Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins,increased invasion,and metastasis of human breast and ovarian cancer cells

To determine how AKT2 might contribute to tumor cell progression, a full-length, wild-type, human AKT2/protein kinase B (PKB)beta cDNA was transfected into a panel of eight human breast and ovarian cancer cells. AKT2 transfectants demonstrated increased adhesion and invasion through collagen IV because of up-regulation of beta1 integrins. In addition, AKT2 cells were more metastatic than control cells in vivo. Increased invasion by AKT2 was blocked by preincubation with an anti-beta1 integrin function blocking antibody, exposure to wortmannin, and by expression of phosphatase and tensin homologue tumor suppressor (PTEN). Confocal microscopy performed on transfected human breast cancer cells showed that unlike AKT1, AKT2 protein predominantly localized adjacent to the collagen IV matrix during cellular attachment. Overexpression of AKT2, but not AKT1 or AKT3, was sufficient to duplicate the invasive effects of phosphoinositide 3-OH kinase (PI3-K) transfected in breast cancer cells. Furthermore, expression of kinase dead AKT2(181 amino acid methionine [M]), and not kinase dead AKT1(179M) or AKT3(177M), was capable of blocking invasion induced by either human epidermal growth factor receptor-2 (HER-2) overexpression or by activation of PI3-K. Taken together, these data indicate that AKT2 mediates PI3-K-dependent effects on adhesion, motility, invasion, and metastasis in vivo.     

Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer

BACKGROUND: HER-2/neu, which encodes a receptor tyrosine kinase, is amplified and overexpressed in 20%-25% of human breast cancers. Such tumors are often resistant to hormone therapy. Despite a general inverse association between HER-2/neu amplification/overexpression and estrogen receptor (ER) and/or progesterone receptor (PR) expression, a fraction of patients are both HER-2/neu- and hormone receptor (HR)-positive. The efficacy of hormone therapy in this group is currently a matter of debate. To better understand the relationship between HER-2/neu positivity and HR expression, we analyzed HER-2/neu, ER, and PR as continuous variables in breast cancer cell lines and two cohorts of primary breast cancer patients. METHODS: HER-2/neu and ER/PR expression was analyzed by enzyme-linked immunosorbent assay (ELISA) and enzyme immunoassay (EIA), respectively, in 14 human breast cancer cell lines, some of which had been transfected with the HER-2/neu gene. For the clinical study population, HER-2/neu protein levels were assessed by ELISA (cohort A, n = 665), and HER-2/neu gene copy number was determined using fluorescence in situ hybridization (cohort B, n = 894). ER/PR expression was analyzed by EIA (cohort A) or radioligand binding (cohort B). Associations between HER-2/neu and ER/PR expression were analyzed using Spearman's rho correlation and the chi-square test, and absolute levels were compared using the Mann-Whitney U test. All statistical tests were two-sided. RESULTS: HR-positive human breast cancer cell lines transfected with the HER-2/neu gene expressed statistically significantly lower levels of ER and PR than parental lines. In the clinical cohorts, levels of HER-2/neu overexpression and gene amplification were inversely correlated with ER/PR levels (Cohort A [n = 112]: for ER, r = -0.34, P<.001; for PR, r = -0.24, P =.010. Cohort B [n = 188]: for ER, r = -0.39, P<.001; for PR, r = -0.26, P<.001). Among patients with HR-positive tumors, HER-2/neu-positive tumors had statistically significantly lower ER/PR levels than HER-2/neu-negative ones (Cohort A: for ER, median = 25 fmol/mg [interquartile range [IQR] = 13-78] versus median = 38.5 fmol/mg [IQR = 17-99] and P =.031; for PR, median = 35 fmol/mg [IQR = 12-119] versus median = 88.5 fmol/mg [IQR = 22-236] and P<.001. Cohort B: for ER, median = 44 fmol/mg [IQR = 13-156] versus median = 92 fmol/mg [IQR = 35-235] and P<.001; for PR, median = 36 fmol/mg [IQR = 13-108] versus median = 84 fmol/mg [IQR = 24-250] and P<.001). Patients with higher levels of HER-2/neu overexpression or amplification had statistically significantly lower levels of ER/PR than patients with lower levels of HER-2/neu overexpression or amplification. CONCLUSION: Because absolute HR levels are strongly related to response to hormone therapy in primary and advanced breast cancer, reduced ER/PR expression may be one mechanism to explain the relative resistance of HER-2/neu-positive:HR-positive tumors to hormone therapy.     

Epigenetic change in e-cardherin and COX-2 to predict chronic periodontitis

Background  

DNA methylation of certain genes frequently occurs in neoplastic cells. Although the cause remains unknown, many genes have been identified with such atypical methylation in neoplastic cells. The hypermethylation of E-Cadherin and Cyclooxygenase 2 (COX-2) in chronic inflammation such as chronic periodontitis may demonstrate mild lesion/mutation epigenetic level. This study compares the hypermethylation status of E-Cadherin and COX-2 genes which are often found in breast cancer patients with that in chronic periodontitis.     

Identification of new gene products coded from X regions of human T-cell leukemia viruses.

Antibodies were raised against oligopeptides deduced from the nucleotide sequence in the conserved region located between env and the 3' long terminal repeat in human T-cell leukemia virus type I (HTLV-I) and type II (HTLV-II) to detect a protein coded from this region in virus-infected cells. Two of these antibodies precipitated a protein of 41 kilo-daltons in HTLV-I-infected cell lines and a protein of 38 kilo-daltons in HTLV-II-infected cells. The protein in HTLV-I-infected cells was precipitated by plasma from patients with adult T-cell leukemia but not by plasma from a normal adult. These results indicate that these proteins were translated from new coding regions (X) present in HTLV-I and HTLV-II.     

长期应用埃索美拉唑是维持已愈合糜烂性食管炎疗效及控制胃食管反流症状的有效方法

要确保糜烂性食管炎的治愈效果 ,长期抑制胃酸是一项必要措施。在不使用维持治疗时 ,已治愈的反流性或溃疡性食管炎 ,在 1年左右有近 80 %的病人会再出现食管黏膜的破损。 1年中奥美拉唑 2 0ｍｇ或兰索拉唑 30ｍｇ每天 1次治疗 ,可使复发率降至 30 %或更低。Ｈ2 受体阻滞剂 (Ｈ2 ＲＡ)维持治疗的效果不及ＰＰＩ。Ｈ2 ＲＡ 1年维持治疗的效果约为 50 %。奥美拉唑的Ｓ 异构体———埃索美拉唑是第一个发展为同分光学异构体的质子泵抑制剂 (ＰＰＩ)。埃索美拉唑 2 0或40ｍｇ剂量的血浆浓度时间曲线下面积 (ＡＵＣ值 )明显大于奥美拉唑 2 0ｍｇ …     

Review article: Interventions for people presenting to emergency departments with a mental health problem: A systematic scoping review

The number of people presenting to EDs with mental health problems is increasing. To enhance and promote the delivery of safe and efficient healthcare to this group, there is a need to identify evidence‐based, best‐practice models of care. This scoping review aims to identify and evaluate current research on interventions commenced or delivered in the ED for people presenting with a mental health problem. A systematic search of eight databases using search terms including emergency department, mental health, psyc* and interventions, with additional reference chaining, was undertaken. For included studies, level of evidence was assessed using the NHMRC research guidelines and existing knowledge was synthesised to map key concepts and identify current research gaps. A total of 277 papers met the inclusion criteria. These were grouped thematically into seven domains based on primary intervention type: pharmacological (n = 43), psychological/behavioural (n = 25), triage/assessment/screening (n = 28), educational/informational (n = 12), case management (n = 28), referral/follow up (n = 36) and mixed interventions (n = 105). There was large heterogeneity observed as to the level of evidence within each intervention group. The interventions varied widely from pharmacological to behavioural. Interventions were focused on either staff, patient or institutional process domains. Few interventions focused on multiple domains (n = 64) and/or included the patient's family (n = 1). The effectiveness of interventions varied. There is considerable, yet disconnected, evidence around ED interventions to support people with mental health problems. A lack of integrated, multifaceted, person‐centred interventions is an important barrier to providing effective care for this vulnerable population who present to the ED.     

Effects of SU101 in combination with cytotoxic agents on the growth of subcutaneous tumor xenografts.

SU101 (leflunomide, N-[4-(trifluoromethyl)-phenyl] 5-methylisoxazole-4-carboxamide), an inhibitor of platelet-derived growth factor receptor signaling, has shown promising clinical activity in Phase I and II studies. Currently, SU101 in combination with cytotoxic agents is in late-stage clinical development for the treatment of cancers. In previous reports, efficacy in vivo versus varied tumor xenografts was observed. As part of the preclinical development of SU101 as a cancer therapy, the combination of SU101 with cytotoxic agents was studied in athymic mice bearing small, established, s.c. human tumor cell xenografts of glioblastoma (SF763T cells), lung (Calu-6 cells), or head and neck (KB cells) origin. In the SF763T model, the combination of SU101 with carmustine resulted in a statistically significant growth inhibition of 74% compared with the vehicle control; this combination was more effective than either agent alone. In the Calu-6 model, the combination of SU101, cisplatin, and etoposide resulted in a growth inhibition of 75% that was statistically greater than that of the vehicle-treated control group and groups treated with one or two agents. In the KB model, the combination of SU101, 5-fluorouracil, and cisplatin resulted in a statistically significant growth inhibition of 69% compared with the vehicle control. Treatment with one or two agents did not significantly inhibit growth in this model. Importantly, in addition to enhanced efficacy resulting from combination therapies, the combination treatments tested were well tolerated, as evidenced by lack of mortality. These data suggest that SU101 in combination with cytotoxic agents may provide clinical benefit and warrant further clinical investigation.