Propranolol Inhibits the Proliferation of Human Glioblastoma Cell Lines through Notch1 and Hes1 Signaling System

Objective@#: The anti-tumor effect of the beta-adrenergic receptor antagonist propranolol in breast cancer is well known; however, its activity in glioblastoma is not well-evaluated. The Notch-Hes pathway is known to regulate cell differentiation, proliferation, and apoptosis. We investigated the effect of propranolol to human glioblastoma cell lines, and the role of Notch and Hes signaling in this process. @*Methods@#: We performed immunohistochemical staining on 31 surgically resected primary human glioblastoma tissues. We also used glioblastoma cell lines of U87-MG, LN229, and neuroblastoma cell line of SH-SY5Y in this study. The effect of propranolol and isoproterenol on cell proliferation was evaluated using the MTT assay (absorbance 570 nm). The impact of propranolol on gene expression (Notch and Hes) was evaluated using real-time polymerase chain reaction (RT-PCR, whereas protein levels of Notch1 and Hes1 were measured using Western blotting (WB), simultaneously. Small interfering RNA (siRNA) was used to suppress the Notch gene to investigate its role in the proliferation of glioblastoma. @*Results@#: Propranolol and isoproterenol caused a dose-dependent decrease in cell proliferation (MTT assay). RT-PCR showed an increase in Notch1 and Hes1 expression by propranolol, whereas WB demonstrated increase in Notch1 protein, but a decrease in Hes1 by propranolol. The proliferation of U87-MG and LN229 was not significantly suppressed after transfection with Notch siRNA. @*Conclusion@#: These results demonstrated that propranolol suppressed the proliferation of glioblastoma cell lines and neuroblastoma cell line, and Hes1 was more closely involved than Notch1 was in glioblastoma proliferation.

Propranolol Inhibits the Proliferation of Human Glioblastoma Cell Lines through Notch1 and Hes1 Signaling System

Objective@#: The anti-tumor effect of the beta-adrenergic receptor antagonist propranolol in breast cancer is well known; however, its activity in glioblastoma is not well-evaluated. The Notch-Hes pathway is known to regulate cell differentiation, proliferation, and apoptosis. We investigated the effect of propranolol to human glioblastoma cell lines, and the role of Notch and Hes signaling in this process. @*Methods@#: We performed immunohistochemical staining on 31 surgically resected primary human glioblastoma tissues. We also used glioblastoma cell lines of U87-MG, LN229, and neuroblastoma cell line of SH-SY5Y in this study. The effect of propranolol and isoproterenol on cell proliferation was evaluated using the MTT assay (absorbance 570 nm). The impact of propranolol on gene expression (Notch and Hes) was evaluated using real-time polymerase chain reaction (RT-PCR, whereas protein levels of Notch1 and Hes1 were measured using Western blotting (WB), simultaneously. Small interfering RNA (siRNA) was used to suppress the Notch gene to investigate its role in the proliferation of glioblastoma. @*Results@#: Propranolol and isoproterenol caused a dose-dependent decrease in cell proliferation (MTT assay). RT-PCR showed an increase in Notch1 and Hes1 expression by propranolol, whereas WB demonstrated increase in Notch1 protein, but a decrease in Hes1 by propranolol. The proliferation of U87-MG and LN229 was not significantly suppressed after transfection with Notch siRNA. @*Conclusion@#: These results demonstrated that propranolol suppressed the proliferation of glioblastoma cell lines and neuroblastoma cell line, and Hes1 was more closely involved than Notch1 was in glioblastoma proliferation.

Impact of metformin on survival outcome in ovarian cancer: a nationwide population-based cohort study / 부인종양

Objective@#Investigation of new drugs (INDs) is a tremendously inefficient process in terms of time and cost. Drug repositioning is another method used to investigate potential new agents in well-known drugs. This study assessed the survival impact of metformin medication on ovarian cancer. @*Methods@#A national sample cohort of the Korean National Health Insurance Service Data was analyzed. Cox proportional hazards regression was used to analyzing hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for underlying diseases and medications as confounding factors for overall survival (OS) and cancer-specific survival (CSS). @*Results@#A total of 866 eligible patients were included from among 1,025,340 cohort participants. Among them, 101 (11.7%) were metformin users. No difference in OS was observed between non-users and users. No difference in OS was observed according to age and Charlson Comorbidity Index. Long-term metformin use (≥720 days) was associated with better OS (adjusted HR=0.244; 95% CI=0.090–0.664; p=0.006). A multivariate Cox proportional hazards model showed that long-term metformin use was an independent favorable prognostic factor for OS (HR=0.193; 95% CI=0.070–0.528; p=0.001) but not for CSS (HR=0.599; 95% CI=0.178–2.017; p=0.408). @*Conclusion@#Long-term metformin use reduced all-cause mortality, but not CSS in ovarian cancer. Whether metformin itself reduces deaths because of ovarian cancer requires further investigation.

Impact of beta blockers on survival outcomes in ovarian cancer: a nationwide population-based cohort study / 부인종양

OBJECTIVE: The impact of beta blockers (BBs) on survival outcomes in ovarian cancer was investigated. METHODS: By using Korean National Health Insurance Service Data, Cox proportional hazards regression was performed to analyze hazard ratios (HRs) with 95% confidence intervals (CIs) adjusting for confounding factors. RESULTS: Among 866 eligible patients, 206 (23.8%) were BB users and 660 (76.2%) were non-users. Among the 206 BB users, 151 (73.3%) were non-selective beta blocker (NSBB) users and 105 (51.0%) were selective beta blocker (SBB) users. BB use in patients aged ≥60 years, longer duration use (≥1 year), in patients with Charlson Comorbidity Index (CCI) ≥3, and in cardiovascular disease including hypertension was associated with better survival outcome. These findings were observed in both NSBB and SBB. When duration of medication was analyzed based on number of days, NSBB (≥180 days) was associated with improved overall survival (OS) with a relatively shorter period of use compared to SBB (≥720 days). In multivariate Cox proportional hazards model, longer duration of BB medication (≥1 year) was an independent favorable prognostic factor for both OS and disease-specific survival in ovarian cancer patients. CONCLUSION: In our nationwide population-based cohort study, BB use was associated with better survival outcomes in ovarian cancer in cases of long term duration of use, in older patients, and in cardiovascular and/or other underlying disease (CCI ≥3).

Nerve Growth Factor Stimulates Glioblastoma Proliferation through Notch1 Receptor Signaling

OBJECTIVE: Notch receptors are heterodimeric transmembrane proteins that regulate cell fate, such as differentiation, proliferation, and apoptosis. Dysregulated Notch pathway signaling has been observed in glioblastomas, as well as in other human malignancies. Nerve growth factor (NGF) is essential for cell growth and differentiation in the nervous system. Recent reports suggest that NGF stimulates glioblastoma proliferation. However, the relationship between NGF and Notch1 in glioblastomas remains unknown. Therefore, we investigated expression of Notch1 in a glioblastoma cell line (U87-MG), and examined the relationship between NGF and Notch1 signaling. METHODS: We evaluated expression of Notch1 in human glioblastomas and normal brain tissues by immunohistochemical staining. The effect of NGF on glioblastoma cell line (U87-MG) was evaluated by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. To evaluate the relationship between NGF and Notch1 signaling, Notch1 and Hes1 expression were evaluated by reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. To confirm the effects of NGF on Notch1 signaling, Notch1 and Hes1 small interfering RNAs (siRNAs) were used. RESULTS: In immunohistochemistry, Notch1 expression was higher in glioblastoma than in normal brain tissue. MTT assay showed that NGF stimulates U87-MG cells in a dose-dependent manner. RT-PCR and Western blot analysis demonstrated that Notch1 and Hes1 expression were increased by NGF in a dose-dependent manner. After transfection with Notch1 and Hes1 siRNAs, there was no significant difference between controls and 100 nM NGF-β, which means that U87-MG cell proliferation was suppressed by Notch1 and Hes1 siRNAs. CONCLUSION: These results indicate that NGF stimulates glioblastoma cell proliferation via Notch1 signaling through Hes 1.

Nerve Growth Factor Stimulates Glioblastoma Proliferation through Notch1 Receptor Signaling

OBJECTIVE: Notch receptors are heterodimeric transmembrane proteins that regulate cell fate, such as differentiation, proliferation, and apoptosis. Dysregulated Notch pathway signaling has been observed in glioblastomas, as well as in other human malignancies. Nerve growth factor (NGF) is essential for cell growth and differentiation in the nervous system. Recent reports suggest that NGF stimulates glioblastoma proliferation. However, the relationship between NGF and Notch1 in glioblastomas remains unknown. Therefore, we investigated expression of Notch1 in a glioblastoma cell line (U87-MG), and examined the relationship between NGF and Notch1 signaling.METHODS: We evaluated expression of Notch1 in human glioblastomas and normal brain tissues by immunohistochemical staining. The effect of NGF on glioblastoma cell line (U87-MG) was evaluated by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. To evaluate the relationship between NGF and Notch1 signaling, Notch1 and Hes1 expression were evaluated by reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. To confirm the effects of NGF on Notch1 signaling, Notch1 and Hes1 small interfering RNAs (siRNAs) were used.RESULTS: In immunohistochemistry, Notch1 expression was higher in glioblastoma than in normal brain tissue. MTT assay showed that NGF stimulates U87-MG cells in a dose-dependent manner. RT-PCR and Western blot analysis demonstrated that Notch1 and Hes1 expression were increased by NGF in a dose-dependent manner. After transfection with Notch1 and Hes1 siRNAs, there was no significant difference between controls and 100 nM NGF-β, which means that U87-MG cell proliferation was suppressed by Notch1 and Hes1 siRNAs.CONCLUSION: These results indicate that NGF stimulates glioblastoma cell proliferation via Notch1 signaling through Hes 1.

Comparison of HE4, CA125, and Risk of Ovarian Malignancy Algorithm in the Prediction of Ovarian Cancer in Korean Women

This study is a multi-center clinical study, which aimed to compare CA125, HE4, and risk of ovarian malignancy algorithm (ROMA) in predicting epithelial ovarian cancer of Korean women with a pelvic mass. Prospectively, serum from 90 Korean women with ovarian mass was obtained prior to surgery. For control group, serum from 79 normal populations without ovarian mass was also obtained. The HE4 and CA125 data were registered and evaluated separately and ROMA was calculated for each sample. Total 67 benign tumors and 23 ovarian cancers were evaluated. Median serum levels of HE4 and CA125, and ROMA score were significantly higher in patients with ovarian cancer than those with benign ovarian tumor and normal population (P < 0.001). In ROC curve analysis for women with a pelvic mass, area under the curve (AUC) for HE4 and ROMA was higher than CA125. Statistical differences in each study compared to CA125 were marginal (P compared to CA125; 0.082 for HE4 and 0.069 for ROMA). Sub-analysis revealed that AUC for HE4 and ROMA was higher than AUC for CA125 in post-menopausal women with a pelvic mass, but there were no statistically significant differences (P compared to CA125; 0.160 for HE4 and 0.127 for ROMA). Our data suggested that both HE4 and ROMA score showed better performance than CA125 for the detection of ovarian cancer in women with a pelvic mass. HE4 and ROMA can be a useful independent diagnostic marker for epithelial ovarian cancer in Korean women.

The Expression and Role of Kruppel-Like Factor 4 in Psoriasis

BACKGROUND: Kruppel-like factor 4 (KLF4) is a transcription factor that regulates a diverse array of cellular processes, including development, differentiation, proliferation, and apoptosis. Although its function in keratinocytes has been widely studied, its exact role in psoriasis has not been elucidated. OBJECTIVE: We designed this study to investigate epidermal expression levels of KLF4 and the change in KLF4 expression after treatment in patients with psoriasis. METHODS: We compared the expression levels of KLF4 in the basal, suprabasal, and superficial epidermal layers, in psoriatic lesional, non-lesional, and normal skin, using an immunoreactivity intensity distribution index (IRIDI). In addition, we measured the change in KLF4 expression on the basis of the IRIDI and by reverse transcription polymerase chain reaction (RT-PCR) analysis after treatment. RESULTS: The combined IRIDI scores in psoriatic lesional skin were significantly higher than the scores in both non-lesional and normal skin. The psoriatic epidermis, particularly the suprabasal layer, showed a significantly increased IRIDI score compared to that of non-lesional and normal skin, which was significantly decreased after treatment. RT-PCR analysis exhibited a slight increase in KLF4 mRNA expression level after treatment; however, this increase was not significant. CONCLUSION: These data indicate that KLF4 could regulate epidermal proliferation and differentiation. Moreover, we believe that KLF4 may play an important role in the physiological reaction to counteract abnormal differentiation and proliferation of keratinocytes.

Malignant Perivascular Epithelioid Cell Tumor of the Uterus with Lung Metastasis

No abstract available.

Feasibility of laparoscopic salpingectomy using one port in tubal pregnancy / 대한산부인과내시경학회지

OBJECTIVE: To evaluate the feasibility of laparoscopic salpingectomy using one-port in tubal pregnancy compared to conventional laparoscopic surgery. METHODS: From June 2008 to June 2011, 63 women were treated with laparoscopic salpingectomy due to tubal pregnancy, which was diagnosed by ultrasonography. These patients were divided into two groups. Of these 63 patients, 32 women were treated with conventional laparoscopic salpingectomy (CLS) in group I, 31 women underwent laparoscopic salpingectomy using one port (OPLS) in group II. In group I, rigid 0degrees or 30degrees, 10 mm laparoscope, rigid instruments were used. In group II, 30degrees, 10 mm laparoscope, rigid or flexible angulated tip instruments were used during the surgery. We reviewed and compared clinical characteristics, clinical outcomes of these patients. RESULTS: Patients in Group I were compatible with the patients in group II in clinical characteristics. Clinical outcomes were not different between two groups in terms of Hemoglobin change (g/dL), hospital stay (days), hemoperitoneum (mL), transfusion. Mean operative time was significantly longer in group II (59.7+/-15.7 min vs. 46.5+/-15.0 min, p=0.001). The mean length of skin incision was obviously shorter in group II; the difference was highly statistically significant (15.5+/-3.0 mm vs 23.5+/-3.0 mm, p<0.001). CONCLUSION: It seems that OPLS is feasible alternative to CLS to treat hemodynamically stable patients without complications. Additionally, this technique also results in better cosmetic outcomes than CLS. Randomized prospective clinical studies with larger scale are necessary in the future to confirm these results.

A comparison of robot assisted and abdominal radical hysterectomy (RH) for early stage cervical and endometrial cancer / 대한산부인과내시경학회지

OBJECTIVE: To compare perioperative outcome of robot-assisted radical hysterectomy with abdominal radical hysterectomy for early-stage cervical cancer and endometrial cancer and to evaluate the feasibility of robotic-assisted radical hysterectomy. METHODS: We reviewed medical record of 37 patients who had radical hysterectomy at Hallym university for cervical cancer stage Ia1 to IIa and endometrial cancer stage Ia to Ib. Abdominal radical hysterectomy was carried out in 27 (Abdominal group) patients and robot-assisted radical hysterectomy carried out in 10 patients (Robotic group). We compared patient's characteristics between two groups. Perioperative characteristics compared included cancer stage, operative time, number of nodes, estimated blood loss, length of hospital stay and complications. RESULTS: There were no differences in age, parity, history of medical disease, body mass index between two groups (p>0.05). Robotic operative times were significantly longer than for abdominal (480.0+/-117.8 vs. 286.9+/-65.6 min, p<0.0001). Blood loss (660.0+/-245.9 vs. 1,137.0+/-608.4 mL. p<0.0001) and length of hospital stay (7.2 versus 17.1 days, p<0.0001) were significantly lower for the robotic group. Lymph node yield in the robotic group was equivalent to that for the abdominal group (30.1+/-8.7 vs. 35.4+/-16.9, p=0.356). No major operative complications occurred with both groups. CONCLUSION: Robot-assisted radical hysterectomy appears safe and feasible in early-stage cervical and endometrial cancer.

Follicular stimulating hormone enhances Notch 1 expression in SK-OV-3 ovarian cancer cells / 부인종양

OBJECTIVE: Notch is known as a transmembranous receptor family with four homologous forms - Notch 1, Notch 2, Notch 3, and Notch 4 and related to cell fate regulation and angiogenesis. The purpose is to investigate the effect of follicular stimulating hormone (FSH) on the Notch 1 expression and proliferation in ovarian cancer cells. METHODS: Human ovarian cancer cell line, SK-OV-3 and FSH were used. XTT cell proliferation and cell migration assay were carried out with FSH 100 mIU/mL and Notch 1 siRNA. Western blots and reverse transcriptase-polymerase chain reactions (RT-PCR) were carried out to determine the expression level of the Notch 1 protein and mRNA with FSH treatment in 0, 1, 5, 10, 100, 200, 300 mIU/mL concentrations. Immunofluorescent (IF) stains were performed in SK-OV-3 cell cultures with FSH 100 mIU/mL. Student-t tests were used in statistical analyses. RESULTS: The SK-OV-3 have Notch 1 receptors in their natural status. FSH stimulated SK-OV-3 cells in XTT cell proliferation and cell migration assays and notch 1 siRNA inhibited. The expression level of Notch 1 protein and mRNA were increased in a dose dependent pattern according to FSH concentrations compared to untreated cells. IF stains also showed brighter Notch1 expressions in the FSH treated cells compared to the control cells. CONCLUSION: FSH enhances proliferation & migration and Notch 1 signaling in SK-OV-3 cells. The Notch signaling probably supports one of the cell proliferating mechanisms of FSH in ovarian cancer cells.

Two cases of immature teratoma / 대한산부인과학회지

About 20~30% of benign or malignant tumors of ovarian origin arise from embryonic cells, and only 3% represent malignancy. But under age of 20, 70% of ovarian tumors arise from embryonic cells, and over 1/3 of them are malignant tumors. Over all the ovarian tumors arising from embryonic cells, immature teratoma is germ cell tumor, components include immature tissues and cells derived from ectoderm, mesoderm, and endomermal origins. Most of the immature tissues are from neuroectodermal origins. The immature teratoma of the ovary is a rare tumor, representing less than 1% of all ovarian neoplasm. These tumors typically present in young age woman (mean age 10~20 years) with pelvic and abdominal pain. Nowadays newly developed combination chemotherapeutic agents such as bleomycin, etoposide, cisplatin give us great survival and disease free prognosis than before. We have experienced two cases of immature teratoma so we report them with a brief review of concerned literatures.

A case of pelvic actinomyosis presenting as an advanced ovarian malignancy / 대한산부인과학회지

Pelvic actinomycosis is an infrequent chronic suppurative granulomatous disease, caused by a gram-positive bands Actinomyces israelii. It is often reported as a complicated case of an intrauterine device (IUD). Ureteral obstruction and subsequent hydronephrosis are rare complications of pelvic inflammatory disease. Sometimes pelvic actinomyosis is simulating ovarian malignancy. We report a case combined with hydronephrosis, multiple pelvic lymph nodes enlargements and elevated CA 125 as complications of pelvic actinomycosis.

A case of pelvic actinomyosis presenting as an advanced ovarian malignancy / 대한산부인과학회지

Pelvic actinomycosis is an infrequent chronic suppurative granulomatous disease, caused by a gram-positive bands Actinomyces israelii. It is often reported as a complicated case of an intrauterine device (IUD). Ureteral obstruction and subsequent hydronephrosis are rare complications of pelvic inflammatory disease. Sometimes pelvic actinomyosis is simulating ovarian malignancy. We report a case combined with hydronephrosis, multiple pelvic lymph nodes enlargements and elevated CA 125 as complications of pelvic actinomycosis.

The expressions of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) in the progression of invasive cervical cancer / 대한산부인과학회지

OBJECTIVE: To evaluate the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) in the progression of cervical cancer. METHODS: A total 87 specimens of uterine cervix, representing 6 normal epithelium, 11 intraepithelial neoplasm, 25 cervical carcioma in situ (CIS), 19 cervical microinvasive carcinoma and 26 cervical invasive carcinoma, were evaluated. All specimens were prepared with tissue array method which can allow evaluation many specimens in one slide. The protein expressions of VEGF and MMPs (MMP-2, MMP-9) were evaluated by immunohistochemical staining. RESULTS: The protein expressions of VEGF and MMP-2 were increased significantly with the progression of cervical cancer (p0.05). The VEGF and MMP-2 expressions revealed positive correlations with the progression of cervical cancer. CONCLUSIONS: The VEGF, MMP-2 in each or together may play a role in the progression of cervical cancer.

A case of lymphangioleiomyomatosis originated in the pelvic cavity / 부인종양

Lymphangioleiomyomatosis is a rare disease that is characterized by proliferation of abnormal smooth muscle-like cells, especially that which occurs in the pulmonary parenchyme. It primarily affects women of child-bearing age. The majority of primary lymphangioleiomyomatosis occurs in the lung, but there are a few reports of extrapulmonary cases. We experienced a rare case of lymphangioleiomyomatosis which originated in the pelvic cavity (in the posterior portion of the uterus), and report with brief review of literatures.

Solitary mesenteric recurrence of ovarian cancer / 대한산부인과학회지

In epithelial ovarian cancer, solitary metastasis to mesentary is rare in the absence of apparent disease in other sites. We experienced one patient who developed isolated, solitary mesenteric metastasis of epithelial ovarian adenocarcinoma and underwent segmental resection of small bowel including mesentary to remove the recurrent disease. Rising CA125 heralded the recurrence and the patient was subsequently documented by computed tomography (CT) and PET-CT of the abdomen and pelvis with a high signal density noted only in the mesentery. There was no major postoperative complicathion. Solitary recurrence of epithelial ovarian cancer can occur in the absence of other demomstrable metastasis, so we report with brief review of literature.

A Case of Vaginal Bleeding after Cesarean Section due to Arteriovenous Malformation (AVM) of Uterus / 대한주산의학회잡지

Uterine arteriovenous malformations are very rare but potentially life threatening lesions. These lesions may be congenital or acquired, but especially occur in patients with a history of curettage, abortion or pregnancy. Color doppler ultrasonography is the preferred method of diagnosing of arteriovenous malformations. In many cases, hysterectomies are performed. But if patients want pregnancies, embolization therapy and conservative treatment are effective therapy. We have experienced a clinical case of uterine arteriovenous malformation, which is presented with a brief review of literature.

A Case of Synchronous Existence of Endometrial cancer and Cervical cancer / 대한산부인과학회지

The synchronous existence of endometrial cancer and cervical cancer is very rare. The reported frequency of concurrent gynecologic neoplasms has ranged from 0.7% to 4.3%, synchronous primary tumors of the female genital tract are relatively rare, comprising only 0.49% to 1.7% of all genital neoplasms. The majority of synchronous multiple primary neoplasm of female reproductive tract are of endometrial and ovarian origin. Multiple primary neoplams involving uterine cervix and endometrium were regarded as rare entity. We experienced a rare case of multiple primary neoplasm involving uterine cervix and endometrium and report with brief review of literatures.