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Biomedical subjects

W Warren

Publications and source records attributed to W Warren.

At least 19 recordsLinked to original sources
PubMed2000

Muscle type-specific myosin isoforms in crustacean muscles.

Differential expression of multiple myosin heavy chain (MyHC) genes largely determines the diversity of critical physiological, histochemical, and enzymatic properties characteristic of skeletal muscle. Hypotheses to explain myofiber diversity range from intrinsic control of expression based on myoblast lineage to extrinsic control by innervation, hormones, and usage. The unique innervation and specialized function of crayfish (Procambarus clarkii) appendicular and abdominal musculature provide a model to test these hypotheses. The leg opener and superficial abdominal extensor muscles are innervated by tonic excitatory motoneurons. High resolution SDS-PAGE revealed that these two muscles express the same MyHC profile. In contrast, the deep abdominal extensor muscles, innervated by phasic motoneurons, express MyHC profiles different from the tonic profiles. The claw closer muscles are dually innervated by tonic and phasic motoneurons and a mixed phenotype was observed, albeit biased toward the phasic profile seen in the closer muscle. These results indicate that multiple MyHC isoforms are present in the crayfish and that differential expression is associated with diversity of muscle type and function.

Animals↗
PubMed2000

Identification of the familial cylindromatosis tumour-suppressor gene.

Familial cylindromatosis is an autosomal dominant genetic predisposition to multiple tumours of the skin appendages. The susceptibility gene (CYLD) has previously been localized to chromosome 16q and has the genetic attributes of a tumour-suppressor gene (recessive oncogene). Here we have identified CYLD by detecting germline mutations in 21 cylindromatosis families and somatic mutations in 1 sporadic and 5 familial cylindromas. All mutations predict truncation or absence of the encoded protein. CYLD encodes three cytoskeletal-associated-protein-glycine-conserved (CAP-GLY) domains, which are found in proteins that coordinate the attachment of organelles to microtubules. CYLD also has sequence homology to the catalytic domain of ubiquitin carboxy-terminal hydrolases (UCH).

Amino Acid Sequence↗
PubMed2000

Health promotion in leg ulcer management in the community.

This article acknowledges the substantial progress that has been made in leg ulcer management in recent years. However, there needs to be greater emphasis on health promotion, quality of life, general patient well being and promoting health within illness. Incorporating health promotion activities within venous leg ulcer management strategies may serve to empower patients to participate more fully in their care. Nurses' awareness needs to be raised to ensure that the assessment process is used as a tool to promote holistic care and not merely as a checklist to provide baseline information on the patient's health status. A series of factors highlighted during assessment are explored to demonstrate the potential for health promotion.

Activities of Daily Living↗
PubMed1999

Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer.

BACKGROUND: Mutations in the BRCA1 and BRCA2 genes are found in most families with cases of both breast and ovarian cancer or with many cases of early-onset breast cancer. However, in an outbred population, the prevalence of BRCA1 and BRCA2 mutations in patients with breast cancer who were unselected for a family history of this disease has not been determined. METHODS: Mutations in the BRCA1 and BRCA2 genes were detected in blood samples from two population-based series of young patients with breast cancer from Britain. RESULTS: Mutations were detected in 15 (5.9%) of 254 women diagnosed with breast cancer before age 36 years (nine [3.5%] in BRCA1 and six [2.4%] in BRCA2) and in 15 (4.1%) of 363 women diagnosed from ages 36 through 45 years (seven [1.9%] in BRCA1 and eight [2.2%] in BRCA2). Eleven percent (six of 55) of patients with a first-degree relative who developed ovarian cancer or breast cancer by age 60 years were mutation carriers, compared with 45% (five of 11) of patients with two or more affected first- or second-degree relatives. The standardized incidence ratio for breast cancer in mothers and sisters was 365 (five observed and 1.37 expected) for 30 mutation carriers and 199 (64 observed and 32.13 expected) for 587 noncarriers. If we assume recent penetrance estimates, the respective proportions of BRCA1 and BRCA2 mutation carriers are 3.1% and 3.0%, respectively, of patients with breast cancer who are younger than age 50 years, 0.49% and 0.84% of patients with breast cancer who are age 50 years or older, and 0.11% and 0.12% of women in the general population. CONCLUSIONS: Mutations in the BRCA1 and BRCA2 genes make approximately equal contributions to early-onset breast cancer in Britain and account for a small proportion of the familial risk of breast cancer.

Adult↗
PubMed1999

Loss of pulmonary function gains after lung volume reduction surgery.

Lung volume reduction surgery (LVRS) has been demonstrated to improve lung function, exercise tolerance and quality of life. However, the duration of improvement is unknown. While the maximal duration of improvement cannot be determined at this time due to an inadequate period of follow-up, we have observed in some patients significant and relatively rapid declines in gains following LVRS. We describe 6 patients who increased FEV1 by at least 10% of the predicted value after LVRS and subsequently experienced rapid loss of the increment in FEV1 (mean loss 79%, 95% CI 58-100%) over a period ranging from 14 to 20 months following surgery.

Aged↗
PubMed1998

Low frequency of somatic mutations in the LKB1/Peutz-Jeghers syndrome gene in sporadic breast cancer.

Germ-line mutations in the LKB1 gene on chromosome 19p are responsible for most cases of the Peutz-Jeghers syndrome, in which intestinal hamartomas are associated with elevated risks of several cancer types, including breast cancer. We have evaluated the role of somatic mutations in LKB1 in breast cancer. Of 40 informative primary breast cancers, 3 showed loss of heterozygosity on chromosome 19p in the vicinity of LKB1, and no somatic mutations of LKB1 were observed in 62 primary breast cancers and 17 established breast cancer cell lines. The results indicate that mutations in LKB1 do not play an important role in the development of sporadic breast cancer.

AMP-Activated Protein Kinase Kinases↗
PubMed1998

A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.

Studies of hereditary cancer syndromes have contributed greatly to our understanding of molecular events involved in tumorigenesis. Here we investigate the molecular background of the Peutz-Jeghers syndrome (PJS), a rare hereditary disease in which there is predisposition to benign and malignant tumours of many organ systems. A locus for this condition was recently assigned to chromosome 19p. We have identified truncating germline mutations in a gene residing on chromosome 19p in multiple individuals affected by PJS. This previously identified but unmapped gene, LKB1, has strong homology to a cytoplasmic Xenopus serine/threonine protein kinase XEEK1, and weaker similarity to many other protein kinases. Peutz-Jeghers syndrome is therefore the first cancer-susceptibility syndrome to be identified that is due to inactivating mutations in a protein kinase.

AMP-Activated Protein Kinase Kinases↗
PubMed1998

The t(8;13)(p11;q11-12) rearrangement associated with an atypical myeloproliferative disorder fuses the fibroblast growth factor receptor 1 gene to a novel gene RAMP.

A recently described atypical myeloproliferative disorder is invariably associated with reciprocal translocations involving 8p11-12. The most common rearrangement is a t(8;13)(p11;q11-12). Here we determine that this translocation results in the fusion of the fibroblast growth factor receptor 1 gene (FGFR1), a member of the receptor tyrosine kinase family at 8p11, to a novel gene at 13q11-12 designated RAMP . The predicted RAMP protein exhibits strong homology to the product of a recently cloned candidate gene for X-linked mental retardation, DXS6673E . We also provide the first report of a novel, putative metal-binding motif, present as five tandem repeats in both RAMP and DXS6673E. RT-PCR detected only one of the two possible fusion transcripts, encoding a product in which the N-terminal 641 amino acids of RAMP become joined to the tyrosine kinase domain of FGFR1. Receptor tyrosine kinases are not commonly involved in the formation of tumour-specific fusion proteins. However, the previous reports of involvement of receptor tyrosine kinases in fusion proteins in non-Hodgkin's lymphoma, chronic myelomonocytic leukaemia and papillary thyroid carcinoma described similar rearrangements. By analogy with these, we propose that the RAMP-FGFR1 fusion product will contribute to progression of this myeloproliferative disorder by constitutive activation of tyrosine kinase function.

Amino Acid Sequence↗
PubMed1997

Screening for ESR mutations in breast and ovarian cancer patients.

In the present study, leukocyte DNA from 143 patients with familial clustering of breast and/or ovarian cancer and tumour DNA from 96 breast carcinomas were screened for base mutations in the estrogen receptor gene (ESR). Three patients with a family history of cancer were carrying a Gly160Cys germline substitution. This alteration was also detected in eight (four females and four males) of 729 controls (366 female, 363 males), indicating that the substitution probably represents a polymorphism. However, in the 229 female controls in whom family history of cancer was known, one of two who had a sister with breast cancer was carrying the variant allele. Hence, a possible clinical significance of the glycine into cysteine cannot be completely ruled out and should be further investigated. Somatic mutations were not detected in any of the tumours studied, and the present data do not provide support for somatic ESR base mutations as an important mechanism for hormonal therapy resistance in estrogen receptor-positive breast carcinomas.

Adult↗
PubMed1997

Postoperative bronchopulmonary complications in stage III lung cancer patients treated with preoperative paclitaxel-containing chemotherapy and concurrent radiation.

We previously observed encouraging results and acceptable toxicity in phase II trials testing preoperative split-course thoracic radiation and simultaneous cisplatin, etoposide, and 5-fluorouracil in stage III non-small cell lung cancer patients. We decided to delete 5-fluorouracil and to incorporate paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) into our combined-modality treatment. The first group of patients received carboplatin dosed at an area under the concentration-time curve of 4 on day 2, etoposide 50 mg orally days 1 to 5 and 8 to 12, cisplatin 50 mg/m2 on day 21, and paclitaxel 35 mg/m2 escalated to 45 mg/m2 on days 1 and 8. Group 2 patients received carboplatin dosed at an area under the concentration-time curve of 4 on day 1, etoposide 45 mg/m2 intravenously daily on days 2 to 5, and paclitaxel 80 mg/m2 (escalating to 120 mg/m2) on day 1. Patients in group 3 received carboplatin dosed at an area under the concentration-time curve of 4 on day 1 and paclitaxel 120 mg/m2 (escalating to 140 mg/m2) on day 1. Each patient received radiation 2 Gy daily on days 1 to 5 and 8 to 12, and a total of two cycles was given at 28-day intervals. Twenty-one patients received preoperative chemoradiotherapy: group 1, five patients; group 2, 11 patients; and group 3, five patients. Thoracotomy was not done in five patients due to cerebrovascular accident in one and progressive tumor in four. The remaining 16 patients had the following procedures: pneumonectomy, eight; lobectomy, six; chest wall resection, one; and no resection, one. Postoperative complications included bronchopleural fistula in one patient each in groups 1 and 3, hypoxia in one patient in group 1, pulmonary hypertension in one patient in group 2, pneumonia in one patient in group 2, and adult respiratory distress syndrome in one patient in group 3, which proved lethal. Thus, six of 16 patients had serious postoperative complications. The relatively high incidence of postoperative bronchopulmonary complications suggests that the use of preoperative paclitaxel-containing chemotherapy and simultaneous thoracic radiation may not be feasible.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Escalating paclitaxel doses combined with carboplatin/etoposide and thoracic radiotherapy as preoperative or definitive treatment for stage III non-small cell lung cancer.

We have evaluated escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in combination with carboplatin, cisplatin, etoposide, and concurrent thoracic radiotherapy in patients with stage III non-small cell lung cancer. Dose-limiting toxicity was observed at paclitaxel 90 mg/m2. Subsequent modifications resulted in a new regimen, which consists of a 3-hour paclitaxel infusion on day 1 (three dose levels: 80, 100, and 120 mg/m2), etoposide 40 mg/m2 intravenously over 1 hour daily on days 2 to 5, and carboplatin given at an area under the concentration-time curve of 4 mg/mL x min on day 1 after paclitaxel. Treatment courses were repeated every 28 days. Eleven patients considered eligible for surgery received two courses. Nonsurgical patients (five) received three courses. No episodes of grade > or = 3 nausea and vomiting, dermatitis, anorexia, esophagitis, or thrombocytopenia were observed. The dose-limiting toxicity (grade 4 granulocytopenia) occurred in three of five patients at 120 mg/m2 paclitaxel (level 3). Grade 3 radiation pneumonitis was observed in three patients. Nine patients have undergone pulmonary resection: four pneumonectomies, four lobectomies, and one segmental resection. No operative deaths, respiratory insufficiency, or cardiovascular complications were observed. Clinical partial remissions have been observed in 11 of 16 patients overall, and two histologic complete remissions were achieved in nine surgical patients. Our preliminary results show that pulmonary resection is feasible following treatment with radiation and concurrent paclitaxel-containing chemotherapy. Although the maximum tolerated paclitaxel dose in the present study was relatively low, favorable initial responses warrant further study of paclitaxel-containing combination chemotherapy and concurrent radiation. We next plan to delete etoposide from our chemoradiotherapy regimen and escalate the paclitaxel dose.

Agranulocytosis↗
PubMed1995

Products from alkylation of DNA in cells by melphalan: human soft tissue sarcoma cell line RD and Escherichia coli WP2.

Alkylation of DNA was studied after treatment with [3H]melphalan (phenylalanine mustard; 1-2 microM) using a human tumour cell line, RD, in culture, or Escherichia coli (WP2 or WP2-uvrA strains) in growth medium. After 6 h at 37 degrees C, treated cells were isolated and re-suspended in fresh growth media. Samples were taken at times up to 48 h for isolation of DNA, and in some cases also RNA and protein (which were found to be alkylated to about the same extent as DNA). Alkylated DNA was analysed as previously described (M.R. Osborne and P.D. Lawley, Chem.-Biol. Interact 89 (1993) 49-60). The four principal products, mono-7-alkylguanine (G-M-OH); mono-3-alkyladenine (A-M-OH); and the cross-linked products G-M-G and A-M-G, were identified in DNA from melphalan treated cells, and quantitatively determined. In each case, alkylation of cellular macromolecules was maximal after about 6 h. In DNA of the human tumour cell line, the relative amounts of adenine products decreased with time, most markedly with A-M-OH to 42% of the 2-h value after 48 h. In DNA of both bacterial strains, A-M-OH was virtually undetectable even at early times. Comparisons between the time course of relative decreases in amounts of these alkylpurine products and the corresponding values for alkylated DNA in vitro suggest that the adenine products are subject to removal by repair enzyme action in E. coli of either strain.

Alkylation↗
PubMed1995

Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation.

Mutations in the BRCA1 gene, discovered in 1994, are associated with an 80-90% lifetime risk of breast cancer. We have analysed 60 families with a history of breast and/or ovarian cancer for germline mutations in BRCA1. Twenty-two different mutations were detected in 32 families (53%), of which 14 are previously unreported. We observed a significant correlation between the location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within each family. Our data suggest a transition in risk such that mutations in the 3' third of the gene are associated with a lower proportion of ovarian cancer. Haplotype analysis supports previous data which suggest some BRCA1 mutation carriers have common ancestors; however, we have found at least two examples where recurrent mutations appear to have arisen independently.

BRCA1 Protein↗
PubMed1995

Mutations in the p53 gene in schistosomal bladder cancer: a study of 92 tumours from Egyptian patients and a comparison between mutational spectra from schistosomal and non-schistosomal urothelial tumours.

Much of bladder cancer in East Africa and the Middle East is attributed to chronic urinary infection with Schistosoma haematobium ('schistosomiasis'). Most schistosomal bladder cancer (SBC) is squamous cell carcinoma (SCC) and occurs in the fifth decade of life. In contrast, nonschistosomal bladder cancer (NSBC) in Western countries usually occurs in the seventh decade of life and is largely transitional cell carcinoma (TCC). To shed light on the mechanisms underlying these different patterns of bladder cancer we looked for mutations in the p53 gene in SBC from 92 patients in Egypt, where schistosomiasis is hyperendemic. Patients' mean age at presentation of bladder cancer was 49.4 +/- 9.9 years and 90% had a clinical history of schistosomiasis and/or histological evidence of schistosomal eggs adjacent to the carcinoma. There were 53 SCC, 23 TCC, 13 adenocarcinomas and three other carcinomas. Thirty patients had tumours with mutations in exons 5-8 of the p53 gene: 17/53 SCC, 8/23 TCC, 4/13 adenocarcinomas and 1/3 other tumours. Of 19 mutations in SCC, 16 were base pair substitutions (BPS), two were deletions and one an insertion. Two tumours each contained two mutations. Of the BPS, nine were transitions at CpG dinucleotides and two were G-->T transversions. All the mutations in TCC were BPS: four were transitions at CpG dinucleotides and three were G-->C transversions. One TCC had two mutations. Of four adenocarcinomas with mutations, two had transitions at CpG dinucleotides. Of the 30 BPS mutations, 16 were transitions at CpG dinucleotides, of which 12 were C-->T. We combined these 33 mutations with six obtained from Egyptian SCC reported by Habuchi et al. (Cancer Res., 53, 3795-3799, 1993) to compile a mutational spectrum. This was compared with a NSBC spectrum assembled from 118 mutations reported in the literature. The proportion of BPS at CpG dinucleotides was significantly higher in SBC than in NSBC (18/34 versus 25/103, P = 0.003). There was also a bias away from mutations in exons 7 and 8 towards mutations in exons 5 and 6. We suggest that the excess of transitions at CpG dinucleotides in SBC results from nitric oxide (NO) produced by the inflammatory response provoked by schistosomal eggs. NO could produce such mutations directly, by deamination of 5-methylcytosine, and indirectly, following conversion to nitrate, bacterial reduction to nitrite and endogenous formation of urinary N-nitroso compounds. These produce O6-alkylguanines in DNA, leading to very high rates of G:C-->A:T transitions, a process possibly augmented by inefficient repair of alkylated bases at CpG dinucleotides.

Adenocarcinoma↗
PubMed1994

Combined modality treatment using BID radiation for locally advanced non-small cell lung carcinoma.

BACKGROUND: From February 1988 to August 1991, 82 patients were treated on Phase II trial of split-course multimodality treatment for locally advanced, non-small cell lung cancer (NSCLC). METHODS: Treatment consisted of twice-daily radiation (150 cGy/fraction) delivered with concomitant infusional cisplatin, etoposide, and fluorouracil for 1 week every third week. Patients were classified before initial treatment as either potentially resectable (eligible for surgery [ES]) or ineligible for surgery (IES). The ES group consisted of 38 Stage IIIA and 7 Stage IIIB patients. The IES group had 5 patients staged as IIIA and 32 staged as IIIB. Most patients were staged clinically. ES patients received three cycles of treatment (39 Gy) before resection. IES patients received four cycles (60 Gy) delivered with curative intent. RESULTS: Thirty-nine of 45 ES patients underwent resection. The pathologic response rate was 27%. Three-year actuarial local control was 86% for 41 evaluable ES patients. Three-year actuarial survival for the whole ES group was 39%, with a median follow-up for living patients of 32 months. The IES group faired less well, with an 18% 3-year actuarial survival. Treatment was well tolerated with a median weight loss of one-half pound, mild or moderate pneumonitis in 5%, mild esophagitis in 15%, and severe nausea and/or vomiting in 10% of patients. Treatment-related mortality was 5%. CONCLUSIONS: Patients treated with conventional radiation alone for Stage III NSCLC are rarely cured. This well tolerated Phase II study demonstrated encouraging results for such patients. Both local control and survival appeared promising, especially in patients rendered resectable after combined-modality treatment.

Adult↗
PubMed1993

Neonatal screening for congenital cytomegalovirus infection by detection of virus in saliva.

A rapid assay for detection of cytomegalovirus (CMV) in saliva was evaluated as a screening method for congenital infection. Samples of saliva were examined by detection of early antigen fluorescent foci (DEAFF) and standard tissue culture (TC). Results were compared with those from urine DEAFF. CMV was detected in saliva from 31 (1.7%) of 1870 newborns, 26 by DEAFF and TC, 1 by DEAFF alone, and 4 by TC alone. Urine DEAFF was positive in 28 of these 31 newborns. The sensitivities of various tests were saliva TC, 96.8%; saliva DEAFF, 87.1%; and urine DEAFF, 90.3%. A change in transport medium for 825 saliva samples resulted in improved sensitivities: saliva TC and saliva DEAFF, 100%; urine DEAFF, 92.3%. Screening saliva of newborns for CMV appears to be at least as sensitive a method for detecting congenital infection as detection of viruria; saliva can be collected with less difficulty and expense than urine.

Cytomegalovirus↗