The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent ...actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in
(OR=0.44,
value=3.27x10
in overall lung cancer and OR=0.41,
value=9.71x10
in non-small cell lung cancer),
(OR=0.73,
value=1.01x10
in adenocarcinoma) and
(OR=1.82,
value=7.62x10
in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.
Anonymization has the potential to foster the sharing of medical data. State-of-the-art methods use mathematical models to modify data to reduce privacy risks. However, the degree of protection must ...be balanced against the impact on statistical properties. We studied an extreme case of this trade-off: the statistical validity of an open medical dataset based on the German National Pandemic Cohort Network (NAPKON), which was prepared for publication using a strong anonymization procedure. Descriptive statistics and results of regression analyses were compared before and after anonymization of multiple variants of the original dataset. Despite significant differences in value distributions, the statistical bias was found to be small in all cases. In the regression analyses, the median absolute deviations of the estimated adjusted odds ratios for different sample sizes ranged from 0.01 minimum = 0, maximum = 0.58 to 0.52 minimum = 0.25, maximum = 0.91. Disproportionate impact on the statistical properties of data is a common argument against the use of anonymization. Our analysis demonstrates that anonymization can actually preserve validity of statistical results in relatively low-dimensional data.
Nephron loss in a diseased kidney invokes adaptations in the remaining nephrons. Whether and how these adaptations condition the response of the kidney to injury is not known. We examined the ...susceptibility of the kidney after subtotal (5/6th) nephrectomy (STN) to ischemic injury in rats. GFR in STN kidneys did not significantly change after ischemia reperfusion (IR), whereas GFR fell by 70% after IR in unilateral nephrectomy controls. In micropuncture experiments, single-nephron GFR responses mirrored the whole-kidney responses: in STN, single-nephron GFR decreased by 7% after IR compared with 28% in controls. Furthermore, we found that tubuloglomerular feedback, a mechanism that links proximal tubular injury to a fall in GFR, was inoperative in STN but was normal in controls. Restoration of normal feedback in STN attenuated the functional resistance to IR. In addition to the functional resilience, the morphology of the kidney was better preserved in STN. In STN kidneys, the S3 segment of the proximal tubule, normally injured after ischemia, constitutively expressed hypoxia-inducible factor-1α (HIF-1α), which is cytoprotective in ischemia. Inducing HIF before IR improved GFR in control animals, and inhibiting the HIF target heme-oxygenase-1 before IR reduced GFR in STN animals. Taken together, these data suggest that fewer functioning nephrons in a diseased kidney do not increase the susceptibility to injury, but rather, hemodynamic and molecular adaptations in the remnant nephrons precondition them against ischemic injury.
Abstract
Staphylococcus aureus bacteremia is a leading cause of morbidity and mortality and yet tools to assess severity of infection and response to treatment are still lacking. This study aimed to ...establish a link between bacterial DNA quantified in blood and clinical severity in bacteremic patients. We developed a workflow coupled with a highly sensitive quantitative PCR method to quantify S. aureus bacterial DNA. This assay was used to measure whole blood S. aureus DNA (SA-DNA) and plasma-derived S. aureus cell-free DNA (SA-cfDNA) in a set of longitudinal samples from 45 patients with confirmed S. aureus bacteremia. SA-DNA was detectable at baseline and declined following treatment with antibiotics. Notably, baseline SA-DNA correlated with disease severity and levels were sustained in cases of complicated infections versus with non-complicated infections. In addition, plasma-derived S. aureus cell-free DNA could be readily detected in bacteremic patients and showed concordance with whole blood SA-DNA. High levels of SA-DNA and SA-cfDNA were associated with metrics of clinical severity, including longer durations of treatment, elevated white blood cell count, and positive blood cultures. Taken together, these data suggest that circulating bacterial DNA is more reflective of whole body bacterial load than blood culture and may aid in monitoring clearance of tissue reservoirs of infection during antibiotic therapy.
Marfan syndrome (MFS) is a rare, severe, chronic, life-threatening disease with multiorgan involvement that requires optimal multidisciplinary care to normalize both prognosis and quality of life. In ...this article, each key team member of all the medical disciplines of a multidisciplinary health care team at the Hamburg Marfan center gives a personal account of his or her contribution in the management of patients with MFS. The authors show how, with the support of health care managers, key team members organize themselves in an organizational structure to create a common meaning, to maximize therapeutic success for patients with MFS. First, we show how the initiative and collaboration of patient representatives, scientists, and physicians resulted in the foundation of Marfan centers, initially in the US and later in Germany, and how and why such centers evolved over time. Then, we elucidate the three main structural elements; a team of coordinators, core disciplines, and auxiliary disciplines of health care. Moreover, we explain how a multidisciplinary health care team integrates into many other health care structures of a university medical center, including external quality assurance; quality management system; clinical risk management; center for rare diseases; aorta center; health care teams for pregnancy, for neonates, and for rehabilitation; and in structures for patient centeredness. We provide accounts of medical goals and standards for each core discipline, including pediatricians, pediatric cardiologists, cardiologists, human geneticists, heart surgeons, vascular surgeons, vascular interventionists, orthopedic surgeons, ophthalmologists, and nurses; and of auxiliary disciplines including forensic pathologists, radiologists, rhythmologists, pulmonologists, sleep specialists, orthodontists, dentists, neurologists, obstetric surgeons, psychiatrist/psychologist, and rehabilitation specialists. We conclude that a multidisciplinary health care team is a means to maximize therapeutic success.
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