Evidence of Genetic Instability in Tumors and Normal Nearby Tissues

We have analyzed the sequence heterogeneity of the transcripts of the human HPRT and G6PD single copy genes that are not considered tumor markers. Analyses have been performed on different colon cancers and on the nearby histologically normal tissues of two male patients. Several copies of each cDNA, which were produced by cloning the RT-PCR-amplified fragments of the specific mRNA, have been sequenced. Similar analyses have been performed on blood samples of two ostensibly healthy males as reference controls. The sequence heterogeneity of the HPRT and G6PD genes was also determined on DNA from tumor tissues. The employed analytical approach revealed the presence of low-frequency mutations not detectable by other procedures. The results show that genetic heterogeneity is detectable in HPRT and G6PD transcripts in both tumors and nearby healthy tissues of the two studied colon tumors. Similar frequencies of mutations are observed in patient genomic DNA, indicating that mutations have a somatic origin. HPRT transcripts show genetic heterogeneity also in healthy individuals, in agreement with previous results on human T-cells, while G6PD transcript heterogeneity is a characteristic of the patient tissues. Interestingly, data on TP53 show little, if any, heterogeneity in the same tissues. CONCLUSIONS/SIGNIFICANCE: These findings show that genetic heterogeneity is a peculiarity not only of cancer cells but also of the normal tissue where a tumor arises

Oil-Based Mud Cutting as an Additional Raw Material in Clinker Production

Oil-Based Mud (OBM) cutting is a hazardous by-product generated during oil-well drilling. Its chemical composition suggests that it might be suitable as a raw material in cement manufacturing. It is rich in calcium oxide, silica, and aluminium oxide, which are the major oxides in raw materials for cement manufacturing. In this research, OBM cutting is used as a constituent of the raw meal for cement clinker production. Raw meal mixtures were prepared by mixing different ratios of raw materials increasing OBM content. The impact of the addition of OBM cutting on the resulting clinker has been investigated. The results demonstrate that OBM cutting could be recycled in the manufacturing of Portland cement clinker. Clinker prepared using OBM cutting had very similar properties to that prepared from limestone. This result could represent an opportunity for solving an environmental problem. The addition of OBM cutting lowers the calcination temperature, and increases the rate of carbonate dissociation. However, it also leads to a higher free lime in clinker, which is a result of the presence of trace elements, such as barium. Overall, its use as a raw material in cement production could provide a cost-effective, environment-friendly route for the management of OBM cutting

Exome sequencing identified MYO1E and NEIL1 as candidate genes for human autosomal recessive steroid-resistant nephrotic syndrome.

To identify gene loci associated with steroid-resistant nephrotic syndrome (SRNS), we utilized homozygosity mapping and exome sequencing in a consanguineous pedigree with three affected siblings. High-density genotyping identified three segments of homozygosity spanning 33.6 Mb on chromosomes 5, 10, and 15 containing 296 candidate genes. Exome sequencing identified two homozygous missense variants within the chromosome 15 segment; an A159P substitution in myosin 1E (MYO1E), encoding a podocyte cytoskeletal protein; and an E181K substitution in nei endonuclease VIII-like 1 (NEIL1), encoding a base-excision DNA repair enzyme. Both variants disrupt highly conserved protein sequences and were absent in public databases, 247 healthy controls, and 286 patients with nephrotic syndrome. The MYO1E A159P variant is noteworthy, as it is expected to impair ligand binding and actin interaction in the MYO1E motor domain. The predicted loss of function is consistent with the previous demonstration that Myo1e inactivation produces nephrotic syndrome in mice. Screening 71 additional patients with SRNS, however, did not identify independent NEIL1 or MYO1E mutations, suggesting larger sequencing efforts are needed to uncover which mutation is responsible for the phenotype. Our findings demonstrate the utility of exome sequencing for rapidly identifying candidate genes for human SRNS

Predictive factors of mortality from nonvariceal upper gastrointestinal hemorrhage: a multicenter study.

OBJECTIVES: From an Italian Registry of patients with upper gastrointestinal hemorrhage (UGIH), we assessed the clinical outcomes and explored the roles of clinical, endoscopic, and therapeutic factors on 30-day mortality in a real life setting. METHODS: Prospective analysis of consecutive patients endoscoped for UGIH at 23 community and tertiary care institutions from 2003 to 2004. Covariates and outcomes were defined a priori and 30-day follow-up obtained. Logistic regression analysis identified predictors of mortality. RESULTS: One thousand and twenty patients were included. A total of 46 patients died for an overall 4.5% mortality rate. In all, 85% of deaths were associated with one or more major comorbidity. Sixteen of 46 patients (35%) died within the first 24 h of the onset of bleeding. Of these, eight had been categorized as ASA class 1 or 2 and none of them was operated upon, despite a failure of endoscopic intention to treatment in four. Regression analysis showed advanced age, presence of severe comorbidity, low hemoglobin levels at presentation, and worsening health status as the only independent predictors of 30-day mortality (P < 0.001). The acute use of a PPI exerted a protective effect (OR 0.23, 95% CI 0.09-0.73). Recurrent bleeding was low (3.2%). Rebleeders accounted for only 11% of the total patients deceased (OR 3.27, 95% CI 1.5-11.2). CONCLUSIONS: These results indicate that 30-day mortality for nonvariceal bleeding is low. Deaths occurred predominantly in elderly patients with severe comorbidities or those with failure of endoscopic intention to treatment