Mouse SLX4 Is a Tumor Suppressor that Stimulates the Activity of the Nuclease XPF-ERCC1 in DNA Crosslink Repair

SLX4 binds to three nucleases (XPF-ERCC1, MUS81-EME1, and SLX1), and its deficiency leads to genomic instability, sensitivity to DNA crosslinking agents, and Fanconi anemia. However, it is not understood how SLX4 and its associated nucleases act in DNA crosslink repair. Here, we uncover consequences of mouse Slx4 deficiency and reveal its function in DNA crosslink repair. Slx4-deficient mice develop epithelial cancers and have a contracted hematopoietic stem cell pool. The N-terminal domain of SLX4 (mini-SLX4) that only binds to XPF-ERCC1 is sufficient to confer resistance to DNA crosslinking agents. Recombinant mini-SLX4 enhances XPF-ERCC1 nuclease activity up to 100-fold, directing specificity toward DNA forks. Mini-SLX4-XPF-ERCC1 also vigorously stimulates dual incisions around a DNA crosslink embedded in a synthetic replication fork, an essential step in the repair of this lesion. These observations define vertebrate SLX4 as a tumor suppressor, which activates XPF-ERCC1 nuclease specificity in DNA crosslink repairope

Detectable clonal mosaicism and its relationship to aging and cancer

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases

Report on the Clinical Trials of the Plexus Membrane Blood Oxygenator

Twenty adult patients gave informed consent to clinical cardiopulmonary bypass (CPB) trials with a new adult hollow fiber membrane oxygenator. Clinical CPB trials averaged 88 ± 25 min (mean ± 1 SD) for these patients that weighed 78 ± 13 Kg and had BSA's = 1.9 ± 0.2 m2. Blood flow averaged 4.0 ± 0.8 L/min, and hypothermia was employed at 26.5 ± 2.4°C. FiO2's = 0.59 ± 0.15, and gas to blood flow ratios= 0.64 ± 0.18 were required to maintain the PaO2>100 mmHg and to accomplish alpha-stat. The oxygenator exhibited a pressure drop of 50-60 mmHg at 5.09 1/min and a heat exchanger performance factor over .55 during most of CPB. Multiple regression analysis of the clinical database demonstrated that the FiO2 required to achieve a desired PaO2 was dependent on the blood flow, gas flow, and SvO2 (r2 = 0.83, standard error = 0.09). The gas flow required to accomplish alpha-stat was dependent on patient age, weight, blood flow, arterial blood temperature, and desired PaCO2 (r2 = 0.71, standard error= 0.6). The Plexus blood oxygenator is safe for adult cardiopulmonary bypass and its clinical performance is statistically predictable