Synthesis, effectiveness and metabolic fate in cows of the caesium complexing compound ammonium ferric hexacyanoferrate labelled with 14C

Adding ammonium ferric hexacyanoferrate (AFCF) to cows' fodder produced after the Chernobyl nuclear accident prevented milk contamination by increasing the faecal elimination of 137Cs. Synthesis of ammonium ferric hexa[14C]-cyanoferrate (AF14CF) and its purification were performed for the study of the metabolic fate of this complex, and the evaluation of the possible release of cyanide. The stability of this colloidal product, tested by anaerobic incubation in rumen juice in vitro, showed no release of free cyanide from AF14CF, but hexacyanoferrate was identified in the rumen juice and 0·13% of the added radioactivity was converted to labelled CO2. AF14CF administered per os to two cows showed a nearly quantitative excretion of radioactivity in faeces during the first 3 d (91-95%). A very low but significant level of radioactivity appeared in plasma, blood cells, expired CO2 and was detected in organs taken 9 d after administration. Total cumulative radioactivity in urine and milk amounted to 0·19-0·47% and 0·068-0·071% respectively for the two cows. Labelled hexacyanoferrate and thiocyanate were identified in the urine and also in faeces. In spite of this relative instability of AFCF in the rumen of cows, the poor absorption of AF14CF degradation products showed that AFCF constitutes an efficient and safe food additive to prevent the absorption of radioactive caesium from ruminant feed and its secretion in mil

Prognostic Significance of Erythropoietin in Pancreatic Adenocarcinoma

BACKGROUND: Erythropoietin (Epo) administration has been reported to have tumor-promoting effects in anemic cancer patients. We investigated the prognostic impact of endogenous Epo in patients with pancreatic ductal adenocarcinoma (PDAC). METHODOLOGY: The clinico-pathological relevance of hemoglobin (Hb, n = 150), serum Epo (sEpo, n = 87) and tissue expression of Epo/Epo receptor (EpoR, n = 104) was analyzed in patients with PDAC. Epo/EpoR expression, signaling, growth, invasion and chemoresistance were studied in Epo-exposed PDAC cell lines. RESULTS: Compared to donors, median preoperative Hb levels were reduced by 15% in both chronic pancreatitis (CP, p<0.05) and PDAC (p<0.001), reaching anemic grade in one third of patients. While inversely correlating to Hb (r = -0.46), 95% of sEPO values lay within the normal range. The individual levels of compensation were adequate in CP (observed to predicted ratio, O/P = 0.99) but not in PDAC (O/P = 0.85). Strikingly, lower sEPO values yielding inadequate Epo responses were prominent in non-metastatic M0-patients, whereas these parameters were restored in metastatic M1-group (8 vs. 13 mU/mL; O/P = 0.82 vs. 0.96; p<0.01)--although Hb levels and the prevalence of anemia were comparable. Higher sEpo values (upper quartile ≥ 16 mU/ml) were not significantly different in M0 (20%) and M1 (30%) groups, but were an independent prognostic factor for shorter survival (HR 2.20, 10 vs. 17 months, p<0.05). The pattern of Epo expression in pancreas and liver suggested ectopic release of Epo by capillaries/vasa vasorum and hepatocytes, regulated by but not emanating from tumor cells. Epo could initiate PI3K/Akt signaling via EpoR in PDAC cells but failed to alter their functions, probably due to co-expression of the soluble EpoR isoform, known to antagonize Epo. CONCLUSION/SIGNIFICANCE: Higher sEPO levels counteract anemia but worsen outcome in PDAC patients. Further trials are required to clarify how overcoming a sEPO threshold ≥16 mU/ml by endogenous or exogenous means may predispose to or promote metastatic progression

Somatic mutations in exocrine pancreatic tumors: association with patient survival.

KRAS mutations are major factors involved in initiation and maintenance of pancreatic tumors. The impact of different mutations on patient survival has not been clearly defined. We screened tumors from 171 pancreatic cancer patients for mutations in KRAS and CDKN2A genes. Mutations in KRAS were detected in 134 tumors, with 131 in codon 12 and only 3 in codon 61. The GGT>GAT (G12D) was the most frequent mutation and was present in 60% (80/134). Deletions and mutations in CDKN2A were detected in 43 tumors. Analysis showed that KRAS mutations were associated with reduced patient survival in both malignant exocrine and ductal adenocarcinomas (PDAC). Patients with PDACs that had KRAS mutations showed a median survival of 17 months compared to 30 months for those without mutations (log-rank P = 0.07) with a multivariate hazard ratio (HR) of 2.19 (95%CI 1.09-4.42). The patients with G12D mutation showed a median survival of 16 months (log-rank-test P = 0.03) and an associated multivariate HR 2.42 (95%CI 1.14-2.67). Although, the association of survival in PDAC patients with CDKN2A aberrations in tumors was not statistically significant, the sub-group of patients with concomitant KRAS mutations and CDKN2A alterations in tumors were associated with a median survival of 13.5 months compared to 22 months without mutation (log-rank-test P = 0.02) and a corresponding HR of 3.07 (95%CI 1.33-7.10). Our results are indicative of an association between mutational status and survival in PDAC patients, which if confirmed in subsequent studies can have potential clinical application

Pancreatic Cancer Susceptibility Loci and Their Role in Survival

Pancreatic cancer has one of the worst mortality rates of all cancers. Little is known about its etiology, particularly regarding inherited risk. The PanScan project, a genome-wide association study, identified several common polymorphisms affecting pancreatic cancer susceptibility. Single nucleotide polymorphisms (SNPs) in ABO, sonic hedgehog (SHH), telomerase reverse transcriptase (TERT), nuclear receptor subfamily 5, group A, member 2 (NR5A2) were found to be associated with pancreatic cancer risk. Moreover the scan identified loci on chromosomes 13q22.1 and 15q14, to which no known genes or other functional elements are mapped. We sought to replicate these observations in two additional, independent populations (from Germany and the UK), and also evaluate the possible impact of these SNPs on patient survival. We genotyped 15 SNPs in 690 cases of pancreatic ductal adenocarcinoma (PDAC) and in 1277 healthy controls. We replicated several associations between SNPs and PDAC risk. Furthermore we found that SNP rs8028529 was weakly associated with a better overall survival (OS) in both populations. We have also found that NR5A2 rs12029406_T allele was associated with a shorter survival in the German population. In conclusion, we found that rs8028529 could be, if these results are replicated, a promising marker for both risk and prognosis for this lethal disease

Recommendations for the implementation of distress screening programs in cancer centers: Report from the American Psychosocial Oncology Society (APOS), Association of Oncology Social Work (AOSW), and Oncology Nursing Society (ONS) joint task force

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108593/1/cncr28750.pd

Structural analysis and DNA binding of the HMG domains of the human mitochondrial transcription factor A

The mitochondrial transcription factor A (mtTFA) is central to assembly and initiation of the mitochondrial transcription complex. Human mtTFA (h-mtTFA) is a dual high mobility group box (HMGB) protein that binds site-specifically to the mitochondrial genome and demarcates the promoters for recruitment of h-mtTFB1, h-mtTFB2 and the mitochondrial RNA polymerase. The stoichiometry of h-mtTFA was found to be a monomer in the absence of DNA, whereas it formed a dimer in the complex with the light strand promoter (LSP) DNA. Each of the HMG boxes and the C-terminal tail were evaluated for their ability to bind to the LSP DNA. Removal of the C-terminal tail only slightly decreased nonsequence specific DNA binding, and box A, but not box B, was capable of binding to the LSP DNA. The X-ray crystal structure of h-mtTFA box B, at 1.35 Å resolution, revealed the features of a noncanonical HMG box. Interactions of box B with other regions of h-mtTFA were observed. Together, these results provide an explanation for the unusual DNA-binding properties of box B and suggest possible roles for this domain in transcription complex assembly

Diagnosis of Pancreatic Ductal Adenocarcinoma and Chronic Pancreatitis by Measurement of microRNA Abundance in Blood and Tissue

A solid process for diagnosis could have a substantial impact on the successful treatment of pancreatic cancer, for which currently mortality is nearly identical to incidence. Variations in the abundance of all microRNA molecules from peripheral blood cells and pancreas tissues were analyzed on microarrays and in part validated by real-time PCR assays. In total, 245 samples from two clinical centers were studied that were obtained from patients with pancreatic ductal adenocarcinoma or chronic pancreatitis and from healthy donors. Utilizing the minimally invasive blood test, receiver operating characteristic (ROC) curves and the corresponding area under the curve (AUC) analysis demonstrated very high sensitivity and specificity of a distinction between healthy people and patients with either cancer or chronic pancreatitis; respective AUC values of 0.973 and 0.950 were obtained. Confirmative and partly even more discriminative diagnosis could be performed on tissue samples with AUC values of 1.0 and 0.937, respectively. In addition, discrimination between cancer and chronic pancreatitis was achieved (AUC = 0.875). Also, several miRNAs were identified that exhibited abundance variations in both tissue and blood samples. The results could have an immediate diagnostic value for the evaluation of tumor reoccurrence in patients, who have undergone curative surgical resection, and for people with a familial risk of pancreatic cancer

Variability in the carbon isotopic composition of foliage carbon pools (soluble carbohydrates, waxes) and respiration fluxes in southeastern U.S. pine forests

Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 117 (2012): G02009, doi:10.1029/2011JG001867.We measured the δ13C of assimilated carbon (foliage organic matter (δCOM), soluble carbohydrates (δCSC), and waxes (δCW)) and respiratory carbon (foliage (δCFR), soil (δCSR) and ecosystem 13CO2 (δCER)) for two years at adjacent ecosystems in the southeastern U.S.: a regenerated 32 m tall mature Pinus palustris forest, and a mid-rotation 13 m tall Pinus elliottii stand. Carbon pools and foliage respiration in P. palustris were isotopically enriched by 2‰ relative to P. elliottii. Despite this enrichment, mean δCER values of the two sites were nearly identical. No temporal trends were apparent in δCSC, δCFR, δCSR and δCER. In contrast, δCOM and δCW at both sites declined by approximately 2‰ over the study. This appears to reflect the adjustment in the δ13C of carbon storage reserves used for biosynthesis as the trees recovered from a severe drought prior to our study. Unexpectedly, the rate of δ13C decrease in the secondary C32–36 n-alkanoic acid wax molecular cluster was twice that observed for δCOM and the predominant C22–26 compound cluster, and provides new evidence for parallel but separate wax chain elongation systems utilizing different carbon precursor pools in these species. δCFR and δCER were consistently enriched relative to assimilated carbon but, in contrast to previous studies, showed limited variations in response to changes in vapor pressure deficit (D). This limited variability in respiratory fluxes and δCSC may be due to the shallow water table as well as the deep taproots of pines, which limit fluctuations in photosynthetic discrimination arising from changes in D.This work was supported by a NSF grants DEB-0343604, DEB-0344562 and DEB-0552202, and DOE grant DE-FC02-06ER64156/06-SC-NICCR-1063.2012-10-1

The dissociation catastrophe in fluctuating-charge models and its implications for the concept of atomic electronegativity

We have recently developed the QTPIE (charge transfer with polarization current equilibration) fluctuating-charge model, a new model with correct dissociation behavior for nonequilibrium geometries. The correct asymptotics originally came at the price of representing the solution in terms of charge-transfer variables instead of atomic charges. However, we have found an exact reformulation of fluctuating-charge models in terms of atomic charges again, which is made possible by the symmetries of classical electrostatics. We show how this leads to the distinguishing between two types of atomic electronegativities in our model. While one is a intrinsic property of individual atoms, the other takes into account the local electrical surroundings. This suggests that this distinction could resolve some confusion surrounding the concept of electronegativity as to whether it is an intrinsic property of elements, or otherwise.Comment: 17 pages, prepared for "Proceedings of QSCP-XIII" in Prog. Theor. Chem. Phy