Inhibition by dietary organoselenium, p-methoxybenzene-selenol, of hepatocarcinogenesis induced by azoxymethane in rats

The effect of dietary p-methoxybenzeneselenol, a new organoselenium compound, on azoxymethane (AOM)-induced hepatocarcinogenesis was examined in female F344 rats. Semipurified diets containing 0 and 5 ppm p-methoxybenzeneselenol were fed to the rats, starting at 5 weeks of age until one week after the carcinogen treatment. At 7 weeks of age, all animals except the vehicle-treated controls were given weekly sc injections of AOM (15 mg/kg body weight, 3 times). At 34 weeks after the last AOM treatment, the liver neoplasm incidence and liver tumor multiplicity as well as the incidence of altered liver cell foci were significantly lower in AOM-treated rats fed the diet containing 50 ppm p-methoxybenzeneselenol (tumor incidence 19%, tumor multiplicity 0.45/rat, foci incidence 3.47/cm2) than in AOM-treated animals fed the diet without p-methoxybenzeneselenol (tumor incidence 66%, tumor multiplicity 2.24/rat, foci incidence 12.08/cm2). These results indicate that dietary p-methoxybenzeneselenol at a dose of 50 ppm inhibits AOM-induced hepatic tumorigenesis.     

DNA-protein cross-linking by the mycotoxin, botryodiplodin, in mammalian cells

Botryodiplodin, a mycotoxin isolated from a strain of Penicilliumroqueforti, induces DNA-protein cross-links in mammalian cells.This action depends upon the presence of the hydroxyl groupat the position 2 of the molecule. The mechanism involved inthe formation of cross-linkings is discussed.     

Enhancement by the tricyclic antidepressant, desipramine, of experimental carcinogenesis in rat colon induced by azoxymethane

The effects of the tricyclic antidepressant drug desipramineon the incidence, number and histology of colon tumors inducedby azoxymethane (AOM), and on the serum norepinephrine (NE)concentration and the labeling index of colon mucosa were investigatedin Wistar rats. Rats were treated s.c. with 7.4 mg AOM/kg bodywt once a week for 10 weeks, and also s.c. with 10 mg desipraminehydrochloride (desipramine)/kg body weight until the end ofthe experiment. Treatment with desipramine significantly increasedthe incidence, but not the number, of colon tumors in week 35.However, it did not influence the location and the histologicalappearance of the colon tumors or the histological types ofcolon adenocarcinomas. Furthermore, it significantly increasedthe serum NE level and the labeling index of colon mucosa duringand after AOM treatment. These findings indicate that desipramineenhanced the development of colon tumors and that its effectmay be related to its effect in increasing proliferation ofcolon epithelial cells.     

Breast cancer statistics, 2017, racial disparity in mortality by state

In this article, the American Cancer Society provides an overview of female breast cancer statistics in the United States, including data on incidence, mortality, survival, and screening. Approximately 252,710 new cases of invasive breast cancer and 40,610 breast cancer deaths are expected to occur among US women in 2017. From 2005 to 2014, overall breast cancer incidence rates increased among Asian/Pacific Islander (1.7% per year), non‐Hispanic black (NHB) (0.4% per year), and Hispanic (0.3% per year) women but were stable in non‐Hispanic white (NHW) and American Indian/Alaska Native (AI/AN) women. The increasing trends were driven by increases in hormone receptor‐positive breast cancer, which increased among all racial/ethnic groups, whereas rates of hormone receptor‐negative breast cancers decreased. From 1989 to 2015, breast cancer death rates decreased by 39%, which translates to 322,600 averted breast cancer deaths in the United States. During 2006 to 2015, death rates decreased in all racial/ethnic groups, including AI/ANs. However, NHB women continued to have higher breast cancer death rates than NHW women, with rates 39% higher (mortality rate ratio [MRR], 1.39; 95% confidence interval [CI], 1.35‐1.43) in NHB women in 2015, although the disparity has ceased to widen since 2011. By state, excess death rates in black women ranged from 20% in Nevada (MRR, 1.20; 95% CI, 1.01‐1.42) to 66% in Louisiana (MRR, 1.66; 95% CI, 1.54, 1.79). Notably, breast cancer death rates were not significantly different in NHB and NHW women in 7 states, perhaps reflecting an elimination of disparities and/or a lack of statistical power. Improving access to care for all populations could eliminate the racial disparity in breast cancer mortality and accelerate the reduction in deaths from this malignancy nationwide. CA Cancer J Clin 2017;67:439‐448. © 2017 American Cancer Society.     

Benefit, risk, and optimization by ROC analysis in cancer radiotherapy

The objective of definitive cancer radiation therapy is cure or control. The attainment of that objective is not without risk of treatment-induced radiation injury. The optimum treatment is, therefore, that level of radiotherapeutic effect with the maximum probability of benefit and the minimum associated probability of injury. An objective of radiotherapy research is the formulation of a model of optimization that is independent of a consensus of what constitutes optimization. Receiver operating characteristic (ROC) analysis is such a model, for it can relate probabilities of benefit and injury yielding a graphical determination of the optimum level of radiotherapeutic effect. ROC analysis is explained, an example taken from the contemporary radiotherapy literature is presented, and clinical research requirements for a general application of ROC analysis to the optimization of definitive cancer radiotherapy are developed.     

Treatment by design in leukemia, a meeting report, Philadelphia, Pennsylvania, December 2002.

Novel approaches have been designed to treat leukemia based on our understanding of the genetic and biochemical lesions present in different malignancies. This meeting report summarizes some of the recent advances in leukemia treatment. Based on the discoveries of cellular oncogenes, chromosomal translocations, monoclonal antibodies, multidrug resistance pumps, signal transduction pathways, genomics/proteonomic approaches to clinical diagnosis and mutations in biochemical pathways, clinicians and basic scientists have been able to identify the particular genetic mutations and signal transduction pathways involved as well as design more appropriate treatments for the leukemia patient. This meeting report discusses these exciting new therapies and the results obtained from ongoing clinical trials. Furthermore, rational approaches to treat complications of tumor lysis syndrome by administration of the recombinant urate oxidase protein, also known as rasburicase, which corrects the biochemical defect present in humans, were discussed. Clearly, over the past 25 years, molecular biology and biotechnology has provided the hematologist/oncologist novel bullets in their arsenal that will allow treatment by design in leukemia.     

DNA Repair by Homologous Recombination, But Not by Nonhomologous End Joining, Is Elevated in Breast Cancer Cells

Aberrant double-stranded break (DSB) repair leads to genomic instability, which is a hallmark of malignant cells. Double-stranded breaks are repaired by two pathways: homologous recombination (HR) and nonhomologous DNA end joining (NHEJ). It is not known whether these repair pathways are affected in sporadic breast tumors. Here, we examined the efficiency of HR and NHEJ repair in a panel of sporadic breast cancer cell lines and tested whether the efficiency of HR or NHEJ correlates with radioresistance. Homologous recombination and NHEJ in breast cancer cells were analyzed using in vivo fluorescent assays. Unexpectedly, our analysis revealed that the efficiency of HR is significantly elevated in breast cancer cells compared with normal mammary epithelial cells. In contrast, the efficiency of NHEJ in breast cancer cells is not different from normal cells. Overall, breast cancer cells were more sensitive to radiation than normal cells, but the levels of resistance did not correlate with either HR or NHEJ efficiency. Thus, we demonstrate that sporadic breast cancers are not associated with a deficiency in DSB repair, but rather with upregulation of the HR pathway. Our finding of elevated HR in sporadic breast cancer cell lines suggests that therapies directed against the components of HR will be highly tumor-specific.     

Regulation of microtubule, apoptosis, and cell cycle-related genes by taxotere in prostate cancer cells analyzed by microarray

Taxotere showed antitumor activity against solid tumors including prostate cancer. However, the molecular mechanism(s) of action of Taxotere has not been fully elucidated. In order to establish such molecular mechanism(s) in both hormone-insensitive (PC3) and hormone-sensitive (LNCaP) prostate cancer cells, comprehensive gene expression profiles were obtained by Affymetrix Human Genome U133A Array. The RNA from the cells treated with 2 nM Taxotere was subjected to microarray analysis. We found that a total of 166, 365, and 1785 genes showed greater than two-fold change in PC3 cells after 6, 36, and 72 hours of treatment, respectively compared to 57, 823, and 964 genes in LNCaP cells. The expression of tubulin was decreased, whereas the expression of microtubule-associated proteins was increased in Taxotere-treated prostate cancer cells, confirming the microtubule-targeting effect of Taxotere. Clustering analysis showed downregulation of some genes for cell proliferation and cell cycle. In contrast, Taxotere upregulated some genes that are related to induction of apoptosis and cell cycle arrest. From these results, we conclude that Taxotere caused alterations of a large number of genes, many of which may contribute to the molecular mechanism(s) by which Taxotere affects prostate cancer cells. Further molecular studies are needed in order to determine the cause and effect relationships between these genes altered by Taxotere. Nevertheless, our results could be further exploited for devising strategies to optimize therapeutic effects of Taxotere for the treatment of prostate cancer.     

Trends in thyroid cancer incidence in Sweden, 1958-1981, by histopathologic type

Time trends in the incidence of malignant neoplasms of the thyroid were examined for Sweden for the period 1958-81, 5,838 cases being studied. Autopsy-diagnosed cases were excluded. Mean annual changes in the age-standardized rates over this period were 1.9% and 1.2% for women and men, respectively, for all thyroid carcinomas combined; 4.9% and 2.1% for papillary carcinoma; 0.9% and 2.1% for follicular carcinoma; and -1.0% and -2.1% for anaplastic carcinoma. Age, period and cohort models were fitted. There was a progressive increase in papillary cancer incidence for cohorts born since 1919. This increase cannot be satisfactorily explained as an artefact of trends in classification, and probably reflects a real increase in incidence. A less marked increase was seen for follicular cancer, and there was a decline for cohorts born since 1939. While the risk of papillary and anaplastic carcinoma was lower in iodine-deficient areas, follicular cancer risk was twice as high in these areas, for men only. There was a steady decline of anaplastic cancer in both sexes after 1965, largely attributable to a decline in cohorts born since 1924.     

RAS mutations in myelodysplasia detected by amplification, oligonucleotide hybridization, and transformation

Members of the RAS gene family have been implicated in many neoplasms with activating mutations around amino acid positions 12 and 61. We have assessed the mutational activation of H, K, and NRAS in myelodysplasia (MDS) by polymerase chain reaction and hybridization with synthetic oligonucleotide probes. Using this method, point mutations in codons 12/13 and 61 of these RAS genes were detected in 20 of 50 patients including two with refractory anemia with ringed sideroblasts (RARS). Ten normal individuals had no detectable RAS mutations. In 11 instances, DNA from patients with detectable RAS mutations were shown to register in either NIH3T3 focus-forming or nude mouse tumorigenicity assays. In addition, one patient (RARS) was shown to have an activated NRAS gene detected by a tumorigenicity assay and Southern blot analyses. Two MDS patients had mutations detected in two different RAS genes. DNA from one of these patients was observed to give rise to transformants with activated N and HRAS. Two patients with detectable NRAS mutations in the MDS stage progressed to AML and DNA from the AML stage registered positively in a transformation assay with NRAS activation. These results show that RAS mutations can occur at early, as well as late, stages of leukemic progression. The incidence of RAS mutations appears to be significantly higher in CMML than in the other subgroups (p = 0.02).     

Numerical chromosome 1, 7, 9, and 11 aberrations in bladder cancer detected by in situ hybridization

Forty transitional cell carcinomas of the human urinary bladder (TCCs) were examined for numerical aberrations of chromosomes 1, 7, 9, and 11 by in situ hybridization using chromosome-specific probes. Our interphase cytogenetic study of 24 low-grade, noninvasive TCCs, which were near-diploid by flow cytometry, showed a numerical aberration for at least 1 of these chromosomes in 14 of these cases. Most strikingly, a monosomy for chromosome 9 was found in 9 of 24 low-grade TCCs. A trisomy for chromosomes 1, 7, and 11 was detected in 5, 2, and 1 case(s), respectively. In 1 case a monosomy for chromosome 1 was detected by in situ hybridization. Monosomy for chromosome 9 was the only detected numerical change in 5 low-grade TCC cases. Examination of 16 invasive TCCs showed extra copies for chromosomes 1 and 7 in 7 flow cytometrically diploid cases with numerical chromosome aberrations; also, loss of chromosome 9 was detected. In 5 invasive and 2 noninvasive aneuploid/tetraploid TCCs a profound imbalance between the different chromosomes was found. In 5 of these cases an evident underrepresentation of chromosome 9 in comparison to chromosomes 1, 7, and 11 was detected. This underrepresentation of chromosome 9 in diploid, as well as aneuploid, TCCs, and in some cases the constant ratio between this chromosome and the other chromosomes, may be explained by a process of tetraploidization. Therefore, loss of chromosome 9 may be one of the primary genetic events in TCC oncogenesis, with secondary events, such as tetraploidization, correlated to tumor progression. Our results show that in situ hybridization can be routinely used to study important cytogenetic changes which occur during the development of a malignant disease.     

Ketone body, glucose, lactic acid, and amino acid utilization by tumors in vivo in fasted rats

Arteriovenous differences for acetoacetate, beta-hydroxybutyrate, glucose, lactic acid, and glutamine and other amino acids were measured across Morris hepatomas 5123C, 7777, and 7288CTCF and Walker sarcocarcinoma 256 in vivo in rats fasted for 2 days. The acetoacetate and beta-hydroxybutyrate concentrations in arterial whole blood of fasted tumor-bearing rats were 0.52 +/- 0.06 and 1.82 +/- 0.19 mM (S.E., n = 38), respectively. Both ketone bodies were utilized by the tumors, and the rates of utilization were directly related to the rates of supply. The mean utilization rates for acetoacetate and beta-hydroxybutyrate were 13.9 +/- 2.9 (range, 0 to 64; n = 30) and 24.7 +/- 4.4 (range, 0 to 145; n = 38) nmol/min/g tumor wet weight, respectively. Eight of the tumors produced acetoacetate, presumably from utilized beta-hydroxybutyrate. An average of 52% of the acetoacetate and 30% of the beta-hydroxybutyrate carried in the arterial blood was removed during one pass through the tumors. The concentrations of glucose and glutamine in the arterial whole blood of fasted tumor-bearing rats (n = 38) were 6.55 +/- 0.3 and 0.76 +/- 0.02 mM, respectively; both of these substrates were utilized at rates that were directly proportional to the rates of supply. The mean rates of glucose and glutamine utilization for all tumors in fasted rats were 101 +/- 11 (range, 3 to 313) and 8.2 +/- 1.1 (range, 0 to 25.1) nmol/min/g tumor wet weight, respectively. Thirty-six % of the glucose and 25% of the glutamine supplied to the tumors was utilized. Comparison (by linear regression and analysis of covariance) of the rates of supply and utilization of glucose and glutamine in tumors growing in fasted versus fed rats indicated that these substrates are utilized more efficiently by tumors growing in fasted animals. Lactic acid was either produced or utilized, depending on the arterial whole-blood concentration. Production or utilization occurred, respectively, when the arterial lactate concentration was less or greater than 1 to 3 mM. The arterial whole-blood amino acids (except glutamine) were utilized at rates that ranged from 1 to 4 nmol/min/g tumor wet weight. The results indicate that energy production for tumor growth in fasted rats is supported, in part, by an increased availability of ketone bodies, by an increased efficiency of utilization of glucose and glutamine, and, under certain circumstances, by utilization of lactic acid.     

Trends in esophageal cancer incidence by histology, United States, 1998-2003

Esophageal adenocarcinoma rates may be increasing, whereas, squamous cell carcinoma rates appear to be decreasing in the United States. Previous population-based research on esophageal cancer has only covered up to 68% of the country. Additional, updated research on a larger percentage of the country is needed to describe racial, ethnic and regional trends in histologic subtypes of esophageal cancer. Invasive esophageal cancer cases diagnosed between 1998 and 2003 (n = 65,926), collected by the National Program of Cancer Registries or the Surveillance, Epidemiology, and End Results program, were included. These data cover 83% of the US population. Esophageal squamous cell carcinoma incidence fell by 3.6%/year, whereas esophageal adenocarcinoma increased by 2.1%/year. Squamous cell carcinoma rates decreased among both sexes in most racial or ethnic groups, whereas adenocarcinoma rates increased primarily among white or non-Hispanic men. Except for white or non-Hispanic men, squamous cell carcinoma rates were similar to, or greater than, adenocarcinoma rates for men and women of all other races and ethnicities. The largest decrease in squamous cell carcinoma rates occurred in the West census region, which also exhibited no increase in adenocarcinoma rates. The rate of regional and distant-staged adenocarcinomas increased, while rates for local-staged adenocarcinoma remained stable. This is the first article to characterize esophageal cancer trends using data covering the majority of the US. Substantial racial, ethnic and regional variation in esophageal cancer is present in the US. Our work may inform interventions related to tobacco and alcohol use, and overweight/obesity prevention, and provide avenues for further research.     

Expression of tachykinins by ileal and lung carcinoid tumors assessed by combined in situ hybridization, immunocytochemistry, and radioimmunoassay

Mid-gut carcinoid tumors have been shown to produce substance P, a tachykinin. A recent addition to this family of peptides is neurokinin A which is cleaved from the same precursor as substance P; beta-pre-pro-tachykinin. The authors have examined mid-gut and pulmonary carcinoid tumors for the presence of the two tachykinins, using immunocytochemical study and radioimmunoassay, and have applied the techniques of in situ hybridization and Northern blot analysis to investigate the expression of mRNA for beta-pre-pro-tachykinin. All gut tumors (n = 8) and three of the six lung tumors examined were found by immunocytochemical study to contain both tachykinins or neurokinin A alone. Chromatographic analysis of tumor extracts suggests that this peptide is being detected as a separate molecule and/or as the C-terminal portion of a larger, uncleaved form. Three of the cases positive for tachykinins showed no detectable serotonin immunoreactivity. Strong hybridization signals for beta-pre-pro-tachykinin mRNA were seen in all but one of the cases studied which contained tachykinin immunoreactivity. Intact mRNA and positive hybridization was found by Northern blot analysis in two mid-gut tumors. Concentrations of tachykinins were found by radioimmunoassay to be higher in mid-gut tumors (substance P 27.2 +/- 19.7 pmol/g; neurokinin A 31.8 +/- 24.2 pmol/g; mean +/- SEM, n = 5) than in lung cases (substance P mean 0.8, range 0.5-1.0 pmol/g; neurokinin A mean 11.0, range 10.0-12.0 pmol/g; n = 3). These results show that mid-gut and pulmonary carcinoid tumors produce tachykinins, which are detected, in some cases, where no serotonin immunoreactivity can be found, possibly because of a high rate of amine secretion. Screening for tachykinins may prove to be a useful diagnostic adjunct for these tumors.