RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction

Intracellular amyloid-β peptide (Aβ) has been implicated in neuronal death associated with Alzheimer''s disease. Although Aβ is predominantly secreted into the extracellular space, mechanisms of Aβ transport at the level of the neuronal cell membrane remain to be fully elucidated. We demonstrate that receptor for advanced glycation end products (RAGE) contributes to transport of Aβ from the cell surface to the intracellular space. Mouse cortical neurons exposed to extracellular human Aβ subsequently showed detectable peptide intracellularly in the cytosol and mitochondria by confocal microscope and immunogold electron microscopy. Pretreatment of cultured neurons from wild-type mice with neutralizing antibody to RAGE, and neurons from RAGE knockout mice displayed decreased uptake of Aβ and protection from Aβ-mediated mitochondrial dysfunction. Aβ activated p38 MAPK, but not SAPK/JNK, and then stimulated intracellular uptake of Aβ-RAGE complex. Similar intraneuronal co-localization of Aβ and RAGE was observed in the hippocampus of transgenic mice overexpressing mutant amyloid precursor protein. These findings indicate that RAGE contributes to mechanisms involved in the translocation of Aβ from the extracellular to the intracellular space, thereby enhancing Aβ cytotoxicity.     

Profiles of autoimmune hepatitis in Brunei Darussalam

BACKGROUND:Autoimmune hepatitis(AIH)is a chronic inflammatory disease of the liver.Data on the disease remain scarce in the Southeast Asia region.This study was undertaken to assess the profiles of AIH in Brunei Darussalam.METHODS:Nineteen patients with AIH treated at the hepatology clinic,RIPAS Hospital(up until December 2008)were reviewed.Demographic,laboratory,histologic,clinical,and therapeutic data of the patients were collected.RESULTS:The median age of the 19 patients at diagnosis was 52 ye...     

Spontaneous gallbladder perforation, pericholecystic abscess and cholecystoduodenal fistula as the first manifestations of gallstone disease

BACKGROUND:Gallstone disease is common,and complications that are frequently encountered include acute cholecystitis and acute pancreatitis,but rarely gallbladder perforation. METHOD:Data were retrospectively collected from clinical case notes and a literature review is presented. RESULTS:A 72-year-old lady presented with spontaneous gallbladder perforation,pericholecystic abscess and cholecystoduodenal fistula as the first manifestations of gallstone disease.She was previously well and had no abdominal com...     

A bone-seeking clone exhibits different biological properties from the ACHN parental human renal cell carcinoma in vivo and in vitro

Metastatic bone disease caused by renal cell carcinoma (RCC) occurs frequently. Very little is currently known about the mechanism of preferential metastasis of RCC to bone. We hypothesize that RCCs that develop bone metastases have the capacity to facilitate their colonization in bone. To examine this hypothesis, we established bone-seeking (ACHN-BO) clones of the human RCC cell line ACHN by repeated four passages in nude mice and in vitro of metastatic cells obtained from bone. These clones were examined for distinguishing biological characteristics and compared with the ACHN parental cells (ACHN-P) in vivo and in vitro. Our results showed that the ACHN-BO cell line could be successfully obtained by in vivo selection through the lateral tail vein. This approach results in the development of multiple osteolytic lesions in the distal femora and proximal tibiae within four weeks after inoculation, with a success rate of 85-100% and no additional comorbidity. ACHN-P cells developed metastases in lung, bone, brain, ovary and adrenal glands. Conversely, ACHN-BO cells exclusively metastasized to bones with larger osteolytic lesions. Compared with the ACHN-P cell line, the proliferation ability in ACHN-BO6 was increased by 9.68 and 6.42%, respectively (P<0.05), while the apoptotic ratio decreased significantly (P<0.05) and cells were blocked in the S phase with suppressed migration and invasion capacities. The ACHN-BO? cell line produced greater amounts of the pro-angiogenic factors VEGF and TGF-β than ACHN-P. Our data suggest that these phenotypic changes allow RCC cells to promote osteoclastic bone resorption, survive and proliferate in bone, which consequently leads to the establishment of bone metastases. This model provides a reliable reproduction of the clinical situation and, therefore, is suitable for designing and evaluating more effective treatments for RCC bone metastasis.     

The impact of kidney function on the outcome of metastatic renal cell carcinoma patients treated with vascular endothelial growth factor-targeted therapy

BACKGROUND:

A study was undertaken to investigate the effect of baseline renal function on treatment outcome in patients treated with vascular endothelial growth factor (VEGF)‐targeted therapy for metastatic renal cell carcinoma (mRCC).

METHODS:

Retrospective data from 6 North American cancer centers (3 US and 3 Canadian) were pooled to identify patients with mRCC treated with VEGF‐targeted therapy. Patient characteristics, response rate, time to treatment failure, and overall survival were collected. The Modification of Diet in Renal Disease formula was used at therapy initiation for calculation of glomerular filtration rate (GFR).

RESULTS:

Five hundred twenty‐nine patients with mRCC who received sunitinib (n = 323), sorafenib (n = 165), or bevacizumab (n = 41) were included in this analysis. Patient characteristics included: 74% male, median age 61 years, and median GFR 60.1 mL/min/1.73 m² (range, 6.5‐174.2). On univariate analysis, patients with a GFR <60 (n = 262) were more likely to have had a previous nephrectomy (P < .0001) and to be older (P < .0001), but were less likely to have poor prognostic features such as anemia (P = .041), hypercalcemia (P = .008), neutrophilia (P = .039), thrombocytosis (P < .0001), short diagnosis to treatment interval (P = .007), and low Karnofsky performance status (P = .051). GFR <60, when adjusted for poor risk factors, did not have an impact on type of objective response (odds ratio, 1.31; 95% confidence interval [CI], 0.74‐2.32; P = .359), time to treatment failure (hazard ratio [HR], 0.97; 95% CI, 0.79‐1.19; P = .772), or overall survival (HR, 0.90; 95% CI, 0.69‐1.17; P = .439).

CONCLUSIONS:

Renal function at therapy initiation does not adversely affect the efficacy of VEGF‐targeted therapy in mRCC. Clinicians should not avoid treating patients with impaired baseline renal function. Cancer 2011;. © 2011 American Cancer Society.     

DEDD interacts with PI3KC3 to activate autophagy and attenuate epithelial-mesenchymal transition in human breast cancer

Epithelial-to-mesenchymal transition (EMT), a crucial developmental program, contributes to cancer invasion and metastasis. In this study, we show that death-effector domain-containing DNA-binding protein (DEDD) attenuates EMT and acts as an endogenous suppressor of tumor growth and metastasis. We found that expression levels of DEDD were conversely correlated with poor prognosis in patients with breast and colon cancer. Both in vitro and in vivo, overexpression of DEDD attenuated the invasive phenotype of highly metastatic cells, whereas silencing of DEDD promoted the invasion of nonmetastatic cells. Via direct interaction with the class III PI-3-kinase (PI3KC3)/Beclin1, DEDD activated autophagy and induced the degradation of Snail and Twist, two master regulators of EMT. The DEDD-PI3KC3 interaction led to stabilization of PI3KC3, which further contributed to autophagy and the degradation of Snail and Twist. Together, our findings highlight a novel mechanism in which the intracellular signaling protein DEDD functions as an endogenous tumor suppressor. DEDD expression therefore may represent a prognostic marker and potential therapeutic target for the prevention and treatment of cancer metastasis.     

Identification of ten serum microRNAs from a genome-wide serum microRNA expression profile as novel noninvasive biomarkers for nonsmall cell lung cancer diagnosis

The detection of nonsmall cell lung cancer (NSCLC) at an early stage presents a daunting challenge due to the lack of a specific noninvasive marker. The discovery of microRNAs (miRNAs), particularly those found in serum, has opened a new avenue for tumor diagnosis. To determine whether the expression profile of serum miRNAs can serve as a NSCLC fingerprint, we performed Taqman probe-based quantitative RT-PCR assay to selected differentially expressed serum miRNAs from a sample set including 400 NSCLC cases and 220 controls, and risk score analysis to evaluate the diagnostic value of the serum miRNA profiling system. After a two-phase selection and validation process, 10 miRNAs were found to have significantly different expression levels in NSCLC serum samples compared with the control serum samples. Risk score analysis showed that this panel of miRNAs was able to distinguish NSCLC cases from controls with high sensitivity and specificity. Under ROC curves, the AUC for tumor identification in training set and validation set were 0.966 and 0.972, respectively. Furthermore, the expression profile of the 10-serum miRNAs was correlated with the stage of NSCLC patients, especially in younger patients and patients with current smoking habits. More importantly, the serum miRNA-based biomarker for early NSCLC detection was supported by a retrospective analysis in which the 10-serum miRNA profile could accurately classify serum samples collected up to 33 months ahead of the clinical NSCLC diagnosis. Taken together, we demonstrate that the profiling of 10-serum miRNAs provides a novel noninvasive biomarker for NSCLC diagnosis.     

某三甲医院血脂异常患者应用调节血脂药物的调查

目的评价血脂异常住院患者应用调节血脂药的情况。方法选择某地区有代表性的三级甲等医院心内科及内分泌科住院病例,均主要应用他汀类药物调节血脂异常。利用Framingham10年CAD危险性预测评分法、患者血脂异常危险分层和患者调血脂用药分析,对住院患者的调血脂用药进行综合评价。结果调查的患者中,未达治疗指标的患者情况:低危100%、中危100%、高危18.1%、极高危28.6%。结论该医院心内科医护人员应用药物基本合理,但是也存在一些不足,尤其细节管理有待加强。