Biomedical subjects

Harry M Cullings

Publications and source records attributed to Harry M Cullings.

4 recordsLinked to original sources

PubMed2006

Heterozygous individuals bearing a founder mutation in the XPA DNA repair gene comprise nearly 1% of the Japanese population.

Individuals who are homozygotes for mutations in DNA repair genes are at high risk for cancer. It is not well documented, however, if the heterozygous carriers of the mutation are also predisposed to cancer. To address the issue, xeroderma pigmentosum (XP) in Japan is an interesting candidate because of three major reasons: XP is an autosomal recessive disorder with an enormously elevated risk of skin cancer, the frequency of XP patients is higher in Japan than in other parts of the world, and more than half of Japanese XP patients are homozygous for the same founder mutation in the XPA gene. We screened archival blood samples from Japanese individuals who resided in Hiroshima or Nagasaki. A simple PCR-RFLP method was developed that is highly specific for detection of XPA heterozygotes carrying the founder mutation. We identified nine XPA heterozygotes among 1,020 individuals screened for a prevalence of 0.88%. This rate, if representative, implies that there are about 1 million carriers of the XPA founder mutation in the Japanese population. Thus, investigation of their cancer risk may be warranted.

Adolescent↗

PubMed2006

Dose estimation for atomic bomb survivor studies: its evolution and present status.

In the decade after the bombings of Hiroshima and Nagasaki, several large cohorts of survivors were organized for studies of radiation health effects. The U.S. Atomic Bomb Casualty Commission (ABCC) and its U.S./Japan successor, the Radiation Effects Research Foundation (RERF), have performed continuous studies since then, with extensive efforts to collect data on survivor locations and shielding and to create systems to estimate individual doses from the bombs' neutrons and gamma rays. Several successive systems have been developed by extramural working groups and collaboratively implemented by ABCC and RERF investigators. We describe the cohorts and the history and evolution of dose estimation from early efforts through the newest system, DS02, emphasizing the technical development and use of DS02. We describe procedures and data developed at RERF to implement successive systems, including revised rosters of survivors, development of methods to calculate doses for some classes of persons not fitting criteria of the basic systems, and methods to correct for bias arising from errors in calculated doses. We summarize calculated doses and illustrate their change and elaboration through the various systems for a hypothetical example case in each city. We conclude with a description of current efforts and plans for further improvements.

Body Burden↗

PubMed2004

Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation.

PURPOSE: BRAF mutations are common in sporadic colorectal cancers (CRCs) with a DNA mismatch repair (MMR) deficiency that results from promoter methylation of hMLH1, whereas KRAS mutations are common in MMR proficient CRCs associated with promoter methylation of MGMT. The aim of this study was to further investigate the link between genetic alterations in the RAS/RAF/ERK pathway and an underlying epigenetic disorder. PATIENTS AND METHODS: Activating mutations of BRAF and KRAS were identified and correlated with promoter methylation of 11 loci, including MINT1, MINT2, MINT31, CACNA1G, p16(INK4a), p14(ARF), COX2, DAPK, MGMT, and the two regions in hMLH1 in 468 CRCs and matched normal mucosa. RESULTS: BRAF V599E mutations were identified in 21 (9%) of 234 CRCs, and KRAS mutations were identified in 72 (31%) of 234 CRCs. Mutations in BRAF and KRAS were never found in the same tumor. CRCs with BRAF mutations showed high-level promoter methylation in multiple loci, with a mean number of methylated loci of 7.2 (95% CI, 6.6 to 7.9) among 11 loci examined (P < .0001). Tumors with KRAS mutations showed low-level promoter methylation, and CRCs with neither mutation showed a weak association with promoter methylation, with an average number of methylated loci of 1.8 (95% CI, 1.5 to 2.1) and 1.0 (95% CI, 0.79 to 1.3), respectively. CONCLUSION: In CRC, the methylation status of multiple promoters can be predicted through knowledge of BRAF and, to a lesser extent, KRAS activating mutations, indicating that these mutations are closely associated with different patterns of DNA hypermethylation. These changes may be important events in colorectal tumorigenesis.

Aged↗

PubMed2004

Effect of recent changes in atomic bomb survivor dosimetry on cancer mortality risk estimates.

The Radiation Effects Research Foundation has recently implemented a new dosimetry system, DS02, to replace the previous system, DS86. This paper assesses the effect of the change on risk estimates for radiation-related solid cancer and leukemia mortality. The changes in dose estimates were smaller than many had anticipated, with the primary systematic change being an increase of about 10% in gamma-ray estimates for both cities. In particular, an anticipated large increase of the neutron component in Hiroshima for low-dose survivors did not materialize. However, DS02 improves on DS86 in many details, including the specifics of the radiation released by the bombs and the effects of shielding by structures and terrain. The data used here extend the last reported follow-up for solid cancers by 3 years, with a total of 10,085 deaths, and extends the follow-up for leukemia by 10 years, with a total of 296 deaths. For both solid cancer and leukemia, estimated age-time patterns and sex difference are virtually unchanged by the dosimetry revision. The estimates of solid-cancer radiation risk per sievert and the curvilinear dose response for leukemia are both decreased by about 8% by the dosimetry revision, due to the increase in the gamma-ray dose estimates. The apparent shape of the dose response is virtually unchanged by the dosimetry revision, but for solid cancers, the additional 3 years of follow-up has some effect. In particular, there is for the first time a statistically significant upward curvature for solid cancer on the restricted dose range 0-2 Sv. However, the low-dose slope of a linear-quadratic fit to that dose range should probably not be relied on for risk estimation, since that is substantially smaller than the linear slopes on ranges 0-1 Sv, 0-0.5 Sv, and 0- 0.25 Sv. Although it was anticipated that the new dosimetry system might reduce some apparent dose overestimates for Nagasaki factory workers, this did not materialize, and factory workers have significantly lower risk estimates. Whether or not one makes allowance for this, there is no statistically significant city difference in the estimated cancer risk.

Adolescent↗