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J M Cowan

Publications and source records attributed to J M Cowan.

At least 19 recordsLinked to original sources
PubMed2006

Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials.

In multiple myeloma, deletion of chromosome 13 (del(13)) is associated with poor prognosis regardless of treatment. This study analyzed the impact of del(13) status on response and survival following treatment with either bortezomib or high-dose dexamethasone in patients in the SUMMIT and APEX trials. Additionally, matched-pairs subset analyses were conducted of patients with and without del(13), balanced for age and International Staging System parameters. In both SUMMIT and APEX, prognosis appeared to be poorer in bortezomib-treated patients with del(13) compared with patients with no del(13) by metaphase cytogenetics. In the SUMMIT and APEX matched-pairs analysis, response and survival appeared comparable in bortezomib-treated patients with or without del(13) by metaphase cytogenetics. However, patients with del(13) receiving dexamethasone in APEX appeared to have markedly decreased survival compared with those without del(13) by metaphase cytogenetics. These matched-pairs analyses suggest that bortezomib may overcome some of the poor impact of del(13) as an independent prognostic factor. However, sample sizes were very small; these findings require confirmation from further studies.

Aged↗
PubMed2000

Dominant transmission of imperforate hymen.

OBJECTIVE: Imperforate hymen is an uncommon anomaly of the reproductive tract, occurring in approximately 0.1% of newborn females. The familial occurrence of imperforate hymen in a child, her mother, and her mother's monozygotic twin is reported. DESIGN: Case report. SETTING: Academic medical center. PATIENT(S): Three affected family members. MAIN OUTCOME MEASURE(S): Karyotype and pedigree analysis. RESULT(S): The proband, presenting with peritonitis, was evaluated at age 12 for imperforate hymen because this condition was diagnosed in her mother at age 14. At age 14, the mother's monozygotic twin was asymptomatic except for primary amenorrhea and was also demonstrated to have imperforate hymen. No other reproductive system abnormalities were known to be present in the remaining family members. Chromosomal structural analysis confirmed that the mother of the proband had no chromosomal abnormalities. CONCLUSION(S): The occurrence of imperforate hymen in two consecutive generations of a family is consistent with a dominant mode of transmission, either sex-linked or autosomal. Previously reported examples of siblings with imperforate hymen suggested a recessive mode of inheritance. Taken together, these cases suggest that imperforate hymen can be caused by mutations in several genes. This case highlights the importance of evaluating all family members of affected patients. Familial examples of other developmental anomalies of the female reproductive tract also suggest a multifactorial genetic etiology.

Adult↗
PubMed2000

Fluorescence in-situ hybridization analysis of chromosomal constitution in spermatozoa from a mosaic 47,XYY/46,XY male.

Sex-chromosome mosaicism in spermatozoa from a mosaic 47,XYY[20%]/46, XY[80%] male with fertility problems was assessed using triple-probe fluorescence in-situ hybridization (FISH) studies. Chromosome-specific probes for X, Y and 18 were used, and the possible outcomes were deduced. In normal haploid spermatozoa of the patient and a normal 46,XY male control, the X:Y ratio was close to 1:1. There was a significant difference in the total incidence of karyotypically abnormal spermatozoa between the patient and the 46, XY male control (2.31% versus 1.46%, P < 0.0001). The incidence of some types of disomic spermatozoa X+Y+18 (24,XY) and X+18+18 (24,X, +18), or diploid X+Y+18+18 (46,XY) spermatozoa was significantly increased in the patient's semen sample. There was, however, no significant difference in the incidence of disomic Y+Y+18 (24,YY) spermatozoa. Because the majority of the patient's spermatozoa was karyotypically normal, the aetiology of his fertility problems was unclear. These results add to the growing body of information regarding chromosome abnormalities in spermatozoa from men who are mosaic for sex chromosome abnormalities. In these men, FISH analysis of spermatozoa may be warranted to determine the relative percentages of abnormal cells, and to determine if in-vitro fertilization with preimplantation genetic diagnosis may increase the likelihood of a successful pregnancy.

Adult↗
PubMed1999

Increased incidence of renal anomalies in patients with chromosome 22q11 microdeletion.

A well-known association exists between the presence of a chromosome 22q11 micro-deletion and conotruncal heart malformations. Recently, there has been an increased appreciation of the expanded clinical phenotype associated with this chromosome abnormality. We performed a medical record review to evaluate the incidence of renal anomalies in a group of 15 patients ascertained in a single medical center over a 33-month period. Of the 15 patients, 13 had a renal sonogram performed. Five of 13 patients studied (38.4%) had a renal anomaly. The specific abnormalities identified included: bilateral duplex kidneys (1 patient), unilateral renal agenesis (1 patient), unilateral multicystic dysplastic kidneys (2 patients, including 1 ascertained prenatally), and bilateral, extremely small (less than 2 SD below mean) kidneys (1 patient). The incidence of renal anomalies in our patient population (38.4%) was higher than expected, and agrees with a recent European collaborative study. The present report and the European study both demonstrate a higher percentage of renal abnormalities than the 10% previously reported in the literature. Because patients affected with chromosome 22q11 micro-deletion often have multiple medical and surgical problems, we recommend obtaining a baseline renal ultrasound examination to identify renal anomalies before they become symptomatic.

Chromosome Deletion↗
PubMed1998

The role for NES1 serine protease as a novel tumor suppressor.

Previously (Liu et al, Cancer Res., 56: 3371-3379, 1996), we isolated a novel serine protease-like gene--Normal Epithelial Cell Specific-1 (NES1)--that is expressed in normal mammary epithelial cells but is down-regulated in most breast cancer cell lines. Here, we demonstrate that stable expression of NES1 in the NES1-negative MDA-MB-231 breast cancer cell line suppressed the oncogenicity as revealed by inhibition of the anchorage-independent growth and tumor formation in nude mice. Fluorescence in situ hybridization localized the NES1 gene to chromosome 19q13.3, a region that contains genes for related proteases (including the prostate-specific antigen) and is rearranged in human cancers. Similar to breast cancer cell lines, prostate cancer cell lines also lacked NES1 mRNA and protein expression. Together, these results strongly suggest a tumor-suppressor role for NES1 in breast and prostate cancer.

Animals↗
PubMed1997

Cytogenetic and immunohistochemical analysis of an adult anaplastic neuroblastoma.

Neuroblastomas in children are common tumors and are characterized by a number of recurrent cytogenetic and molecular changes. Adult neuroblastomas are rare, and their relationship to pediatric neuroblastomas is not clear. We report an anaplastic neuroblastoma presenting in a 28-year-old man. Histopathologic identification of the tumor as a neuroblastoma was problematic, and the initial diagnosis was poorly differentiated sarcoma. Tumor cells expressed immunoreactivity for tyrosine hydroxylase in addition to generic neuroendocrine markers, consistent with catecholamine-synthesizing ability. They also extended long, branching neurites in vitro. The tumor was positive for immunoreactive trkA. The karyotype after 6 days in culture was found to be 42,XY with multiple chromosomal abnormalities. The only abnormality shared with pediatric neuroblastomas was a rearrangement of chromosome 17q. Double minute chromosomes or homogeneously staining regions associated with N-myc amplification were not present. To our knowledge, this is the first reported karyotype of an adult neuroblastoma. The cytogenetic findings, together with expression of trkA, suggest that the tumor was more closely related to the favorable prognosis neuroblastomas of infancy than to the poor prognosis tumors that occur in older children, despite its unfavorable histology.

Abdominal Neoplasms↗
PubMed1996

Determination of volume of distribution for ethanol in male and female subjects.

Ten nonalcoholic subjects gave written informed consent. Six men (aged 25-43) and four women (aged 25-35) were hydrostatically weighed to determine their percentage of body fat and lean weight. Each subject fasted for at least 10 h and then received an oral dose of alcohol (0.9 g per kilogram of lead body weight) calculated to yield a peak alcohol concentration of 0.100 g/210-L breath. Breath alcohol measurements were conducted at 20-min intervals until each subject's alcohol concentration returned to 0.000 g/210-L breath. All alcohol analyses were conducted on the Intoxilyzer 5000 and reported as g/210-L breath. Female subjects on average reached a lower peak alcohol concentration (mean, 0.086; range, 0.074-0.091 g/210 L) than male subjects (mean, 0.096; range, 0.093-0.101 g/210 L). Females demonstrated a higher average rate of elimination (mean, 0.017; range, 0.014-0.021 g/210 L) than males (mean, 0.015; range, 0.013-0.017 g/210 L). Female subjects on average had a higher percentage of body fat (mean, 26.0; range, 16.7-36.8%) than males (mean, 18.0; range, 10.2-25.3%). The average volume of distribution (Vd), as calculated from percentage of body fat, for the women (mean, 0.63; range, 0.54-0.71) was less than for the men (mean, 0.69; range, 0.63-0.76). The average Vd as calculated from linear regression of the alcohol concentration curve, for the women (mean 0.64, range, 0.56-0.71) was also less than for the men (mean, 0.72; range, 0.67-0.77). The data from this limited study indicate that hydrostatic weighing is an acceptable way of determining Vd for both men and women.

Adipose Tissue↗
PubMed1995

Physical findings in 21q22 deletion suggest critical region for 21q- phenotype in q22.

Multiple abnormalities were observed in a newborn infant with a deletion in the long arm of chromosome 21, from band 22q22.1-->qter. The phenotype of this infant was similar to that previously described in infants with deletions spanning the long arm of chromosome 21, from the centromere to 21q22 [Rethoré et al., 1972, Exp Cell Res 70:455-456, 1973, Ann Genet (Paris) 16:271-275]. However, as a phenotypically normal child with normal intelligence and with deletion of 21q11.1-21q21.3 has also been identified [Korenberg et al., 1991, Hum Genet 87:112-118], this case suggests that the critical region of deletion for the 21q- phenotype lies distal to 21q21, within 21q22.1-22.2.

Abnormalities, Multiple↗
PubMed1993

Chromosome changes characterizing in vitro response to radiation in human squamous cell carcinoma lines.

We have analyzed the karyotypes of a series of 16 cell lines derived from human squamous cell carcinomas of the head and neck. When the cell lines were grouped according to their in vitro response to radiation, it was observed that some recurrent chromosomal changes occurred with differing frequencies between groups. Radiation resistance was associated with clusters of breakpoints in bands 1p22, 3p21, and 8p11.2 and deletion of distal 14q, while relative radiation sensitivity was associated with a high frequency of breakpoints in 11q13 and duplication of distal 14q. The regions identified point to the possible locations of genes involved in the response to radiation and could provide a series of markers with which to predict response to radiation therapy.

Carcinoma, Squamous Cell↗
PubMed1993

Resistance of human squamous carcinoma cells to transforming growth factor beta 1 is a recessive trait.

Because most human squamous carcinoma cell lines of the aerodigestive and genital tracts are refractory to the antiproliferative action of transforming growth factor beta 1 (TGF beta 1) in vitro, we have begun to identify the causes for resistance of squamous carcinoma cell lines to TGF beta 1 by using somatic cell genetics. Two stable hybrid cell lines (FaDu-HKc.1 and FaDu-HKc.2) were obtained by fusing a TGF beta 1-resistant human squamous carcinoma cell line, FaDu-HygR, with a human papilloma virus 16-immortalized, TGF beta 1-sensitive, human foreskin keratinocyte cell line, HKc-neoR. Whereas TGF beta 1 did not inhibit DNA synthesis in parental FaDu-HygR cells, it reduced DNA synthetic activity of HKc-neoR, FaDu-HKc.1, and FaDu-HKc.2 cells by 75-85% (IC50, 2-5 pM). Although squamous carcinoma cells express lower than normal levels of TGF beta 1 type II receptors on their cell surface, TGF beta 1 type II receptor mRNA was detected in all four cell lines. Recessive genes involved in TGF beta 1 signaling may be localized to the distal portion of chromosome 18q, as this was the sole chromosomal region of homozygous deletion in parental FaDu-HygR cells. Furthermore, our previous observation that mutant p53 decreases sensitivity of keratinocytes to TGF beta 1 was supported by the finding that the level of the mutant p53 protein expressed by the hybrid cell lines was greatly reduced. In summary, TGF beta 1 resistance of FaDu cells appears to be recessive and is presumably due to the loss of one or more post-receptor elements of the signaling pathway.

Base Sequence↗
PubMed1993

Regulation of the Salmonella typhimurium metF gene by the MetR protein.

The metF gene in Escherichia coli and Salmonella typhimurium is under negative transcriptional control by the MetJ repressor. Expression of an S. typhimurium metF-lacZ gene fusion is repressed up to 10-fold by methionine addition to the growth medium in E. coli hosts encoding wild-type MetJ repressor; this repression is not seen in metJ mutants. metR mutations which eliminate the MetR activator protein result in two- to threefold-more-severe repression by the MetJ repressor. In a metJ metR double mutant, however, the level of metF-lacZ expression is the same as in a metJ mutant, suggesting that MetR antagonizes MetJ-mediated methionine repression of the metF promoter. A DNA footprint analysis showed that MetR binds to a DNA fragment carrying the metF promoter and protects two separate regions from DNase I digestion: a 46-bp region from position -50 to -95 upstream of the transcription initiation site and a 24-bp region from about position +62 to +85 downstream of the transcription initiation site and within the metF structural gene. Nucleotide changes in each of the MetR-binding sites away from the consensus sequence disrupt MetR-mediated regulation of the metF-lacZ fusion.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1992

Cytogenetic evidence of the multistep origin of head and neck squamous cell carcinomas.

BACKGROUND: Head and neck squamous cell carcinomas are associated with tobacco and alcohol use; therefore, the incidence of this type of tumor is expected to rise in the future as a result of the increasing numbers of female and adolescent smokers. Previous reports of cytogenetic analysis of this type of tumor have implicated a number of chromosomal regions in recurring changes, but no clear pattern of characteristic changes has emerged. PURPOSE: We have undertaken cytogenetic analysis of 10 cell lines which were established from squamous cell carcinomas of the head and neck, to determine the possible sites of additional tumor suppressor genes and oncogenes that may contribute to malignant transformation. METHODS: Metaphases were harvested from cultures of cells in the exponential growth phase, following exposure to Colcemid (demecolcine) at a final concentration of 30 ng/mL for 5 hours. Air-dried slides were G-banded using trypsin and Giemsa. Fifteen metaphases were photographed and fully karyotyped. RESULTS: We observed that several chromosomal regions were lost at high frequency, including 18q (10 of 10 lines), 10p (eight of 10 lines), 3p (six of 10 lines), 8p (seven of 10 lines), and the short arms of the acrocentric chromosomes (seven of 10 lines). Nine of 10 lines had additional copies of 7p. We also noted clustering of breakpoints in a number of chromosome bands, including 1p22, 10q11.2, 11q13, and the short arms of the acrocentric chromosomes. CONCLUSION: The observation of loss of multiple chromosomal regions in a significant number of lines analyzed is consistent with the theory that tumorigenesis occurs as the result of the accumulation of a number of genetic alterations, as proposed for colorectal carcinoma. The high frequency with which these changes are seen suggests that genes located in these regions have a role in the etiology of this type of tumor.

Carcinoma, Squamous Cell↗
PubMed1992

Molecular analysis of deletions of the short arm of chromosome 9 in human gliomas.

Previous studies have suggested that structural abnormalities involving the short arm of chromosome 9 are frequently associated with gliomas. The alpha-, beta-, and omega-interferon (IFNA, IFNB1, and IFNW, respectively) and the methylthioadenosine phosphorylase (MTAP) genes have been mapped to the short arm of chromosome 9, band p22. Homozygous deletions of these genes have been reported in many leukemia- and glioma-derived cell lines. In this report, we present a detailed analysis of partial and complete homozygous or hemizygous deletions of DNA sequences on 9p in human cell lines and primary tumor samples of glioma patients. Ten of 15 (67%) glioma-derived cell lines had hemizygous or homozygous deletion of IFN genes or rearrangement of sequences around these genes, while 13 of 35 (37%) primary glioma tumor samples had hemizygous (8 tumors) or homozygous (5 tumors) deletion of the IFN genes. The shortest region of overlap of these deletions maps in the interval between the centromeric end of the IFN gene cluster and the MTAP gene. In the cell lines and primary tumors examined, these gross genomic alterations were seen only in association with high grade or recurrent gliomas. Our observations confirm that loss of DNA sequences on 9p, particularly the IFN genes, occurs at a significant frequency in gliomas, and may represent an important step in the progression of these tumors. These results are consistent with a model of tumorigenesis in which the development or progression of cancer involves the loss or inactivation of a gene or several genes that normally act to suppress tumorigenesis. One such gene may be located on 9p; this gene may be closely linked to the IFN genes. Nevertheless, loss of the IFN genes, when it occurs, may play an additional role in the progression of these tumors.

Brain Neoplasms↗
PubMed1992

Differential retention of tumor- and differentiation-suppressor functions in cells derived from a human squamous cell carcinoma.

Three morphologically distinct cell lines--F.2a, V, and B.2--were isolated from a single human squamous cell carcinoma. Although all three cell lines can grow indefinitely in culture, they differ in a number of important transformation-related phenotypes. Only B.2 is strongly tumorigenic when injected into the flanks of nude mice, and only V can efficiently grow in semisolid media. The dominance of these traits was investigated by generating somatic cell hybrids among the three cell lines. F.2a was able to suppress the tumorigenicity of B.2 cells, whereas B.2 inhibited the capacity for anchorage-independent growth of V, the latter trait being a function of the ability of these epithelial cells to differentiate when deprived of support. The influence of exogenously added growth factors was also evaluated. This study indicates that the particular tumor we examined consisted of a heterogeneous population of cells with distinct growth and differentiation capacities.

Animals↗
PubMed1992

Cytogenetics in head and neck cancer.

Cytogenetic analysis of cell lines has identified a number of chromosomal regions that are likely to contain the genes important in malignant transformation in HNSCC. Further work needs to be done comparing results from cells grown in culture with tumors from which they are derived to determine the applicability of cytogenetic analysis. Preliminary results suggest that some of the chromosome changes observed may correlate with a cell's response to radiation and as such could provide a tool for evaluating a patient's response to planned therapy.

Carcinoma, Squamous Cell↗