PURPOSE: Lapatinib is a candidate drug for treatment of trastuzumab-resistant, human epidermal growth factor receptor 2 (HER2)–positive gastric cancer (GC). Unfortunately, lapatinib resistance renders this drug ineffective. The present study investigated the implication of forkhead box O1 (FOXO1) signaling in the acquired lapatinib resistance in HER2-positive GC cells. MATERIALS AND METHODS: Lapatinib-resistant GC cell lines (SNU-216 LR2-8) were generated in vitro by chronic exposure of lapatinib-sensitive, HER2-positive SNU-216 cells to lapatinib. SNU-216 LR cells with FOXO1 overexpression were generated by stable transfection of a constitutively active FOXO1 mutant (FOXO1A3). HER2 and MET in SNU-216 LR cells were downregulated using RNA interference. The sensitivity of GC cells to lapatinib and/or cisplatin was determined by crystal violet assay. In addition, Western blot analysis, luciferase reporter assay and reverse transcription–polymerase chain reaction were performed. RESULTS: SNU-216 LR cells showed upregulations of HER2 and MET, but downregulation of FOXO1 compared to parental SNU-216 cells. FOXO1 overexpression in SNU-216 LR cells significantly suppressed resistance to lapatinib and/or cisplatin. In addition, FOXO1 negatively controlled HER2 and MET at the transcriptional level and was negatively controlled by these molecules at the post-transcriptional level. A positive crosstalk was shown between HER2 and MET, each of which increased resistance to lapatinib and/or cisplatin. CONCLUSION: FOXO1 serves as an important linker between HER2 and MET signaling pathways through negative crosstalks and is a key regulator of the acquired lapatinib resistance in HER2-positive GC cells. These findings provide a rationale for establishing a novel treatment strategy to overcome lapatinib resistance in a subtype of GC patients.
Blotting, Western ; Cell Line ; Cisplatin ; Down-Regulation ; Drug Resistance ; Gentian Violet ; Humans ; In Vitro Techniques ; Luciferases ; Parents ; Receptor, Epidermal Growth Factor ; Receptor, ErbB-2 ; RNA Interference ; Stomach Neoplasms ; Transfection ; Up-Regulation

PURPOSE: We previously reported that forkhead transcription factors of the O class 1 (FOXO1) expression in gastric cancer (GC) was associated with angiogenesis-related molecules. However, there is little experimental evidence for the direct role of FOXO1 in GC. In the present study, we investigated the effect of FOXO1 on the tumorigenesis and angiogenesis in GC and its relationship with SIRT1. MATERIALS AND METHODS: Stable GC cell lines (SNU-638 and SNU-601) infected with a lentivirus containing FOXO1 shRNA were established for animal studies as well as cell culture experiments. We used xenograft tumors in nude mice to evaluate the effect of FOXO1 silencing on tumor growth and angiogenesis. In addition, we examined the association between FOXO1 and SIRT1 by immunohistochemical tissue array analysis of 471 human GC specimens and Western blot analysis of xenografted tumor tissues. RESULTS: In cell culture, FOXO1 silencing enhanced hypoxia inducible factor-1alpha (HIF-1alpha) expression and GC cell growth under hypoxic conditions, but not under normoxic conditions. The xenograft study showed that FOXO1 downregulation enhanced tumor growth, microvessel areas, HIF-1alpha activation and vascular endothelial growth factor (VEGF) expression. In addition, inactivated FOXO1 expression was associated with SIRT1 expression in human GC tissues and xenograft tumor tissues. CONCLUSION: Our results indicate that FOXO1 inhibits GC growth and angiogenesis under hypoxic conditions via inactivation of the HIF-1alpha-VEGF pathway, possibly in association with SIRT1. Thus, development of treatment modalities aiming at this pathway might be useful for treating GC.
Angiogenesis Modulating Agents ; Animals ; Anoxia ; Blotting, Western ; Carcinogenesis ; Cell Culture Techniques ; Cell Line ; Down-Regulation ; Forkhead Transcription Factors ; Heterografts ; Humans ; Lentivirus ; Mice ; Mice, Nude ; Microvessels ; RNA, Small Interfering ; Stomach Neoplasms* ; Tissue Array Analysis ; Transcription Factors* ; Vascular Endothelial Growth Factor A

Breast cancer is the second most common malignancy among Korean women. The 2002 National Cancer Center screening guideline breast cancer was revised via an evidence-based approach to provide medical personnel with a standard protocol of screening breast cancer. There is moderate-level evidence that biennial screening mammography in asymptomatic women aged 40 to 69 reduces breast cancer mortality, while low-level evidence suggests that screening mammography in women 70 years or older does not reduce breast cancer mortality. The committee concluded that the current evidence is insufficient to assess the benefits and harms of either ultrasonography or clinical breast examination as screening modalities for breast cancer. Future researches about the benefits and harms of the National Breast Cancer Screening Program in Korea are strongly required because the characteristics of breast cancer in Korea are different from those in the West, especially regarding dense breast. In conclusion, the committee recommends biennial screening mammography in asymptomatic women aged 40 to 69 years (grade B recommendation). The committee recommends selective screening mammography in women 70 years or older according to individual risk and preference (grade C recommendation). The committee neither recommends nor opposes ultrasonography and clinical breast examination as screening modalities (grade I recommendation). Symptomatic and high-risk women, however, should be offered complementary measures including ultrasonography and clinical breast examination under clinical supervision.
Breast ; Breast Neoplasms* ; Female ; Humans ; Korea ; Mammography ; Mass Screening* ; Mortality ; Organization and Administration ; Ultrasonography

BACKGROUND: The Maasai are the most widely known African ethnic group located in Kenya and northern Tanzania. Most spend their days either barefoot or in their traditional shoes made of car tires. Although they walk long distances of up to sixty kilometers a day, they do not suffer from any foot ailments. Little is known about their foot structure and gait. The goal of this investigation was to characterize various aspects of Maasai foot in standing and walking. METHODS: Foot length, calf circumference, hindfoot alignment, step length, cadence, and walking velocity were obtained from 1,096 adult Maasai people (545 males and 551 females; mean age, 40.28 +/- 14.69 years; age range, 16 to 65 years). All included subjects were from rural areas, where the primary terrain was sandy soil, who spend most of their lifetime barefoot, walking. They all denied any medical history or previous symptoms related to foot problems. A trained clinician scanned all feet for deformities. Static (standing) and dynamic (walking) Harris mat footprints were taken to determine the distribution of forefoot pressure patterns during walking. RESULTS: The average foot length was 250.14 +/- 18.12 mm (range, 210 to 295 mm) and calf circumference was 32.50 +/- 3.22 cm (range, 25 to 41 cm). The mean hindfoot alignment was 6.21degrees +/- 1.55degrees of valgus. Sixty-four subjects (5.84%) had bilateral flat-shaped feet with a low medial longitudinal arch that exactly matched the broad pattern of their static footprints. Step length, cadence, and walking velocity were 426.45 +/- 88.73 cm (range, 200 to 690 cm), 94.35 steps/min (range, 72 to 111 steps/min), and 40.16 +/- 8.36 m/min (range, 18.20 to 63.36 m/min), respectively. A total of 83.39% subjects showed unilateral or bilateral deformities of multiple toes regardless of age. The most frequent deformity was clawing (98.79%) of which the highest incidence occurred with the fifth toe (93.23%). Dynamic footprints showed even pressure patterns throughout the forefoot (64.87%), followed by lateral forefoot pressure concentration patterns (21.81%). CONCLUSIONS: Our study shows the distinct parameters that provide more insight into the Maasai foot.
Adolescent ; Adult ; Aged ; Biomechanical Phenomena ; Ethnic Groups ; Female ; Foot/*anatomy & histology/*physiology ; Foot Deformities, Acquired/*epidemiology/ethnology ; Gait/*physiology ; Humans ; Kenya ; Male ; Middle Aged ; Rural Population ; Tanzania ; Walking/*physiology ; Young Adult

BACKGROUND: Valvular heart surgery (VHS) utilizing cardiopulmonary bypass (CPB) is inevitably associated with ischemic-reperfusion injury, which is known to depend on oxygen tension during reperfusion. The aim of this study was to evaluate the effect of arterial oxygen tension during reperfusion on myocardial recovery in patients undergoing VHS. METHODS: Fifty-six patients undergoing isolated VHS were randomly exposed to an oxygen fraction of 0.7 (hyperoxic group, n = 28) or 0.5 (normoxic group, n = 28) during reperfusion. All patients received an oxygen fraction of 0.7 during CPB. In the normoxic group, the oxygen fraction was lowered to 0.5 from the last warm cardioplegia administration to 1 minute after aortic unclamping, and was then raised back to 0.7. Hemodynamic data were measured after induction of anesthesia, weaning from CPB, and sternum closure. The frequency of cardiotonic medications used during and after weaning from CPB, and the short-term outcomes during the hospital stay were also assessed. RESULTS: The frequency of vasopressin and milrinone use during weaning from CPB, but not norepinephrine, was significantly less in the normoxic group. The post-operative cardiac enzyme levels and short-term outcomes were not different between the groups. CONCLUSIONS: Normoxic reperfusion from the last cardioplegia administration to 1 minute after aortic unclamping in patients undergoing VHS resulted in significantly less frequent use of vasopressin and inotropics during weaning from CPB than hyperoxic reperfusion, although it did not affect the post-operative myocardial enzyme release or short-term prognosis.
Anesthesia ; Cardiopulmonary Bypass ; Heart ; Heart Arrest, Induced ; Hemodynamics ; Humans ; Length of Stay ; Milrinone ; Norepinephrine ; Oxygen ; Prognosis ; Reperfusion ; Reperfusion Injury ; Sternum ; Thoracic Surgery ; Vasopressins ; Weaning

Aged ; Aged, 80 and over ; Esophagus ; pathology ; virology ; Herpes Simplex ; diagnosis ; genetics ; pathology ; Humans ; In Situ Hybridization ; Male ; Middle Aged ; Simplexvirus ; genetics

OBJECTIVE: The purpose of this study is to survey the clinical practice pattern of postterm pregnancy in Korea. METHODS: A questionnaire was mailed to 1114 physicians who are registered in Korean Society of Obstetrics and Gynecology (KSOG) and work in primary and secondary hospital as well as tertiary care center. The questions included information about the practice pattern implicating definition of postterm pregnancy, the time and the method of routine fetal surveillance and induction of labor as well as demographic information such as age, sex, location, professional part and the number of delivery. We got 23.2% (258/1114) of surveys returned and analyzed the data. RESULTS: Seventy-four percent (73.6%) of the respondents define 42 weeks gestation or greater to be postterm. However, 84.5% consider induction of labor at 41 weeks of gestation. Sixty-eight percent (68.3%) of the respondents start postterm pregnancy fetal testing at 40 weeks and 59.3% of them perform testing every week. For fetal surveillance testing, 85.7% of the respondents use NST and 39.5% of them use modified BPP. As for induction of labor, 65% of practitioners use oxytocin and 45% of them use prostaglandins (misoprostol and dinoprostone) when inducing both nulliparous and multiparous women with unfavorable cervix. CONCLUSION: Most of the respondents (84.5%) routinely induce low-risk singleton pregnancy at 41 weeks gestation, whereas the majority of them (73.6%) define postterm pregnancy beyond 42 weeks gestation.
Cervix Uteri ; Surveys and Questionnaires ; Female ; Gynecology ; Humans ; Korea* ; Obstetrics ; Oxytocin ; Physician's Practice Patterns* ; Postal Service ; Pregnancy* ; Prostaglandins ; Surveys and Questionnaire ; Tertiary Care Centers

OBJECTIVE:The purpose of this study was to investigate the role of sonographic findings and tumor markers in predicting malignancy of adnexal masses in pregnancy. METHODS:From January 1995 to September 2005, 190 cases of adnexal masses were operated during pregnancy. We reviewed their sonographic findings and medical records retrospectively. Sonographic features and tumor markers were correlated with malignant pathology. Pregnancy and neonatal outcomes were also studied after treatment of adnexal mass during pregnancy. RESULTS:From 190 cases, there were 10 cases (5.3%) of malignant tumor or tumors of borderline malignancy. In the 180 cases of benign adnexal mass, the most common type was mature cystic teratoma (36.7%). Preoperative sonographic findings were available in 110 cases. The median size was 6.3 cm for benign masses and 7.7 cm for malignant masses (p=0.05). Mixed echogenecity, septa and mural nodule were more frequently found in malignant masses (p=0.003, 0.029, 0.013, respectively). Tumor markers were available in 47 cases. In the 1st trimester, the level of serum CA-125 of the patients with benign masses were not different from those with malignant masses. However, in the 2nd and 3rd trimester, the difference was statistically significant (p=0.031). Forty- six patients underwent antepartum surgery and the overall pregnancy outcome was similar between the laparoscopic group and the laparotomy group. CONCLUSION:Mixed echogenecity, septa and mural nodule showed significant correlation with malignant adnexal mass in pregnancy.
Female ; Humans ; Laparotomy ; Medical Records ; Pathology* ; Pregnancy Outcome ; Pregnancy* ; Retrospective Studies ; Teratoma ; Biomarkers, Tumor ; Ultrasonography*

OBJECTIVE: To compare the clinical outcomes of first trimester discordant twins with second or third trimester discordant twins and concordant twins. METHODS: Pregnancy outcomes of twin pregnancies delivered from October 1994 to February 2006 were analyzed retrospectively. Subjects were categorized into following three groups: 1) group 1, first trimester discordant twins defined as intertwin CRL difference > or =5 days at 10-14 weeks of gestation (n=32), 2) group 2, second or third trimester discordant twins defined as intertwin AC difference >20 mm at 20-28 weeks of gestation or intertwin fetal weight difference >25% beyond 29 weeks of gestation (n=42), 3) group 3, concordant twins with no discordancy throughout the whole gestation (n=723). Perinatal complications analyzed for were congenital anomaly, fetal growth restriction (FGR), fetal death in utero (FDIU). RESULTS: The three groups were similar with respect to maternal characteristics and chorionicity. Overall, the group 2 had higher perinatal complications compared to the group 3. Congenital anomaly was more common in the group 1 than the group 2 (21.9% vs. 11.9%, p<0.001). However, FGR rate was higher in the group 2 than the group 1 (32.3% vs. 71.8%, p<0.01). Congenital anomaly, FGR and FDIU were more common in the group 1 compared to the group 3 (21.9% vs. 3.5%, p<0.001, 32.3% vs. 9.1%, p<0.01, 6.3% vs. 1.0%, p<0.05, respectively). CONCLUSIONS: First trimester discordant twins have an increased risk of congenital anomaly, FGR and FDIU, and therefore, they should be regarded as a high-risk pregnancy likewise second or third trimester discordant twins.
Chorion ; Female ; Fetal Death ; Fetal Development ; Fetal Weight ; Humans ; Perinatal Mortality ; Pregnancy ; Pregnancy Outcome ; Pregnancy Trimester, First* ; Pregnancy Trimester, Third ; Pregnancy, High-Risk ; Pregnancy, Twin ; Retrospective Studies

OBJECTIVE: To investigate the effect of multiple courses of antenatal corticosteroid (ACS) therapy on perinatal outcomes, especially the respiratory distress syndrome (RDS), of the premature neonates. METHODS: We retrospectively evaluated the pregnancy and neonatal outcomes of 622 singleton pregnancies delivered at 24-34 weeks of gestation from January 1996 to December 2005. Subjects were categorized into three groups according to ACS exposure: (1) a non-user group (n=234), (2) a single-course group (n=299) and (3) a repeated-course group (n=89). Univariate and multiple logistic regression analyses were used for the incidences of RDS. RESULTS: Pregnancy outcomes including gestational age at delivery, occurrence of clinical and histological chorioamnionitis, birth weight, neonatal intensive care unit (NICU) admission rate, duration of NICU stay and neonatal mortality were similar in the three groups. The incidence of RDS was significantly lower in ACS user groups than the non-user group, with lowest incidence in multiple-course group (44.9% vs. 37.8% vs. 12.4%, p<0.001). The incidence of bronchopulmonary dysplasia and overall neonatal composite morbidity were also lowest in multiple-course group. Multivariate analysis showed that multiple courses of ACS were associated with reduced incidence of RDS (OR 0.100, 95% CI 0.042, 0.240, p<0.001) independently with gestational age at delivery, admission-to-delivery interval and premature rupture of membranes. CONCLUSION: Multiple courses of ACS administered to women with risk of preterm delivery were found to be associated with decreased incidence of RDS of the premature neonates.
Birth Weight ; Bronchopulmonary Dysplasia ; Chorioamnionitis ; Female ; Gestational Age ; Humans ; Incidence ; Infant ; Infant Mortality ; Infant, Newborn* ; Intensive Care, Neonatal ; Logistic Models ; Membranes ; Multivariate Analysis ; Pregnancy ; Pregnancy Outcome ; Retrospective Studies ; Rupture