The Current Palestinian Uprising: Al-Aqsa Intifadah

Facing a September 13, 2000 deadline for concluding a comprehensive Israeli- Palestinian agreement on all permanent status issues, President Bill Clinton convened a trilateral summit with Israeli Prime Minister Ehud Barak and Palestine Liberation Organization (PLO) Chairman Yasser Arafat at Camp David on July 11, 2000. The summit, which lasted until July 24, 2000, did not produce an agreement. Members of 106th Congress responded to the al-Aqsa Intifadah by introducing bills that supported Israel’s actions, encouraged the U.S. Administration to oppose any anti-Israel resolutions in the United Nations, called upon Palestinians to negotiate a resolution, and proposed cutting foreign assistance to the Palestinians if they did not stop the uprising

Expression and Regulation of Retinoic Acid Receptor Responders in the Human Placenta

Introduction: Retinoic acid (RA) signaling through its receptors (RARA, RARB, RARG, and the retinoic X receptor RXRA) is essential for healthy placental and fetal development. An important group of genes regulated by RA are the RA receptor responders (RARRES1, 2, and 3). We set out to analyze their expression and regulation in healthy and pathologically altered placentas of preeclampsia (PE) and intrauterine growth restriction (IUGR) as well as in trophoblast cell lines. Methods: We performed immunohistochemical staining on placental sections and analyzed gene expression by real-time polymerase chain reaction. Additionally, we performed cell culture experiments and stimulated Swan71 and Jeg-3 cells with different RA derivates and 2′-deoxy-5-azacytidine (AZA) to induce DNA demethylation. Results: RARRES1, 2, and 3 and RARA, RARB, RARG, and RXRA are expressed in the extravillous part of the placenta. RARRES1, RARA, RARG, and RXRA were additionally detected in villous cytotrophoblasts. RARRES gene expression was induced via activation of RARA, RARB, and RARG in trophoblast cells. RARRES1 was overexpressed in villous trophoblasts and the syncytiotrophoblast from PE placentas, but not in IUGR without PE. Promoter methylation was detectable for RARRES1 and RARB based on their sensitivity toward AZA treatment of trophoblast cell lines. Discussion: RARRES1, 2 and 3 are expressed in the functional compartments of the human placenta and can be regulated by RA. We hypothesize that the epigenetic suppression of trophoblast RARRES1 and RARB expression and the upregulation of RARRES1 in PE trophoblast cells suggest an involvement of environmental factors (eg, maternal vitamin A intake) in the pathogenesis of this pregnancy complication

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

Photosensitizer Drug Delivery via an Optical Fiber

: An optical fiber has been developed with a maneuverable miniprobe tip that sparges O2 gas and photodetaches pheophorbide (sensitizer) molecules. Singlet oxygen is produced at the probe tip surface which reacts with an alkene spacer group releasing sensitizer upon fragmentation of a dioxetane intermediate. Optimal sensitizer photorelease occurred when the probe tip was loaded with 60 nmol sensitizer, where crowding of the pheophorbide molecules and self-quenching were kept to a minimum. The fiber optic tip delivered pheophorbide molecules and singlet oxygen to discrete locations. The 60 nmol sensitizer was delivered into petrolatum; however, sensitizer release was less efficient in toluene-d8 (3.6 nmol) where most had remained adsorbed on the probe tip, even after the covalent alkene spacer bond had been broken. The results open the door to a new area of fiber optic-guided sensitizer delivery for the potential photodynamic therapy of hypoxic structures requiring cytotoxic control

RhoE Is Regulated by Cyclic AMP and Promotes Fusion of Human BeWo Choriocarcinoma Cells

Fusion of placental villous cytotrophoblasts with the overlying syncytiotrophoblast is essential for the maintenance of successful pregnancy, and disturbances in this process have been implicated in pathological conditions such as pre-eclampsia and intra-uterine growth retardation. In this study we examined the role of the Rho GTPase family member RhoE in trophoblast differentiation and fusion using the BeWo choriocarcinoma cell line, a model of villous cytotrophoblast fusion. Treatment of BeWo cells with the cell permeable cyclic AMP analogue dibutyryl cyclic AMP (dbcAMP) resulted in a strong upregulation of RhoE at 24h, coinciding with the onset of fusion. Using the protein kinase A (PKA)-specific cAMP analogue N6-phenyl-cAMP, and a specific inhibitor of PKA (14–22 amide, PKI), we found that upregulation of RhoE by cAMP was mediated through activation of PKA signalling. Silencing of RhoE expression by RNA interference resulted in a significant decrease in dbcAMP-induced fusion. However, expression of differentiation markers human chorionic gonadotrophin and placental alkaline phosphatase was unaffected by RhoE silencing. Finally, we found that RhoE upregulation by dbcAMP was significantly reduced under hypoxic conditions in which cell fusion is impaired. These results show that induction of RhoE by cAMP is mediated through PKA and promotes BeWo cell fusion but has no effect on functional differentiation, supporting evidence that these two processes may be controlled by separate or diverging pathways