Archaeological Investigations at Site 41BX66 Along Loop 1604, Bexar County, Texas

Archaeologists from the State Department of Highways and Public Transportation conducted surface collection and test excavations at Site 41BX66 in 1988 and 1989. The site, located along Loop 1604 in northern Bexar County, contained a surface scatter of lithic artifacts and fire-cracked rock. Expansion of the Loop 1604 right-of-way impacted the site area, necessitating a testing program. The results of that subsurface testing indicate that the site area of 41BX66 within the highway right-of-way (ROW) was not eligible to the National Register of Historic Places and no further work was recommended. TXDO

Magnitude of the Difference Between Clinic and Ambulatory Blood Pressures and Risk of Adverse Outcomes in Patients With Chronic Kidney Disease.

Background Obtaining 24-hour ambulatory blood pressure ( BP ) is recommended for the detection of masked or white-coat hypertension. Our objective was to determine whether the magnitude of the difference between ambulatory and clinic BP s has prognostic implications. Methods and Results We included 610 participants of the AASK (African American Study of Kidney Disease and Hypertension) Cohort Study who had clinic and ambulatory BPs performed in close proximity in time. We used Cox models to determine the association between the absolute systolic BP ( SBP ) difference between clinic and awake ambulatory BPs (primary predictor) and death and end-stage renal disease. Of 610 AASK Cohort Study participants, 200 (32.8%) died during a median follow-up of 9.9 years; 178 (29.2%) developed end-stage renal disease. There was a U-shaped association between the clinic and ambulatory SBP difference with risk of death, but not end-stage renal disease. A 5- to <10-mm Hg higher clinic versus awake SBP (white-coat effect) was associated with a trend toward higher (adjusted) mortality risk (adjusted hazard ratio, 1.84; 95% CI, 0.94-3.56) compared with a 0- to <5-mm Hg clinic-awake SBP difference (reference group). A ≥10-mm Hg clinic-awake SBP difference was associated with even higher mortality risk (adjusted hazard ratio, 2.31; 95% CI, 1.27-4.22). A ≥-5-mm Hg clinic-awake SBP difference was also associated with higher mortality (adjusted hazard ratio, 1.82; 95% CI, 1.05-3.15) compared with the reference group. Conclusions A U-shaped association exists between the magnitude of the difference between clinic and ambulatory SBP and mortality. Higher clinic versus ambulatory BPs (as in white-coat effect) may be associated with higher risk of death in black patients with chronic kidney disease

Fast-Track Remedial Design of Full-Scale ISCO Application Using Pilot Scale Testing and Field Screening Parameters

As a result of drum re-finishing operations, soil and groundwater at the Ottati and Goss Superfund Site in Kingston, NH are contaminated with chlorinated volatile organic compounds (VOCs); benzene, toluene, ethylbenzene, and xylene (BTEX); and 1,4-dioxane. After re-evaluation of the selected remedy for groundwater, pump and treat, EPA changed the remediation approach to in-situ chemical oxidation (ISCO) through an Amended Record of Decision in September 2007. At that time, EPA established a goal for the site to attain construction complete status within one year, by September 30, 2008. Activated persulfate was selected as the chemical oxidant for its capability to oxidize 1,4-dioxane, in addition to the other VOC contaminants of concern. Bench-scale and field pilot scale test were completed in three source areas to collect site-specific information to evaluate persulfate\u27s ability to destroy the contaminants of concern and to optimize full-scale remediation design in three discrete source areas at the site. Base-activated persulfate was injected in Areas A and B in December 2007, and pilot test injection was completed in Area C in early February 2008, after vertical profiling was completed throughout Area C. Groundwater sampling for laboratory analysis was planned for 6 and 12 weeks after injection in each area; however, it was known during pilot test planning that the full-scale design would need to be completed by the end of March 2008, before all laboratory results would be available. In order to complete the design, an intensive evaluation of field geochemistry parameters and field screening chemical analysis was performed to assess radius of influence, oxidant persistence, and aquifer behavior. Field screening analyses included residual persulfate via a permanganate titration, sulfate via colorimetry, and sodium via an ion-selective electrode. The field screening and field geochemistry results were used heavily in completing the full-scale ISCO design. The laboratory analytical results noted significant decreases in concentrations of chemicals of concern in wells where geochemistry and field parameters were observed to change. This article discusses pilot test planning, performance monitoring, and full-scale design using data collected from the pilot test for this fast-track remediation. The full-scale application was completed between July and September 2008, and was the third largest single-site application of persulfate performed to date

Allele-Specific Amplification in Cancer Revealed by SNP Array Analysis

Amplification, deletion, and loss of heterozygosity of genomic DNA are hallmarks of cancer. In recent years a variety of studies have emerged measuring total chromosomal copy number at increasingly high resolution. Similarly, loss-of-heterozygosity events have been finely mapped using high-throughput genotyping technologies. We have developed a probe-level allele-specific quantitation procedure that extracts both copy number and allelotype information from single nucleotide polymorphism (SNP) array data to arrive at allele-specific copy number across the genome. Our approach applies an expectation-maximization algorithm to a model derived from a novel classification of SNP array probes. This method is the first to our knowledge that is able to (a) determine the generalized genotype of aberrant samples at each SNP site (e.g., CCCCT at an amplified site), and (b) infer the copy number of each parental chromosome across the genome. With this method, we are able to determine not just where amplifications and deletions occur, but also the haplotype of the region being amplified or deleted. The merit of our model and general approach is demonstrated by very precise genotyping of normal samples, and our allele-specific copy number inferences are validated using PCR experiments. Applying our method to a collection of lung cancer samples, we are able to conclude that amplification is essentially monoallelic, as would be expected under the mechanisms currently believed responsible for gene amplification. This suggests that a specific parental chromosome may be targeted for amplification, whether because of germ line or somatic variation. An R software package containing the methods described in this paper is freely available at http://genome.dfci.harvard.edu/~tlaframb/PLASQ

High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines.

Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity in vivo

Stop Atherosclerosis in Native Diabetics Study (SANDS): Baseline Characteristics of the Randomized Cohort

Objectives: To present baseline characteristics of American Indians in the Stop Atherosclerosis in Native Diabetics Study (SANDS) and compare them with population-based data from American Indians and other ethnic groups. Design: 499 people with type 2 diabetes ≥ age 40, without known CVD, were recruited for a randomized 3-year trial to evaluate treatment targets for LDL-C (70 vs. 100 mg/dL) and systolic blood pressure (BP) (115 vs. 130 mmHg). Baseline evaluations included physical exam, collection of blood and urine samples, and carotid ultrasound and echocardiographic measures. Results: Mean age was 56 years; 66% were female. Average BMI was 33 kg/m2. Average duration of both hypertension and diabetes was 10 years, average A1c was 8.0 %, and mean LDL-C was 104 mg/dL. Participants in the conventional treatment group had slightly higher systolic BPs than participants in the aggressive treatment group (133 mm Hg vs. 128 mm Hg, p \u3c 0.002). Compared with the population-based cohorts of the Strong Heart Study (SHS), NHANES, and the TRIAD registry, SANDS participants had similar values for lipids, BP, and CRP, as well as degree of obesity, smoking rates, and renal function as indicated by estimated glomerular filtration rate. Conclusions: The baseline characteristics of the SANDS cohort are similar to those of a population-based sample of American Indian diabetic men and women and closely resemble diabetic men and women of other ethnic groups. Results from this study can be used to identify appropriate targets for LDL-C and BP lowering in diabetic American Indians and diabetic patients in other ethnic groups

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale loss-of-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustain PIK3CA mutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy within PIK3CA mutant cells. Reduced levels of aspartate deregulated the malate-aspartate shuttle, which is important for cytoplasmic NAD + regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, because PIK3CA mutant cells exhibit a profound reliance on glucose metabolism, malate-aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD + /NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene. Keyword: PIK3CA; 2OG; OGDH; TCA cycle; glycolysisDamon Runyon Cancer Research Foundation (HHMI Fellowship

Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

Palliative Care for People with Advanced Liver Disease: A Feasibility Trial of a Supportive Care Liver Nurse Specialist

Background:Liver disease is an increasing cause of death worldwide but palliative care is largely absent for these patients.Aim:We conducted a feasibility trial of a complex intervention delivered by a supportive care liver nurse specialist to improve care coordination, anticipatory care planning and quality of life for people with advanced liver disease and their carers.Design:Patients received a 6-month intervention (alongside usual care) from a specially trained liver nurse specialist. The nurse supported patients/carers to live as well as possible with the condition and acted as a resource to facilitate care by community professionals. A mixed-method evaluation was conducted. Case note analysis and questionnaires examined resource use, care planning processes and quality-of-life outcomes over time. Interviews with patients, carers and professionals explored acceptability, effectiveness, feasibility and the intervention.Setting/participants:Patients with advanced liver disease who had an unplanned hospital admission with decompensated cirrhosis were recruited from an inpatient liver unit. The intervention was delivered to patients once they had returned home.Results:We recruited 47 patients, 27 family carers and 13 case-linked professionals. The intervention was acceptable to all participants. They welcomed access to additional expert advice, support and continuity of care. The intervention greatly increased the number of electronic summary care plans shared by primary care and hospitals. The Palliative care Outcome Scale and EuroQol-5D-5L questionnaire were suitable outcome measurement tools.Conclusion:This nurse-led intervention proved acceptable and feasible. We have refined the recruitment processes and outcome measures for a future randomised controlled trial