Prospective, open, multi-centre phase I/II trial to assess safety and efficacy of neoadjuvant radiochemotherapy with docetaxel and oxaliplatin in patients with adenocarcinoma of the oesophagogastric junction

Background: This phase I/II-trial assessed the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of neoadjuvant radiochemotherapy (RCT) with docetaxel and oxaliplatin in patients with locally advanced adenocarcinoma of the oesophagogastric junction. Methods: Patients received neoadjuvant radiotherapy (50.4 Gy) together with weekly docetaxel (20 mg/m2 at dose level (DL) 1 and 2, 25 mg/m2 at DL 3) and oxaliplatin (40 mg/m2 at DL 1, 50 mg/m2 at DL 2 and 3) over 5 weeks. The primary endpoint was the DLT and the MTD of the RCT regimen. Secondary endpoints included overall response rate (ORR) and progression-free survival (PFS). Results: A total of 24 patients were included. Four patients were treated at DL 1, 13 patients at DL 2 and 7 patients at DL 3. The MTD of the RCT was considered DL 2 with docetaxel 20 mg/m2 and oxaliplatin 50 mg/m2. Objective response (CR/PR) was observed in 32% (7/22) of patients. Eighteen patients (75%) underwent surgery after RCT. The median PFS for all patients (n = 24) was 6.5 months. The median overall survival for all patients (n = 24) was 16.3 months. Patients treated at DL 2 had a median overall survival of 29.5 months. Conclusion: Neoadjuvant RCT with docetaxel 20 mg/m2 and oxaliplatin 50 mg/m2 was effective and showed a good toxicity profile. Future studies should consider the addition of targeted therapies to current neoadjuvant therapy regimens to further improve the outcome of patients with advanced cancer of the oesophagogastric junction. Trial Registration: NCT0037498

High emission rate of sulfuric acid from Bezymianny volcano, Kamchatka

High concentrations of primary sulfuric acid (H2SO4) in fumarolic gases and high emission rate of sulfuric acid aerosol in the plume were measured at Bezymianny volcano, an active dome-growing andesitic volcano in central Kamchatka. Using direct sampling, filter pack sampling, and differential optical absorption spectroscopy measurements, we estimated an average emission of H2SO4 at 243 ± 75 t/d in addition to an average SO2 emission of 212 ± 65 t/d. The fumarolic gases of Bezymianny correspond to arc gases released by several magma bodies at different stages of degassing and contain 25-92% of entrained air. H2SO4 accounts for 6-87 mol% of the total sulfur content, 42.8 mol% on average, and SO2 is the rest. The high H2SO4 in Bezymianny fumaroles can be explained by catalytic oxidation of SO2 inside the volcanic dome. Because sulfate aerosol is impossible to measure remotely, the total sulfur content in a plume containing significant H2SO4 may be seriously underestimated

Epigenetic Drifts during Long-Term Intestinal Organoid Culture

Organoids retain the morphological and molecular patterns of their tissue of origin, are self-organizing, relatively simple to handle and accessible to genetic engineering. Thus, they represent an optimal tool for studying the mechanisms of tissue maintenance and aging. Long-term expansion under standard growth conditions, however, is accompanied by changes in the growth pattern and kinetics. As a potential explanation of these alterations, epigenetic drifts in organoid culture have been suggested. Here, we studied histone tri-methylation at lysine 4 (H3K4me3) and 27 (H3K27me3) and transcriptome profiles of intestinal organoids derived from mismatch repair (MMR)-deficient and control mice and cultured for 3 and 20 weeks and compared them with data on their tissue of origin. We found that, besides the expected changes in short-term culture, the organoids showed profound changes in their epigenomes also during the long-term culture. The most prominent were epigenetic gene activation by H3K4me3 recruitment to previously unmodified genes and by H3K27me3 loss from originally bivalent genes. We showed that a long-term culture is linked to broad transcriptional changes that indicate an ongoing maturation and metabolic adaptation process. This process was disturbed in MMR-deficient mice, resulting in endoplasmic reticulum (ER) stress and Wnt activation. Our results can be explained in terms of a mathematical model assuming that epigenetic changes during a long-term culture involve DNA demethylation that ceases if the metabolic adaptation is disturbed

Microarray-Based Gene Expression Analysis of Hepatocellular Carcinoma

Microarray studies have successfully shed light on various aspects of the molecular mechanisms behind the development of hepatocellular carcinoma (HCC), such as the identification of novel molecular subgroups and the genetic profiles associated with metastasis and venous invasion. These experiments, mainly comprising genome wide profiling, potentially represent the basis of novel targeted therapeutic strategies in HCC. In response, we summarize the multiple reported expression profiles in HCC associated with HCC development, novel subgroups, venous invasion and metastasis

X-Ray photoelectron spectroscopy and mass spectrometry studies of X-ray-processed solid CO2

Solid CO2 films have been grown on a stainless steel substrate and processed by X-ray bombardment for up to 6 hr.. The reactions induced were monitored using X-ray photoelectron spectroscopy (XPS) and mass spectrometry. The XPS results are twofold: direct X-ray photolysis of the CO2 ice produced CO and an unidentified O product, possibly atomic O; secondary effects resulting from surface reactions between CO, O, and residual H from the vacuum environment produced H2CO, CH3OH, and a water ice cap on the CO2 film. The rate of production of CO from direct X-ray photolysis of CO2 is measured to be 5.4 × 102 molecule photon-1, corresponding to a formation cross section of 4.7 × 10-20 cm2. The growth rate for the water cap is calculated to be 2.6 × 10-4 monolayers s-1 for a partial pressure of H equal to 2 × 10-10 Torr. The appearance of gas-phase products from the film showed a time lag which indicates that the diffusion of the product species in the bulk CO2 is affected by some time-dependent process, possibly the creation of defects in the film. A model for the observed time dependence of the dissociation products in the gas phase yields diffusion coefficients in the CO2 of 5 × 10-12 and 1 × 10-12 cm2 s-1, for O and CO, respectively

Ion Microscopy: A New Approach for Subcellular Localization of Labelled Molecules

Secondary ion mass spectroscopy (SIMS) was used to obtain images representing the intracellular distribution of molecules labelled with carbon 14. Deoxyadenosine labelled with carbon 14 was added to a cultured human fibroblast cell medium, and the intracellular distribution of this molecule was studied using three different SIMS instruments: the CAMECA IMS 3F and SMI 300 ion microscopes and the UC-HRL scanning ion microprobe. Carbon 14 distribution images obtained by this method show that deoxyadenosine U-C14 is present in the cytoplasm as well as the nucleus, with a higher concentration in\u27 the nucleoli. Our study clearly demonstrates that ion microscopy is well suited for carbon 14 detection and localization at the subcellular level, permitting a wide variety of microanalytical tracer experiments

Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27

The immune response to bacterial infections must be tightly controlled to guarantee pathogen elimination while preventing tissue damage by uncontrolled inflammation. Here, we demonstrate a key role of interleukin (IL)-27 in regulating this critical balance. IL-27 was rapidly induced during murine experimental peritonitis induced by cecal ligation and puncture (CLP). Furthermore, mice deficient for the EBI3 subunit of IL-27 were resistant to CLP-induced septic peritonitis as compared with wild-type controls, and this effect could be suppressed by injection of recombinant single-chain IL-27. EBI3−/− mice displayed significantly enhanced neutrophil migration and oxidative burst capacity during CLP, resulting in enhanced bacterial clearance and local control of infection. Subsequent studies demonstrated that IL-27 directly suppresses endotoxin-induced production of reactive oxygen intermediates by isolated primary granulocytes and macrophages. Finally, in vivo blockade of IL-27 function using a newly designed soluble IL-27 receptor fusion protein led to significantly increased survival after CLP as compared with control-treated mice. Collectively, these data identify IL-27 as a key negative regulator of innate immune cell function in septic peritonitis. Furthermore, in vivo blockade of IL-27 is a novel potential therapeutic target for treatment of sepsis

Covariate-adjusted analysis of the Phase 3 REFLECT study of lenvatinib versus sorafenib in the treatment of unresectable hepatocellular carcinoma.

BACKGROUND: In the Phase 3 REFLECT trial in patients with unresectable hepatocellular carcinoma (uHCC), the multitargeted tyrosine kinase inhibitor, lenvatinib, was noninferior to sorafenib in the primary outcome of overall survival. Post-hoc review revealed imbalances in prognostic variables between treatment arms. Here, we re-analyse overall survival data from REFLECT to adjust for the imbalance in covariates. METHODS: Univariable and multivariable adjustments were undertaken for a candidate set of covariate values that a physician panel indicated could be prognostically associated with overall survival in uHCC. The values included baseline variables observed pre- and post-randomisation. Univariable analyses were based on a stratified Cox model. The multivariable analysis used a "forwards stepwise" Cox model. RESULTS: Univariable analysis identified alpha-fetoprotein (AFP) as the most influential variable. The chosen multivariable Cox model analysis resulted in an estimated adjusted hazard ratio for lenvatinib of 0.814 (95% CI: 0.699-0.948) when only baseline variables were included. Adjusting for post-randomisation treatment variables further increased the estimated superiority of lenvatinib. CONCLUSIONS: Covariate adjustment of REFLECT suggests that the original noninferiority trial likely underestimated the true effect of lenvatinib on overall survival due to an imbalance in baseline prognostic covariates and the greater use of post-treatment therapies in the sorafenib arm. TRIAL REGISTRATION: Trial number: NCT01761266 (Submitted January 2, 2013)