Citations

OBJECTIVE—The deuterated water method uses the ratio of deuterium on carbons 5 and 2 (C5/C2) or 3 and 2 (C3/C2) to estimate the fraction of glucose derived from gluconeogenesis. The current studies determined whether C3 and C5 glucose enrichment is influenced by processes other than gluconeogenesis. RESEARCH DESIGN AND METHODS—Six nondiabetic subjects were infused with [3,5-2H2]glucose and insulin while glucose was clamped at ∼5 mmol/l; the C5-to-C3 ratio was measured in the in UDP-glucose pool using nuclear magnetic resonance and the acetaminophen glucuronide method. RESULTS—Whereas the C5-to-C3 ratio of the infusate was 1.07, the ratio in UDP-glucose was <1.0 in all subjects both before (0.75 ± 0.07) and during (0.67 ± 0.05) the insulin infusion. CONCLUSIONS—These data indicate that the deuterium on C5 of glucose is lost more rapidly relative to the deuterium on C3. The decrease in the C5-to-C3 ratio could result from exchange of the lower three carbons of fructose-6-phosphate with unlabeled three-carbon precursors via the transaldolase reaction and/or selective retention of the C3 deuterium at the level of triosephosphate isomerase due to a kinetic isotope effect. After ingestion of 2H2O, these processes would increase the enrichment of C5 and decrease the enrichment of C3, respectively, with the former causing an overestimation of gluconeogenesis using the C2-to-C5 ratio and the latter an underestimation using the C3-to-C2 ratio. Future studies will be required to determine whether the impact of these processes on the measurement of gluconeogenesis differs among the disease states being evaluated (e.g., diabetes or obesity).

Abstract Current users of postmenopausal hormones (PMH) have ∼30% to 40% lower risk of colorectal cancer (CRC), although associations with specific types of hormones have been inconsistent. Further, it is not clear whether some tumor types have a different risk. We conducted a case-control study to examine the relationship between PMH and CRC. Cases (n = 1,004), ages 50 to 74 years, were identified from the Surveillance Epidemiology and End Results registry in Washington from 1998 to 2002; controls (n = 1,062) were randomly selected from population lists. Case tissue samples were obtained for microsatellite instability (MSI) analyses. Interviews collected risk-factor data for CRC, including detailed information on PMH. Multivariable logistic regression models estimated odds ratios (OR) and 95% confidence intervals (95% CI). Current use of any PMH was associated with a 20% reduction in CRC risk (95% CI 0.6–0.9). This reduction in risk was limited to women who had taken estrogen plus progestin (EP) preparations only (OR = 0.6, 95% CI 0.5–0.9); there was no association with estrogen-only (E alone) use (OR = 0.9, 95% CI 0.7–1.1). For women with MSI-low or MSI-stable tumors, there was a statistically significant 40% reduction in CRC risk associated with EP use (95% CI 0.4–0.9); there was no clear association with MSI-high tumors. EP use was associated with a decreased risk of CRC; however, there seemed to be no association with E alone data that are consistent with the recent Women's Health Initiative findings. Progestin may enhance the estrogenic effect of conjugated estrogen so the combination may be more biologically active in the colon than E alone. [Cancer Res 2007;67(15):7534–9]

Abstract Recent evidence suggests that there is etiologic heterogeneity among the various subtypes of lymphoid neoplasms. However, epidemiologic analyses by disease subtype have proven challenging due to the numerous clinical and pathologic schemes used to classify lymphomas and lymphoid leukemias over the last several decades. On behalf of the International Lymphoma Epidemiology Consortium (InterLymph) Pathology Working Group, we present a proposed nested classification of lymphoid neoplasms to facilitate the analysis of lymphoid neoplasm subtypes in epidemiologic research. The proposed classification is based on the World Health Organization classification of lymphoid neoplasms and the International Classification of Diseases–Oncology, Third Edition (ICD-O-3). We also provide a translation into the proposed classification from previous classifications, including the Working Formulation, Revised European-American Lymphoma (REAL) classification, and ICD-O-2. We recommend that epidemiologic studies include analyses by lymphoma subtype to the most detailed extent allowable by sample size. The standardization of groupings for epidemiologic research of lymphoma subtypes is essential for comparing subtype-specific reports in the literature, harmonizing cases within a single study diagnosed using different systems, as well as combining data from multiple studies for the purpose of pooled analysis or meta-analysis, and will probably prove to be critical for elucidating etiologies of the various lymphoid neoplasms.

AbstractA role for genetic susceptibility in non-Hodgkin lymphoma (NHL) is supported by the accumulating evidence of common genetic variations altering NHL risk. However, the pattern of NHL heritability remains poorly understood. We conducted a pooled analysis of 10 211 NHL cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph) to evaluate NHL risk among those with hematopoietic malignancies in first-degree relatives. Odds ratios (ORs) and 95% confidence intervals (CIs) of NHL and its subtypes were estimated from unconditional logistic regression models with adjustment for confounders. NHL risk was elevated for individuals who reported first-degree relatives with NHL (OR = 1.5; 95% CI = 1.2-1.9), Hodgkin lymphoma (OR = 1.6; 95% CI = 1.1-2.3), and leukemia (OR = 1.4; 95% CI = 1.2-2.7). Risk was highest among individuals who reported a brother with NHL (OR = 2.8; 95% CI = 1.6-4.8) and was consistent for all NHL subtypes evaluated. If a first-degree relative had Hodgkin lymphoma, NHL risk was highest if the relative was a parent (OR = 1.7; 95% CI = 1.0-2.9). If a first-degree relative had leukemia, NHL risk was highest among women who reported a sister with leukemia (OR = 3.0; 95% CI = 1.6-5.6). The pattern of NHL heritability appeared to be uniform across NHL subtypes, but risk patterns differed by specific hematopoietic malignancies and the sex of the relative, revealing critical clues to disease etiology.

Abstract Background: The International Lymphoma Epidemiology Consortium (InterLymph) provides an opportunity to analyze the relationship between cigarette smoking and non-Hodgkin lymphoma with sufficient statistical power to consider non-Hodgkin lymphoma subtype. The results from previous studies of this relationship have been inconsistent, likely due to the small sample sizes that arose from stratification by disease subtype. To clarify the role of cigarette smoking in the etiology of non-Hodgkin lymphoma, we conducted a pooled analysis of original patient data from nine case-control studies of non-Hodgkin lymphoma conducted in the United States, Europe, and Australia. Methods: Original data were obtained from each study and uniformly coded. Risk estimates from fixed-effects and two-stage random-effects models were compared to determine the impact of interstudy heterogeneity. Odds ratios (OR) and 95% confidence intervals (95% CI) were derived from unconditional logistic regression models, controlling for study center, age, sex, and race. Results: In our pooled study population of 6,594 cases and 8,892 controls, smoking was associated with slightly increased risk estimates (OR, 1.07; 95% CI, 1.00-1.15). Stratification by non-Hodgkin lymphoma subtype revealed that the most consistent association between cigarette smoking and non-Hodgkin lymphoma was observed among follicular lymphomas (n = 1452). Compared with nonsmokers, current smokers had a higher OR for follicular lymphoma (1.31; 95% CI, 1.12-1.52) than former smokers (1.06; 95% CI, 0.93-1.22). Current heavy smoking (≥36 pack-years) was associated with a 45% increased OR for follicular lymphoma (1.45; 95% CI, 1.15-1.82) compared with nonsmokers. Conclusions: Cigarette smoking may increase the risk of developing follicular lymphoma but does not seem to affect risk of the other non-Hodgkin lymphoma subtypes we examined. Future research is needed to determine the biological mechanism responsible for our subtype-specific results.

Abstract Prostate cancer is a leading and increasingly prevalent cause of cancer death in men. Whereas family history of disease is one of the strongest prostate cancer risk factors and suggests a hereditary component, the predisposing genetic factors remain unknown. We first showed that KLF6 is a tumor suppressor somatically inactivated in prostate cancer and since then, its functional loss has been further established in prostate cancer cell lines and other human cancers. Wild-type KLF6, but not patient-derived mutants, suppresses cell growth through p53-independent transactivation of p21. Here we show that a germline KLF6 single nucleotide polymorphism, confirmed in a tri-institutional study of 3,411 men, is significantly associated with an increased relative risk of prostate cancer in men, regardless of family history of disease. This prostate cancer–associated allele generates a novel functional SRp40 DNA binding site and increases transcription of three alternatively spliced KLF6 isoforms. The KLF6 variant proteins KLF6-SV1 and KLF6-SV2 are mislocalized to the cytoplasm, antagonize wtKLF6 function, leading to decreased p21 expression and increased cell growth, and are up-regulated in tumor versus normal prostatic tissue. Thus, these results are the first to identify a novel mechanism of self-encoded tumor suppressor gene inactivation and link a relatively common single nucleotide polymorphism to both regulation of alternative splicing and an increased risk in a major human cancer.

ABSTRACTSignaling lymphocytic activation molecule (SLAM, CD150) is the universal morbillivirus receptor. Based on the identification of measles virus (MV) hemagglutinin (H) amino acids supporting human SLAM-dependent cell entry, we mutated canine distemper virus (CDV) H and identified residues necessary for efficient canine SLAM-dependent membrane fusion. These residues are located in two nearby clusters in a new CDV H structural model. To completely abolish SLAM-dependent fusion, combinations of mutations were necessary. We rescued a SLAM-blind recombinant CDV with six mutations that did not infect ferret peripheral blood mononuclear cells while retaining full infectivity in epithelial cells.