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Biomedical subjects

P Russell

Publications and source records attributed to P Russell.

At least 127 records · Page 7Linked to original sources
PubMed1997

Cancer pathology in the year 2000.

The last one hundred and fifty years has produced the mature and sophisticated discipline of histopathology, yet still leaves the diagnosis of human cancer, by the best available technique, as more art than science. Proton magnetic resonance spectroscopy (1H MRS) ex vivo identifies the chemical markers of established pathobiological disorders within excised biopsies and fine needle aspirates, in particular, those associated with the development and progression of malignant disease. Alterations to cellular chemistry monitored by 1H MRS allows distinction between invasive and pre-invasive lesions of the uterine cervix, and separate truly benign follicular neoplasms from follicular carcinomas on analysis of fine needle aspirates containing as few as 10(6) cells. 1H chemical shift imaging (CSI) determines the spatial location of these chemical changes and provides insight into the chemistry of neoplastic transformation. It is our hypothesis that, by the year 2000, CSI will aid image guided biopsy techniques and that correlation of biopsy histology with in vivo localised 1H MRS data will: (a) lead to improved assessment of the extent of malignant disease and (b) establish the sensitivity and specificity of in vivo 1H MRS for the simultaneous determination of the size, location and neoplastic potential of a tumour mass.

Forecasting↗
PubMed1997

Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene.

The breast cancer susceptibility gene BRCA2 on chromosome 13q12-13 has recently been identified. Germline mutations of BRCA2 are predicted to account for approximately 35% of families with multiple case, early onset female breast cancer, and they are also associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer and pancreatic cancer. Germline mutations of a second cancer susceptibility gene BRCA1 (ref. 5), are associated with a strong predisposition to ovarian cancer as well as female breast cancer. Recent studies have suggested that the phenotype in BRCA1 families with respect to the ratio of breast to ovarian cancer varies with the location of the BRCA1 mutation. To determine whether germline mutations in BRCA2 are associated with a similar variation in phenotypic risk, we have analysed the distribution of mutations in 25 families with multiple cases of breast and/or ovarian cancer ascertained in the United Kingdom and Eire. These mutations all lead to premature truncation of BRCA2 as a result of frameshift deletions/insertions or nonsense mutations. Analysis of the mutation distribution along the length of the gene indicates a significant genotype-phenotype correlation. Truncating mutations in families with the highest risk of ovarian cancer relative to breast cancer are clustered in a region of approximately 3.3 kb in exon 11 (P = 0.0004). Published data on mutations in 45 other BRCA2-linked families provide support for this correlation.

BRCA2 Protein↗
PubMed1997

Mcs4 mitotic catastrophe suppressor regulates the fission yeast cell cycle through the Wik1-Wis1-Spc1 kinase cascade.

Spc1 in Schizosaccharomyces pombe is a member of the stress-activated protein kinase family, an evolutionary conserved subfamily of mitogen-activated protein kinases (MAPKs). Spc1 is activated by a MAPK kinase homologue, Wis1, and negatively regulated by Pyp1 and Pyp2 tyrosine phosphatases. Mutations in the spc1+ and wis1+ genes cause a G2 cell cycle delay that is exacerbated during stress. Herein, we describe two upstream regulators of the Wis1-Spc1 cascade. wik1+ (Wis1 kinase) was identified from its homology to budding yeast SSK2, which encodes a MAPKK kinase that regulates the HOG1 osmosensing pathway. Delta wik1 cells are impaired in stress-induced activation of Spc1 and show a G2 cell cycle delay and osmosensitive growth. Moreover, overproduction of a constitutively active form of Wik1 induces hyperactivation of Spc1 in wis1(+)-dependent manner, suggesting that Wik1 regulates Spc1 through activation of Wis1. A mutation of mcs4+ (mitotic catastrophe suppressor) was originally isolated as a suppressor of the mitotic catastrophe phenotype of a cdc2-3w wee1-50 double mutant. We have found that mcs4- cells are defective at activation of Spc1 in response to various forms of stress. Epistasis analysis has placed Mcs4-upstream of Wik1 in the Spc1 activation cascade. These results indicate that Mcs4 is part of a sensor system for multiple environmental signals that modulates the timing of entry into mitosis by regulating the Wik1-Wis1-Spc1 kinase cascade. Inactivation of the sensor system delays the onset of mitosis and rescues lethal premature mitosis in cdc2-3w wee1-50 cells.

Amino Acid Sequence↗
PubMed1997

Association properties of betaB2- and betaA3-crystallin: ability to form dimers.

The beta-crystallins are a major constituent of the mammalian lens, where they associate into dimers, tetramers and higher order aggregates. Appropriate association of lens crystallins is important for lens transparency. To examine the associative properties of betaB2-crystallin, we have expressed mouse betaB2-crystallin using a baculovirus system. Recombinant mouse betaB2-crystallin has an estimated monomer molecular weight of 24 kDa by SDS-PAGE, appropriate immunoreactivity and appropriate secondary structure as assessed by circular dichroism analysis. The recombinant betaB2-crystallin associates into a homodimer with a weight average molecular mass of 39 kDa. The betaB2-crystallin homodimer has an estimated Kd of 5 x 10(-6) M, slightly greater than that of betaA3-crystallin, 0.8 x 10(-6) M. When recombinant betaB2-crystallin is combined with recombinant betaA3-crystallin, a heterodimer is formed within 10 min of incubation at room temperature. When equilibrium is reached in 4-6 h, approximately half of each crystallin associates into heterodimers. Subunit exchange between betaB2-crystallin and betaA3-crystallin occurs readily in the absence of any denaturing agents. Thus, rbetaA3-rbetaB2 heterodimer formation can occur under conditions similar to those found in the eye lens.

Animals↗
PubMed1997

Transitional (urothelial) cell metaplasia of the uterine cervix: morphological assessment of 31 cases.

Thirty-one cases of transitional cell metaplasia (TCM) of the uterine cervix were studied. The mean age of patients was 62 years (range 30-87); 25 (81%) were postmenopausal and six premenopausal. In 24 of 25 postmenopausal patients, TCM was an incidental finding at operation for a variety of gynecological lesions, and in such patients the distribution of TCM included the endocervical canal, transformation zone, native ectocervix and vagina. In five of six premenopausal patients, TCM was identified in the cervices of women investigated for abnormal Papanicolaou smears. In all six premenopausal patients, as well as in the remaining postmenopausal patient who also presented with an abnormal Papanicolaou smear, TCM was confined to the endocervical canal and transformation zone. TCM was typified by a multilayer epithelium, clearly distinguishable from the atrophic ectocervical epithelium of most postmenopausal patients by its thickness (averaging 12 cells thick). TCM was identified on the surface epithelium or in sequestered endocervical glands resembling Walthard cell nests of the fallopian tube serosa. There was loss of the usual basal "picket fence" layer seen in cervical squamous epithelia; the cells had crowded nuclei oriented vertically and swirling to give a superficial appearance of disorder. Although lack of "differentiation" from the basal to superficial layers was characteristic, in many examples there was an obvious surface umbrella layer. Intraepithelial glandular differentiation and lesions resembling cystitis glandularis of the urinary bladder were occasionally noted on the ectocervix and vagina. Cellular detail included large pale oval nuclei, oriented vertically, with finely stippled chromatin, small inconspicuous nucleoli, and frequently a deep longitudinal groove. Although the nuclear/cytoplasmic ratio was high, cell-to-cell variation was negligible, and mitoses were rare and never atypical, which, with the nuclear details, distinguished TCM from high-grade squamous dysplasias. The nature of the metaplasia and its biological function are unclear. In postmenopausal patients, it presumably arises occasionally as a consequence of the altered hormonal environment of the cervix and vagina and is of interest only for the possibility of misinterpreting it as a high-grade squamous intraepithelial lesion. In premenopausal patients, it may represent a cellular variation of either physiologic or atypical metaplastic squamous epithelium of the cervical transformation zone.

Adult↗
PubMed1997

Roles of Wee1 and Nim1 protein kinases in regulating the switch from mitotic division to sexual development in Schizosaccharomyces pombe.

In self-fertile strains of the fission yeast Schizosaccharomyces pombe, nitrogen starvation initiates a program of sexual development in which cells express mating pheromones and receptors, arrest cell cycle progression in G1, and conjugate. This process is dependent on Rum1, an inhibitor of the Cdc2-Cdc13 and Cdc2-Cig2 cyclin B kinases. The M-phase induction activity of Cdc2-Cdc13 is inhibited by Wee1 tyrosine kinase, which phosphorylates Cdc2 on tyrosine-15. We report here that Wee1 activity is also important for mating. This discovery arose from studies of Nim1, a kinase which promotes mitosis by inhibiting Wee1. Nim1 was previously thought to have an important role in promoting mitosis during nitrogen starvation, but our studies revealed that Nim1 protein drops to an undetectable level within 15 min of nitrogen depletion. In contrast, Wee1 remains abundant, and tyrosine-phosphorylated Cdc2 is detected for at least 4 h after resuspension of cells in nitrogen-free medium. This suggested that maintenance of Wee1 activity may be important during the early stages of nitrogen starvation, a proposal confirmed by the observation that mating efficiency is reduced ca. fivefold in wee1- cells. Transcriptional induction of genes encoding mating factors and receptors is also delayed in wee1- cells. The wee1- mating defect is suppressed by deletion of cig2+, which encodes a B-type cyclin that promotes the onset of S and inhibits conjugation. These findings indicate that Wee1 and Rum1 act jointly to inhibit Cdc2 and promote sexual development in nitrogen-starved cells.

Ammonium Chloride↗
PubMed1997

Discrete roles of the Spc1 kinase and the Atf1 transcription factor in the UV response of Schizosaccharomyces pombe.

Exposure of mammalian cells to UV irradiation or alkylating agents leads to the activation of the c-Jun N-terminal kinase and p38 stress-activated protein kinase cascades, phosphorylation of c-Jun and ATF-2 bZIP transcription factors, and finally to selective induction of gene expression. This UV response is believed to be crucially important for cell survival, although conclusive evidence is lacking. Here, we address this issue by investigating a homologous UV response pathway in the fission yeast Schizosaccharomyces pombe. In fission yeast cells, UV irradiation induces activation of Spc1 stress-activated protein kinase, which in turn phosphorylates the Atf1 bZIP transcription factor. spc1 mutants are hypersensitive to killing by UV at a level equivalent to some checkpoint rad mutants. Whereas checkpoint rad mutants fail to arrest division in response to DNA damage, spc1 mutants are defective at resuming cell division after UV exposure. Levels of basal and UV-induced transcription of ctt1+, which encodes a catalase believed important for combating oxidative stress caused by UV, are extremely low in spc1 mutants. Atf1 is required for UV-induced transcription of ctt1+, but atf1 mutants are not hypersensitive to killing by UV. This surprising finding is explained by the observation that ctt1+ basal expression is unaffected in atf1 single mutant and spc1 atf1 double mutant cells, suggesting that unphosphorylated Atf1 represses ctt1+ expression in spc1 cells. In fact, the level of UV sensitivity of spc1 atf1 double mutant cells is intermediate between those of the wild type and spc1 mutants. These findings suggest the following. (i) Key properties of UV response mechanisms are remarkably similar in mammals and S. pombe. (ii) Activation of Spc1 kinase greatly enhances survival of UV-irradiated cells. (iii) Induction of gene expression by activation of Atf1 may not be the most important mechanism by which stress-activated kinases function in the UV response.

Activating Transcription Factor 1↗
PubMed1997

Fine-needle biopsy specimens of benign breast lesions distinguished from invasive cancer ex vivo with proton MR spectroscopy.

PURPOSE: To determine whether invasive breast cancer can be distinguished from benign lesions with proton magnetic resonance (MR) spectroscopy ex vivo on the basis of altered cellular chemistry. MATERIALS AND METHODS: Two hundred eighteen fine-needle biopsy specimens were obtained in 191 patients undergoing surgery and were analyzed with proton MR spectroscopy. MR spectroscopic and histopathologic findings were compared. RESULTS: Invasive carcinoma produced increased signal at 3.25 ppm, attributable to choline-containing metabolites. Discrimination between invasive carcinoma (n = 82), benign lesions (n = 106), or carcinoma in situ (n = 17) was based on the resonance intensity at 3.25 ppm standardized to the resonance at 3.05 ppm (P < .001). The ratio of peak height intensities of resonances at 3.25 to those at 3.05 ppm was less than 1.7 in 102 of the 106 normal or benign lesions. All carcinoma in situ specimens with comedonecrosis or a microinvasive component (n = 6) were categorized at MR spectroscopy with invasive carcinoma, while others with in situ disease alone were categorized with benign lesions (n = 11). The sensitivity and specificity of MR spectroscopy in fine-needle biopsy specimens in distinguishing benign lesions from invasive cancer were 95% and 96%, respectively. CONCLUSION: Proton MR spectroscopy of fine-needle biopsy specimens provides objective diagnostic information that complements findings of conventional preoperative investigations of breast lesions.

Adult↗
PubMed1997

Reducing the incidence of needlestick injuries.

Needlestick injuries are the most common type of occupational injury among nurses. At least 20 pathogens can be transmitted via a needlestick injury. Needlestick injuries should be reported immediately. Ongoing education of health-care staff is essential to ensure safe practice in the disposal of sharps.

Health Personnel↗
PubMed1997

The clinicopathological features of primary ovarian failure.

Premature ovarian failure is the end result of depletion of responsive ovarian follicles. While, in some cases, this is caused by a reduced complement of oocytes present in the ovaries at birth, in most patients the cause is thought to be accelerated atresia of uncertain aetiology. Central to the processes of development and atresia of normal follicles is the cyclical activation of a cytokine cascade initiated by interferon-gamma. It is thought that disturbances of the immune system induce a continuous rather than cyclical production of these cytokines and such a mechanism is a key to the pathogenesis of premature ovarian failure. The role of autoimmunity in triggering of these events is still uncertain but appears important. Less important is the role of the diagnostic pathologist.

Adult↗
PubMed1997

Laboratory diagnosis of plague.

In response to an outbreak of a plague-like disease in India, the Public Health Laboratory Service (PHLS) in the UK distributed advice on the isolation and identification of Yersinia pestis. Some of the procedures outlined were evaluated using a number of isolates of Y. pestis, complemented with in-house techniques detecting virulence genes or their products. These laboratory investigations are limited in that they are either only indicative or they take too long (48 hours or more), and thus represent a serious delay to the patient. Successful patient management must be based on a case history, and therapy should be started immediately. Laboratory diagnosis will subsequently rule out most pathogens which cause similar infections, yet will still require confirmation by a reference laboratory.

Bacteriological Techniques↗
PubMed1996

Cysteine protease activated by expression of HIV-1 protease in transgenic mice. MIP26 (aquaporin-0) cleavage and cataract formation in vivo and ex vivo.

Transgenic mice, homozygous for HIV-1 protease expression in the eye lens, display degradation of some lens crystallins and cytoskeletal proteins prior to cataract formation on postnatal days 23-25. Alterations to the internal lens hydration state also occur; therefore, the status of the aquaporin protein MIP26 was examined over postnatal days 16-25 to determine if it was altered during cataractogenesis. The MIP was identical in transgenic and control lenses until day 21. By postnatal day 25 (frank cataract), in the lenses obtained from transgenic animals, the 26-kDa band was absent and there was a concurrent increase in the proportion of MIP23. Immunoblotting demonstrated cleavage at the C terminus. Lenses were also maintained in an organ culture system to demonstrate that the cataractogenic process is inherent to the isolated lens and to determine the contribution of cysteine protease action. Organ culture experiments revealed a similar progression to nuclear cataract formation as seen in vivo. Two-dimensional gel analysis of the soluble lens crystallin fraction of organ cultured lenses revealed the same cleavage pattern as occurs in vivo. Organ culture of transgenic lenses with E64, a cysteine protease inhibitor, dramatically delayed cataractogenesis and prevented proteolytic cleavage of both MIP26 and crystallins. HIV-1 protease, while the trigger of cataract formation, does not appear to be the protease responsible for cleavage of MIP or lens crystallins. These results suggest that activation of endogenous cysteine protease activity is involved in the cleavage of these proteins and occurs downstream of HIV-1 protease action.

Animals↗
PubMed1996

Conjugation, meiosis, and the osmotic stress response are regulated by Spc1 kinase through Atf1 transcription factor in fission yeast.

The stress-activated Wis1-Spc1 protein kinase cascade links mitotic control with environmental signals in Schizosaccharomyces pombe. Fission yeast spc1- mutants are delayed in G2 during normal growth and undergo G2 arrest when exposed to osmotic or oxidative stress. Here we report that Spc1 also has an important role in regulating sexual development in S. pombe. This discovery arose from the observation that Spc1 is activated in response to nitrogen limitation, a key signal that promotes conjugation in fission yeast. Mutant spc1- cells are defective at arresting in G2 during nitrogen starvation and exhibit a poor mating ability. These deficiencies correlate with a failure to induce transcription of ste11+, a gene that encodes a transcription factor responsible for expression of various meiotic genes. Two genes, atf1+ and atf21+, were cloned as multicopy suppressors of the spc1- mating defect. Atf1 and Atf21 are bZIP transcription factors that are most closely related to human ATF-2/CRE-BP1. Spc1 is required for stress-induced phosphorylation of Atf1. Atf1 is required for induction of meiotic genes and stress-response genes, such as gpd1+ and pyp2+, that are transcriptionally regulated by Spc1. atf1- and spc1- mutants are sensitive to osmotic stress and impaired for sexual development, showing that fission yeast uses a common pathway to respond to cytotoxic stress and nitrogen starvation. However, unlike spc1- mutants, atf1- cells have no mitotic cell-cycle defect, indicating that the stress response pathway bifurcates at Spc1 to regulate independently meiosis and mitosis.

Activating Transcription Factor 1↗
PubMed1996

Somatic and germline mutations of the BRCA2 gene in sporadic ovarian cancer.

The breast and ovarian cancer susceptibility gene BRCA2 has recently been isolated. A role for BRCA2 in sporadic breast and ovarian cancer has been suggested by loss of heterozygosity (LOH) studies which show frequent LOH in the BRCA2 region at chromosome 13q12. In addition, the observation of nonrandom loss of the wild-type chromosome in a breast/ovarian cancer family which shows linkage to BRCA2 suggests it may act as a tumor suppressor gene. To determine the extent of somatic alteration involving BRCA2 in sporadic ovarian cancer, 50 tumors were analyzed for mutations throughout the entire BRCA2 coding region. Mutations predicted to result in truncation of the BRCA2 protein were detected in four tumors. Analysis of germline DNA revealed two of these alterations to be of somatic origin. In addition, all four tumors exhibited loss of the second BRCA2 allele as predicted by Knudson's hypothesis for a tumor suppressor gene. These results suggest that, as is the case with BRCA1, somatic mutations of BRCA2 are infrequent in sporadic ovarian cancer, despite the relatively high frequency of LOH detected around the BRCA2 locus.

BRCA2 Protein↗
PubMed1996

Expression of cell regulatory proteins in ovarian borderline tumors.

BACKGROUND: Tumors of borderline malignancy are still a controversial subgroup of ovarian neoplasms. The expression of several cell regulatory proteins was studied to characterize the molecular phenotype of these tumors, and to compare them with their benign and malignant counterparts. METHODS: Specimens from 22 patients with tumors of borderline malignancy (11 serous and 11 mucinous tumors), 12 patients with benign tumors, and 16 patients with invasive ovarian carcinomas were evaluated for expression of epidermal growth factor receptor (EGFR), HER-2/neu, PTP1B, and p53 by immunohistochemical techniques. RESULTS: One or both of the tyrosine kinase growth factor receptors EGFR and HER-2/neu was expressed by 42% of benign, 59% of borderline, and 81% of malignant ovarian tumors. EGFR was expressed in a significantly greater fraction of malignant lesions (69%) than borderline lesions (18%) (P< 0.004). EGFR expression was not observed among the 11 mucinous borderline tumors. HER-2/neu was expressed by 50% of borderline tumors and was not a marker for malignancy. The tyrosine phosphatase PTP1B was expressed by a similar fraction of benign (17%), borderline (27%), and malignant (19%) tumors. The number of cases studied precluded correlation of kinase and phosphatase activity. However, among 12 tumors with PTP1B expression, 9 also expressed EGFR or HER-2/neu. Overexpression of p53 was observed only in malignant serous tumors and was not found in malignant mucinous, borderline, or benign lesions. CONCLUSIONS: Either EGFR or HER-2/neu was detected in a majority of borderline cancers. PTP1B was present only in a minority of these cancers. Frankly malignant serous lesions differed from borderline and benign tumors with regard to expression of EGFR and overexpression of p53.

Carcinoma↗
PubMed1996

Interaction of Cdc2 and Cdc18 with a fission yeast ORC2-like protein.

In fission yeast, Cdc2 kinase has both positive and negative roles in regulating DNA replication, being first necessary for the transition from G1 to S phase and later required to prevent the re-initiation of DNA replication during G2. We report here that Cdc2 interacts with Orp2, a protein similar to the Orc2 replication factor subunit of Saccharomyces cerevisiae origin recognition complex (ORC). ORC binds chromosomal origins and is essential for chromosomal replication initiation. Fission yeast Orp2 is required for DNA replication and interacts with the rate-limiting replication activator Cdc18. Cells lacking Orp2 undergo aberrant mitosis, indicating that Orp2 is involved in generating a checkpoint signal. These findings suggest that ORC functions are conserved among eukaryotes and provide evidence that Cdc2 controls DNA replication initiation by acting directly at chromosomal origins.

Amino Acid Sequence↗