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Biomedical subjects

R F Jones

Publications and source records attributed to R F Jones.

At least 19 recordsLinked to original sources
PubMed1992

Chemical carcinogenesis of the urinary bladder--a status report.

Cigarette smoking and certain types of occupational exposure to arylamines appear to be the main cause of human urinary bladder cancer. Little is known of the promotion of bladder cancer in humans, although this stage has been demonstrated in rodents. Perhaps as a consequence of initiation, multifactorial alterations of cellular genes occur. These genes include the epidermal growth factor receptor gene, erbB-2, int-2, hst, and H-ras, which exert positive control over cell growth, as well as the suppressor genes Rb-1, and the gene coding for p53. Chromosomal changes such as deletions, translocations and/or amplifications related to these genes may be of significance for prognosis of this disease.

Animals↗
PubMed1992

Early-retirement incentive programs for medical school faculty.

The Association of American Medical Colleges surveyed the principal business officers of all 126 accredited U.S. medical schools in late 1991 in order to learn about their retirement benefit programs for faculty and whether early-retirement incentive programs were being used. A total of 115 of the schools provided usable responses, which the author reports for all schools, public schools, and private schools. For all schools, defined-contribution plans (based on employer's and employee's contributions plus investment earnings) were the preferred type of retirement benefit program (77%, or 89, of the responding schools). Defined-benefit plans (based on a formula that uses variables of age at retirement, years of service, and salary) were available at 37% (43) of the schools. Early-retirement incentive programs had been used by 70% of the responding schools in the five-year period 1987-1991. Sixteen schools provided descriptions of their formal early-retirement programs, which are summarized. The author observes that, although nearly three-fourths of the responding schools are familiar with the use of the incentive programs, these programs have resulted in few actual early retirements. He discusses why this may be true and compares the pros and cons of formal and ad hoc programs. He concludes that no single program can be considered best; each institution must work with its faculty to design programs to meet institutional goals and faculty interests.

Faculty, Medical↗
PubMed1991

The role of Ha-ras oncogenes in growth factor independence in rat mammary carcinoma cells.

To determine if activation of the c-Ha-ras-1 gene is involved in the acquisition of growth factor independence in 7,12-dimethylbenz[a]anthracene (DMBA)--and N-nitrosomethylurea (NMU)--induced rat mammary carcinomas, three strategies were used. First, Ha-ras DNA from growth factor-independent DMBA-induced rat mammary tumor cells was amplified using the polymerase chain reaction and examined for the presence of mutations in the first and second exons of Ha-ras-1 by restriction fragment length polymorphism analysis, allele-specific oligonucleotide hybridization, and direct sequencing. No mutations were found in the codon 12/13 or codon 61 regions of the Ha-ras-1 gene. Second, a similar analysis of an NMU-induced mammary carcinoma showed that it harbored an activating mutation in codon 12 of Ha-ras-1. When analyzed for growth factor requirements, these cells were found to express limited growth potential in all media tested, in contrast to growth factor-independent cells, which proliferated extensively in the presence or absence of exogenous growth factors. Third, growth factor-dependent rat mammary tumor cells and spontaneously immortalized rat normal mammary epithelial cells were transfected with an activated form of the Ha-ras-1 (T24) gene, and the growth factor requirements of the transfected cells were examined. The ras-transfected cells retained the growth factor requirements of the normal cells. In addition, ras-transfected cells were transplanted into syngeneic rats and nude mice, and no tumors developed after 6 mo in vivo. These results indicate that, in rat mammary tumor cells, neither growth factor independence in vitro nor transplantability are directly mediated by Ha-ras oncogenes. The results also suggest that ras activation and growth factor independence may be associated with independent pathways to malignancy in rat mammary tumorigenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

The end of mandatory retirement and its implications for academic medicine.

The prohibition against age-based mandatory retirement, codified in amendments to the Age Discrimination in Employment Act (ADEA) in 1986, remains a concern in the academic medical community. A seven-year exemption covering tenured faculty expires at the end of 1993. The author reviews the legislative history of the ADEA and explores in detail the planning and management issues--and the available projections of likely faculty behavior in the future--concerning the banning of age-based mandatory retirement of higher education faculty, with special reference to the academic medical community. Although the major studies concerning the probable course of events after the seven-year exemption expires indicate that there will not be a cataclysmic effect on institutions of higher education, it is still not certain how tenured faculty will behave and how that will affect medical schools. The author cautions that the management acumen of institutional leaders will be taxed, and that medical school deans should realize this and begin the transition into the new era by improving systems for faculty evaluation and development, clarifying the financial guarantees of tenure, implementing space utilization reviews, and developing programs to make retirement attractive.

Aged↗
PubMed1991

Characterization of Int-5, a locus associated with early events in mammary carcinogenesis.

Three chemically-induced precancerous mammary hyperplasias, independently isolated in BALB/c mice, all contained mouse mammary tumor virus (MMTV) proviral DNA integrated into a common region in chromosomal DNA, designated Int-5 (Formerly Int-H, Gray et al., 1986). This site was cloned from a hyperplastic outgrowth (D2) into lambda phage. A 1.7 Kb Hind III DNA fragment, which flanks the 5' end of the MMTV insert, was generated from the cloned Int-5 region. This fragment was used as probe (IH-2) to localize Int-5 to mouse chromosome 9. The IH-2 sequence was highly conserved in DNA of several mammalian species including man, in three other widely divergent vertebrate phyla, and in C. elegans. The Int-5 region, containing 5.6 Kb 5' and 12.8 Kb 3' to the MMTV integration site in D2, was cloned in EMBL-3 from a BALB/c genomic DNA library. cDNA complementary to poly A+ lactating mammary gland RNA, annealed with Sst-1 fragments spanning most of the BALB/c Int-5 clone. The highest level of Int-5 specific poly A+ mRNA was detected in D2 tumor. Lactating mammary gland and D2 hyperplastic alveolar nodule contained 5-fold less Int-5 RNA while liver contained 8-fold less Int-5 RNA. Int-5 cDNA (IH-3) annealed with two RNA species of approximately 3.3 and 4.0 Kb. These data are consistent with the hypothesis that Int-5 contains an oncogene, different from any other previously described, involved in early events in some models of chemical carcinogenesis.

Animals↗
PubMed1990

Oncogene expression of FANFT- or BBN-induced rat urothelial cells.

Proto-oncogene expression by cultured urothelial cells prepared from the bladders of male F344 rats that had been treated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT) or N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were examined. Although all of the cultured cells showed varying degrees of anchorage-independent growth, only 9 of them were transplantable into nude mice. A Northern blot technique was employed for the detection of proto-oncogene transcripts. The c-Ha-ras transcripts were detected in all the cultured urothelial cells prepared from the carcinogen-treated rats and in normal urothelial cells. However, the transcript levels were several-fold higher in the former than in normal cells. Increased expression of p21, as determined by immunohistochemical techniques, was also observed in all the original bladder tissues from which the cultures were derived. c-myc transcripts were detected in the cells from carcinogen-treated rats but not in the normal cells. The presence of myc product in hyperplastic urothelial lesions and carcinomas of original bladder tissues was confirmed by immunohistochemical methods. Transcripts of mos, erb B, Ki-ras, abl and src were not detected. Since increased expression of c-myc and c-Ha-ras were present in both transplantable and non-transplantable cell lines, and the expression of p21 occurs in preneoplastic cells, this suggests that elevated expression of these 2 genes may be an early genetic event during bladder carcinogenesis in the rat and further alteration of these 2 genes or mutation of additional genes may be required for the completion of malignant transformation.

Animals↗
PubMed1990

Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10.

Two sublines of a breast epithelial cell culture, MCF-10, derived from human fibrocystic mammary tissue exhibit immortality after extended cultivation in low calcium concentrations (0.03-0.06 mM) and floating transfers in low calcium (MCF-10F), or by trypsin-Versene passages in the customary (normal) calcium levels, 1.05 mM (MCF-10A). Both sublines have been maintained as separate entities after 2.3 years (849 days) in vitro and at present have been in culture for longer than 4 years. MCF-10 has the characteristics of normal breast epithelium by the following criteria: (a) lack of tumorigenicity in nude mice; (b) three-dimensional growth in collagen; (c) growth in culture that is controlled by hormones and growth factors; (d) lack of anchorage-independent growth; and (e) dome formation in confluent cultures. Cytogenetic analysis prior to immortalization showed normal diploid cells; although later passages showed minimal rearrangement and near-diploidy, the immortal cells were not karyotypically normal. The emergence of an immortal culture in normal calcium media was not an inherent characteristic of the original tissue from which MCF-10 was derived since reactivated cryo-preserved cells from cultures grown for 0.3 and 1.2 years in low calcium were incapable of sustained growth in normal calcium.

Animals↗
PubMed1990

Role of growth factor synthesis in the acquisition of insulin/insulin-like growth factor I independence in rat mammary carcinoma cells.

In previous work, we demonstrated that a subset of carcinogen-induced rat mammary carcinomas consists of cells that are independent of growth factors strictly required by normal rat mammary epithelial (RME) cells for long-term growth in serum-free medium. Furthermore, only those tumors that expressed growth factor independence in vitro were serially transplantable in vivo. The present studies were aimed at determining if the independence of insulin (IN)/insulin-like growth factor I (IGF-I) is mediated by autocrine factors synthesized by the rat mammary tumor (RMT) cells. The results of these experiments indicate that IN/IGF-I-independent RMT cells do not synthesize IGF-I that is detectable at the message or peptide level. Both normal and neoplastic cells do, however, secrete IGF-I-binding activity. Conditioned medium, cell lysates, and cell extracts obtained from growth factor-independent cells do not contain growth factor activity that can substitute for IN for growth of IN-dependent RMT cells. Growth factor-independent cells do not express a density dependence for growth in IN-free medium nor do they respond to exogenous IN or IGF-I in low density growth assays. By contrast, growth factor-dependent cells that were rendered IN/IGF-I independent by transfection with an expression vector containing the IGF-I gene secrete IGF-I-like biological activity that is readily detectable and maintain responsiveness to exogenous IN at low densities. Taken together, these results suggest that growth factor-independent RMT cells are truly autonomous of IN/IGF-I for growth and are not synthesizing a growth factor that satisfies their IN/IGF-I requirement in an autocrine manner.

Animals↗
PubMed1990

Activating missense mutations in Ha-ras-1 genes in a malignant subset of bladder lesions induced by N-butyl-N-(4-hydroxybutyl)nitrosamine or N-[4-(5-nitro-2-furanyl)-2-thiazolyl]formamide.

Urothelial cell cultures generated from urinary bladders from a series of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)- or N-[4-(5-nitro-2-furanyl)-2-thiazolyl]formamide (FANFT)-treated Fischer 344 rats were examined for activating missense mutations in Ha-ras-1 genes. Our overall objective was to identify oncogene-activating mutations in this system and to determine what altered biological properties correlate with such genetic changes. The urinary bladders from the treated animals showed a spectrum of histopathologies, from simple hyperplasia to transitional cell carcinoma (TCC). Using restriction analysis, oligonucleotide hybridization, and DNA sequencing, we found that approximately 20% (3/14) of the bladder cell cultures had acquired oncogenic single-base substitutions in codon 61 of Ha-ras-1 genes (CAA----AAA or CGA). The donor bladder lesions for these three cultures, which also harbored the same ras-activating mutations, were all classified as stage A or B TCCs. However, four other TCCs also arising in this series were found to have normal Ha-ras genes. Whereas approximately half of the bladder cultures derived from the carcinogen-treated rats were nontumorigenic in athymic mice, the three cultures containing ras oncogenes were all highly tumorigenic (forming tumors within 5 wk of injection into athymic mice). These cultures also displayed a high degree of anchorage-independent growth and NIH 3T3-transforming activity in gene transfer assays. The nontumorigenic cultures were derived from bladder lesions that included three hyperplasias and three stage A TCCs. We conclude that ras-activating missense mutations were present in a malignant subset of bladder lesions induced by BBN or FANFT, but most of the lesions in this system appeared to involve genetic alterations elsewhere. Thus other oncogenes besides activated Ha-ras may apparently be associated with the same bladder histopathologies and transformation markers.

Animals↗
PubMed1990

Endoscopic third ventriculostomy.

Long-term extracranial shunting for hydrocephalus has numerous drawbacks related to shunt malfunction and infection. In some cases outcome has been very disappointing. We successfully managed 5 patients with acquired aqueductal stenoses with no significant morbidity by the use of an intracranial cerebrospinal fluid diversion, namely a third ventriculostomy. First advocated by Dandy, ventriculostomy was largely passed over in favor of extracranial procedures. With improved surgical techniques, however, ventriculostomy is now considered to be a viable alternative in selected cases. In a further 19 patients, we subsequently broadened our patient selection to include those with Arnold-Chiari malformations, congenital noncommunicating hydrocephalus, and tumors. Two thirds of these children remain without shunts and apart from 1 child developing hemiplegia postoperatively, there has been no significant morbidity. Although the best results have been seen in the late onset groups, even early onset, noncommunicating hydrocephalus has been successfully managed. Even in patients in whom third ventriculostomy has failed and who have subsequently required ventriculoperitoneal shunts, we anticipate that they will remain less dependent on shunts because their hydrocephalus is now communicating, which tends not to have such a rapid onset or extreme levels of raised intracranial pressure.

Adolescent↗
PubMed1989

Suprasellar arachnoid cysts: management by cyst wall resection.

Five children with ventricular dilatation (4 boys, 1 girl) had features seen on computer tomographic scan that were consistent with suprasellar arachnoid cysts. All children were investigated with a CT ventriculogram and/or CT cisternogram, and no communication with the cyst was demonstrated. Three children were seen in the 1st year of life and the remaining 2 children were between 1 and 5 years of age. Hydrocephalus and developmental delay were the most common presenting features, followed by visual disturbance, squint, or ataxia. Direct surgical decompression was performed in all 5 patients to avoid long-term placement of a ventriculoperitoneal shunt. A temporary shunt was placed in 2 children because of high intracranial pressure. Direct partial excision of the cyst wall to allow long-term drainage into the basal cisterns or ventricular system was successful in all children. The presence of subdural collections postoperatively required temporary shunting in 2 children. After follow-up for between 10 and 22 months no clinical endocrinological sequelae have been detected, but 2 children have raised serum prolactin levels. Three children are developmentally delayed; one of these has regained some skills since surgery. Direct surgical decompression of suprasellar arachnoid cysts to avoid long-term shunt placement is the preferred method of surgical treatment for this condition.

Arachnoid↗
PubMed1988

Ventriculopleural shunts for hydrocephalus: a useful alternative.

From 1969 to 1979, ventriculopleural shunts were inserted in 29 children with progressive hydrocephalus. A standard Pudenz pump with a Raimondi catheter was used for all but 1 child for whom a Holter valve was used. The shunt functioned adequately in 7, but in 18 it had to be changed as a result of symptomatic pleural effusion. From 1979 to 1982, a further series of 52 other patients received ventriculopleural shunts, and these cases have recently been reviewed. The apparatus used was a Portnoy ventricular catheter or a medium or high pressure Heyer Schulte pump with an antisiphon device and a Salmon distal catheter. Three patients developed a shunt infection. One died with a functioning shunt. Four catheters became blocked by adhesions, and in only 1 patient was a peritoneal shunt substituted as a result of symptomatic effusion.

Adolescent↗