Observations on the distribution of serum uric acid levels in participants of the Tecumseh, Michigan, Community Health Studies : A comparison of results of one method used at two different times and of two methods used simultaneously

Individuals participating in the Tecumseh Community Health Study, in 1959-1960 (TCHS I) and 1962-1965 (TCHS II), had serum uric acid determinations by an enzymatic spectrophotometric method, SUA(ES), as part of a comprehensive health examination.Among the 1633 male and 1725 female subjects, the mean serum uric acid concentration had increased by 0.32 mg per 100 ml for males, and by 0.18 for females, over the the average of 4.1 yr between determinations. It was found that, approximately, 40 per cent of subjects had a decrease, and 56 per cent, an increase, in serum uric acid concentration. The change was greater than plus or minus 2.0 mg per 100 ml for 28.7 per cent of males and 19.4 per cent of females. Decreases of as much as 8.2, and increases of as much as 9.9 mg per 100 ml were observed. How much of the average increase, in an average 4.1 yr interval between tests, is due to ageing, except for males in the age range of 10-19 yr, is problematical. It seems probably that most of the average increase was due to technical factors in performance of the test.In the study of 1962-1965, serum uric acid determinations were done by two methods. An automated colorimetric method was compared with an enzymatic spectrophotometric method. Both methods showed the same types of distribution curves of serum uric acid concentrations and curves of age-sex specific mean serum uric acid.The values obtained by the automated colorimetric method were slightly, but, consistently, higher to a statistically significant degree than those of the enzymatic spectro-photometric method.For 2092 male subjects, the mean SUA(AC) was 0.21 mg per 100 ml greater than the mean SUA(ES), while for 2104 females subjects, this difference was 0.14.Of 4196 study subjects, whose sera were tested by both methods, about 90.0 per cent showed an agreement of the two values within +/- 0.9 mg per 100 ml. However, 1.9 per cent of males and 1.6 per cent of females, had ES values which exceeded AC values by 2.0 mg per 100 ml, while 2.8 per cent of male and 2.3 per cent of female subjects had AC values greater than ES values by 2.0 mg per 100 ml. The extremes of differences range from 4.4 to 7.3 mg per 100 ml.The data in this paper gives us increased confidence in the essential validity of the mean age and sex distributions of serum uric acid values, from the Tecumseh Community Health Studies, published in an earlier paper [2].It is concluded that, for the purposes of population studies, the automated colorimetric method is more advantageous than the enzymatic spectrophotometric method, because of its lesser cost.Comparison of the results of the two studies emphasizes the problems of definition of hyperuricemia. Further mathematical analysis of the distribution curves obtained in such studies may lead to definitions of normo- and hyperuricemia of greater precision for clinical purposes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32701/1/0000068.pd

Age-sex specific prevalence of radiographic abnormalities of the joints of the hands, wrists and cervical spine of adult residents of the Tecumseh, Michigan, Community Health Study area, 1962-1965

Radiographs of the hands and wrists and cervical spine of 4415 residents of Tecumseh, Michigan, aged 16 yr and over, have been reviewed. Evidence of rheumatoid arthritis was observed in the hands and wrists of 0.19 per cent of males and 0.34 per cent of females. The prevalence of cervical spine changes, which could be attributed to rheumatoid arthritis or ankylosing spondylitis, was insignificant.Degenerative changes in both examined regions occurred much more frequently and showed a marked positive correlation with advancing age. Radiographic evidence of osteoarthrosis of the hands and wrists was observed in 19.5 per cent of males and 23 per cent of females. In the cervical spine, degenerative disc disease (16-19 per cent) was noted somewhat more frequently than osteoarthrosis (11 per cent).Among the other radiographic lesions which were observed, those of post traumatic changes, including amputation of digits, in the hands and wrists and fusion of cervical vertebral bodies, thought to represent a failure of segmentation in embryonic life, were most frequent.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32700/1/0000067.pd

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

The choice for EU theorists: Establishing a common framework for analysis

European Union (EU) studies have entered a highly contentious and, arguably, creative phase. A range of theoretical perspectives, seemingly quite highly differentiated from one another, now compete for influence and lsquospacersquo. However, the questions remain: is EU studies developing theories which are truly competing theories? Or is it developing theories that do not compete so much as they aim to explain distinctly different pieces of the EU puzzle? This paper responds directly to these two questions, while reviewing recent literature on EU governance. It argues, first, that we lack theories of EU governance that are true rivals; and, second, that leading models explain different outcomes at different levels in a multi-level system of governance. The result is somewhat phoney debates between compatible theories masquerading as rivals, and between lsquocomparative politicsrsquo and lsquointernational relationsrsquo approaches. Above all, perhaps, we find middle range theories posing as general or lsquometa-theoriesrsquo. In the absence of a plausible general theory of EU governance, theorists must choose precisely which type of outcome theywish to explain

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Renal cell carcinoma(RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival

Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN. We present a computational study determining the frequency and extent of alterations of the MYC network across the 33 human cancers of TCGA. These data, together with MYC, positively correlated pathways as well as mutually exclusive cancer genes, will be a resource for understanding MYC-driven cancers and designing of therapeutics