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P Jordan

Publications and source records attributed to P Jordan.

At least 19 recordsLinked to original sources
PubMed1998

Cisplatin inhibits synthesis of ribosomal RNA in vivo.

Cis -diammininedichloroplatinum(II) (cisplatin or cis -DDP) is a DNA-damaging agent that is widely used in cancer chemotherapy. Cisplatin crosslinks DNA and the resulting adducts interact with proteins that contain high-mobility-group (HMG) domains, such as UBF(upstream binding factor). UBF is a transcription factor that binds to the promoter of ribosomal RNA (rRNA) genes thereby supporting initiation of transcription by RNA polymerase I. Here we report that cisplatin causes a redistribution of UBF in the nucleolus of human cells, similar to that observed after inhibition of rRNA synthesis. A similar redistribution was observed for the major components of the rRNA transcription machinery, namely TBP, TAFIs and RNA polymerase I. Furthermore, we provide for the first time direct in vivo evidence that cisplatin blocks synthesis of rRNA, while activity of RNA polymerase II continues to be detected throughout the nucleus. The clinically ineffective trans isomer (trans -DDP) does not alter the localization of either UBF or other components of the RNA polymerase I transcription machinery. These results suggest that disruption of rRNA synthesis, which is stimulated in proliferating cells, plays an important role in the clinical success of cisplatin.

Antineoplastic Agents↗
PubMed1997

Myosin light chain-activating phosphorylation sites are required for oogenesis in Drosophila.

The Drosophila spaghetti squash (sqh) gene encodes the regulatory myosin light chain (RMLC) of nonmuscle myosin II. Biochemical analysis of vertebrate nonmuscle and smooth muscle myosin II has established that phosphorylation of certain amino acids of the RMLC greatly increases the actin-dependent myosin ATPase and motor activity of myosin in vitro. We have assessed the in vivo importance of these sites, which in Drosophila correspond to serine-21 and threonine-20, by creating a series of transgenes in which these specific amino acids were altered. The phenotypes of the transgenes were examined in an otherwise null mutant background during oocyte development in Drosophila females. Germ line cystoblasts entirely lacking a functional sqh gene show severe defects in proliferation and cytokinesis. The ring canals, cytoplasmic bridges linking the oocyte to the nurse cells in the egg chamber, are abnormal, suggesting a role of myosin II in their establishment or maintenance. In addition, numerous aggregates of myosin heavy chain accumulate in the sqh null cells. Mutant sqh transgene sqh-A20, A21 in which both serine-21 and threonine-20 have been replaced by alanines behaves in most respects identically to the null allele in this system, with the exception that no heavy chain aggregates are found. In contrast, expression of sqh-A21, in which only the primary phosphorylation target serine-21 site is altered, partially restores functionality to germ line myosin II, allowing cystoblast division and oocyte development, albeit with some cytokinesis failure, defects in the rapid cytoplasmic transport from nurse cells to cytoplasm characteristic of late stage oogenesis, and some damaged ring canals. Substituting a glutamate for the serine-21 (mutant sqh-E21) allows oogenesis to be completed with minimal defects, producing eggs that can develop normally to produce fertile adults. Flies expressing sqh-A20, in which only the secondary phosphorylation site is absent, appear to be entirely wild type. Taken together, this genetic evidence argues that phosphorylation at serine-21 is critical to RMLC function in activating myosin II in vivo, but that the function can be partially provided by phosphorylation at threonine-20.

Amino Acid Sequence↗
PubMed1997

DNA aneuploidy, S-phase fraction, nuclear p53 positivity, and survival in non-small-cell lung carcinoma.

Inactivation of the p53 gene plays a key role in tumour biology, probably through a disturbed cell cycle control and an increased genetic instability in p53-inactivated tumours. To learn more about the relationship between p53 alterations, proliferation and genetic instability (DNA aneuploidy) in lung cancer patients, specimens of 220 surgically resected lung carcinomas with clinical follow-up information were examined by immunohistochemistry (p53; CM1) and flow cytometry. Nuclear p53 positivity--found in 49.5% of the tumours--was associated with both high S-phase fraction (SPF) and DNA ploidy aberrations. SPF was higher in p53-positive tumours (15.9 +/- 10.2) than in p53-negative tumours (10.3 +/- 8.7; P = 0.03). The rate of p53 positivity was higher in 101 DNA-aneuploid and DNA-multiploid tumours (55%) than in 27 diploid and peridiploid carcinomas (33%; P = 0.0512). These results are consistent with an in vivo role of p53 inactivation for increased proliferative activity and development of genomic instability in lung cancer. There was no association between SPF and prognosis. Although prognosis was worse in DNA-aneuploid and multiploid tumours than in diploid, peridiploid and tetraploid carcinomas (P = 0.029), DNA ploidy was not an independent predictor of poor prognosis in multivariate analysis. These data show that DNA-flow cytometry has little prognostic value for patients with resected non-small-cell lung carcinoma.

Aneuploidy↗
PubMed1997

The cdk7-cyclin H-MAT1 complex associated with TFIIH is localized in coiled bodies.

TFIIH is a general transcription factor for RNA polymerase II that in addition is involved in DNA excision repair. TFIIH is composed of eight or nine subunits and we show that at least four of them, namely cdk7, cyclin H, MAT1, and p62 are localized in the coiled body, a distinct subnuclear structure that is transcription dependent and highly enriched in small nuclear ribonucleoproteins. Although coiled bodies do not correspond to sites of transcription, in vivo incorporation of bromo-UTP shows that they are surrounded by transcription foci. Immunofluorescence analysis using antibodies directed against the essential repair factors proliferating cell nuclear antigen and XPG did not reveal labeling of the coiled body in either untreated cells or cells irradiated with UV light, arguing that coiled bodies are probably not involved in DNA repair mechanisms. The localization of cyclin H in the coiled body was predominantly detected during the G1 and S-phases of the cell cycle, whereas in G2 coiled bodies were very small or not detected. Finally, both cyclin H and cdk7 did not colocalize with P80 coilin after disruption of the coiled body, indicating that these proteins are specifically targeted to the small nuclear ribonucleoprotein-containing domain.

Carrier Proteins↗
PubMed1997

Modelling of mortality data from a multi-centre study in Japan by means of Poisson regression with error in variables.

BACKGROUND: Death rates of particular categories in epidemiological studies are often based on a small number of occurrences which can be well described by a Poisson distribution. METHOD: We applied this model for the analysis of a multi-centre study in five Japanese counties where the death rates of stomach cancer (ICD-9 code 151) in four age groups are known. In our example some covariates of the cases (e.g. plasma lycopene levels) are unknown values and are estimated from a randomly chosen collective. Therefore these values are subject to a sampling error. The inclusion of errors in variables (e-i-v) into the statistical model can adequately describe such a situation. The model is estimated in a Bayesian framework by means of resampling techniques. RESULTS: Based on the posterior distribution of the parameters the relative risk of stomach cancer is 0.46 (95% confidence interval: 0.23-0.79) comparing the maximum of the population medians of lycopene with the minimum. The estimated overdispersion is close to zero indicating only minor interference with other possible explanatory variables. In addition, we show that inclusion of e-i-v can give more accurate estimates of the parameters even from small sample sizes. CONCLUSIONS: Appropriate statistical methods allow the accurate estimation of relative risks from small sample sizes and from low number of cases. Lycopene plasma levels are good predictors for stomach cancer.

Adult↗
PubMed1997

Carbon dioxide laser as a surgical instrument for sarcoid therapy--a retrospective study on 60 cases.

The objective of this retrospective clinical study was to evaluate the carbon dioxide laser in the treatment of single and multiple sarcoids in 60 animals (44 horses, 13 donkeys, 2 mules, and 1 pony). Only animals that had been operated on 6 mo or more ago were included. Recurrence, new manifestation rate, and cosmetic outcome were determined. Recurrence was observed in 23 (38%) individuals. Animals with new sarcoid manifestation with or without recurrence of a sarcoid were observed in 35 cases (58%). Cases of scar tissue formation and, rarely, leukotrichia were observed. Animals presented with multiple sarcoids were more predisposed to recurrence. Donkeys showed a significantly lower recurrence rate than horses.

Animals↗
PubMed1996

The topography of chromosomes and genes in the nucleus.

At present several lines of evidence indicate that the nucleus is functionally compartmentalized into discrete structures with defined properties. For instance, it is well established that the molecular machines involved in replication, transcription, and RNA processing assemble into morphological entities but it remains unclear whether these correspond to autonomous "organelles" or rather represent temporary accumulations of either active factors recruited onto DNA templates or inactive factors stored in the vicinity of genes. According to the latter view, the spatial distribution of genes during interphase should play a major role in the subnuclear organization of nonchromatin components such as replication, transcription, and processing factors, and in this article we discuss current ideas on the functional compartmentalization of chromosomes and genes within the nucleus.

Binding Sites↗
PubMed1996

Spectroscopic and voltammetric characterisation of the bacterioferritin-associated ferredoxin of Escherichia coli.

The bacterioferritin-associated ferredoxin (Bfd) of Escherichia coli is a 64-residue polypeptide encoded by the bfd gene located upstream of the gene (bfr) encoding the iron-storage haemoprotein, bacterioferritin. The Bfd sequence resembles those of the approximately 60-residue domains found in NifU proteins (required for metallocluster assembly), nitrite reductases, and Klebsiella pneumoniae nitrate reductase. These related-domains contain four well-conserved cysteine residues, which are thought to function as ligands to a [2Fe-2S] cluster. The Bfd protein was over-produced, purified, and characterised. Bfd was found to be a positively-charged monomer containing two iron atoms and two labile sulphides. Ultraviolet-visible, EPR, variable-temperature magnetic-circular dichroism and resonance Raman spectroscopies, together with cyclic voltogram measurements, revealed the presence of a [2Fe-2S]2+,+ centre (E1/2 = -254 mV) having remarkably similar properties to the Fe-S cluster of NifU. Bfd may thus be a 2Fe ferredoxin participating either in release/delivery of iron from/to bacterioferritin (or other iron complexes), or in iron-dependent regulation of bfr expression.

Amino Acid Sequence↗
PubMed1996

Reconstitution of the [4Fe-4S] cluster in FNR and demonstration of the aerobic-anaerobic transcription switch in vitro.

The FNR protein of Escherichia coli is a redox-responsive transcription regulator that activates and represses a family of genes required for anaerobic and aerobic metabolism. Reconstitution of wild-type FNR by anaerobic treatment with ferrous ions, cysteine and the NifS protein of Azotobacter vinelandii leads to the incorporation of two [4Fe-4S]2+ clusters per FNR dimer. The UV-visible spectrum of reconstituted FNR has a broad absorbance at 420 nm. The clusters are EPR silent under anaerobic conditions but are degraded to [3Fe-4S]+ by limited oxidation with air, and completely lost on prolonged air exposure. The association of FNR with the iron-sulphur clusters is confirmed by CD spectroscopy. Incorporation of the [4Fe-4S]2+ clusters increases site-specific DNA binding about 7-fold compared with apo-FNR. Anaerobic transcription activation and repression in vitro likewise depends on the presence of the iron-sulphur cluster, and its inactivation under aerobic conditions provides a demonstration in vitro of the FNR-mediated aerobic-anaerobic transcriptional switch.

Aerobiosis↗
PubMed1996

Genetic aberrations detected by comparative genomic hybridization are associated with clinical outcome in renal cell carcinoma.

The clinical behavior of renal cell carcinoma (RCC) cannot be predicted by histological and other markers. In this study, comparative genomic hybridization was used to evaluate whether the number of genomic aberrations has prognostic significance in 41 nonmetastatic clear cell RCC extending beyond the renal capsule. Losses were most prevalent at 3p (56%) and 9p and 13q (24% each). The number of DNA losses per tumor was associated with recurrence-free survival (P = 0.03). DNA gains most often involved chromosome 5q (17%) and chromosome 7 (15%). The number of DNA gains was not associated with clinical outcome. Loss of chromosome 9p was the only individual locus associated with recurrence (P = 0.04), suggesting that a tumor suppressor gene on chromosome 9p may play a role in RCC progression.

Carcinoma, Renal Cell↗
PubMed1996

Nuclear p53 overexpression is an independent prognostic parameter in node-negative non-small cell lung carcinoma.

The prognosis of operated patients with non-small cell lung cancer (NSCLC) is poor despite thorough pre-operative staging. An improved preselection is needed of patients likely to profit from surgery. This study was undertaken to evaluate the prognostic significance of nuclear p53 overexpression in a cohort of 247 surgically treated patients with NSCLC. It showed that the prevalence of immunohistochemically detectable p53 overexpression varied between different tumour types. p53 overexpression was equally frequent in large cell carcinoma (53 per cent) and in squamous cell carcinoma (54 per cent), but significantly less frequent in adenocarcinoma (34 per cent; P = 0.009). p53 overexpression was particularly rare in bronchioloalveolar carcinoma (positivity in 1 of 17 cases). These variations may reflect aetiological differences between the histological subtypes. p53 overexpression was also associated with high tumour grade (P = 0.0157) and the presence of lymph node metastasis (P = 0.0259), but not with advanced tumour stage. Survival analysis showed no difference in clinical outcome between p53-positive and p53-negative tumours within 101 node-positive tumours. In contrast, survival time was significantly better in p53-negative tumours than in p53-positive tumours within the group of 113 node-negative tumours (P = 0.032). Stepwise regression analysis showed that p53 overexpression is an independent prognostic factor in node-negative NSCLC.

Biomarkers, Tumor↗
PubMed1996

Ki67 labelling index: an independent predictor of progression in prostate cancer treated by radical prostatectomy.

The clinical course of prostate cancer is highly variable and cannot satisfactorily be predicted by histological criteria alone. Both tumour cell proliferation and neuroendocrine differentiation have been suggested as additional prognostic parameters, neuroendocrine differentiation being considered to enhance tumour cell proliferation. This study investigated the prognostic value of tumour cell proliferation [Ki67 labelling index (LI), MIB 1] and neuroendocrine differentiation and their relationship to each other. One hundred and thirty-seven paraffin-embedded radical prostatectomy specimens were examined. Neuroendocrine differentiation was found in 58 per cent of cases, but was not associated with pTN stage, Gleason score, Ki67 LI, or tumour progression. Ki67 LI was not significantly associated with pTN stage or with Gleason score. High grade (P = 0.0005), advanced local stage (P = 0.0004), positive lymph nodes (P = 0.02), and high Ki67 LI (P = 0.0203) were predictors of tumour progression if univariate analysis was performed, but Cox stepwise regression showed that only advanced local stage (P = 0.0025) and Ki67 LI (P = 0.0105) were independent predictors of tumour progression, the relative risk being 3.6 and 2.5, respectively. It is concluded that Ki67 is an important prognostic marker in prostate cancer with a potential for routine application.

Aged↗
PubMed1996

Utility of the Pediatric Symptom Checklist as a psychosocial screen to meet the federal Early and Periodic Screening, Diagnosis, and Treatment (EPSDT) standards: a pilot study.

OBJECTIVE: To examine the usefulness of the Pediatric Symptom Checklist (PSC) as the psychosocial screening measure to meet federal Medicaid/Early and Periodic Screening, Diagnosis, and Treatment (EPSDT) standards in a low-income Hispanic community. DESIGN AND SETTING: Three hundred seventy-nine children (aged 6 to 16 years) were screened with the PSC in a 10-month period during well child visits to three clinics in Ventura and San Mateo counties in California. The PSC was available in English and Spanish and was administered both in written (paper-and-pencil) and oral formats. Follow-up services were provided for children identified as needing evaluation. RESULTS: The Cronbach alpha was high (r = 0.91) for the PSC in the whole sample and virtually identical for English, Spanish, oral, and written formats. All the PSC items were significantly associated with total score on the PSC in English, Spanish, oral, and written formats. Overall, the PSC identified 10.6% of the sample as at risk for psychosocial problems. Thirty-six children (9.5% of sample) were referred for mental health follow-up. Public health data from Ventura County showed a statistically significant increase in referrals for psychologic problems during the study period in two locations using the PSC: from 0.5% to 2.9% of the school-aged children seen. CONCLUSION: The PSC provides a feasible, well-accepted method for screening for psychosocial problems during EPSDT examinations of school-aged children. Psychosocial screening using a validated instrument such as the PSC, as well as increased efforts to refer positive screening results, track outcomes, and assess cost benefits should be essential requirements in capitated Medicaid approaches to caring for poor children.

Adolescent↗
PubMed1996

In vivo evidence that TATA-binding protein/SL1 colocalizes with UBF and RNA polymerase I when rRNA synthesis is either active or inactive.

Here we show that the TATA-binding protein (TBP) is localized in the nucleoplasm and in the nucleolus of mammalian cells, consistent with its known involvement in transcription by RNA polymerase I, II, and III. In the nucleolus of actively growing cells, TBP colocalizes with upstream binding factor (UBF) and RNA polymerase I at the sites of rRNA transcription. During mitosis, when rRNA synthesis is down-regulated, TBP colocalizes with TBP-associated factors for RNA polymerase I (TAF(I)s), UBF, and RNA polymerase I on the chromosomal regions containing the rRNA genes. Treatment of cells with a low concentration of actinomycin D inhibits rRNA synthesis and causes a redistribution of the rRNA genes that become concentrated in clusters at the periphery of the nucleolus. A similar redistribution was observed for the major components of the rRNA transcription machinery (i.e., TBP, TAF(I)s, UBF, and RNA polymerase I), which still colocalized with each other. Furthermore, anti-TBP antibodies are shown to coimmunoprecipitate TBP and TAF(I)63 in extracts prepared from untreated and actinomycin D-treated cells. Collectively, the data indicate that in vivo TBP/promoter selectivity factor, UBF, and RNA polymerase I remain associated with both active and inactive rRNA genes.

3T3 Cells↗
PubMed1996

Screening for psychosocial problems in 4-5-year-olds during routine EPSDT examinations: validity and reliability in a Mexican-American sample.

The effectiveness of the Pediatric Symptom Checklist (PSC) as a psychosocial screening measure to meet Federal Medicaid/Early and Periodic Screening, Diagnosis, and Treatment (EPSDT) requirements was examined in 117 low-income preschool (aged 4-5 years old) Hispanic children during well-child examinations in three clinics over an 8-month period. The PSC identified 7% of the sample as at risk for psychosocial problems. The PSC was significantly associated with parental ratings of the children's problems in functioning, with pediatric clinicians' decisions to make mental health referrals, with degrees of associations similar to those found between PSC scores, and with the same measures with school-aged children in the same clinics. Cronbach's alpha was high (r = .87) and virtually identical in English, Spanish, oral, and written formats. Although it identified a slightly lower rate of psychosocial problems in 4-5-year-olds than it had in school-aged children, the PSC appeared to provide an effective method of screening for psychosocial problems during EPSDT examinations.

California↗
PubMed1996

Pulmonary function and exercise capacity after lung resection.

The influence of pulmonary resection on functional capacity can be assessed in different ways. The aim of this study was to compare the effect of lobectomy and pneumonectomy on pulmonary function tests (PFT), exercise capacity and perception of symptoms. Sixty eight patients underwent functional assessment with PFT and exercise testing before (Preop), and 3 and 6 months after lung resection. In 50 (36 males and 14 females; mean age 61 yrs) a lobectomy was performed and in 18 (13 males and 5 females; mean age 59 yrs) a pneumonectomy was performed. Three months after lobectomy, forced vital capacity (FVC), forced expiratory volume in one second (FEV1), total lung capacity (TLC), transfer factor of the lungs for carbon monoxide (TL,CO) and maximal oxygen uptake (V'O2,max) were significantly lower than Preop values, increasing significantly from 3 to 6 months after resection. Three months after pneumonectomy, all parameters were significantly lower than Preop values and significantly lower than postlobectomy values and did not recover from 3 to 6 months after resection. At 6 months after resection significant deficits persisted in comparison with Preop: for FVC 7% and 36%, FEV1 9% and 34%, TLC 10% and 33% for lobectomy and pneumonectomy, respectively; and V'O2,max 20% after pneumonectomy only. Exercise was limited by leg muscle fatigue in 53% of all patients at Preop. This was not altered by lobectomy, but there was a switch to dyspnoea as the limiting factor after pneumonectomy (61% of patients at 3 months and 50% at 6 months after resection). Furthermore, pneumonectomy compared to lobectomy led to a significantly smaller breathing reserve (mean +/- SD) (28 +/- 13 vs 37 +/- 16% at 3 months; and 24 +/- 11% vs 33 +/- 12% at 6 months post resection) and lower arterial oxygen tension at peak exercise 10.1 +/- 1.5 vs 11.5 +/- 1.6 kPa (76 +/- 11 vs 86 +/- 12 mmHg) at 3 months; 10.1 +/- 1.3 vs 11.3 +/- 1.6 kPa (76 +/- 10 vs 85 +/- 12 mmHg) at 6 months postresection. We conclude that measurements of conventional pulmonary function tests alone overestimate the decrease in functional capacity after lung resection. Exercise capacity after lobectomy is unchanged, whereas pneumonectomy leads to a 20% decrease, probably due to the reduced area of gas exchange.

Adult↗
PubMed1996

Prognostic significance of Bcl-2 in clinically localized prostate cancer.

The clinical course of prostate cancer is highly variable and cannot satisfactorily be predicted by histological criteria alone. To study the prognostic significance of Bcl-2 and p53 overexpression in prostate cancer, 137 consecutive radical prostatectomy specimens were examined by immunohistochemistry. Both Bcl-2 and p53 were associated with malignant phenotype. Bcl-2 expression was more frequent in pT3 tumors (31% positive) than in pT2 tumors (5% positive, P = 0.001). p53 overexpression (found in 8%) was associated with high Gleason score (P = 0.03) and increased tumor growth fraction (Ki67 labeling index (LI); P = 0.017). Survival analysis showed that Bcl-2 expression (P = 0.03), high Ki67 LI (P = 0.018), high grade (P = 0.0037), advanced local stage (P = 0.0005), and positive lymph nodes (P = 0.026) were predictors of progression. The combined analysis of Ki67 LI and Bcl-2 allowed the distinction of three groups with different clinical outcome. Prognosis was best in Bcl-2-negative tumors with low Ki67 LI, worst in Bcl-2-positive tumors with high Ki67 LI, and intermediate in the remaining tumors (P = 0.03). These data suggest that altered expression of both Bcl-2 and p53 play a role in prostate cancer progression. Combined analysis of factors regulating both apoptosis and cell proliferation may be relevant in prostate cancer.

Aged↗