Translocation breakpoints in FHIT and FRA3B in both homologs of chromosome 3 in an esophageal adenocarcinoma

Common fragile sites have been proposed to play a mechanistic role in chromosome translocations and other rearrangements in cancer cells in vivo based on their behavior in vitro and their co-localization with cancer translocation breakpoints. This hypothesis has been the subject of controversy, because associations have been made at the chromosomal level and because of the large number of both fragile sites and cancer chromosome breakpoints. Tests of this hypothesis at the molecular level are now possible with the cloning of common fragile site loci and the use of fragile site clones in the analysis of rearranged chromosomes. FRA3B, the most frequently seen common fragile site, lies within the large FHIT gene. It is now well established that this region is the site of frequent, large intragenic deletions and aberrant transcripts in a number of tumors and tumor cell lines. In contrast, only one tumor-associated translocation involving the FHIT gene has been reported. We have found translocations in both homologs of chromosome 3 in an early-passage esophageal adenocarcinoma cell line. This cell line showed no normal FHIT transcripts by reverse transcription polymerase chain reaction. Subsequent chromosome analysis showed translocations of the short arms of both homologs of chromosome 3: t(3;16) and t(3;4). The breakpoints of both translocations were shown by fluorescence in situ hybridization and polymerase chain reaction to be in the FHIT gene, at or near the center of the fragile site region. Using rapid amplification of cDNA ends with FHIT primers, a noncoding chimeric transcript resulting from t(3;16) was identified. These data provide direct support for the hypothesis that FRA3B , and likely other common fragile sites, may be “hot spots” for translocations in certain cancers, as they are for deletions, and that such translocations have the potential to form abnormal chimeric transcripts. In addition, the results suggest selection for loss of a functional FHIT gene by the translocation events. © 2001 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35130/1/1095_ftp.pd

Control of Gene Expression by the Retinoic Acid-Related Orphan Receptor Alpha in HepG2 Human Hepatoma Cells

Retinoic acid-related Orphan Receptor alpha (RORα; NR1F1) is a widely distributed nuclear receptor involved in several (patho)physiological functions including lipid metabolism, inflammation, angiogenesis, and circadian rhythm. To better understand the role of this nuclear receptor in liver, we aimed at displaying genes controlled by RORα in liver cells by generating HepG2 human hepatoma cells stably over-expressing RORα. Genes whose expression was altered in these cells versus control cells were displayed using micro-arrays followed by qRT-PCR analysis. Expression of these genes was also altered in cells in which RORα was transiently over-expressed after adenoviral infection. A number of the genes found were involved in known pathways controlled by RORα, for instance LPA, NR1D2 and ADIPOQ in lipid metabolism, ADIPOQ and PLG in inflammation, PLG in fibrinolysis and NR1D2 and NR1D1 in circadian rhythm. This study also revealed that genes such as G6PC, involved in glucose homeostasis, and AGRP, involved in the control of body weight, are also controlled by RORα. Lastly, SPARC, involved in cell growth and adhesion, and associated with liver carcinogenesis, was up-regulated by RORα. SPARC was found to be a new putative RORα target gene since it possesses, in its promoter, a functional RORE as evidenced by EMSAs and transfection experiments. Most of the other genes that we found regulated by RORα also contained putative ROREs in their regulatory regions. Chromatin immunoprecipitation (ChIP) confirmed that the ROREs present in the SPARC, PLG, G6PC, NR1D2 and AGRP genes were occupied by RORα in HepG2 cells. Therefore these genes must now be considered as direct RORα targets. Our results open new routes on the roles of RORα in glucose metabolism and carcinogenesis within cells of hepatic origin

Effect of automated head-thorax elevation during chest compressions on lung ventilation: a model study

Abstract Our goal was to investigate the effects of head-thorax elevation (HUP) during chest compressions (CC) on lung ventilation. A prospective study was performed on seven human cadavers. Chest was automatically compressed-decompressed in flat position and during progressive HUP from 18 to 35°. Lung ventilation was measured with electrical impedance tomography. In each cadaver, 5 sequences were randomly performed: one without CC at positive end-expiratory pressure (PEEP) 0cmH2O, 3 s with CC at PEEP0, 5 or 10cmH2O and 1 with CC and an impedance threshold device at PEEP0cmH2O. The minimal-to-maximal change in impedance (VTEIT in arbitrary unit a.u.) and the minimal impedance in every breathing cycle (EELI) the) were compared between flat, 18°, and 35° in each sequence by a mixed-effects model. Values are expressed as median (1st–3rd quartiles). With CC, between flat, 18° and 35° VTEIT decreased at each level of PEEP. It was 12416a.u. (10,689; 14,442), 11,239 (7667; 13,292), and 6457 (4631; 9516), respectively, at PEEP0. The same was true with the impedance threshold device. EELI/VTEIT significantly decreased from − 0.30 (− 0.40; − 0.15) before to − 1.13 (− 1.70; − 0.61) after the CC (P = 0.009). With HUP lung ventilation decreased with CC as compared to flat position. CC are associated with decreased in EELI

Improving Cancer Immunotherapy by Targeting the Hypoxic Tumor Microenvironment: New Opportunities and Challenges

Initially believed to be a disease of deregulated cellular and genetic expression, cancer is now also considered a disease of the tumor microenvironment. Over the past two decades, significant and rapid progress has been made to understand the complexity of the tumor microenvironment and its contribution to shaping the response to various anti-cancer therapies, including immunotherapy. Nevertheless, it has become clear that the tumor microenvironment is one of the main hallmarks of cancer. Therefore, a major challenge is to identify key druggable factors and pathways in the tumor microenvironment that can be manipulated to improve the efficacy of current cancer therapies. Among the different tumor microenvironmental factors, this review will focus on hypoxia as a key process that evolved in the tumor microenvironment. We will briefly describe our current understanding of the molecular mechanisms by which hypoxia negatively affects tumor immunity and shapes the anti-tumor immune response. We believe that such understanding will provide insight into the therapeutic value of targeting hypoxia and assist in the design of innovative combination approaches to improve the efficacy of current cancer therapies, including immunotherapy

Mildly Reduced Doses of Adrenaline Do Not Affect Key Hemodynamic Parameters during Cardio-Pulmonary Resuscitation in a Pig Model of Cardiac Arrest

International audienceAdrenaline is recommended for cardiac arrest resuscitation, but its effectiveness has been questioned recently. Achieving return of spontaneous circulation (ROSC) is essential and is obtained by increasing coronary perfusion pressure (CPP) after adrenaline injection. A threshold as high as 35 mmHg of CPP may be necessary to obtain ROSC, but increasing doses of adrenaline might be harmful to the brain. Our study aimed to compare the increase in CPP with reduced doses of adrenaline to the recommended 1 mg dose in a pig model of cardiac arrest. Fifteen domestic pigs were randomized into three groups according to the adrenaline doses: 1 mg, 0.5 mg, or 0.25 mg administered every 5 min. Cardiac arrest was induced by ventricular fibrillation; after 5 min of no-flow, mechanical chest compression was resumed. The Wilcoxon test and Kruskal–Wallis exact test were used for the comparison of groups. Fisher’s exact test was used to compare categorical variables. CPP, EtCO2 level, cerebral, and tissue near-infrared spectroscopy (NIRS) were measured. CPP was significantly lower in the 0.25 mg group 90 s after the first adrenaline injection: 28.9 (21.2; 35.4) vs. 53.8 (37.8; 58.2) in the 1 mg group (p = 0.008), while there was no significant difference with 0.5 mg 39.6 (32.7; 52.5) (p = 0.056). Overall, 0.25 mg did not achieve the threshold of 35 mmHg. EtCO2 levels were higher at T12 and T14 in the 0.5 mg than in the standard group: 32 (23; 35) vs. 19 (16; 26) and 26 (20; 34) vs. 19 (12; 22) (p < 0.05). Cerebral and tissue NIRS did not show a significant difference between the three groups. CPP after 0.5 mg boluses of adrenaline was not significantly different from the recommended 1 mg in our model of cardiac arrest

Predicting the efficacy of anthracyclines in breast cancer (BC) patients: Results of the neoadjuvant TOP trial.

Abstr. 523info:eu-repo/semantics/publishe

Investigating the predictive value of topoisomerase II alpha (TOP2A) gene, mRNA and protein levels in anthracycline-treated estrogen receptor (ER) negative breast cancer patients.

Abstr.11065info:eu-repo/semantics/publishe

Gene expression signatures can predict the efficacy of anthracyclines in HER2-negative and HER-2 positive breast cancer (BC) patients: the results of the TOP trial and their validation in the BIG 1-00 trial, on behalf of the TOP trial investigators.

info:eu-repo/semantics/nonPublishe

Gene expression signatures can predict the efficacy of anthracyclines in HER2-negative and HER2-positive breast cancer (BC) patients: The results of the TOP trial and their validation in the BIG1-00 trial.

Abstract 1250info:eu-repo/semantics/publishe

Gene expression signatures can predict the efficacy of anthracyclines in HER2-negative and HER-2 positive breast cancer (BC) patients: the results of the TOP trial and their validation in the BIG 1-00 trial, on behalf of the TOP trial investigators.

info:eu-repo/semantics/nonPublishe