A repeating fast radio burst.

Fast radio bursts are millisecond-duration astronomical radio pulses of unknown physical origin that appear to come from extragalactic distances. Previous follow-up observations have failed to find additional bursts at the same dispersion measure (that is, the integrated column density of free electrons between source and telescope) and sky position as the original detections. The apparent non-repeating nature of these bursts has led to the suggestion that they originate in cataclysmic events. Here we report observations of ten additional bursts from the direction of the fast radio burst FRB 121102. These bursts have dispersion measures and sky positions consistent with the original burst. This unambiguously identifies FRB 121102 as repeating and demonstrates that its source survives the energetic events that cause the bursts. Additionally, the bursts from FRB 121102 show a wide range of spectral shapes that appear to be predominantly intrinsic to the source and which vary on timescales of minutes or less. Although there may be multiple physical origins for the population of fast radio bursts, these repeat bursts with high dispersion measure and variable spectra specifically seen from the direction of FRB 121102 support an origin in a young, highly magnetized, extragalactic neutron star.

Role of the UGT2B17 deletion in exemestane pharmacogenetics.

Exemestane (EXE) is an aromatase inhibitor used for the prevention and treatment of breast cancer. The major metabolic pathway for EXE is reduction to form the active 17ß-dihydro-EXE (17ß-DHE) and subsequent glucuronidation to 17ß-hydroxy-EXE-17-O-ß-D-glucuronide (17ß-DHE-Gluc) by UGT2B17. The aim of the present study was to determine the effects of UGT2B17 copy number variation on the levels of urinary and plasma 17ß-DHE-Gluc and 17ß-DHE in patients taking EXE. Ninety-six post-menopausal Caucasian breast cancer patients with ER+ breast tumors taking 25 mg EXE daily were recruited into this study. UGT2B17 copy number was determined by a real-time PCR copy number variant assay and the levels of EXE, 17ß-DHE and 17ß-DHE-Gluc were quantified by UPLC/MS in patients' urine and plasma. A 39-fold decrease (P<0.0001) in the levels of creatinine-adjusted urinary 17ß-DHE-Gluc was observed among UGT2B17 (*2/*2) subjects vs subjects with the UGT2B17 (*1/*1) genotype. The plasma levels of 17ß-DHE-Gluc was decreased 29-fold (P<0.0001) in subjects with the UGT2B17 (*2/*2) genotype vs subjects with UGT2B17 (*1/*1) genotype. The levels of plasma EXE-adjusted 17ß-DHE was 28% higher (P=0.04) in subjects with the UGT2B17 (*2/*2) genotype vs subjects with the UGT2B17 (*1/*1) genotype. These data indicate that UGT2B17 is the major enzyme responsible for 17ß-DHE-Gluc formation in vivo and that the UGT2B17 copy number variant may play a role in inter-individual variability in 17ß-DHE levels in vivo.

Limits on Anisotropy in the Nanohertz Stochastic Gravitational Wave Background.

The paucity of observed supermassive black hole binaries (SMBHBs) may imply that the gravitational wave background (GWB) from this population is anisotropic, rendering existing analyses suboptimal. We present the first constraints on the angular distribution of a nanohertz stochastic GWB from circular, inspiral-driven SMBHBs using the 2015 European Pulsar Timing Array data. Our analysis of the GWB in the ~2-90 nHz band shows consistency with isotropy, with the strain amplitude in l>0 spherical harmonic multipoles ≲40% of the monopole value. We expect that these more general techniques will become standard tools to probe the angular distribution of source populations.

An isolated case of lissencephaly caused by the insertion of a mitochondrial genome-derived DNA sequence into the 5' untranslated region of the PAFAH1B1 (LIS1) gene.

A 130 base pair (bp) insertion (g.-8delCins130) into the 5' untranslated region of the PAFAH1B1 (LIS1) gene, seven nucleotides upstream of the translational initiation site, was detected in an isolated case of lissencephaly. The inserted DNA sequence exhibited perfect homology to two non-contiguous regions of the mitochondrial genome (8479 to 8545 and 8775 to 8835, containing portions of two genes, ATP8 and ATP6 ), as well as near-perfect homology (1 bp mismatch) to a nuclear mitochondrial pseudogene (NUMT) sequence located on chromosome 1p36. This lesion was not evident on polymerase chain reaction (PCR) sequence analysis of either parent, indicating that the mutation had occurred de novo in the patient. Experiments designed to distinguish between a mitochondrial and a nuclear genomic origin for the inserted DNA sequence were, however, inconclusive. Mitochondrial genome sequences from both the patient and his parents were sequenced and found to be identical to the sequence inserted into the PAFAH1B1 gene. Analysis of parental PCR products from the chromosome 1-specific NUMT were also consistent with the interpretation that the inserted sequence had originated directly from the mitochondrial genome. The chromosome 1-specific NUMT in the patient proved to be refractory to PCR analysis, however, suggesting that this region of chromosome 1 could have been deleted or rearranged. Although it remains by far the most likely scenario, in the absence of DNA sequence information from the patient's own chromosome 1-specific NUMT, we cannot unequivocally confirm that the 130 bp insertion originated from mitochondrial genome rather than from the NUMT.

Design and evaluation of a new synthetic wrist procedural simulator (Wristsim®) for training of distal radius fracture fixation by volar plating.

Legislation concerning workload of surgical trainees and pressure to reduce learning curves have forced us reconsider surgical training. Our goal was to evaluate a synthetic procedural simulator for teaching open reduction and internal fixation (ORIF) of distal radius fractures (DRF). Twenty surgeons used a synthetic procedural simulator (Wristsim®) made by 3D printing for ORIF of DRF with a volar plate (Newclip Technics®). The evaluation consisted of grading the simulator's realism compared to the surgeons' own experience with surgery on cadavers. The Wristsim® was graded 5.10/10, compared to 8.18/10 for the cadaver specimen for introduction of the plate under pronator quadratus. For fracture reproduction, Wristsim® scored 6.40/10, with the cadaver specimen scoring 7.15/10. For fracture reduction, Wristsim® scored 5.62/10, with the cadaver specimen scoring 7.38/10. Plate application was scored 7.05/10 for Wristsim® and 8.23/10 for the cadaver. Drilling was scored 6.60/10 for the Wristsim® and 8.23/10 for the cadaver. Screw fixation was scored 7.40/10 for the Wristsim® and 8.12/10 for the cadaver. Our results demonstrated that Wristsim® is still inferior to a cadaver specimen for teaching ORIF by volar plating of DRF. A new model of Wristsim® is being developed that will address shortcomings in pronator quadratus thickness, passive ROM in flexion/extension and bone size.

Rotational stability test for the diagnosis of radial collateral ligament rupture in the fingers: Anatomical study.

Diagnosing rupture of the radial collateral ligament (RCL) of the finger metacarpophalangeal (MCP) joints is difficult. The aim of this cadaver study was to validate a rotational test for the MCP after RCL transection. With the MCP and proximal interphalangeal joints in flexion, rotation along the axis of the proximal phalanx was applied through an extended distal interphalangeal joint to 36 cadaver fingers. Each finger's pulp described an arc of pronation and supination that was noted on the palm. The test was repeated three times: before transection, after transection of the proper collateral ligament (CL) and after transection of both the proper and accessory CLs. Rotational arcs were measured in pronation and supination. Mean length of the pronation arc after transection of the main RCL was 17.53mm, while it was only 12.41mm before transection for the supination arc. Mean length of the pronation arc after transection of both CLs was 22.83mm compared to only 11.93mm before transection. Our results show a significant difference in pronation stability of the MCP joint after transection of the RCL proper. We can conclude that this rotational stability test is a valid test for diagnosing RCL rupture in MCP joints.

Tobacco carcinogen-detoxifying enzyme UGT1A7 and its association with orolaryngeal cancer risk.

BACKGROUND: UDP-glucuronosyltransferase 1A7 (UGT1A7) detoxifies several tobacco carcinogens. We determined whether UGT1A7 expression is observed in normal orolaryngeal tissue and whether UGT1A7 allelic variations are associated with the risk for orolaryngeal cancer. METHODS: UGT1A7 expression in normal orolaryngeal tissue was determined by semiquantitative reverse transcription-polymerase chain reaction (PCR). Buccal cell DNA isolated from 194 case subjects with orolaryngeal cancer and from 388 control subjects who were matched by sex, age, and race was subjected to UGT1A7 genotyping with the use of combined PCR-restriction fragment length polymorphism and allelic discrimination analysis. All statistical tests were two-sided. RESULTS: UGT1A7 messenger RNA was expressed at similar levels in the esophagus, tongue, tonsil, floor of the mouth, and larynx. Genotyping revealed the presence of three variant reduced-activity UGT1A7 alleles in both Caucasians and African-Americans. Individuals with any of the predicted low-activity UGT1A7 genotypes had an increased risk of orolaryngeal cancer (odds ratio [OR] = 3.7; 95% confidence interval [CI] = 1.7 to 8.7) relative to subjects with the wild-type genotype. Both Caucasians and African-Americans with the low-activity genotypes had statistically significantly increased orolaryngeal cancer risk compared with Caucasians and African-Americans with the wild-type genotype (OR = 2.8 [95% CI = 1.1 to 7.6] and OR = 6.2 [95% CI = 1.2 to 31], respectively). For subjects with the predicted low-activity genotypes, the risks of oral cavity cancer (OR = 4.2; 95% CI = 1.7 to 10) and laryngeal cancer (OR = 3.7; 95% CI = 0.99 to 14) were similar. There was no association between UGT1A7 genotype and orolaryngeal cancer risk in never smokers, whereas subjects with predicted low-activity UGT1A7 genotypes who were light smokers (OR = 3.7; 95% CI = 1.1 to 12) or heavy smokers (OR = 6.1; 95% CI = 1.5 to 25) had an increased risk. CONCLUSIONS: The tissue expression of UGT1A7 is consistent with the possibility of a physiologic role in orolaryngeal cancer. Variations in the UGT1A7 gene that reduce UGT1A7 activity may affect the risk of smoking-related orolaryngeal cancer.

Mechanism of decrease of protein synthesis by sodium cyanate in murine P388 leukemia cells.

Sodium cyanate is a selective in vivo inhibitor of protein synthesis in a variety of mammalian tumor cells without a corresponding effect on the normal tissues of tumor-bearing animals. The in vivo decrease of protein synthesis observed 4 h post-NaOCN i.p. administration in the murine P388 leukemia cell cannot be explained by decreased amino acid pools in the mouse peritoneal cavity. In addition, the decrease in protein synthesis observed with NaOCN in isolated P388 cells was shown not to be secondary to (a) alterations in the kinetics of amino acid transport or (b) effects on total nucleotide pools. The incorporation of [14C]phenylalanine in P388 cell-free lysates from NaOCN-pretreated mice was significantly decreased to approximately 55% of control lysates in the presence of exogenous amino acids. The addition of exogenous calf liver tRNA to the lysates did not alter this result. However, no difference was observed in polyuridylic acid-directed [14C]phenylalanine incorporation into polypeptides in micrococcal nuclease-treated P388 lysates from NaOCN-pretreated or control mice. Quaternary initiation complex (48S) formation and mRNA synthesis were found to be significantly decreased by 35 and 38%, respectively, in P388 cells from NaOCN-pretreated mice. DNA synthesis was decreased by 66% of control at 1 h and 62% at 4 h post-NaOCN i.p. administration. No apparent effect with NaOCN was observed on total RNA synthesis in P388 cells. These results suggest that the decrease in P388 cell protein synthesis observed with NaOCN in vivo appears to be due to alterations manifested in the synthesis of cellular mRNA and protein synthesis initiation processes. NaOCN does not appear to affect the P388 cell ribosomal machinery, tRNA, or protein synthesis elongation processes.

Frequent and specific mutations of the rat p53 gene in hepatocarcinomas induced by tamoxifen.

Tamoxifen (TAM) is a triphenylethylene antiestrogen used for the treatment, and in clinical trials for the prevention, of breast cancer in women. In rats, TAM is a strong liver carcinogen which induces the formation of liver DNA adducts. The DNA of 24 hepatocarcinomas (HCCs) collected at necropsy from individual female Sprague-Dawley rats that were given 22.6 mg/kg TAM daily for 12 months was studied for the presence of mutations in exons 5-9 of the p53 gene by single-strand conformation polymorphism and DNA sequencing analysis. The sequences of introns 5-8 of the rat p53 gene were determined in order to design primers homologous to regions located in these introns. p53 mutations were found in 50% (12 of 24) of the HCCs. These mutations were all specifically clustered in two sites, codons 231 (exon 6-7) and 294 (exon 8). Nine HCCs contained a transition from adenine to guanine in the second base of codon 231 (CAC to CGC), which resulted in a histidine to arginine amino acid substitution; 4 HCCs contained a nonmiscoding transition from cytosine to thymidine in the third base of codon 294 (TGC to TGT; cysteine to cysteine). One HCC contained both mutations. The present report supports previous observations on the genotoxicity of TAM in rodents and raises concerns about its use as a chemopreventive agent against breast cancer in women.

The regulation of translation by the 5' untranslated region of Xenopus c-myc I mRNA during early development.

The translational efficiency of chloramphenicol acetyltransferase (CAT) mRNA containing 5' untranslated region (UTR) sequences of Xenopus c-myc I mRNA was examined in the Xenopus oocyte and early embryo. In contrast to their reduced translation in the oocyte, CAT mRNAs containing 5' UTR sequences located between the c-myc I P0 and P2 promoters translate as efficiently as CAT mRNA controls when injected into early embryos. This pattern of differential regulation of c-myc I translation is similar to that observed for mouse c-myc 5' UTR-containing CAT transcripts during Xenopus oogenesis and early embryogenesis [Lazarus, P., Parkin, N. & Sonenberg, N. (1988). Oncogene, 3, 517-521]. Oocyte-specific translational inhibition was not observed for CAT mRNAs containing c-myc I 5' UTR sequences located 3' of the P2 promoter. No significant alteration in c-myc I 5' UTR/CAT mRNA stability was observed in the oocyte as compared with CAT mRNA controls. The significance of this promoter-dependent translational regulation with respect to c-myc expression and early Xenopus development is discussed.

Developmental regulation of translation by the 5' noncoding region of murine c-myc mRNA in Xenopus laevis.

The translational efficiency of chloramphenicol acetyltransferase (CAT) mRNA containing a 5' noncoding sequence derived from exon 1 of the murine c-myc gene (360CAT) has been examined at different stages of Xenopus egg development. In contrast to its reduced translation in the Xenopus oocyte, 360CAT mRNA is translated as efficiently as CAT mRNA when injected into either mature Xenopus eggs or Xenopus embryos. No significant alteration of 360CAT mRNA stability was observed up to 10 h post-fertilization in Xenopus embryos as compared to that of CAT mRNA. The increase in 360CAT mRNA translational efficiency in Xenopus embryos was not observed with CAT mRNAs possessing other inhibitory 5' noncoding sequences. The increase in 360CAT mRNA translational efficiency is attributed to a trans-acting factor synthesized or activated following Xenopus oocyte maturation. The possible significance of the 5' noncoding region of c-myc mRNA in developmental expression of c-myc is discussed.

Characterization of L-threonine and L-glutamine transport in murine P388 leukemia cells in vitro. Presence of an N-like amino acid transport system.

The transport of L-threonine and L-glutamine into murine P388 leukemia cells has been characterized. Threonine appears to be a specific substrate for a Na+-dependent amino acid transport system similar to system ASC of the HTC hepatoma cell. Threonine transport is uninhibited by 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid and alpha-(methylamino)isobutyric acid, shows a pattern of transport similar to that seen in HTC hepatoma cells over the pH range of 5.5-7.5, and is inhibited by L-serine and L-cysteine. Approximately two-thirds of glutamine transport into P388 cells also appears to enter P388 cells via this ASC-analogous system. However, based upon (a) inhibition studies with threonine (where the K1 of threonine inhibition of glutamine transport was 7-fold the Km of threonine transport), (b) inhibition analysis of glutamine transport with various amino acids and amino acid analogues, and (c) different patterns of transport between threonine and glutamine over the pH range of 5.5-7.5, approximately one-third of glutamine transport can be attributed to a second Na+-dependent amino acid transport system. This system appears to be similar to the system N of rat hepatocytes. Glutamine and threonine do not appear to enter P388 cells via systems A or L to any significant degree. P388 cells do not appear to exhibit 'adaptive regulation' of amino acid transport. Differences in 'adaptive regulation' could therefore not be utilized for comparing threonine and glutamine transport.

Further studies on amino acid transport in murine P388 leukemia cells in vitro. Presence of system y+.

The transport of glycine and L-lysine into murine P388 leukemia cells has been examined. Glycine transport appears to be shared by both systems A and ASC in P388 cells. Glycine transport is Na+-dependent and is effectively blocked by alpha-(methylamino)isobutyric acid, threonine and alanine but only a marginal reduction in transport is seen with 100-fold excess cold 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid. System gly is not expressed in P388 cells. Lysine is largely transported by a Na+-independent, pH-insensitive system with a Km of 0.079 mM. Lysine transport is relatively unaffected by the addition of 100-fold excess cold alpha-(methylamino)isobutyric acid, 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid and the anionic amino acids, L-glutamate and L-aspartate. A partial inhibition of lysine transport was observed with L-threonine and L-leucine while L-arginine and L-histidine radically decreased lysine transport. Lysine appears to be transported by a system similar to the system y+ seen in cultured human fibroblasts, Ehrlich ascites cells, and hepatoma cell lines.

Aldolase-DNA interactions in a SEWA cell system.

In this report we demonstrate the novel finding that aldolase A interacts with DNA sequences in mouse SEWA sarcoma cells. This interaction was initially observed through the identification of a 40 kDa protein which was eluted from a DNA affinity chromatography column consisting of the long terminal repeat (LTR) of the endogenous intracisternal A-type particle (IAP). Microsequencing analysis identified this 40 kDa protein as the glycolytic enzyme, aldolase A. The use of specific anti-aldolase antibodies enabled the identification and subsequent purification of aldolase from the nuclear protein fraction of two SEWA sublines, one that is adherent and one that grows in suspension. In order to confirm our initial finding that aldolase is capable of interacting with DNA, proteins from each subline were immunopurified with anti-aldolase antibodies, eluted and then tested for their ability to interact with IAP-LTR DNA sequences. Interestingly, only aldolase derived from the anchorage dependent SEWA cells was capable of interacting with the IAP-LTR, however, several cell lines derived from human tumors also exhibited this activity. Subsequent studies revealed the ability of aldolase to interact with some but not every DNA sequence tested, implying that there may be a minimal DNA conformation and/or sequence requirement for this activity. The presence of aldolase A in the nuclei and its ability to interact with certain DNA sequences suggest a novel role for this metabolic enzyme.

Recombinant hirudin (lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction: results of the HIT-4 trial.

OBJECTIVES: The purpose of this study was to compare recombinant hirudin and heparin as adjuncts to streptokinase thrombolysis in patients with acute myocardial infarction (AMI). BACKGROUND: Experimental studies and previous small clinical trials suggest that specific thrombin inhibition improves early patency rates and clinical outcome in patients treated with streptokinase. METHODS: In a randomized double-blind, multicenter trial, 1,208 patients with AMI < or =6 h were treated with aspirin and streptokinase and randomized to receive recombinant hirudin (lepirudin, i.v. bolus of 0.2 mg/kg, followed by subcutaneous (s.c.) injections of 0.5 mg/kg b.i.d. for 5 to 7 days) or heparin (i.v. placebo bolus, followed by s.c. injections of 12,500 IU b.i.d. for 5 to 7 days). A total of 447 patients were included in the angiographic substudy in which the primary end point, 90-min Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 of the infarct-related artery, was evaluated, while the other two-thirds served as "safety group" in which only clinical end points were evaluated. As an additional efficacy parameter the ST-segment resolution at 90 and 180 min was measured in all patients. RESULTS: TIMI flow grade 3 was observed in 40.7% in the lepirudin and in 33.5% in the heparin group (p = 0.16), respectively. In the entire study population the proportion of patients with complete ST resolution at 90 min (28% vs. 22%, p = 0.05) and at 180 min (52% vs. 48%, p = 0.18) after start of therapy tended to be higher in the lepirudin group. There was no significant difference in the incidence of hemorrhagic stroke (0.2% vs. 0.3%) or total stroke (1.2% vs. 1.5%), reinfarction rate (4.6% vs. 5.1%) and total mortality rate (6.8% vs. 6.4%) at 30 days, as well as the combined end point of death, nonfatal stroke, nonfatal reinfarction, rescue-percutaneous transluminal coronary angioplasty and refractory angina (22.7 vs. 24.3%) were not statistically different between the two groups. CONCLUSIONS: Lepirudin as adjunct to thrombolysis with streptokinase did not significantly improve restoration of blood flow in the infarct vessel as assessed by angiography, but was associated with an accelerated ST resolution. There was no increase in the risk of major bleedings with lepirudin compared to heparin.

Genetic analysis of microsomal epoxide hydrolase gene and its association with lung cancer risk.

The human microsomal epoxide hydrolase (EH) gene contains polymorphic alleles, which may be linked to increased risk for tobacco-related lung cancer. The purpose of this study is to screen new polymorphisms and determine whether these polymorphisms can be used to predict individual susceptibility to lung cancer. The polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis was used to screen for polymorphisms in the coding region of the EH gene. Eleven polymorphisms, including previously reported polymorphisms, were identified and the prevalence of these variants was assessed in at least 50 healthy Caucasians and African-Americans. Among the 11 polymorphisms, the prevalence of the amino acid-changing EH polymorphisms in codons 43, 113 and 139 was examined in 182 Caucasian incident cases with primary lung cancer, as well as in 365 frequency-matched controls to examine the role of EH polymorphisms in lung cancer risk. A significant increase in lung cancer risk was observed for predicted high EH activity genotypes (odds ratio (OR) 2.3, 95% confidence interval (CI) 1.2-4.3) as compared with low EH activity genotypes. This association was more pronounced among patients with lung adenocarcinoma (OR 4.7, 95% CI 1.7-13.1). These results suggest that the EH polymorphism plays an important role in lung cancer risk and is linked to tobacco smoke exposure.

Association between glutathione S-transferase pi genetic polymorphisms and oral cancer risk.

Polymorphisms in the gene encoding the glutathione S-transferase (GST) pi metabolizing enzyme have previously been associated with susceptibility to various cancers. In this study, the importance of GSTP1 genotypes as determinants of risk for oral cancer was assessed by examining the prevalence of GSTP1 alleles in 157 incident oral cancer cases and 260 non-cancer control individuals frequency-matched by race, sex, and age at diagnosis (+/- 5 years). The GSTP1*A, GSTP1*B, GSTP1*C, and GSTP1*D alleles were elucidated by polymerase chain reaction-restriction fragment length polymorphism analysis of polymorphisms present in codons 105 (isoleucine:valine) and 114 (alanine:valine) of the GSTP1 gene. Increased risk for oral cancer was observed in individuals who were homozygous for any combination of GSTP1 polymorphic alleles (i.e. *B, *C, and/or *D alleles; odds ratio = 2.4, 95% confidence interval = 1.2-4.8). Similar risk was observed in both Caucasians (odds ratio = 2.6, 95% confidence interval = 1.1-6.2) and African-Americans (odds ratio = 2.3, 95% CI = 0.68-7.5). A greater risk was observed in individuals with the GSTP1 (Var/Var) genotype who were exposed to low levels of smoking (i.e. < or = 20 pack-years [py], odds ratio = 3.4, 95% confidence interval = 1.1-11) than among heavier smokers (i.e. > 20 pack-years [py], odds ratio = 1.4, 95% confidence interval = 0.48-4.0). These results suggest that GSTP1 genotype may play a role in risk for oral cancer particularly among lighter smokers.

Comparison of GSTM polymorphisms and risk for oral cancer between African-Americans and Caucasians.

Two members of the mu class of glutathione S-transferase (GST) genes, GSTM1 and GSTM3, have polymorphic alleles which have been associated with altered levels of GST mu protein expression and may be linked to increased risk for several tobacco-related cancers. Oral cancer is a tobacco-related disease that affects African-American men at a significantly higher incidence than Caucasian men. To examine the potential role of GSTM polymorphisms in risk for oral cancer in African-Americans and Caucasians, the prevalences of the GSTM1 null and GSTM3 intron 6 polymorphisms were examined in 63 African-American and 101 Caucasian patients with histologically confirmed primary oral cancer, as well as in 133 African-American and 213 Caucasian matched control subjects. In African-Americans, the odds ratio for oral cancer associated with the GSTM1 (0/0) genotype was 3.1 [95% confidence interval (CI) = 1.1-8.5], with the association between the GSTM1 (0/0) genotype and oral cancer risk strongest in heavy smokers [i.e. > 24 pack-years; odds ratio (OR) = 5.4, 95% CI = 1.2-24]. Using the potentially most protective GSTM1 [+]/GSTM3 (B/B) genotype as the reference group, increased risk for oral cancer was observed in African-Americans with the GSTM1 [+]/GSTM3 [(A/A) + (A/B)] (OR = 2.2, 95% CI = 0.82-6.0), GSTM1 (0/0)/GSTM3 (B/B) (OR = 4.3, 95% CI = 1.1-16), and GSTM1 (0/0)/GSTM3 [(A/A) + (A/B)] (OR = 6.6, 95% CI = 1.2-38) genotypes (P < 0.01, trend test). No significant associations were observed between GSTM genotype and oral cancer risk in Caucasians. These results suggest that the GSTM1 null and GSTM3 intron 6 polymorphisms play an important role in risk for oral cancer among African-Americans and implicates the mu class of GSTs as important tobacco carcinogen detoxifying enzymes in this population.

CYP1A1 and GSTM1 polymorphisms and oral cancer risk.

The importance of both the CYP1A1 exon 7 (ile:val) and GSTM1 (0/0) polymorphisms in oral cancer susceptibility was assessed by examining polymorphic prevalences in 135 patients with oral cancer and 135 noncancer controls frequency-matched by age at diagnosis (+/- 5 years), race, sex, and institute of patient recruitment. The prevalence of the GSTM1 (0/0) genotype was approximately 51% in both cases and controls. The prevalence of the CYP1A1 (ile:val) polymorphism [including both the (ile/val) and (val/val) genotypes] was significantly higher in cases as compared to controls (17.6% versus 7.6%, respectively; crude odds ratio, 2.6; confidence interval, 1.2-5.7). No association was observed between polymorphic prevalence and levels of smoking or alcohol consumption in cases. These results suggest that the GSTM1 null genotype is not associated with oral cancer risk. These results also suggest that individuals with the CYP1A1 exon 7 ile:val polymorphism are at increased risk for oral cancer, and that this risk may not be influenced by differences in exposure to tobacco smoke.

Role of polymorphisms in codons 143 and 160 of the O6-alkylguanine DNA alkyltransferase gene in lung cancer risk.

O6-Alkylguanine DNA alkyltransferase (AGT) plays an important role in the repair of alkylating agent-induced DNA damage and protection from the carcinogenic effects of environmental agents. To examine the importance of the AGT codon 143 and codon 160 polymorphisms in risk for lung cancer and to assess the prevalence of these polymorphisms in different racial groups, we performed genotype analysis of lung cancer patients and matched controls. The prevalence of the AGT143Val allele in controls was 0.07 in Caucasians and 0.03 in African Americans. The AGT143Val allele was not detected in an unmatched Asian control cohort. The prevalence of the AGT160Arg variant allele was 0.01 in Caucasians, 0.02 in African Americans, and 0.03 in Asians. A marginally significant association was observed between the AGT codon 143 (isoleucine/valine) genotype and risk for lung cancer (odds ratio = 2.1; 95% confidence interval = 1.01-4.7). The prevalence of the AGT160Arg variant allele was similar in lung cancer cases versus matched controls. These results suggest that the AGT codon 143 polymorphism may play an important role in risk for lung cancer.