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S M Powell

Publications and source records attributed to S M Powell.

At least 37 records · Page 2Linked to original sources
PubMed1999

Origin of microsatellite instability in gastric cancer.

Microsatellite instability (MSI) is observed in 13-44% of gastric carcinoma. The etiology of MSI in gastric carcinoma has not been clearly defined. To assess the role of mismatch repair in the development of MSI in gastric cancer, expression of hMSH2 and hMLH1 was explored. We examined 117 gastric carcinomas for MSI and observed instability at one or more loci in 19 (16%) of these tumors. Of the 19 tumors with MSI, nine exhibited low-rate MSI (MSI-L) with instability at <17% of loci, whereas the remaining 10 exhibited high-rate MSI (MSI-H) with instability at >33% of loci examined. Immunohistochemical staining for hMLH1 and hMSH2 was performed on eight of the tumors with MSI-H, five with MSI-L, and 15 tumors without MSI. All eight tumors with MSI-H showed loss of staining for either hMLH1 (n = 5) or hMSH2 (n = 3). In contrast, tumors with MSI-L or without MSI all showed normal hMSH2 and hMLH1 protein expression patterns. Moreover, all eight of the tumors with MSI-H also showed instability at BAT-26, whereas none of the MSI-L tumors or tumors without instability showed instability at BAT-26. These findings suggest that the majority of high-level MSI in gastric cancer is associated with defects of the mismatch repair pathway. Although larger studies are needed, BAT-26 appears to be a sensitive and specific marker for the MSI-H phenotype in gastric carcinoma.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Mapping of genetic deletions on the long arm of chromosome 4 in human esophageal adenocarcinomas.

Loss of the long arm of chromosome 4 has been identified previously as a common occurrence in adenocarcinomas of the esophagus and gastroesophageal junction by relatively low resolution genetic surveys. To better define the extent of 4q deletion in these neoplasms we isolated DNA from 29 primary carcinomas using microdissection, and used DNA obtained from xenografts of 14 carcinomas grown in immunodeficient mice in an assay of loss of heterozygosity of 25 polymorphic microsatellite markers distributed along the chromosomal arm. Two carcinomas exhibited widespread microsatellite instability and were excluded from deletion mapping. In the remaining 41 carcinomas, loss of heterozygosity was detected in 33 (80%). Twenty-three cancers showed complete or extensive reduction to homozygosity along the length of the long arm. Ten cancers had smaller discrete areas of loss and were principally useful in discerning three non-overlapping areas of consensus genetic deletion. Area 1 centered on marker D4S1534 at 4q21.1-22, area 2 centered on marker D4S620 at 4q32-33, and area 3 centered on marker D4S426 at 4q35. No known tumor suppressor genes map to these loci, but the frequent deletion of these areas in gastroesophageal carcinomas and in other carcinomas suggests that undiscovered tumor suppressor genes may reside here.

Adenocarcinoma↗
PubMed1999

The problems of rubber hypersensitivity (Types I and IV) in chronic leg ulcer and stasis eczema patients.

The prevalence of Type I and Type IV hypersensitivity to rubber allergens in patients with stasis eczema and/or venous leg ulcers over an 18-month period was studied by prick and patch testing. Results from 109 patients were analysed. Positive patch tests were found in 71 patients (65%). Delayed-type hypersensitivity to rubber chemicals was found in 17 patients (15.6%). However, only 1 patient who had additional risk factors showed Type I hypersensitivity to natural rubber latex. We therefore conclude that, although Type IV hypersensitivity to rubber chemicals is relatively common in our patients, Type I hypersensitivity to natural rubber latex remains rare.

Adult↗
PubMed1999

Detection of Helicobacter pylori DNA in fecal samples from infected individuals.

Stool, gastric biopsy, and serum samples were collected from 22 subjects. DNA from stool was extracted, amplified, and hybridized with primers specific for the 16S rRNA gene of Helicobacter pylori. DNA from gastric biopsy specimens was analyzed similarly for comparison. Universal primers were used to confirm successful extraction of DNA from samples. Histologic, serologic, and DNA analyses were scored in a blinded fashion. Universal primer amplification verified successful DNA extraction from all stool and gastric tissue specimens. The gastric tissue DNA assay was positive for H. pylori in 11 of the 22 subjects, correlating completely with histologic and serologic results. Stool DNA was positive for H. pylori by our molecular assay in 8 of these 11 H. pylori-positive subjects. All subjects who were negative by histologic, serologic, and gastric tissue DNA analyses were also negative by stool DNA analysis. Compared to histology, serology, and gastric tissue DNA analyses, the sensitivity of our stool DNA assay was 73%, with a specificity of 100%.

DNA, Bacterial↗
PubMed1999

Hereditary desmoid disease in a family with a germline Alu I repeat mutation of the APC gene.

Two families with autosomal dominantly inherited desmoid tumors have recently been shown to have germline mutations at the 3' end of the APC gene. We subsequently identified an Amish family with autosomal dominantly inherited desmoid tumors. Genetic analysis performed on one family member, a 47-year-old man with multiple desmoid tumors and no colon polyps, revealed a protein truncating mutation in the middle of the APC gene. The truncating mutation is the result of a 337-bp insertion of an Alu I sequence into codon 1526 of the APC gene. The presence of a poly(A) tail at the 3' end of the insertion suggests that the Alu I sequence was inserted by a retrotranspositional event. Germline insertions of Alu I sequences have occasionally been reported to cause other genetic diseases including type I neurofibromatosis, hereditary site-specific breast cancer (BRCA2), and hemophilia B. However, this is the first report of a germline mutation of the APC gene resulting from an Alu I insertion.

Adenomatous Polyposis Coli↗
PubMed1999

Familial gastric cancer: overview and guidelines for management.

Families with autosomal dominant inherited predisposition to gastric cancer have been described. More recently, germline E-cadherin/CDH1 mutations have been identified in hereditary diffuse gastric cancer kindred. The need to have protocols to manage and counsel these families in the clinic led a group of geneticists, gastroenterologists, surgeons, oncologists, pathologists, and molecular biologists to convene a workshop to produce consensus statements and guidelines for familial gastric cancer. Review of the available cancer pathology from people belonging to families with documented germline E-cadherin/CDH1 mutations confirmed that the gastric cancers were all of the diffuse type. Criteria to define the different types of familial gastric cancer syndromes were agreed. Foremost among these criteria was that review of histopathology should be part of the evaluation of any family with aggregation of gastric cancer cases. Guidelines for genetic testing and counselling in hereditary diffuse gastric cancer were produced. Finally, a proposed strategy for clinical management in families with high penetrance autosomal dominant predisposition to gastric cancer was defined.

Cadherins↗
PubMed1998

Identification of germ-line E-cadherin mutations in gastric cancer families of European origin.

E-cadherin germ-line mutations have recently been described as a molecular basis for early-onset familial gastric cancer in Maori kindred. We screened 18 gastric cancer families of European origin for germ-line mutations to determine the proportion in which E-cadherin mutations occur and the clinical characteristics of the affected families. Truncating mutations were identified in three kindred with familial diffuse gastric cancer. In these families, the age of onset of gastric cancer was variable, the penetrance was incomplete, and one kindred contained individuals with cancers at other sites. Here, we show that a proportion of diffuse gastric cancer families of European origin have germ-line E-cadherin mutations; however, these mutations are absent in intestinal gastric cancer families.

Adult↗
PubMed1998

Consistent genetic alterations in xenografts of proximal stomach and gastro-esophageal junction adenocarcinomas.

The genetic alterations underlying the development of gastric and gastro-esophageal carcinoma remain largely undefined. DNA copy number changes were determined by comparative genomic hybridization in eight xenografts of proximal gastric and gastro-esophageal junction adenocarcinomas of the intestinal type. All tumors exhibited DNA copy number changes, with a total of 139 changes detected (range, 11-24 per tumor; mean = 17), indicating numerous and widespread alterations within these cancers. Gains (65%) in DNA copy number were more frequent than losses (35%). Our most striking finding was gain (all eight cases) or high-level amplification (four cases) in 20q, with a minimal common overlapping region at 20q13. Other frequent gains were observed at 6p, 7q, and 17q (six cases each) and at 1q, 2q, and 8q (five cases each). Frequent losses were observed at 4q and 5q (six cases each) and at 9p (five cases). No differences in DNA copy number changes were seen in tumors arising from the gastro-esophageal junction compared to those of the proximal stomach. The presence of common and consistent DNA copy number changes in these tumors implicate a number of chromosomal regions that may harbor important genes that are involved in tumorigenesis of the proximal stomach and gastro-esophageal junction.

Adenocarcinoma↗
PubMed1998

Assessment of the effect of malaria infection on hepatic clearance of dihydroartemisinin using rat liver perfusions and microsomes.

1. The clearance of dihydroartemisinin (DHA) in control and malaria-infected (MI) rats was investigated using the isolated perfused rat liver (IPRL) model and hepatic microsomal studies. 2. In the recirculating IPRL, clearance of DHA was reduced from a mean (s.d.) of 8.2+/-1.8 ml min(-1) in controls (n=8) to 6.0+/-1.0 ml min(-1) in MI (n=8; P<0.01). Clearance in control livers was similar to the perfusion flow rate, suggesting a high hepatic extraction ratio for DHA. 3. Single-pass IPRL studies in controls (n=8) showed that DHA bioavailability at 1.3, 8 and 38 microm was 0.026+/-0.020, 0.043+/-0.025 and 0.14+/-0.06, respectively (P<0.001 for 8 microM vs 38 microM). In MI livers (n=5), DHA bioavailability at 8 and 38 microM was 0.18+/-0.07 and 0.40+/-0.08, respectively (P=0.002). Bioavailability was higher in the MI group than in controls (P=0.01 at 8 microM and P<0.001 at 38 microM). DHA-glucuronide was the sole biliary metabolite. 4. Hepatic microsomal studies of DHA-glucuronide formation showed a significantly lower Vmax but no significant change in Km, in MI compared to control livers (n=6). Intrinsic metabolic clearance (Vmax/Km) was higher in control than in MI livers (5.2+/-1.3 and 2.5+/-1.4 microl min(-1) mg(-1), respectively; P=0.006). 5. These studies demonstrate that DHA has a high, concentration-dependent hepatic extraction ratio that is reduced by 20-30% in the P. berghei rodent malaria model. The impaired hepatic clearance of DHA in MI is attributable to a reduction in intrinsic metabolic clearance.

Animals↗
PubMed1998

A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria.

AIMS: To obtain comprehensive pharmacokinetic and pharmacodynamic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.v. and oral administration of ARTS to patients with acute, uncomplicated falciparum malaria. METHODS: Twenty-six Vietnamese patients with falciparum malaria were randomized to receive either i.v. ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2), with the alternative preparation given 8 h later in an open crossover design. Mefloquine (750 mg) was administered at 24 h. Plasma concentrations of ARTS and DHA were determined by h.p.l.c. assay. Pharmacokinetic parameters were calculated by non-compartmental methods. The time to 50% parasite clearance (PCT50) was calculated by linear interpolation of parasite density determinations. Linear least squares and multiple linear regression analyses were used to evaluate pharmacokinetic-pharmacodynamic relationships. RESULTS: Following i.v. bolus, ARTS had a peak concentration of 29.5 microM (11 mg l[-1]), elimination t1/2 = 2.7 min, CL = 2.33 l h(-1) kg(-1) and V = 0.14 l kg(-1). The Cmax for DHA was 9.3 microM (2.64 mg l[-1]), t1/2 = 40 min, CL =0.75 l h(-1) kg(-1) and V = 0.76 l kg(-1). Following oral ARTS, relative bioavailability of DHA was 82%, Cmax was 2.6 microM (0.74 mg l[-1]), t1/2 = 39 min, and MAT = 67 min. Overall, the PCT50 and fever clearance time (FCT) were 6.5 h and 24 h, respectively. There was no correlation between PCT50 or FCT and AUC, Cmax or MRT for DHA. CONCLUSIONS: Despite rapid clearance of ARTS and DHA in patients with uncomplicated falciparum malaria, prompt parasite and fever clearance were achieved. High relative bioavailability of DHA following oral ARTS administration, and clinical outcomes comparable with those after i.v. ARTS, support the use of the oral formulation in the primary care setting.

Administration, Oral↗
PubMed1998

Cutaneous reactivity of the hands in nickel-sensitive patients with hand eczema.

This study compares the cutaneous reactivity between the hand and the back for 7 female patients with active hand eczema, who were found to be nickel-sensitive on routine patch testing with the European standard series. Patients were patch tested to a dilution series of nickel sulfate on the back in order to determine the threshold concentration for elicitation of allergic contact dermatitis, and based upon this result a lower concentration of nickel was then used for patch tests on the hand. We found that in the majority of patients (6/7) the cutaneous responsiveness of the hand was not increased compared with that of the back. However, the hand of 1 patient was more sensitive to nickel and patch testing was accompanied with a flare of her eczema, which suggests that cutaneous hyperreactivity may be important in individual patients with hand eczema.

Adolescent↗
PubMed1998

Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene.

BACKGROUND: Germline mutation in the adenomatous polyposis coli (APC) gene on chromosome 5 causes familial adenomatous polyposis. "Attenuated" phenotype has been reported with mutation in the 5' end of the gene (5' to codon 158), but genotype-phenotype relations at the 3' end (3' to codon 1596) have not been described fully. AIMS: To describe and compare colorectal and extracolonic phenotypes in a case series of families with mutation in the 3' end of the APC gene. METHODS: Thirty one at risk or affected members from four families with a mutation in the APC gene located at codon 1979 or 2644 were evaluated. RESULTS: Variable intrapedigree colorectal phenotype was observed: some members at older age had oligopolyposis (fewer than one hundred colorectal adenomas) whereas other members had classic polyposis at young age. Colorectal cancer was diagnosed at older mean age (50 (7) years) in the four families than in classic FAP pedigrees (39 (14) years). Extracolonic lesions characteristic of FAP occurred with 3' APC mutations, but variability in intrapedigree and interpedigree extracolonic phenotype and dissociation of severity of extracolonic manifestations from number of colorectal polyps was noted. CONCLUSIONS: Families with 3' mutations of the APC gene exhibit variable intrapedigree phenotype similar to the heterogeneity noted in families with proximal 5' mutations. Genotyping of FAP and oligopolyposis pedigrees can guide appropriate surveillance of the upper and lower gastrointestinal tract in affected members.

Adenomatous Polyposis Coli↗
PubMed1998

A pharmacokinetic and pharmacodynamic study of artesunate for vivax malaria.

To investigate the pharmacokinetic and pharmacodynamic properties of artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) in Plasmodium vivax infections, 12 male Vietnamese adults with slide-positive vivax malaria received either intravenous ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2) with the alternative preparation given 8 hr later in a randomized, open, cross-over study. Following intravenous injection, ARTS had a peak plasma drug concentration (Cmax) of 35.6 microM (13.7 mg/L), an elimination half-life (t1/2) of 2.2 min, a clearance (CL) of 3.0 L/hr/kg, and a volume of distribution (V) of 0.16 L/kg. Dihydroartemisinin had a Cmax of 7.7 microM (2.2 mg/L), a tmax of 8 min, a t1/2 of 37 min, an apparent CL of 1.1 L/hr/kg, and an apparent V of 0.9 L/kg. Following oral ARTS, the mean relative bioavailability of DHA was 85%, the Cmax was 3.0 microM (0.85 mg/L), the tmax was 75 min, and t1/2 was 40 min. The mean time to 50% reduction in the parasite count (PCT50) and median fever clearance time were 3 hr and 16 hr, respectively. Following intravenous ARTS (group 1), the PCT50 for total parasites, rings, trophozoites, and gametocytes was 3.3 hr, 3.2 hr, 4.0 hr, and 3.6 hr, respectively. This study confirms that ARTS is effective against P. vivax, with rapid clearance of sexual and asexual forms of the parasite. Artesunate is a suitable initial treatment for vivax malaria, or when the plasmodial species cannot be reliably identified.

Administration, Oral↗
PubMed1997

Inactivation of Smad4 in gastric carcinomas.

Allelic loss of chromosome 18q has been noted in intestinal type gastric adenocarcinomas. Smad4 is a gene located at 18q that was recently cloned in humans and found to be significantly altered in pancreatic cancers. We sought to determine whether Smad4 genetic alterations played a significant role in gastric tumorigenesis by studying 35 gastric adenocarcinomas of all histopathological types and pathological stages. Microdissected specimens were used for mutational analysis of Smad4 at the nucleotide level, including the entire coding region and intron/exon boundaries. Allelic imbalance was also analyzed at the Smad4 locus using two nearby microsatellite markers. One case of apparent biallelic inactivation of Smad4 was found in our study of 35 gastric carcinomas. A nonsense point mutation at codon 334 was demonstrated, which, similar to other Smad4 mutations, is predicted to truncate the conserved COOH-terminal domain of this protein. This Smad4 C to T transition mutation was proven to be somatically acquired. Allelic loss was also noted on chromosome 18q at a marker near Smad4 in this mutated gastric cancer, apparently producing complete inactivation of Smad4 in this tumor. Significant 18q allelic loss (56% of 34 informative cases) was noted in our gastric carcinomas using microsatellite markers near the Smad4 locus, regardless of histological subtype or pathological stage. Additionally, three cases of microsatellite instability were observed. Thus, Smad4 inactivation was noted in our gastric carcinomas; however, this event was rare. The frequent loss of chromosomal arm 18q observed in gastric cancers suggests the presence of other tumor suppressor genes in this region that are involved in gastric tumorigenesis. Further studies are needed to identify these other targets of inactivation during gastric cancer development.

Adenocarcinoma↗
PubMed1997

Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors.

The E2F group of transcription factors transactivates genes that promote progression through the G1-S transition of the cell cycle. Members of the retinoblastoma (Rb) family of proteins bind to E2Fs and inhibit this function. E2F-4, one example of the E2F group, functions as an oncogene when transfected into nontransformed cells in vitro. On the other hand, mice that are homozygously lacking a normal E2F-1 gene develop cancers, consistent with a tumor-suppressive role for this gene. The exact function of E2Fs has thus been unclear; moreover, direct involvement of this gene in primary human tumorigenesis has not been shown. We, therefore, investigated mutation within the E2F-4 coding region in 16 primary gastric adenocarcinomas, 12 ulcerative colitis-associated neoplasms, 46 sporadic colorectal carcinomas, 9 endometrial cancers, and 3 prostatic carcinomas. We limited our investigation to the serine repeat within E2F-4, reasoning that this tract might be altered in genetically unstable tumors (replication error-positive, or RER+). All tumors were RER+, with the exception of a control group of 15 RER- sporadic colorectal carcinomas. PCR with incorporation of [32P]dCTP was performed using primers flanking the serine trinucleotide (AGC) repeat. Twenty-two of 59 gastrointestinal tumors (37%) contained E2F-4 mutations; these comprised 5 of 16 gastric tumors (31%), 4 of 12 ulcerative colitis-associated neoplasms (33%, including 1 dysplastic lesion), and 13 of 31 sporadic colorectal cancers (42%). No mutation was present in any of the endometrial, prostate, or RER- colorectal tumors. Of note, homozygous mutations occurred in three cases, and two of seven informative patients showed loss of one E2F-4 allele in their tumors. Furthermore, the RER+ sporadic colorectal tumors were evaluated at trinucleotide repeats within the genes for N-cadherin and B-catenin; no tumors demonstrated mutation of these genes. These data suggest that E2F-4 is a target of defective DNA repair in these tumors.

Adenocarcinoma↗
PubMed1997

Mutation of hMSH3 and hMSH6 mismatch repair genes in genetically unstable human colorectal and gastric carcinomas.

Mutations within microsatellite sequences, consisting of additions or deletions of repeat units, are known as the replication/repair error positive (RER+) phenotype or micorsatellite instability (MI). Microsatellite instability has been demonstrated in hereditary and sporadic colorectal carcinomas and is usually observed in noncoding regions of genomic DNA. However, relatively few coding region targets of MI have been identified thus far. Using PCR, we amplified regions encompassing (A)8 and (C)8 microsatellite tracts within hMSH3 and hMSH6 from 31 RER+ sporadic colorectal tumors, 8 hereditary colon cancers, 23 RER+ gastric carcinomas, and 32 RER- gastric tumors. Mutations were found in 11 (36%) of 31 sporadic colon carcinomas, 4 (50%) of 8 hereditary colorectal cancers, and 5 (22%) of 23 RER+ gastric carcinomas, but in only 2 (6%) of 32 RER- gastric carcinomas. These frameshift mutations cause premature stop codons downstream that are predicted to abolish normal protein function. Our results and those of others suggest that DNA mismatch repair genes, such as hMSH3 and hMSH6, are targets for the mutagenic activity of upstream mismatch repair gene mutations and that this enhanced genomic instability may accelerate the accumulation of mutations in RER+ tumors.

Adenocarcinoma↗