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The high frequency of chemotherapy resistance is ultimately responsible for clinical relapse in acute lymphoblastic leukemia (ALL). Nevertheless, the molecular mechanism relevant to glucocorticoid (GC) resistance remains ambiguous. Quantitative real-time polymerase chain reaction and Western blot were performed to detect the expressions of paraoxonase 2 (PON2), Bcl-2 and Bax. shRNA was used to knockdown PON2 expression in SUP-B15 and REH cell. CCK-8 and flow cytometry assay were conducted to monitor the changes of proliferation and apoptosis in ALL cells. The growth of ALL REH cells in vivo was determined using transplanted tumor model. This study was designed to identify GC resistance-associated genes by means of the transcriptome chip from the public Gene Expression Omnibus database, and preliminarily investigation of dexamethasone (DEX)-resistance mechanism in ALL. We disclosed that PON2 expression was elevated in ALL patients and especially higher in DEX-resistance ALL patients. Then, cell apoptosis assay suggested that silencing of PON2 dramatically promoted in DEX-resistant ALL cells apoptosis and the activity of Caspase 3 induced by DEX administration. In xenograft tumor model, PON2 knockdown significantly reduced DEX-resistant ALL cells growth in immunodeficient mice. Collectively, inhibition of PON2 may represent a novel method to restore the sensitivity of treatment-resistant ALL to GC-induced cell death. [ABSTRACT FROM AUTHOR]

Am J Physiol Renal Physiol 298: F24-F34, 2010. First published September 16, 2009; doi: 10.1152/ajprenal.00450.2009.--Claudin-7, a member of the claudin family, is highly expressed in distal nephrons of kidneys and has been reported to be involved in the regulation of paracellular [Cl.sup.-] permeability in cell cultures. To investigate the role of claudin-7 in vivo, we generated claudin-7 knockout mice ([Cln7.sup.-/-] ) by the gene-targeting deletion method. Here we report that [Cln7.sup.-/-] mice were born viable, but died within 12 days after birth. [Cln7.sup.-/-] mice showed severe salt wasting, chronic dehydration, and growth retardation. We found that urine [Na.sup.+], [Cl.sup.-], and [K.sup.+] were significantly increased in [Cln7.sup.-/-] mice compared with that of [Cln7.sup.+/+] mice. Blood urea nitrogen and hematocrit were also significantly higher in [Cln7.sup.-/-] mice. The wrinkled skin was evident when [Cln7.sup.-/-] mice were ~ 1 wk old, indicating that they suffered from chronic fluid loss. Transepidermal water loss measurements showed no difference between [Cln7.sup.+/+] and [Cln7.sup.-/-] skin, suggesting that there was no transepidermal water barrier defect in [Cln7.sup.-/-] mice. Claudin-7 deletion resulted in the dramatic increase of aldosterone synthase mRNA level as early as 2 days after birth. The significant increases of epithelial [Na.sup.+] channel [alpha], [Na.sup.+]-[C1.sup.-] cotransporter, and aquaporin 2 mRNA levels revealed a compensatory response to the loss of electrolytes and fluid in [Cln7.sup.-/-] mice. [Na.sup.+]-[K.sup.+]-ATPase [[alpha].sub.1] expression level was also greatly increased in distal convoluted tubules and collecting ducts where claudin-7 is normally expressed. Our study demonstrates that claudin-7 is essential for NaCl homeostasis in distal nephrons, and the paracellular ion transport pathway plays indispensable roles in keeping ionic balance in kidneys. claudin-7; tight junction; kidney; knockout mice; salt wasting

Formation of the blastocoel in early Xenopus embryos was studied with a novel biotin-permeability assay and newly generated tight junction markers. The blastocoel forms at the first cleavage division since functional tight junctions which excluded biotin and established a segregated intraembryonic compartment were found at the 2-cell and all subsequent developmental stages. Unexpectedly, tight junctions before the 64-cell stage were not at their normal apical positions, but were found deep in the embryos, up to 200 [[micro]meter] from the apical surface. In these positions, the tight junctions left large areas of ion permeable lateral membranes exposed to the extraembryonic environment, explaining why electrophysiological experiments record a decrease in embryonic input resistances concomitant with early cleavage stages. Immunohistochemistry revealed that the recessed tight junctions did not influence the distribution of C-cadherin and [Na.sup.+], [K.sup.+]ATPase. Both markers were present apical to recessed tight junctions, indicating that the maintenance of polarization of these basolateral markers does not require tight junctions. With further development, tight junctions assumed an increasingly apical location until, by the 2000-cell stage, they occupied their conventional positions between the blastomeres at the apical/lateral membrane boundaries.

Dependence of junctional conductance on voltage in some embryonic chick heart cells is asymmetrical due to the heterochannels formed by the proteins, connexins (Cxs), present at the junctional surfaces of the cells. Embryonic heart cells express three Cxs mRNA, which are immunolocalized at the junctional surface between cell pairs. The interactions between the Cxs form both homotypic ion channels with symmetric voltage dependence and heterotypic ion channels with asymmetric voltage dependence. The number of heterochannels in the junctions reduce with cardiac development.

Background: The Maastricht V/Florence Consensus Report recommends amoxicillin‐fluoroquinolone triple or quadruple therapy as a second‐line treatment for Helicobacter pylori infection. An important caveat of amoxicillin‐fluoroquinolone rescue therapy is poor eradication efficacy in the presence of fluoroquinolone resistance. The study aimed to investigate the efficacies of tetracycline‐levofloxacin (TL) quadruple therapy and amoxicillin‐levofloxacin (AL) quadruple therapy in the second‐line treatment of H. pylori infection. Methods: Consecutive H. pylori‐infected subjects after the failure of first‐line therapies were randomly allocated to receive either TL quadruple therapy (tetracycline 500 mg QID, levofloxacin 500 mg QD, esomeprazole 40 mg BID, and tripotassium dicitrato bismuthate 300 mg QID) or AL quadruple therapy (amoxicillin 500 mg QID, levofloxacin 500 mg QD, esomeprazole 40 mg BID, and tripotassium dicitrato bismuthate 300 mg QID) for 10 days. Post‐treatment H. pylori status was assessed 6 weeks after the end of therapy. Results: The study was early terminated after an interim analysis. In the TL quadruple group, 50 out of 56 patients (89.3%) had successful eradication of H. pylori infection. Cure of H. pylori infection was achieved only in 39 of 52 patients (69.6%) receiving AL quadruple therapy. Intention‐to‐treat analysis showed that TL quadruple therapy achieved a markedly higher eradication rate than AL quadruple therapy (95% confidence interval: 4.8% to 34.6%; p = 0.010). Further analysis revealed that TL quadruple therapy had a high eradication rate for both levofloxacin‐susceptible and resistant strains (100% and 88.9%). In contrast, AL quadruple therapy yielded a high eradication for levofloxacin‐susceptible strains (90.9%) but a poor eradication efficacy for levofloxacin‐resistant strains (50.0%). The two therapies exhibited comparable frequencies of adverse events (37.5% vs 21.4%) and drug adherence (98.2% vs 94.6%). Conclusions: Ten‐day TL quadruple therapy is more effective than AL quadruple therapy in the second‐line treatment of H. pylori infection in a population with high levofloxacin resistance. [ABSTRACT FROM AUTHOR]