Evolutionary histories of breast cancer and related clones.

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1-3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.

Ineffectiveness of antenatal guidance intervention for vitamin D insufficiency and deficiency in pregnant women in Kyoto, Japan.

AIM: The aim of this study was to investigate the vitamin D status among healthy pregnant women in Japan, and to evaluate the effectiveness of the antenatal health guidance intervention for the pregnant women who were informed about their low vitamin D levels. METHODS: We measured the level of 25-hydroxyvitamin D (25[OH]D) using chemiluminescent immunoassay among the singleton pregnant women who received at antenatal routine check-up (8-24 weeks of gestation) with written consent during September 2017-September 2018. The measurement values were informed by the concerned physician and health guidance intervention was given to the pregnant women with inadequate Vitamin D status (25[OH]D < 30 ng/mL). At around 36 weeks of gestation, the measurement of 25(OH)D and a questionnaire regarding behavioral changes after the guidance was conducted. RESULTS: The average value of 25(OH)D of 1192 pregnant women before the guidance was 14.89 ± 4.85 ng/mL, and the prevalence of sufficient vitamin D status (25(OH)D ≥ 30 ng/mL) was 0.67% (8/1192). Nine hundred eighty-two pregnant women who had inadequate vitamin D status were followed, thereafter-guidance prevalence of sufficiency was 1.02% (10/982); insufficiency, 14.66% (144/982); and deficiency, 84.32% (828/982), respectively. Although the prevalence of deficiency was decreased after guidance intervention significantly, the prevalence was still high and the effect on behavioral changes was a little. CONCLUSION: The prevalence of vitamin D sufficient status among pregnant women in Japan was extremely low, which is a serious condition. It was also revealed the effectiveness of the antenatal health guidance intervention for pregnant women was not enough.

Early feasibility surveillance of gynecologic robotic-assisted surgeries in Japan.

AIM: To evaluate the clinical relevance of robotic-assisted surgeries (RAS) for gynecologic malignancies in a Japanese multi-institutional cohort. METHODS: A retrospective review of perioperative outcomes of 357 gynecologic RAS procedures was conducted in 24 hospitals accredited to perform RAS by the Japanese Society of Obstetrics and Gynecology (JSOG) over a 4-year period, January 2014 to December 2017. RESULTS: More than 25 (high), 10-24 (middle) and less than 10 cases (low) were enrolled from 3, 8 and 13 hospitals, respectively. A total of 247 patients underwent RAS for malignant indications. Radical hysterectomy (RH) was conducted for 200 patients, while para-aortic node excision (PAN) for 47 patients. RAS with RH or PAN was more feasible in high-volume centers with significantly shorter operation time and lesser blood loss than that in middle-volume centers. The total rate of perioperative injury and complications in RAS with PAN reached 33.3% in high-volume centers, which was almost equal to those in middle-volume centers (35.5%) but much higher than RAS without PAN (8.5%). CONCLUSION: Perioperative surveillance demonstrated high feasibility of gynecologic RAS procedures conducted in JSOG accredited hospitals for these 4 years. It is mandatory for RAS conducting hospitals to have careful attitudes to realize their learning curves in conducting advanced procedures.

Multi-institutional phase II study of neoadjuvant irinotecan and nedaplatin followed by radical hysterectomy and the adjuvant chemotherapy for locally advanced, bulky uterine cervical cancer: A Kansai Clinical Oncology Group study (KCOG-G1201).

AIM: A multi-institutional phase II trial was conducted to determine the efficacy and toxicity of neoadjuvant chemotherapy with irinotecan and nedaplatin followed by radical hysterectomy and adjuvant chemotherapy for locally advanced, bulky stage IB2-IIB cervical cancer. METHODS: Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB2-II, bulky type (>4 cm in diameter) squamous cell carcinoma of the uterine cervix were enrolled. Irinotecan (60 mg/m2 ) was administered intravenously on days 1 and 8 and nedaplatin (80 mg/m2 ) was also administered on day 1 of every 21-day cycle. After two cycles of chemotherapy, a radical hysterectomy was performed. Until 6 weeks after the surgery, three to five cycles of the regimen were added as adjuvant chemotherapy. The primary endpoint was the 2-year relapse-free survival rate. The response rates and toxicities were evaluated as secondary endpoints. RESULTS: Thirty-two patients from seven institutions were enrolled in this study. The median age was 48 years (range 25-75 years). The average follow-up period was 37.8 months (15-71 months). Twenty-three patients completed the regimen as planned. The objective response rate (complete response + partial response) for the neoadjuvant chemotherapy regimen was 81.2%. The 2-year and 5-year relapse-free-survival rates were 87.5% and 78.8%, respectively. The incidence of grade 3/4 neutropenia was 6.3% and 34.4% during neoadjuvant and adjuvant treatment, respectively. All other toxicities were well tolerated. CONCLUSION: Our treatment showed efficacy and tolerability for patients with locally advanced, bulky stage IB2-IIB cervical cancer. This suggests that treatment has the potential to improve the prognosis compared to concurrent chemo-radiotherapy.

Loss of AF-6/afadin induces cell invasion, suppresses the formation of glandular structures and might be a predictive marker of resistance to chemotherapy in endometrial cancer.

BACKGROUND: AF-6/afadin plays an important role in the formation of adherence junctions. In breast and colon cancer, loss of AF-6/afadin induces cell migration and cell invasion. We aimed to elucidate the role of AF-6/afadin in human endometrial cancer. METHODS: Morphology and AF-6/afadin expression in endometrial cancer cell lines was investigated by 3-dimensional culture. We used Matrigel invasion assay to demonstrate AF-6/afadin knockdown induced invasive capability. Cell proliferation assay was performed to estimate chemoresistance to doxorubicin, paclitaxel and cisplatin induced by AF-6/afadin knockdown. The associations between AF-6/afadin expression and clinicopathological status were determined by immunohistochemical analysis in endometrial cancer tissues. Informed consent was obtained from all patients before the study. RESULTS: The majority of cell clumps in 3-dimensional cultures of Ishikawa cells that strongly expressed AF-6/afadin showed round gland-like structures. In contrast, the cell clumps in 3-dimensional cultures of HEC1A and AN3CA cells-both weakly expressing AF-6/afadin-showed irregular gland-like structures and disorganized colonies with no gland-like structures, respectively. AF-6/afadin knockdown resulted in reduced number of gland-like structures in 3-dimensional cultures and enhancement of cell invasion and phosphorylation of ERK1/2 and Src in the highly AF-6/afadin-expressing endometrial cancer cell line. Inhibitors of MAPK/ERK kinase (MEK) (U0126) and Src (SU6656) suppressed the AF-6/afadin knockdown-induced invasive capability. AF-6/afadin knockdown induced chemoresistance to doxorubicin, paclitaxel and cisplatin in Ishikawa cells, not in HEC1A. Immunohistochemical analysis showed that AF-6/afadin expression was significantly associated with myometrial invasion and high histological grade. CONCLUSIONS: AF-6/afadin regulates cell morphology and invasiveness. Invasive capability is partly regulated through the ERK and Src pathway. The inhibitors to these pathways might be molecular-targeted drugs which suppress myometrial invasion in endometrial cancer. AF-6/afadin could be a useful selection marker for fertility-sparing therapy for patients with atypical hyperplasia or grade 1 endometrioid adenocarcinoma with no myometrial invasion. AF-6/afadin knockdown induced chemoresistance especially to cisplatin. Therefore, loss of AF-6/afadin might be a predictive marker of chemoresistance to cisplatin.

Estrogen-related receptor-γ regulates estrogen receptor-α responsiveness in uterine endometrial cancer.

OBJECTIVE: Estrogen-related receptors (ERRs) are orphan nuclear receptors that modulate the estrogen receptor (ER)-mediated pathway and play roles in the regulation of breast and prostate cancer cell growth. However, the significance of the localization and the function of ERRs in uterine endometrial cancer remain unclear. We aimed to measure the expression of ERRγ and determine its association with the ER-mediated pathway in human endometrial cancer. METHODS: Proliferation, luciferase, and quantitative polymerase chain reaction assays were performed in ERα-positive (Ishikawa) and ERα-negative (HEC1A) endometrial cancer cell lines. The association between ERRγ and ERα expressions was determined by immunohistochemical analysis in uterine endometrial cancer tissues. RESULTS: Estrogen-induced estrogen response element transcriptional activity was repressed by ERRγ in ERα-positive cells but was stimulated by ERRγ in ERα-negative cells. The stable overexpression of ERRγ regulated the in vitro cell growth in the ERα-positive and ERα-negative endometrial cancer cell lines. A selective ERRγ agonist, DY131, inhibited the growth of the ERα-positive endometrial cancer cells but promoted that of the ERα-negative cancer cells. Furthermore, we found that ERRγ is expressed in the nuclei of human uterine endometrial cancer tissues. Estrogen-related receptor γ was not associated with pathological parameters such as the International Federation of Gynecology and Obstetrics stage and histological type. The uterine endometrial cancer tissues with ERRγ-positive/ERα-negative status may have a significantly poor prognosis. CONCLUSIONS: The relationship between ERRγ and ERα status could be a predictive marker for the treatment of uterine endometrial cancer, which provides an impetus for the identification of ligands for nuclear orphan receptor ERRγ.

Prognostic impact of the history of breast cancer and of hormone therapy in uterine carcinosarcoma.

OBJECTIVE: Recent studies reveal an association between hormone therapy for breast cancer (BC), such as tamoxifen (TAM) and toremifene (TOR), and uterine carcinosarcoma (UCS). The aim of this study was to investigate the characteristics and prognosis of patients with UCS after BC and hormone therapy. METHODS: Between January 1997 and December 2007, we treated 51 patients with UCS. The medical records of these patients were reviewed, and factors that influenced their survival were retrospectively analyzed using univariate and multivariate analyses. RESULTS: Ten (19.6%) of the 51 patients had a history of BC; 6 (11.8%) had received hormone therapy with TAM or TOR. The characteristics of the patients with UCS were similar regardless of whether they had a history of BC or hormone therapy. On univariate analysis, age greater than 56 years, elevated serum lactate dehydrogenase levels, residual tumors, FIGO (International Federation of Gynecology and Obstetrics) stage higher than stage IIIa, and non-endometrioid carcinomatous components were identified as prognostic factors. On multivariate analysis, in addition to residual tumors, FIGO stage higher than stage IIIa, and non-endometrioid carcinomatous components, a history of BC (relative risk, 0.14), a history of TAM use (relative risk, 15.9), and a history of TOR use (relative risk, 16.9) were also identified as independently significant prognostic factors. CONCLUSIONS: Our data suggest that a history of BC and hormone therapy for BC is a risk factor for developing UCS without obvious impacts on the characteristics of UCS. Both of these factors had statistically significant impacts on the prognosis of patients with UCS. Further studies are necessary to clarify and validate these associations.

Percutaneous drainage with a one-step technique under real-time computed tomography fluoroscopic guidance.

BACKGROUND/AIMS: The goal of our study was to determine the usefulness of the percutaneous placement of a drainage catheter using a one-step technique under guidance of computed tomography (CT) fluoroscopy. METHODOLOGY: Subjects were 11 patients (3 women, 8 men; mean age 65 years) who underwent percutaneous thoracic, abdominal, and pelvic drainage procedures for fluid collections between August 2010 and June 2011. The mean maximum diameter of the lesions was 53.8mm (range 30 to 82 mm) and the mean depth was 37.6mm (range 18 to 70mm). A drainage catheter that can be inserted by a one- step technique without a guide wire was used. The procedures were guided by use of a helical CT scanner that provided real-time fluoroscopic reconstruction. RESULTS: Percutaneous drainage was successfully achieved in every procedure. Use of real-time CT-fluoroscopy and a drainage catheter that can be inserted with a one-step technique allowed rapid assessment of catheter placement. No patient had a serious complication related to the drainage procedure. The mean procedure time required to drain one lesion was 21.1 minutes (range 12 to 41 minutes). CONCLUSIONS: Thoracic, abdominal, and pelvic drainage procedures using the one-step technique under CT-fluoroscopy guidance were accurate, safe and easy.

Estrogen-related receptor α expression and function are associated with vascular endothelial growth factor in human cervical cancer.

INTRODUCTION: Estrogen-related receptor α (ERRα), one of orphan nuclear receptors with an unknown ligand, is expressed in various types of cancer. Increased ERRα levels are associated with a higher risk of recurrence and poor clinical outcome in breast cancer, suggesting that ERRα could be a negative prognostic factor. Recently, it has been suggested that vascular endothelial growth factor (VEGF) could be one of the transcriptional targets of ERRα in breast cancer. Here, we examined the expression of ERRα and the association of ERRα with VEGF in uterine cervical cancer cells and tissues. METHODS: We evaluated the expression of ERRα and VEGF by immunohistologic analysis using specimens from 40 patients with invasive cervical cancer. We also evaluated the VEGF promoter activity of ERRα in cervical cancer cell lines by transfection and luciferase assay. We overexpressed or knocked down ERRα and examined VEGF expression by real-time polymerase chain reaction. Finally, cell proliferation assay was performed to examine whether ERRα affects tumor growth in cervical cancer. RESULTS: Immunohistologic analysis demonstrated that ERRα expression in cervical cancer tissues was higher than that in noncancerous tissues and that there was a positive association between ERRα and VEGF expression in cancer tissues (P < 0.05). We showed that ERRα stimulated the VEGF promoter activity in cervical cancer cell lines. We further showed the overexpression and knockdown of ERRα-regulated VEGF expression level by real-time polymerase chain reaction. Moreover, we showed that ERRα and VEGF knockdown by small interfering RNA or an inverse agonist of ERRα, XCT 790, could suppress cell growth compared with control cells in cervical cancer. CONCLUSIONS: We have provided compelling evidence that ERRα affects VEGF expression and tumor growth in cervical cancer. These results justify further investigation into the use of ERRα as a therapeutic target for patients with uterine cervical cancer.

Primary extraskeletal myxoid chondrosarcoma of the vulva.

Primary extraskeletal myxoid chondrosarcoma (EMC) of the vulva is extremely rare. There is little available information about the biological behavior and treatment strategy for primary EMC of the vulva. We report a rare case of primary EMC of the vulva treated surgically. A 24-year-old Japanese woman had demonstrated a small and elastic mass of the vulva and underwent enucleation of the mass at a previous hospital, but a definitive histopathological diagnosis was not obtained. Therefore, the patient was referred to our hospital for further evaluation and treatment. We histopathologically diagnosed the tumor as primary EMC of the vulva and performed vulvectomy with vulvoperineal reconstruction. Microscopic examination of the resected specimens demonstrated residual tumor nodules of EMC. However, there were no viable tumor cells at the surgical margin. Approximately two years after wide local excision was performed, the patient is doing well and there is no apparent recurrence of EMC.

Neoadjuvant weekly carboplatin and paclitaxel followed by radical hysterectomy for locally advanced cervical cancer: long-term results.

INTRODUCTION: To determine the long-term effect of neoadjuvant chemotherapy with paclitaxel and carboplatin on a weekly schedule followed by radical surgery for patients with locally advanced cervical cancer. MATERIALS AND METHODS: Thirty patients with stage IB2 to IIIB uterine cervical cancer were treated with paclitaxel (60 mg/m) and carboplatin (area under the curve, 2-an area under the time-concentration curve of 2 mg x min/mL based on creatinine clearance) every week for 6 cycles. A radical hysterectomy was performed 6 days after the final administration of neoadjuvant chemotherapy. The patients were followed up, and 5-year progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Of 30 patients, 28 were followed up. The median follow-up period was 55.6 months (range, 26-83 months). An objective response (complete response + partial response) to the treatment was observed in 26 patients (87%; 95% confidence interval, 70%-95%). Two had complete response, 4 had stable disease, and the remaining patients had partial response; progressive disease was not seen in this study. A radical hysterectomy was performed in 28 patients without delay. Thirteen patients with high-risk factors received radiotherapy after surgery. The 5-year PFS and OS rates were 78.6% and 81.8%, respectively. The 5-year PFS and OS for patients with stage IB2 to IIB cervical cancer were 79.2% and 83.1%, respectively, which were comparable with those in the concurrent chemoradiation therapy study previously reported. There was no significant correlation in survival between preoperative staging and cell type, whereas larger initial tumor size and lymph node metastasis tended to be negatively correlated with survival. CONCLUSIONS: Neoadjuvant chemotherapy with paclitaxel and carboplatin on a weekly schedule followed by radical surgery for patients with locally advanced cervical cancer is a promising mode of therapy that may improve the prognosis. It would be worthwhile to conduct larger-scale trials for comparison with the results of the chemoradiation therapy study.

A case of vaginal clear cell adenocarcinoma complicated with congenital anomalies of the genitourinary tract and metanephric remnant without prenatal diethylstilbestrol exposure.

Vaginal clear cell adenocarcinoma (CCA) is well known to be associated with prenatal diethylstilbestrol exposure. We present a vaginal CCA with congenital anomalies of the genitourinary tract without prenatal diethylstilbestrol exposure. A 54-year-old woman complained of a 3-month history of genital bleeding. The examination revealed CCA at the anterior vagina and congenital anomalies. An anterior pelvic exenteration was performed. Macroscopically, bicornuate uterus, vaginal septum and left ureteral agenesis were found. Microscopically, vaginal CCA coexisted with adenosis and both metanephric and mesonephric remnants. The vaginal CCA was supposed to derive from coexisting adenosis. The adenosis was also supposed to occur as a congenital basis, together with genitourinary tract anomalies. Relations between congenital anomalies of the genitourinary tract and vaginal adenocarcinoma were suspected, resultantly.

Radical hysterectomy for FIGO stage IIB cervical cancer: clinicopathological characteristics and prognostic evaluation.

OBJECTIVE: To clarify the clinicopathological features and prognostic factors of patients with FIGO stage IIB cervical cancer who were treated with radical hysterectomy. METHODS: One hundred thirty-nine FIGO stage IIB patients with squamous or adenosquamous cell carcinoma (median age, 51 years) who were treated with primary radical hysterectomy were examined retrospectively. Sixty-six FIGO stage IIB patients who were treated with primary radiotherapy (median age, 70 years) were included for comparison of survival. RESULTS: Fifty percent (70/139) of the patients had pathological parametrial involvement. Among them, the positive rate of pelvic lymph nodes was 71% (50/70). Ninety-nine percent (138/139) of the tumors were completely removed, and the pelvic control rate was 88%. Major complications requiring surgery were found in 2.9% (4/139). Significant differences in survival were found among patients in subgroups according to pathological parametrial involvement, pelvic lymph node status, tumor size, lymph-vascular space invasion, and depth of myometrial invasion (log-rank test, P<0.05). Of these, the Cox proportional-hazard model revealed that parametrial involvement (P=0.001, 95% CI 1.992-6.297) and lymph node metastasis (P=0.042, 95% CI 1.023-3.298) were independent prognostic factors. The 5-year survival rate and relapse-free survival at 36 months were 69% and 72% among the radical hysterectomy group, and 69% and 75% among the radiotherapy group. The Cox model adjusted for age showed no significant differences in survival and relapse-free survival between these two groups. CONCLUSION: Pathological parametrial involvement and positive nodes were prognostic factors for surgically treated patients with FIGO stage IIB cervical cancer.

Role of carbon-11 choline PET/CT in the management of uterine carcinoma: initial experience.

PURPOSE: The present study was conducted to clarify the role of carbon-11 choline ((11)C-choline) positron emission tomography (PET)/computed tomography (CT) in the management of uterine carcinoma. MATERIALS AND METHODS: Twenty-two patients who underwent (11)C-choline PET/CT and pelvic MRI were evaluated retrospectively. The images were reviewed by a board-certified radiologist and a nuclear medicine specialist who were unaware of any clinical information, and a consensus was reached. Diagnostic accuracy of PET/CT was evaluated for staging. The reference standard consisted of histological examination (n = 17) and follow-up conventional CT (n = 5). In five patients with cervical carcinoma, (11)C-choline PET/CT was performed before and after treatment that consisted of cisplatin infusion and subsequent radiotherapy. Standardized uptake value (SUV) was compared with uni-dimensional and volumetric measurements that were made on magnetic resonance images (MRI) before and after treatment. RESULTS: Based on PET/CT interpretations, the reviewers correctly classified T stage in 8 patients (47%), N stage in 21 patients (96%), M stage in 20 patients (91%), and TNM stage in 15 patients (88%). Tumor size, volume, and SUV decreased after treatment in five patients with cervical carcinoma. Using the Pearson correlation test, a significant correlation was found between the reduction rate of SUV and reduction rate of tumor volume. CONCLUSIONS: (11)C-choline PET/CT is an accurate means for the management of patients with uterine carcinoma. The combination of (11)C-choline PET/CT and MRI increases the accuracy of staging in patients with uterine carcinoma.

Increased expression of DNA methyltransferase 1 (DNMT1) protein in uterine cervix squamous cell carcinoma and its precursor lesion.

Aberrant DNA methylation has been shown to play important roles during multistage carcinogenesis in various human organs. The aim of this study was to evaluate the significance of DNA methyltransferase 1 (DNMT1) protein expression during cervical carcinogenesis. We carried out an immunohistochemical examination for DNMT1 in 34 samples of histologically normal squamous epithelium, 36 samples of low-grade cervical intraepithelial neoplasia (CIN), 61 samples of higher-grade CIN and 30 samples of squamous cell carcinoma of the uterine cervix. The DNMT1 protein expression score, reflecting the intensity and incidence of DNMT1 nuclear immunoreactivity, was increased even in low-grade CIN (P<0.0001) in comparison with histologically normal squamous epithelium and was further increased in higher-grade CIN (P<0.0001 compared to low-grade CIN). The DNMT1 protein expression score remained at a plateau in microinvasive carcinoma (Stage IA, P=0.0690 compared to higher-grade CIN) and then decreased with cancer invasion (Stage IB or more, P=0.0176 compared to Stage IA), whereas the proliferating cell nuclear antigen (PCNA) labeling index did not decrease with cancer invasion (P=0.8259 between Stage IA and Stage IB or more). Thus, the DNMT1 protein expression score and the PCNA labeling index were not mutually correlated in squamous cell carcinoma of the uterine cervix (P=0.2304). These data suggest that progressively increasing expression of DNMT1 protein is not entirely a secondary result of increased cell proliferative activity, but is associated with an early step of multistage cervical carcinogenesis.

Apocrine Adenocarcinoma of the Vulva: A Case Report and Review of the Literature.

Primary vulvar adenocarcinomas are very rare. We describe the rare case of primary vulvar apocrine adenocarcinoma, a histologically rare subtype of vulvar adenocarcinoma. A 57-year-old Japanese woman presented with an enlarging vulvar mass. A dark-red, hemorrhagic, ulcerated tumor was on the right side of the anterior labial commissure measuring approximately 3.5 × 3.5 cm. Preoperative biopsy showed poorly differentiated carcinoma with partial differentiation to adenocarcinoma. Systemic examination revealed lymph node metastases in both inguinal regions and no other primary source. We performed radical vulvectomy and bilateral inguinal and pelvic lymphadenectomy. Histopathologic diagnosis was apocrine adenocarcinoma of the vulva with inguinal lymph node metastases, pT1bN2bM0. Surgical margins were negative. The patient received no adjuvant chemotherapy or radiation. Inguinal lymph node recurrence occurred after six months. Reresection and adjuvant tomotherapy were performed. After a further 12 months of observation, no rerecurrence was observed. The patient is now on follow-up.

Two chalcones, 4-hydroxyderricin and xanthoangelol, stimulate GLUT4-dependent glucose uptake through the LKB1/AMP-activated protein kinase signaling pathway in 3T3-L1 adipocytes.

4-Hydroxyderricin (4HD) and xanthoangelol (XAG) are major components of n-hexane/ethyl acetate (5:1) extract of the yellow-colored stem juice of Angelica keiskei. 4-Hydroxyderricin and XAG have been reported to increase glucose transporter 4 (GLUT4)-dependent glucose uptake in 3T3-L1 adipocytes, but the detailed mechanism of this phenomenon remains unknown. This present study was aimed at clarifying the detailed mechanism by which 4HD and XAG increase GLUT4-dependent glucose uptake in 3T3-L1 adipocytes. Both 4HD and XAG increased glucose uptake and GLUT4 translocation to the plasma membrane. 4-Hydroxyderricin and XAG also stimulated the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase. In addition, phosphorylation of liver kinase B1 (LKB1), which acts upstream of AMPK, was also increased by 4HD and XAG treatment. Small interfering RNA knockdown of LKB1 attenuated 4HD- and XAG-stimulated AMPK phosphorylation and suppressed glucose uptake. These findings demonstrate that 4HD and XAG can increase GLUT4-dependent glucose uptake through the LKB1/AMPK signaling pathway in 3T3-L1 adipocytes.

Late, isolated metastasis from poorly differentiated gastric cancer to the uterine cervix.

•Metastases from extrapelvic organs to the uterine cervix are rare.•Cervical metastases from the stomach are often accompanied by extrauterine metastases.•We report a case of cervical metastasis of gastric cancer, occurring 10 years after the first surgical treatment.