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M W Anderson

Publications and source records attributed to M W Anderson.

At least 37 records · Page 2Linked to original sources
PubMed1998

A prospective controlled study of diagnostic imaging for acute shin splints.

OBJECTIVE: The purpose of this prospective, observational study was to examine the relationship of clinical examination, plain radiograph (XR), triple-phase bone scan (TPBS), and magnetic resonance imaging (MRI) in the investigation of patients presenting with acute shin splints. METHODS: 23 subjects with exercise induced lower leg pain and diffuse tibial tenderness of less than 3 months' duration were recruited. Subjects were excluded if there was clinical evidence of compartment syndrome, muscle hernia, or stress fracture. Each subject underwent XR, TPBS, and MRI within 2 wk of physical examination. Four asymptomatic controls underwent TPBS and MRI. Clinical findings, XR, TPBS, and MRI findings were independently recorded using a consistent template and subsequently analyzed. A single consensus lesion was chosen that provided the greatest overlap and highest grade to allow comparison of clinical and imaging findings. Sensitivity and specificity were calculated from data relating to clinical findings and diagnostic imaging. RESULTS: Eighteen subjects had bilateral symptoms and five unilateral with a mean duration of symptom of 5.4 wk (+/- 3.5). Of 41 symptomatic lower legs, there were TPBS abnormalities in 36 and MRI findings in 34. Analysis of clinical findings to TPBS and MRI demonstrated a sensitivity and specificity of 84%, 33% and 79%, 33%, respectively. Assuming TPBS as the "gold-standard," MRI findings demonstrated a sensitivity of 95% and specificity of 67%. There was poor agreement between the grading of TPBS and MRI (k = 0.3). In the 5/46 asymptomatic limbs, 3/5 demonstrated uptake on bone scan and 4/5 signal change with MRI. Imaging abnormalities were similarly seen in the four control patients. CONCLUSIONS: MRI may be used rather than TPBS and radiographs for evaluating acute tibial pain in athletes where avoidance of radiation exposure is desirable. Similar sensitivity and specificity may be expected from both investigations; however, in the light of abnormal TPBS and MRI findings in control and asymptomatic limbs, we recommend further studies be performed to define the extent of nonpathological TPBS and MRI changes.

Acute Disease↗
PubMed1997

Identification of a novel region of homozygous deletion on chromosome 9p in squamous cell carcinoma of the lung: the location of a putative tumor suppressor gene.

Cytogenetic and molecular studies have implied the presence of tumor suppressor genes (TSGs) on chromosome 9p that are critical in the development of lung and other cancers. The p16/CDKN2 gene, a cyclin dependent kinase inhibitor, is a well-defined TSG on 9p21. Although the frequency of mutations in the p16/CDKN2 gene has been detected in approximately 30% of non-small cell lung cancer, loss of heterozygosity on 9p has been observed in greater than 70% of non-small cell lung cancers. These and other deletion mapping studies have suggested the existence of additional TSGs on 9p. This study examined chromosome 9p for TSG loci by analyzing 23 squamous cell carcinomas of the lung with 21 microsatellite markers. Loss of heterozygosity was detected in all of the tumors, and homozygous deletions of the p16/ CDKN2 locus were observed in 6 of the 23 tumors (26%). In addition, a novel region of homozygous deletion was detected in six tumors (26%) at D9S126, approximately 2.5 cM proximal to p16/CDKN2. A single tumor contained a homozygous deletion at both the p16/CDKN2 locus and the D9S126 locus. The possibility of homozygous loss was confirmed by multiplex PCR using both the D9S126 marker and a chromosome 9p control marker. Fluorescence in situ hybridization analysis with P1 and cosmid probes containing D9S126 also confirmed these data. The minimum region of homozygous deletion was determined by testing markers immediately proximal and distal to the D9S126 region. The data identify a homozygous loss on the short arm of chromosome 9 suggesting the presence of a novel TSG locus, proximal to p16/CDKN2 and located between D9S265 and D9S259.

Carcinoma, Squamous Cell↗
PubMed1997

Wound botulism associated with black tar heroin.

The incidence of wound botulism is increasing and the epidemiology of the disease is changing. The majority of new cases are associated with injection drug use, in particular, the use of Mexican black tar heroin. This case report and discussion of wound botulism illustrate the following important points: Dysphagia, dysphonia, diplopia, and descending paralysis, in association with injection drug use, should alert the treating physician to the possibility of wound botulism. In such patients, the onset of respiratory failure may be sudden and without clinically obvious signs of respiratory weakness. For the reported patient, maximum inspiratory force measurements were the only reliable indicator of respiratory muscle weakness. This is a measurement not routinely performed in the ED, but may prove essential for patients with suspected wound botulism. To minimize the effect of the botulinum toxin and to decrease length of hospital stay, antitoxin administration and surgical wound debridement should be performed early.

Botulism↗
PubMed1997

Shin splints: MR appearance in a preliminary study.

PURPOSE: To investigate the magnetic resonance (MR) imaging appearance of activity-related lower leg pain (shin splints syndrome) and evaluate the relative involvement of bone and soft tissues. MATERIALS AND METHODS: Nineteen patients with activity-related lower leg pain and tenderness on palpation along the posteromedial tibia (shin splints) underwent clinical examination and MR imaging. Five also underwent plain radiography. MR findings were compared with patient demographics, clinical findings, and plain radiographs when available. RESULTS: Four MR patterns were identified: normal appearance (n = 7), periosteal fluid only (n = 5), abnormal marrow signal intensity (n = 5), and stress fracture (n = 2). Increased symptom duration correlated strongly with a normal MR image (P = .002). Plain radiographs appeared normal in all five patients for whom they were available. CONCLUSION: Patients with acute shin splints have a spectrum of MR findings, which suggests this clinical entity is part of a continuum of stress response in bone. The strong association between chronic symptoms and a normal-appearing MR image implies that this modality has less utility in these patients.

Acute Disease↗
PubMed1997

Alterations in the K-ras and p53 genes in rat lung tumors.

Activation of the K-ras protooncogene and inactivation of the p53 tumor suppressor gene are events common to many types of human cancers. Molecular epidemiology studies have associated mutational profiles in these genes with specific exposures. The purpose of this paper is to review investigations that have examined the role of the K-ras and p53 genes in lung tumors induced in the F344 rat by mutagenic and nonmutagenic exposures. Mutation profiles within the K-ras and p53 genes, if present in rat lung tumors, would help to define some of the molecular mechanisms underlying cancer induction by various environmental agents. Pulmonary adenocarcinomas or squamous cell carcinomas were induced by tetranitromethane (TNM), 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), beryllium metal, plutonium-239, X-ray, diesel exhaust, or carbon black. These agents were chosen because the tumors they produced could arise via different types of DNA damage. Mutation of the K-ras gene was determined by approaches that included DNA transfection, direct sequencing, mismatch hybridization, and restriction fragment length polymorphism analysis. The frequency for mutation of the K-ras gene was exposure dependent. Only two agents, TNM and plutonium, led to mutation frequencies of > 10%. In both cases, the transition mutations formed could have been derived from deamination of cytosine. The identification of non-ras transforming genes in rat lung tumors induced by mutagenic and nonmutagenic exposures such as NNK and beryllium would help define some of the mechanisms underlying cancer induction by different types of DNA damage. Alteration in the p53 gene was assessed by immunohistochemical analysis for p53 protein and single-strand conformation polymorphism (SSCP) analysis of exons 4 to 9. None of the 93 adenocarcinomas examined was immunoreactive toward the anti-p53 antibody CM1. In contrast, 14 to 71 squamous cell carcinomas exhibited nuclear p53 immunoreactivity with no correlation to type of exposure. However, SSCP analysis only detected mutations in 2 of 14 squamous cell tumors that were immunoreactive, suggesting that protein stabilization did not stem from mutations within the p53 gene. Thus, the p53 gene does not appear to be involved in the genesis of most rat lung tumors.

Animals↗
PubMed1997

Genetic markers for early detection of lung cancer and outcome measures for response to chemoprevention.

Lung cancer is one of the leading causes of cancer death in the world. The high mortality rate for lung cancer probably results, at least in part, from the absence of standard clinical procedures for diagnosis of the disease at early and more treatable stages compared to breast, prostate, and colon cancers. The delineation of genetic alterations that occur in lung tumorigenesis may aid in both developing molecular markers for early detection and predicting of response to chemoprevention/chemotherapy. Cytogenetic and molecular genetic studies have shown that mutations in protooncogenes and tumor suppressor genes (TSGs) are critical in the multi-step development and progression of lung tumors. Inactivation of TSGs are by far the most common mutational events documented during the development of lung cancer. For example, loss of function of the Rb and/or p53 genes has been detected in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). In addition, allelic loss analyses have implicated the existence of other tumor suppressor gene loci on 9p as well as on 3p, 5q, 8p, 9q, 11q, 11q, and 17q. We examined the short arm of chromosomes 3 and 9 for TSG loci by analyzing 23 squamous cell carcinomas of the lung with numerous microsatellite markers. On chromosome 9p, loss of heterozygosity was detected in all of the 23 tumors and homozygous deletions of the p16/CDKN2 locus were detected in 6 of the 23 (26%) tumors. In addition, a novel region of homozygous deletion was detected in 6 of the tumors (26%) at D9S126. The homozygous deletion of D9S126 was confirmed by fluorescent in situ hybridization (FISH) analysis of tumor tissue touch preparations and isolated nuclei using P1 and cosmid probes that contain D9S126. Only one tumor harbored a homozygous deletion at both the p16/CDKN2 locus and the D9S126 locus. The data identify a region of homozygous loss on the short arm of chromosome 9, suggesting the presence of a novel TSG locus approximately 2.5 cM proximal to p16/CDKN2. On chromosome 3p, a similar high percentage of the tumors exhibited loss of heterozygosity. Also, homozygous deletions were detected in several tumors at 3p21.3. Thus, FISH analysis with probes containing the D9S126 or p16 locus could be used as molecular markers to assay sputum samples for premalignant cells exfoliated from the bronchial epithelium. Probes from other chromosome regions such as 3p21 could be used in a similar manner.

Chemoprevention↗
PubMed1996

Homozygous codeletion and differential decreased expression of p15INK4b, p16INK4a-alpha and p16INK4a-beta in mouse lung tumor cells.

The genes of murine cyclin D-dependent kinase inhibitors, p15INK4b and p16INK4a, are located in a region of chromosome 4 where overlapping deletions were found in lung adenocarcinomas. The p16INK4a gene uniquely consists of alternative first exons (E1alpha and E1beta), which are spliced to exon 2 in alternative reading frames to either encode p16INK4a (alpha form) or another potential tumor suppressor, p19ARF (beta form). We examined 99 lung adenocarcinomas of C3H/HeJ x A/J F1(C3AF1) and A/J x C3H/HeJ F1(AC3F1) mouse hybrids and 18 (13 metastatic, 5 nonmetastatic) tumorigenic mouse lung epithelial cell lines for p15INK4b and p16INK4a gene inactivation. Homozygous codeletion occurred in eight of the 13 (62%) metastatic, four of the five (80%) nonmetastatic cell lines, but in only six of 99 (6%) adenocarcinomas. Neither p15INK4b nor p16INK4a gene was individually deleted in any of the tumors or cell lines, and all deletions of the p16INK4a gene extended into exon 2, which would be expected to disrupt the functions of both p16INK4a and p19ARF. We also detected no intragenic mutations of either gene in 44 tumors that displayed loss of heterozygosity at the p16INK4a locus or in any of the cell lines. Transcript levels of p16INK4a-alpha, p16INK4a-beta and p15INK4b also were examined in each of the cell lines that retained copies of these genes. Whereas an immortal mouse lung epithelial cell line (E10) and two metastatic tumor cell lines (LM1 and E9) expressed p16INK4a-beta and p15INK4b mRNA, the alpha transcript of p16INK4a was detected in only the LM1 cell line. These results suggest that both p15INK4b and p16INK4a (alpha and beta) are targets of inactivation in mouse lung tumorigenesis.

Adenocarcinoma↗
PubMed1996

A comparison between the localization of lung tumors in uranium miners and in nonminers from 1947 to 1991.

BACKGROUND: Lung cancer was noted to be increased in cigarette smoking miners and nonminers. Carcinogen particulates deposit differentially in the central, middle, and peripheral zones of the bronchial tree depending on the size of the particle. The object of this study was to evaluate the incidence of tumors; their cell types; and the relationship of particulate size to their position in the bronchial tree. METHODS: Tumor position in the bronchial tree was studied for a cohort of 467 uranium miners and 311 nonminers with lung cancer. RESULTS: An examination of all histologic subtypes showed that the proportion of lung cancers in the central zone was significantly greater in miners than in nonminers presumably due to the deposition of radon decay products attached to the silica dust particles. The higher percentage of central tumors in the miners was primarily due to the distribution of a greater proportion of squamous cell and small-cell tumors. The ratio of 0.75 for the central to middle and peripheral location for adenocarcinomas was much lower than for squamous cell and small-cell carcinomas with ratios of 1.4 and 7.3, respectively. In the mining cohort, there were ten times as many small-cell tumors in the central area as in the middle and peripheral regions, whereas, for the nonminers there were only five times as as many centrally located small-cell tumors as middle and peripheral (chi square is 7.0 degrees, P < 0.01). These data suggest that radon may be deposited preferentially to the central region of the lungs in uranium miners. CONCLUSIONS: Based on our observations of the differential positions of lung tumors in the bronchial tree for miners and nonminers and previous studies by others regarding size-dependent deposition of particulates in the bronchial tree, it is concluded that inhaled dust, radon, and cigarette smoke combine to form large particulates that deposit in the central bronchial tree. Filtered cigarette smoke or other small carcinogens from smaller particulates that deposit more peripherally.

Bronchial Neoplasms↗
PubMed1996

Activation of K-ras in aflatoxin B1-induced lung tumors from AC3F1 (A/J x C3H/HeJ) mice.

In addition to being a potent hepatocarcinogen, aflatoxin B1 (AFB1) is a pulmonary carcinogen in experimental animals and epidemiological studies have shown an association between AFB1 exposure and lung cancer in humans. Since point mutations at codons 12, 13 and 61 of the K-ras protooncogene are often implicated in chemically induced mouse lung tumors and in human lung adenocarcinomas, we undertook an investigation of the role of K-ras activation in AFB1-induced pulmonary carcinogenesis. Female AC3F1 (A/J x C3H/HeJ) mice were treated with AFB1 (150 mg/kg i.p., divided into 24 doses over 8 weeks), and 6-14 months after the completion of dosing mice were killed and pulmonary adenomas and carcinomas removed. Of the 76 AFB1-induced lung tumors analyzed by single strand conformation polymorphism (SSCP) and direct sequencing, 75 possessed K-ras codon 12 mutations (46 GTT, 14 GAT, 13 TGT and 2 TTT; normal, GGT) and one had a GGC-->CGC mutation in codon 13. The observation that K-ras mutations occurred only at G:C base pairs is in agreement with N7-guanine being the primary site of AFB1-DNA adduct formation and with guanine residues being targets for AFB1-induced oxidative DNA damage via formation of 8-hydroxydeoxyguanosine (8-OHdG). The AFB1-specific nature of the observed K-ras mutation spectrum and the fact that 100% of the tumor samples examined contained K-ras mutations is consistent with K-ras activation being an early, critical event in AFB1-induced pulmonary carcinogenesis in AC3F1 mice. The parental origin of the observed K-ras mutations was determined by allele-specific PCR amplification of AFB1-induced lung tumor DNA followed by SSCP analysis. In the vast majority of tumors (73/76), the mutated K-ras allele was derived from the lung tumor susceptible A/J parent. This finding supports the existence of a link between K-ras and differences in mouse lung tumor susceptibility.

Aflatoxin B1↗
PubMed1996

Stress fractures.

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Adolescent↗
PubMed1995

Hepatic and pulmonary carcinogenicity of methylene chloride in mice: a search for mechanisms.

An inhalation study utilizing over 1400 female B6C3F1 mice was undertaken to study mechanistic factors associated with liver and lung tumor induction following exposure to 2000 ppm of methylene chloride. Mice were exposed to methylene chloride (treated) or chamber air (controls) 6 h per day, for varying durations up to 104 weeks. Several interim sacrifices and 'stop exposures' were included. Exposure to 2000 ppm methylene chloride caused an increase in liver and lung neoplasia in the absence of overt cytotoxicity. Measurement of replicative DNA synthesis done after 13, 26, 52 and 78 weeks of exposure showed a significant decrease in the hepatocyte labeling index at 13 weeks. Replicative DNA synthesis in pulmonary airways after 1, 2, 3, 4, 13 and 26 weeks of exposure to methylene chloride was significantly lower than in air-exposed controls. Likewise, the increase in tumor induction in treated mice was not associated with increased replicative DNA synthesis in liver foci or in alveolar parenchyma. The frequency and pattern of H-ras gene activation were similar in control and methylene chloride-induced liver neoplasms. Similarly, the frequency and pattern of K-ras activation in lung neoplasms were not altered by exposure to methylene chloride. Early exposure to methylene chloride for only 26 weeks was sufficient to cause an increase in lung tumors by 2 years, suggesting that methylene chloride may cause early and persistent loss of growth control in lung cells. This implies that risk management strategies should be aimed at minimizing or eliminating exposure to methylene chloride. Liver neoplasms continued to increase in incidence and multiplicity as exposure continued, suggesting that methylene chloride-induced hepatocarcinogenesis is facilitated by continuing exposure to methylene chloride. Since methylene chloride is a more potent inducer of lung than liver neoplasia, it is recommended that health risk assessment be based on the lung data. While no novel molecular lesions have been found to explain the induction of lung and liver neoplasia in mice, ongoing studies may identify other molecular changes that are important in the genesis of these neoplasms. Hence, it may be necessary to revise risk assessment and management strategies in light of future research findings.

Administration, Inhalation↗
PubMed1995

Traumatic hip dislocation: early MRI findings.

PURPOSE: Objective of this study was to present the spectrum of early magnetic resonance imaging (MRI) findings following traumatic dislocation of the femoral head, and to identify any associated injuries that may have therapeutic or prognostic significance and be better delineated by MRI than by conventional radiography. PATIENTS AND METHODS: Prospective MRI of both hips was formed on 18 patients (14 male, 4 female; age range 14-54 years; average age 30.5 years) within 5 weeks of a traumatic femoral head dislocation. The interval between the time of injury and the time of injury and the imaging studies ranged from 2 to 35 days (average 13.2 days). Posterior dislocation was present in 14 patients and anterior dislocation in 4 patients. In the majority of cases, we performed axial T1, coronal T1, and coronal T2* (MPGR) sequences. Images were retrospectively evaluated by consensus of three radiologists for possible abnormalities of the bone and cartilage, joint space, and soft tissues. Because all patients were treated with closed reduction, surgical correlation was not obtained. RESULTS: All patients had a joint effusion or hemarthrosis. Of the 14 patients with posterior dislocation, isolated femoral head contusions (trabecular microfractures) were identified in 6 patients. Four patients had small femoral head fractures, and one had an osteochondral defect. Acetabular lip fractures were seen in six patients, and one patient had a labral tear. Four patients had intra-articular loose bodies and one had ligamentum teres entrapment. Twelve patients had iliofemoral ligament injury. All patients had muscle injury involving the gluteal region and medical fascial compartment, and 13 patients had anterior fascial compartment muscle injury. Seven patients with posterior dislocation had posterior fascial compartment injury. Of the four patients with anterior dislocation, two had bony contusion, two had cortical infraction, one had a labral tear, and all four had an iliofemoral ligament injury. All four patients in this group had muscle injury of the gluteal region and of the anterior and medial fascial compartments. CONCLUSIONS: MRI can effectively identify and quantify the muscle injury and joint effusion that invariably accompany traumatic hip dislocations. It is also useful for demonstrating trabecular bone contusion (trabecular injury) and iliofemoral ligament injury, which occur commonly with acute hip dislocation.

Acetabulum↗
PubMed1995

Evaluation of meniscal tears: fast spin-echo versus conventional spin-echo magnetic resonance imaging.

RATIONALE AND OBJECTIVES: We compared the performance of fast spin-echo (FSE) with conventional spin-echo (CSE) magnetic resonance (MR) imaging sequences in the detection of meniscal tears. METHODS: Seventy-three patients underwent MR examination of the knee for suspected internal derangement. Each patient was scanned with a CSE sequence and one of two FSE sequences. The primary difference between the two FSE sequences consisted of the echo train length (ETL). Thirty-seven patients (group 1) were scanned with the FSE I sequence (ETL = 8), and 36 patients (group 2) were scanned with the FSE II sequence (ETL = 4). Menisci were graded as torn or not torn on the basis of their MR appearance. The sequences were compared with each other and with the surgical findings in 31 patients who underwent arthroscopy. RESULTS: In group 1, there was a significant discrepancy between the CSE and FSE I techniques (p = .006). The FSE I sequence detected only 11 of 19 surgically proven torn menisci as opposed to 18 of 19 detected with the CSE sequence. The FSE II sequence performed significantly better in group 2, with an accuracy equal to that of the CSE sequence. CONCLUSION: FSE sequences are extremely technique dependent with regard to detecting meniscal tears and should not replace CSE sequences in this setting until further studies are performed to optimize the technique.

Adolescent↗
PubMed1995

K-ras mutations in lung tumors from A/J and A/J x TSG-p53 F1 mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and phenethyl isothiocyanate.

The purpose of this study was to evaluate the effects of the loss of a p53 allele and phenethyl isothiocyanate (PEITC) pre-treatment on the tumorigenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and K-ras mutation frequency in a hybrid mouse model. Male TSG-p53 'knock-out' mice were bred with A/J female mice to produce (A/J x TSG-p53) F1 mice either homozygous (p53+/+) or heterozygous (p53+/-) for p53 alleles. These mice, together with female A/J mice, were treated at 6-8 weeks of age with NNK or dosed with PEITC prior to administration of NNK. The A/J mice treated with NNK had a 100% incidence of lung tumors, with 9.7 +/- 3.4 tumors/mouse. A/J mice pre-treated with PEITC prior to NNK administration had 3.5 +/- 2.1 lung tumors/animal, although the incidence remained at 100%. In (A/J x TSG-p53) F1 mice with either the p53(+/-) or p53(+/+) genotype PEITC pre-treatment significantly decreased tumor incidence (100 to 40 and 36%, respectively) and multiplicity (2.0 +/- 0.5 to 0.5 +/- 0.4 and 2.1 +/- 0.5 to 0.5 +/- 0.4, respectively), indicating that PEITC is an effective chemopreventive agent in both A/J mice and (A/J x TSG-p53) F1 mice. Analysis of lung tumor DNA from A/J mice treated with NNK or NNK/PEITC indicated that 15 of 17 (88%) and 20 of 23 (87%) of the tumors, respectively, contained G-->A transitions at the second base of codon 12 in the K-ras gene. Similarly, in lung tumors from (A/J x TSG-p53) F1 mice treated with NNK or NNK/PEITC 29 of 30 (96%) and 9 of 10 (90%), respectively contained G-->A transitions at the second base of codon 12 of the K-ras gene. No mutations of the p53 gene were found in any of the tumors analyzed, suggesting minimal involvement of this gene in the development of lung adenomas. These data indicate that absence of a p53 allele in (A/J x TSG-p53) F1 mice does not alter the incidence or multiplicity of NNK-induced lung tumors and that PEITC inhibition of NNK tumorigenesis does not affect the frequency or spectrum of K-ras gene mutations found consistently with NNK carcinogenesis.

Animals↗
PubMed1995

High frequency of K-ras mutations in spontaneous and vinyl carbamate-induced lung tumors of relatively resistant B6CF1 (C57BL/6J x BALB/cJ) mice.

The murine K-ras proto-oncogene is hypothesized to be a pulmonary adenoma susceptibility gene. This postulate is supported by the previous demonstration of a preference for mutation of the K-ras allele from the susceptible parent in lung tumors of A/J x C3H F1 mice. We have examined K-ras activation in control and vinyl carbamate (VC) (single dose 0.03 mumol/g i.p.) treated B6CF1 mice, the progeny of resistant C57BL/6J and intermediately sensitive BALB/cJ parents. Thirty-four of 37 tumors from VC-treated mice and 17 of 23 from controls contained activating K-ras mutations. The spectra of mutations in codons 12 and 61 of K-ras were similar for the two groups, except that 7 tumors from VC-treated mice had A-->T transversions in the second base of codon 61; none were observed in tumors from saline-treated animals. PCR-based genotyping of first exon K-ras mutations revealed that the vast majority (15 of 18) of the mutations were in the BALB/cJ allele. Furthermore, the three tumors with mutated C57BL/6J K-ras were among the smallest tumors analyzed. These results are consistent with previous findings in other mouse hybrids showing parental bias for K-ras mutations and suggest that mutation of the allele of the susceptible parent may provide a growth advantage to the tumor.

Alleles↗
PubMed1995

H-ras oncogene mutation spectra in B6C3F1 and C57BL/6 mouse liver tumors provide evidence for TCDD promotion of spontaneous and vinyl carbamate-initiated liver cells.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent environmental toxin which has been found to be non-genotoxic in short term in vitro tests but strongly carcinogenic in two stage models of hepatocellular carcinogenesis in female rats. Many recent studies have shown that after treatment of mice with various genotoxic or non-genotoxic compounds, the H-ras oncogene mutational patterns exhibited by hepatocellular tumors appear to vary specifically with the chemical. To gain insight into the mechanism of TCDD-associated carcinogenesis, susceptible B6C3F1 mice and resistant C57BL/6 mice were treated with a single dose of vinyl carbamate (VC) or vehicle, and TCDD was administered once every 2 weeks for 1 year to half of the animals in each group. Liver tumor prevalence was assessed and found to be highest in the VC + TCDD treatment groups, reaching nearly 100% at 600 days in both sexes and both strains of mice. DNA was isolated from 20 or more frozen liver tumors (if available) from each exposure group and analyzed for H-ras mutations in codon 61 by sequencing after PCR amplification of exon 2. Fifty-one percent of tumors analyzed from B6C3F1 mice treated with TCDD alone had H-ras codon 61 mutations with a pattern similar to that detected in spontaneous tumors. Seventy-eight percent of tumors from B6C3F1 mice treated with both VC and TCDD had codon 61 mutations, and most mutations were A-->T transversions in the second base as observed similarly with VC alone. In the C57BL/6 strain comparable results were found in the respective exposure groups. These data suggest that TCDD is acting as a promoter of lesions previously initiated either spontaneously or by VC. Moreover, the intrinsic resistance of both male and female C57BL/6 mice to liver tumor formation seemed to disappear after treatment with TCDD.

Animals↗