). The preoperative diagnosis was CIN 1 in 27 patients, CIN 2 in 485 patients, and CIN 3 in 558 patients. Over a median follow-up period of 15 months, the 2-year recurrence rate was 18.9%, and the 5-year recurrence rate was 46.5%. The 2-year retreatment rate was 12.6%, and the 5-year retreatment rate was 30.5%. We diagnosed 9 patients with invasive cancer after treatment; all patients underwent combined multidisciplinary treatment, and there were no deaths during follow-up. The recurrence-free interval was correlated with patient age (hazard ratio [HR], 1.028; 95% CI 1.005-1.051; P = 0.0167), body mass index (HR, 1.052; 95% CI 1.008-1.098; P = 0.0191), and glandular involvement (HR, 1.962; 95% CI 1.353-2.846; P = 0.0004). CONCLUSIONS: Cervical laser vaporization is effective and useful for patients with CIN who wish to preserve fertility. However, patients with glandular involvement, older age, and higher body weight require close follow-up for recurrence.

Ameliorative Effects of Combined Revascularization Surgery on Abnormal Collateral Channels in Moyamoya Disease.

OBJECT: Abnormal collateral channels, so-called moyamoya vessels, play a critical role to compensate cerebral ischemia, but carry the risk for hemorrhagic stroke in moyamoya disease (MMD). The present study was aimed to clarify if superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis and encephalo-myo-duro-arterio-pericranial synangiosis (EDMAPS) can efficiently regress the abnormal collateral channels in MMD patients. METHODS: This study included 92 hemispheres of 61 MMD patients who underwent STA-MCA anastomosis combined with EDMAPS between 2013 and 2019. There were 17 children and 44 adults. We retrospectively analyzed the findings on cerebral angiography before and 3 to 6 months after surgery, including Suzuki's angiographical stage, the development of surgical collaterals, and the extent of abnormal collateral channels such as lenticulostriate, thalamic, and choroidal channels. RESULTS: Following surgery, no pediatric and adult patients experienced any stroke during follow-up periods (40.2±25.5 and 54.9±19.7 months, respectively). Suzuki's stage significantly advanced in both adult and pediatric patients after surgery (P=0.042 and P<0.001). In adult patients, all of the lenticulostriate, thalamic, and choroidal channels significantly regressed after surgery (P<0.001, P=0.012, and P=0.004, respectively). In pediatric patients, however, lenticulostriate and choroidal channels significantly regressed (P=0.005 and P=0.034, respectively). Correlation analysis revealed that the development of surgical collaterals determined the postoperative regression of choroidal channels (P<0.001). CONCLUSION: STA-MCA anastomosis and EDMAPS may be one of the most effective procedures to widely provide surgical collaterals to the operated hemispheres and prevent not only ischemic but also hemorrhagic stroke by regressing the hemorrhage-prone abnormal collateral channels in MMD.

Downregulation of 5-hydroxymethylcytosine is associated with the progression of cervical intraepithelial neoplasia.

Around the world, cervical cancer is one of the most common neoplastic diseases among women, and the prognosis of patients in an advanced stage remains poor. To reduce the mortality rate of cervical cancer, early diagnosis and treatment are essential. DNA methylation is an important aspect of gene regulation, and aberrant DNA methylation contributes to carcinogenesis and cancer progression in various cancers. Although 5-methylcytosine (5mC) has been analyzed intensively, the function of 5-hydroxymethylcytosine (5hmC) has not been clarified. The purpose of our study was to identify the molecular biomarkers for early diagnosis of cervical tumors due to epigenetic alterations. To assess the clinical relevance of DNA methylation, we used immunohistochemistry (IHC) to characterize the level of 5hmC in 102 archived human cervical intraepithelial neoplasia (CIN) samples and cervical cancer specimens. The level of 5hmC was significantly decreased between CIN2 and CIN3. The progression of cervical tumors is caused by a reduction of TP53 and RB1 because of HPV infection. We observed that Tp53 and Rb1 were knocked down in mouse embryonic fibroblasts (MEF), a model of normal cells. The level of 5hmC was reduced in Tp53-knockdown cells, and the expression levels of DNA methyltransferase 1 (DNMT1) and ten-eleven translocation methylcytosine dioxygenase 1 (TET1) were induced. In contrast, there was no significant change in Rb1-knockdown cells. Mechanistically, we focused on apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) 3B (A3B) as a cause of 5hmC reduction after TP53 knockdown. In the human cell line HHUA with a wild-type TP53 gene, A3B was induced in TP53-knockdown cells, and A3B knockdown recovered 5hmC levels in TP53-knockdown cells. These data indicate that TP53 suppression leads to 5hmC reduction in part through A3B induction. Moreover, IHC showed that expression levels of A3B in CIN3 were significantly higher than those in both normal epithelium and in CIN2. In conclusion, 5hmC levels are decreased between CIN2 and CIN3 through the TP53-A3B pathway. Since A3B could impair genome stability, 5hmC loss might increase the chances of accumulating mutations and of progressing from CIN3 to cervical cancer. Thus, these epigenetic changes could predict whether CINs are progressing to cancer or disappearing.

[An Intraabdominal Hemorrhage Affected by Catecholamine Surges Caused by Subarachnoid Hemorrhage:A Case Report].

Intraabdominal hemorrhage is a rare complication of subarachnoid hemorrhage(SAH). Recently, there have been a number of reports about the coexistence of intracranial and Intraabdominal aneurysms caused by segmental arterial mediolysis(SAM). The etiology of SAM is still unclear, but catecholamine is known to be one of the causes of SAM. The authors report a rare case in which an increase of catecholamine by SAH affected the Intraabdominal hemorrhage during the perioperative period of SAH. A 67-year-old woman was admitted to our hospital with SAH. Cerebral angiography revealed a right internal carotid-posterior communicating artery aneurysm, and an emergent neck clipping was performed. The intraoperative finding was a saccular aneurysm with a partial red wall of the internal carotid artery. Thirteen days after SAH, the patient complained of abdominal pain, but there were no particular findings on abdominal CT. The next day, anemia progressed suddenly because of Intraabdominal hemorrhage caused by rupture of the splenic artery aneurysm. She developed shock and consciousness disturbance, and left hemiparesis due to vasospasm appeared. She recovered from shock after receiving transfusion and coil embolization of the splenic artery aneurysm. Her consciousness and left hemiparesis improved after two months of rehabilitation. The radiological findings of the splenic artery aneurysm are compatible with SAM. We believe that an increase in catecholamine by SAH affected the development and rupture of the splenic artery aneurysm. In cases of SAH with abdominal pain, a detailed examination of the abdomen might be needed, and the use of catecholamine for symptomatic vasospasm should be carefully performed.

Dual-specificity phosphatase 6 plays a critical role in the maintenance of a cancer stem-like cell phenotype in human endometrial cancer.

The prognosis of patients with high-grade or advanced-stage endometrial cancer remains poor. As cancer stem-like cells (CSCs) are thought to be associated with endometrial cancers, it is essential to investigate the molecular mechanisms that regulate endometrial CSCs. Dual-specificity phosphatase 6 (DUSP6) functions as a negative-feedback regulator of MAPK-ERK1/2 signaling, but its role in endometrial cancer remains unknown. We investigated whether DUSP6 is involved in cancer cell stemness using endometrial cancer cell lines and specimens from endometrial cancer patients. DUSP6 induced the expression of CSC-related genes including ALDH1, Nanog, SOX2 and Oct4A, increased the population of cells in the G0/G1 phase, and promoted sphere formation ability. DUSP6 knockdown resulted in reduced cell invasion and metastasis, whereas DUSP6 overexpression inhibited apoptosis under serum-free conditions. Moreover, DUSP6 decreased phosphorylated ERK1/2 and increased phosphorylated Akt levels, which potentially induces CSC features. In patients with endometrial cancers, DUSP6 expression was determined using immunohistochemistry, and based on the results, the patients were dichotomized into high- and low-DUSP6-expression groups. Progression-free survival and overall survival were significantly shorter in the high-DUSP6-expression group. These results suggest that DUSP6 has potential value as a biomarker of CSCs and as a target of therapies designed to eliminate CSCs in endometrial cancer.

Late (5-20 years) outcomes after STA-MCA anastomosis and encephalo-duro-myo-arterio-pericranial synangiosis in patients with moyamoya disease.

OBJECTIVE: Surgical revascularization is known to reduce the incidence of further ischemic and hemorrhagic events in patients with moyamoya disease, but the majority of previous studies report only short-term (< 5 years) outcomes. Therefore, in this study the authors aimed to evaluate late (5-20 years) outcomes of moyamoya patients after superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis and indirect bypass (encephalo-duro-myo-arterio-pericranial synangiosis [EDMAPS]). METHODS: Cumulative incidences of late morbidity/mortality and disease progression were evaluated among 93 patients who underwent STA-MCA anastomosis and EDMAPS. All of the patients were prospectively followed up for longer than 5 years postsurgery (10.5 ± 4.4 years). There were 35 pediatric and 58 adult patients. Initial presentation included transient ischemic attack/ischemic stroke in 80 patients and hemorrhagic stroke in 10 patients, and 3 patients were asymptomatic. Surgery was performed in a total of 141 hemispheres. Follow-up MRI/MRA was performed within a 6- or 12-month interval during the follow-up periods. RESULTS: During the follow-up periods, 92/93 patients were free from any stroke or death, but 1 patient had a recurrence of hemorrhagic stroke (0.10% per patient-year). Disease progression occurred in the territory of the contralateral carotid or posterior cerebral artery (PCA) in 19 hemispheres of 15 patients (1.5% per patient-year). The interval between initial surgery and disease progression varied widely, from 0.5 to 15 years. Repeat bypass surgery for the anterior and posterior circulation resolved ischemic attacks in all 10 patients. CONCLUSIONS: The study results indicate that STA-MCA anastomosis and EDMAPS would be the best choice to prevent further ischemic and hemorrhagic stroke for longer than 10 years on the basis of the demonstrated widespread improvement in cerebral hemodynamics in both the MCA and ACA territories in the study patients. However, after 10 years postsurgery regular follow-up is essential to detect disease progression in the territory of the contralateral carotid artery and PCA and prevent late cerebrovascular events.