Newly diagnosed patients with advanced non-small cell lung cancer: A clinical description of those with moderate to severe depressive symptoms.

OBJECTIVES: The aims of this observational study were to 1) accrue newly diagnosed patients with advanced-stage non-small cell lung cancer (NSCLC) awaiting the start of first-line treatment and identify those with moderate to severe depressive symptoms and, 2) provide a clinical description of the multiple, co-occurring psychological and behavioral difficulties and physical symptoms that potentially exacerbate and maintain depressive symptoms. MATERIALS AND METHODS: Patients with stage IV NSCLC (N = 186) were enrolled in an observational study (ClinicalTrials.gov Identifier: NCT03199651) and completed the American Society of Clinical Oncology-recommended screening measure for depression (Patient Health Questionnaire-9 [PHQ-9]). Individuals with none/mild (n = 119; 64 %), moderate (n = 52; 28 %), and severe (n = 15; 8 %) depressive symptoms were identified. Patients also completed measures of hopelessness, generalized anxiety disorder (GAD) symptoms, stress, illness perceptions, functional status, and symptoms. RESULTS: Patients with severe depressive symptoms reported concomitant feelings of hopelessness (elevating risk for suicidal behavior), anxiety symptoms suggestive of GAD, and traumatic, cancer-specific stress. They perceived lung cancer as consequential for their lives and not controllable with treatment. Pain and multiple severe symptoms were present along with substantial functional impairment. Patients with moderate depressive symptoms had generally lower levels of disturbance, though still substantial. The most salient differences were low GAD symptom severity and fewer functional impairments for those with moderate symptoms. CONCLUSIONS: Depressive symptoms of moderate to severe levels co-occur in a matrix of clinical levels of anxiety symptoms, traumatic stress, impaired functional status, and pain and other physical symptoms. All of the latter factors have been shown, individually and collectively, to contribute to the maintenance or exacerbation of depressive symptoms. As life-extending targeted and immunotherapy use expands, prompt identification of patients with moderate to severe depressive symptoms, referral for evaluation, and psychological/behavioral treatment are key to maximizing treatment outcomes and quality of life for individuals with advanced NSCLC.

Understanding resolution limit of displacement Talbot lithography.

Displacement Talbot lithography (DTL) is a new technique for patterning large areas with sub-micron periodic features with low cost. It has applications in fields that cannot justify the cost of deep-UV photolithography, such as plasmonics, photonic crystals, and metamaterials and competes with techniques, such as nanoimprint and laser interference lithography. It is based on the interference of coherent light through a periodically patterned photomask. However, the factors affecting the technique's resolution limit are unknown. Through computer simulations, we show the mask parameter's impact on the features' size that can be achieved and describe the separate figures of merit that should be optimized for successful patterning. Both amplitude and phase masks are considered for hexagonal and square arrays of mask openings. For large pitches, amplitude masks are shown to give the best resolution; whereas, for small pitches, phase masks are superior because the required exposure time is shorter. We also show how small changes in the mask pitch can dramatically affect the resolution achievable. As a result, this study provides important information for choosing new masks for DTL for targeted applications.

Prognosis of uveal melanoma based on race in 8100 patients: The 2015 Doyne Lecture.

A retrospective, nonrandomized, interventional case series of 8100 patients with uveal melanoma were evaluated for melanoma-related metastasis based on patient race. The patient race was Caucasian (n=7918, 98%), Hispanic (n=105, 1%), Asian (n=44, <1%), or African American (n=33, <1%). On the basis of race (Caucasian, Hispanic, Asian, and African American), significant differences were noted in mean age at presentation (58, 48, 44, and 52 years; P<0.001), distance of posterior tumor margin to foveola (5, 5, 6, and 4 mm; P<0.001), distance of posterior tumor margin to optic disc (5, 5, 6, and 4 mm) (P<0.001), tumor base (11, 12, 12, and 13 mm; P<0.001), tumor thickness (5.4, 7.1, 6.5, and 7.5 mm; P<0.001), intraocular hemorrhage (10, 14, 11, and 24%; P=0.02), and rupture of Bruch's membrane (20, 27, 39, and 36%; P=0.001). On the basis of multivariate analysis, the rate of metastasis increased with increasing age (P<0.001), ciliary body location (P<0.001), increasing tumor base (P<0.001), increasing tumor thickness (P<0.001), pigmented tumor (P=0.001), subretinal fluid (P=0.001), intraocular hemorrhage (P=0.045), and extraocular extension (P=0.036). Kaplan-Meier estimates of metastasis at 3, 5, and 10 were 8, 15, and 25% in Caucasians; 13, 13, and 13% in Hispanics; 4, 4, and 36% in Asians; and 8, 8, and 8% in African Americans. Compared with Caucasians, despite relative risk for metastasis of 0.31 for African Americans, 0.73 for Hispanics, and 1.42 for Asians, there was no statistical difference in metastasis, or death from uveal melanoma based on race. In summary, uveal melanoma showed similar prognosis for all races.

Exposures in early life: associations with DNA promoter methylation in breast tumors.

There is evidence that epigenetic changes occur early in breast carcinogenesis. We hypothesized that early-life exposures associated with breast cancer would be associated with epigenetic alterations in breast tumors. In particular, we examined DNA methylation patterns in breast tumors in association with several early-life exposures in a population-based case-control study. Promoter methylation of E-cadherin, p16 and RAR-ß2 genes was assessed in archived tumor blocks from 803 cases with real-time methylation-specific PCR. Unconditional logistic regression was used for case-case comparisons of those with and without promoter methylation. We found no differences in the prevalence of DNA methylation of the individual genes by age at menarche, age at first live birth and weight at age 20. In case-case comparisons of premenopausal breast cancer, lower birth weight was associated with increased likelihood of E-cadherin promoter methylation (OR = 2.79, 95% CI, 1.15-6.82, for ⩽2.5 v. 2.6-2.9 kg); higher adult height with RAR-ß2 methylation (OR = 3.34, 95% CI, 1.19-9.39, for ⩾1.65 v. <1.60 m); and not having been breastfed with p16 methylation (OR = 2.75, 95% CI, 1.14-6.62). Among postmenopausal breast cancers, birth order was associated with increased likelihood of p16 promoter methylation. Being other than first in the birth order was inversely associated with likelihood of ⩾1 of the three genes being methylated for premenopausal breast cancers, but positively associated with methylation in postmenopausal women. These results suggest that there may be alterations in methylation associated with early-life exposures that persist into adulthood and affect breast cancer risk.

Angle dependent optical properties of polymer films with a biomimetic anti-reflecting surface replicated from cylindrical and tapered nanoporous alumina.

Anodic porous alumina nanostructures have been fabricated with tapered and cylindrical pores with a spacing of 100 and 200 nm and depth of 180-500 nm. The porous nanostructures were replicated into polymer films to create a moth-eye anti-reflecting surface by a roll-to-roll UV replication process. The angle dependent optical transmission of the resulting polymer films exhibited up to a 2% increase in transmission at a normal angle and up to a 5% increase in transmission at a 70° angle of incidence to an equivalent film with a surface replicated from polished aluminum. No significant difference was observed between the optical performance of moth-eye surfaces formed from cylindrical and tapered nano-pores.

Clinically significant human papilloma virus in squamous cell carcinoma of the head and neck in UK practice.

AIMS: The association between squamous cell carcinoma of the head and neck (HNSCC) and infection with human papilloma viruses (HPV) has created considerable interest. Rates of primary oropharyngeal cancers have shown increasing incidence and declining age at presentation over the last decade, believed to relate to infection with oncogenic or high-risk subtypes of HPV (HR-HPV). HR-HPV-associated tumours have reportedly improved outcomes when compared with HPV-negative cancers. Within the UK, rates of HR-HPV in HNSCC have not yet been reported. MATERIALS AND METHODS: We analysed consecutive retrospective cases of oropharyngeal cancer presenting between 2004 and 2007. RESULTS: Thirty-seven per cent of 83 oropharyngeal tumours stained positively for p16(INK4A), a marker of HPV infection (73% tonsillar cancers being p16 (INK4A) positive, 30% tongue and 43% floor of mouth tumours). HPV16 DNA was demonstrated in 75% p16 (INK4A) cases. Despite being more advanced with higher T-stage and nodal burden at presentation, HR-HPV-associated HNSCC showed significantly improved rates of disease-free and overall survival, in particular with improved rates of response to radical radiotherapy. CONCLUSION: HPV16 infection seems to be a clinically significant cause of oropharyngeal HNSCC in the UK and the collection of national data should be supported.

Single nucleotide polymorphisms in uracil-processing genes, intake of one-carbon nutrients and breast cancer risk.

BACKGROUND/OBJECTIVES: The misincorporation of uracil into DNA leads to genomic instability. In a previous study, some of us identified four common single nucleotide polymorphisms (SNPs) in uracil-processing genes (rs2029166 and rs7296239 in SMUG1, rs34259 in UNG and rs4775748 in DUT) that were associated with significantly altered levels of uracil in human DNA. We investigated whether any of these SNPs are associated with an altered risk of developing breast cancer and if one-carbon nutrients intake can modify their effects. SUBJECTS/METHODS: We genotyped the four SNPs in 1077 cases of incident breast cancer and 1910 age and race-matched controls in the Western New York Exposures and Breast Cancer (WEB) Study and examined associations with breast cancer risk and interactions with intake of folate, vitamins B6 and B12. RESULTS: After adjustment for known risk factors for breast cancer, there was increased risk of breast cancer among postmenopausal women who were heterozygous for either of the two SMUG1 SNPs (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.07-1.56) and OR 1.29, 95% CI 1.07-1.55, respectively). Among premenopausal women, increased risk associated with the SMUG1 rs2029166 genotype was limited to those with low folate intake. There were no other interactions with vitamins B(6) or B(12) intake. CONCLUSIONS: Our study suggests that the four selected SNPs are not robust determinants of breast cancer risk, but that the two SNPs in SMUG1 might modestly alter the risk of breast cancer. However, the increase in risk among heterozygotes in the two SNPs in SMUG1, which is thought to be the most active glycosylase in vivo, raises the possibility that subtle 'heterosis' effects on cancer risk might be produced by these SNPs.

Selenium levels in cows fed pasture and concentrates or a total mixed ration and supplemented with selenized yeast to produce milk with supra-nutritional selenium concentrations.

Seventy multiparous Holstein-Friesian cows were fed different amounts of pasture and concentrates, or a total mixed ration (TMR), for 42 d in mid-lactation to test the hypothesis that the concentration of Se in milk would depend on the amount of Se consumed, when the Se is primarily organic in nature, regardless of the diet of the cows. Of the 70 cows, 60 grazed irrigated perennial pasture at daily allowances of either 20 or 40 kg of dry matter (DM)/cow. These cows received 1 of 3 amounts of concentrates, either 1, 3, or 6 kg of DM/cow per day of pellets, and at each level of concentrate feeding, the pellets were formulated to provide 1 of 2 quantities of Se from Se yeast, either about 16 or 32 mg of Se/d. The other 10 cows were included in 2 additional treatments where a TMR diet was supplemented with 1 kg of DM/d of pellets formulated to include 1 of the 2 quantities of supplemental Se. Total Se intakes ranged from 14.5 to 35.9 mg/d, and of this, the Se-enriched pellets provided 93, 91, and 72% of the Se for cows allocated 20 and 40 kg of pasture DM/d or the TMR, respectively. No effects of the amount of Se consumed on any milk production variable, or on somatic cell count, body weight, and body condition score, for either the pasture-fed or TMR-fed cows were found. Milk Se concentrations responded quickly to the commencement of Se supplementation, reaching 89% of steady state levels at d 5. When milk Se concentrations were at steady state (d 12 to 40), each 1mg of Se eaten increased the Se concentration of milk by 5.0 µg/kg (R(2)=0.97), and this response did not seem to be affected by the diet of the cows or their milk production. The concentration of Se in whole blood was more variable than that in milk, and took much longer to respond to change in Se status, but it was not affected by diet at any time either. For the on-farm production of Se-enriched milk, it is important to be able to predict milk Se concentration from Se input. In our study, type of diet did not affect this relationship.

Pathological confirmation of primary lung cancer following breast cancer.

PURPOSE: Studies have shown that women who survive breast cancer have an increased risk of a future primary lung cancer, though many are based only on data recorded in tumor registries and none have conducted pathological confirmation. Previous studies and future use of large registries may be affected by misdiagnosis. METHODS: Pathological analysis was conducted on tumors from 110 women with breast cancer followed by lung cancer using morphology, Estrogen Receptor-alpha (ER), and Thyroid Transcription Factor-1 (TTF1). We developed an algorithm to classify lung tumors as unlikely lung cancer (score=1) to likely lung cancer (score=5). RESULTS: Mean time to diagnosis of lung cancer after breast cancer was 13 years. 76% of breast tumors and 20% of lung tumors were positive for ER and 51% of lung tumors were positive for TTF-1. 86% of the lung tumors were probable primaries, 7% were probable metastases from the breast, and 7% were of undetermined status. 70% of probable metastases had a latency of longer than 10 years. CONCLUSION: Prior studies identifying the association of breast cancer and breast cancer treatments with lung cancer are likely to reflect true associations not confounded by misdiagnosis, as evidenced by the low rate of misclassification detected in this study. Analysis of the years of diagnosis suggests that latency may not be an accurate criterion for assignment of primary status, which could be significant in a clinical setting. These data may also benefit future retrospective studies using large registries.

Familial and racial determinants of tumour suppressor genes promoter hypermethylation in breast tissues from healthy women.

To determine the hypermethylation status of the promoter regions of tumour suppressor genes in breast tissues from healthy women and identify the determinants of these epigenetic changes. Questionnaires and breast tissues were collected from healthy women without a history of cancer and undergoing reduction mammoplasty (N= 141). Methylation for p16(INK4), BRCA1, ERalpha and RAR-beta promoter regions from breast tissues were determined by methylation specific PCR. Associations were examined with chi-square and Fisher's exact test as well as logistic regression. All statistical tests were two-sided. p16(INK4), BRCA1, ERalpha and RAR-beta hypermethylation were identified in 31%, 17%, 9% and 0% of the women, respectively. Women with BRCA1 hypermethylation had an eight-fold increase in the risk of ERalpha hypermethylation (P= 0.007). p16(INK4) hypermethylation was present in 28% of African-Americans, but 65% in European-Americans (P= 0.02). There was an increased likelihood of p16(INK4) or BRCA1 hypermethylation for women with family history of cancer (OR 2.3; 95%CI: 1.05-4.85 and OR 5.0; 95%CI: 1.55-15.81, respectively). ERalpha hypermethylation was associated with family history of breast cancer (OR 6.6; 95%CI: 1.58-27.71). After stratification by race, p16(INK4) in European-Americans and BRCA1 hypermethylation in African-Americans were associated with family history of cancer (OR 3.8; 95%CI: 1.21-12.03 and OR 6.5; 95%CI: 1.33-31.32, respectively). Gene promoter hypermethylation was commonly found in healthy breast tissues from women without cancer, indicating that these events are frequent and early lesions. Race and family history of cancer increase the likelihood of these early events.

Increasing selenium concentration in milk: effects of amount of selenium from yeast and cereal grain supplements.

Two experiments were conducted to establish responses in milk Se concentrations in grazing dairy cows to different amounts of dietary Se yeast, and to determine the effects of the Se concentration of the basal diet. The hypothesis tested was that the response in milk, blood, and tissue Se concentrations to supplemental Se would not be affected by whether the Se was from the basal diet or from Se yeast. In addition, by conducting a similar experiment in either early (spring; experiment 1) or late (autumn; experiment 2) lactation, we hypothesized that different Se input-output relationships would result. Both 6-wk experiments involved 60 multiparous Holstein-Friesian cows, all of which had calved in spring. They were allocated to 1 of 10 dietary Se treatments that included 2 types of crushed triticale grain (low Se, approximately 165 microg of Se/kg of DM; or high Se, approximately 580 microg/kg of DM) fed at 4 kg of DM/d, and 1 kg of DM/d of pellets formulated to carry 5 quantities of Se yeast (0, 4, 8, 12, or 16 mg of Se). Daily total Se intakes ranged from <2 to >18 mg/cow in both experiments. Milk Se concentrations plateaued after 15 and 7 d of supplementation in experiments 1 and 2, respectively, and then remained at plateau concentrations. Average milk Se concentrations for the plateau period increased as the amount of Se yeast increased, and low- and high-Se grain treatments were different at all quantities of Se yeast, although there was a tendency for this difference to diminish at the greatest concentrations of yeast. There were significant positive, linear relationships between Se intake and the concentrations of Se in milk, which were not affected by the source of Se, and the relationships were similar for both experiments. Therefore, the output of Se in milk in experiment 1 was greater than that in experiment 2 because the milk yield of the cows in early lactation was greater. The estimated proportions of Se partitioned to destinations other than milk and feces increased with the amount of Se in the diet and were greater in experiment 2 than in experiment 1, a result that was supported by Se concentrations in whole blood and plasma and in semitendinosus muscle tissue. If high-Se products are to be produced for human nutrition, it is important to be able to develop feeding systems that produce milk with consistent and predictable Se concentrations so that products can consistently meet specifications. The results indicate that this objective is achievable.

Meta- and pooled analysis of GSTT1 and lung cancer: a HuGE-GSEC review.

Lung cancer is the most common malignancy in the Western world, and the main risk factor is tobacco smoking. Polymorphisms in metabolic genes may modulate the risk associated with environmental factors. The glutathione S-transferase theta 1 gene (GSTT1) is a particularly attractive candidate for lung cancer susceptibility because of its involvement in the metabolism of polycyclic aromatic hydrocarbons found in tobacco smoke and of other chemicals, pesticides, and industrial solvents. The frequency of the GSTT1 null genotype is lower among Caucasians (10-20%) than among Asians (50-60%). The authors present a meta- and a pooled analysis of case-control, genotype-based studies that examined the association between GSTT1 and lung cancer (34 studies, 7,629 cases and 10,087 controls for the meta-analysis; 34 studies, 7,044 cases and 10,000 controls for the pooled analysis). No association was observed between GSTT1 deletion and lung cancer for Caucasians (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.87, 1.12); for Asians, a positive association was found (OR = 1.28, 95% CI: 1.10, 1.49). In the pooled analysis, the odds ratios were not significant for either Asians (OR = 0.97, 95% CI: 0.83, 1.13) or Caucasians (OR = 1.09, 95% CI: 0.99, 1.21). No significant interaction was observed between GSTT1 and smoking on lung cancer, whereas GSTT1 appeared to modulate occupational-related lung cancer.

Chirality assignment of single-walled carbon nanotubes with strain.

Strain-induced band gap shifts that depend strongly on the chiral angle have been observed by optical spectroscopy in single-walled carbon nanotubes (SWCNTs). Uniaxial and torsional strains are generated by changing the environment surrounding the SWCNTs, using the surrounding D2O ice temperature or the hydration state of a wrapping polymer. These methods are used as diagnostic tools to determine the quantum number q and examine chiral vector indices for specific nanotubes.

The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial.

To determine whether the functional mu-opioid receptor (OPRM1) Asn40Asp variant predicts the comparative efficacy of different forms of NRT, we conducted a clinical trial of transdermal nicotine (TN) vs nicotine nasal spray (NS) in 320 smokers of European ancestry. Smokers carrying the OPRM1 Asp40 variant (n=82) were significantly more likely than those homozygous for the Asn40 variant (n=238) to be abstinent at the end of treatment, and reported less mood disturbance and weight gain. The genotype effect on treatment outcome was most pronounced among smokers receiving TN, particularly during the 21 mg dose phase. Smokers who carry the OPRM1 Asp40 variant are likely to have a favorable response to TN and may benefit from extended therapy with the 21 mg dose.

Lung cancer risks in women with previous breast cancer.

Evaluation of the adverse effects of breast cancer treatment is becoming increasingly important in light of the earlier detection and prolonged survival of the patients. The beneficial effect of post-surgical radiotherapy has lately been challenged. The Swedish Cancer Registry (SCR) was used to identify approximately 141000 women with breast cancer, diagnosed between 1958 and 1997, followed-up for the occurrence of lung cancer. Standardised incidence ratios and expected number of lung cancers were calculated using incidence rates from the SCR. There were 613 subsequent lung cancers and a statistically significant increased risk of lung cancer was seen >5 years after breast cancer diagnosis, in contrast to a significantly decreased risk the first five years after the breast cancer diagnosis. The latter finding was confined to those >60 years of age when diagnosed with breast cancer. When restricting the analyses to those cases with information on the laterality of breast and lung cancer, an increased risk of a lung cancer on the same side as the breast cancer was seen >10 years after the breast cancer diagnosis. Birth cohorts with a higher smoking prevalence, i.e. 1930-1949, revealed a higher risk of lung cancer, than previous birth cohorts. Women with breast cancer have a significantly increased risk of developing a subsequent lung cancer possibly related to an interaction between radiotherapy and smoking.

Intelligibility, subjective ratings and completion time scores using the FAAF test with hearing-impaired subjects and noisy reverberant environments.

A series of experiments have been performed with the primary aim of assessing the performance of a signal-processing algorithm for a possible future hearing aid application. As part of this work the four alternative auditory feature (FAAF) test was used to obtain a quantitative assessment of speech intelligibility and a subjective assessment of speech quality. This paper reports results of experiments using normal hearing (NH) subjects that provide partial verification of the FAAF test originators' prior work. Also reported are intelligibility score, mean opinion score (MOS) and completion time data obtained by use of the

Tryptophan hydroxylase gene variant and smoking behavior.

Approximately 50% of the variance in smoking behavior is attributable to genetic factors. Genes in the serotonin system are plausible candidates because of serotonin's role in mood regulation. The present study examined the association of smoking behavior with a polymorphism in the TPH gene, which codes for a rate limiting enzyme in the biosynthesis of serotonin. A polymorphism in intron 7 has been linked with a variety of traits involving poor impulse control. Participants in this study were 249 Caucasian smokers and 202 nonsmokers recruited through newspaper advertisements. Smokers completed smoking history and nicotine dependence assessments. The overall frequencies of the A- and C-allele were 42% and 58%, respectively. There was no association of TPH alleles with smoking status. However, case series analysis indicated that individuals with the A/A genotype started smoking at age 15.6 years, compared with 17.3 years among smokers with other genotypes. This association was significant in a multivariate regression model controlling for age, education, body mass index (BMI), alcohol use, and medication use. This finding is consistent with previous studies relating the A-allele to impulsive behavior and suggests that it may predispose to early smoking initiation. Future family-based studies are needed to confirm this finding. Published 2001 Wiley-Liss, Inc.

Mutability of p53 hotspot codons to benzo(a)pyrene diol epoxide (BPDE) and the frequency of p53 mutations in nontumorous human lung.

p53 mutations are common in lung cancer. In smoking-associated lung cancer,the occurrence of G:C to T:A transversions at hotspot codons, e.g., 157, 248, 249,and 273, has been linked to the presence of carcinogenic chemicalsin tobacco smoke including polycyclic aromatic hydrocarbons suchas benzo(a)pyrene (BP). In the present study, we have used a highly sensitive mutation assay to determine the p53 mutation load in nontumorous human lung and to study the mutability of p53 codons 157, 248, 249, and 250 to benzo(a)pyrene-diol-epoxide (BPDE), an active metabolite of BP in human bronchial epithelial BEAS-2B cells. We determined the p53 mutational load at codons 157, 248, 249, and 250 in nontumorous peripheral lung tissue either from lung cancer cases among smokers or noncancer controls among smokers and nonsmokers. A 5-25-fold higher frequency of GTC(val) to TTC(phe) transversions at codon 157 was found in nontumorous samples (57%) from cancer cases (n = 14) when compared with noncancer controls (n = 8; P < 0.01). Fifty percent (7/14) of the nontumorous samples from lung cancer cases showed a high frequency of codon 249 AGG(arg) to AGT(ser) mutations (P < 0.02). Four of these seven samples with AGT(ser) mutations also showed a high frequency of codon 249 AGG(arg) to ATG(met) mutations, whereas only one sample showed a codon 250 CCC to ACC transversion. Tumor tissue from these lung cancer cases (38%) contained p53 mutations but were different from the above mutations found in the nontumorous pair. Noncancer control samples from smokers or nonsmokers did not contain any detectable mutations at codons 248, 249, or 250. BEAS-2B bronchial epithelial cells exposed to doses of 0.125, 0.5, and 1.0 microM BPDE, showed G:C to T:A transversions at codon 157 at a frequency of 3.5 x 10(-7), 4.4 x 10(-7), and 8.9 x 10(-7), respectively. No mutations at codon 157 were found in the DMSO-treated controls. These doses of BPDE induced higher frequencies, ranging from 4-12-fold, of G:C to T:A transversions at codon 248, G:C to T:A transversions and G:C to A:T transitions at codon 249, and C:G to T:A transitions at codon 250 when compared with the DMSO-treated controls. These data are consistent with the hypothesis that chemical carcinogens such as BP in cigarette smoke cause G:C to T:A transversions at p53 codons 157, 248, and 249 and that nontumorous lung tissues from smokers with lung cancer carry a high p53 mutational load at these codons.