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Biomedical subjects

L S Friedman

Publications and source records attributed to L S Friedman.

At least 19 recordsLinked to original sources
PubMed2001

Gastrointestinal bleeding in the elderly.

Among patients with acute gastrointestinal bleeding, older age is associated with an increased rate of comorbidity, greater medication use, and atypical clinical presentations. The aging of the population makes the evaluation and management of gastrointestinal bleeding in the elderly a special and increasingly common clinical challenge. The unique features and common causes of upper and lower gastrointestinal bleeding in the elderly are reviewed. Important management issues considered include hemodynamic resuscitation; anticoagulation; and medical, surgical, and endoscopic therapy.

Aged↗
PubMed2000

Gastrointestinal bleeding in older people.

Aging is associated with an increased rate of comorbidity, greater medication use, and atypical clinical presentations. The aging of the population makes the evaluation and management of gastrointestinal bleeding in older people a special and increasingly common clinical challenge. The unique features and common causes of upper and lower gastrointestinal bleeding in older people are reviewed. Important management issues considered include hemodynamic resuscitation, anticoagulation, and endoscopic and surgical therapy.

Age Factors↗
PubMed1999

Increased frequency of TP53 mutations in BRCA1 and BRCA2 ovarian tumours.

We screened 81 ovarian tumours (30 BRCA1 associated, 18 BRCA2 associated, and 33 sporadic) for somatic TP53 mutations using both DNA analysis and immunostaining. TP53 mutations were significantly more frequent in tumours with mutations in BRCA1 (70% by immunostaining and 60% by DNA analysis) and BRCA2 (67% and 50%) compared to sporadic controls (39% and 30%) (P = 0.009). A higher proportion of tumours with BRCA1 and BRCA2 mutations were poorly differentiated, and TP53 mutant tumours in all categories were also more likely to be poorly differentiated. The poor differentiation of tumours with BRCA1 and BRCA2 mutations may be directly related to the role of these genes in DNA repair, and the need to overcome cell cycle checkpoints, often through loss of TP53. These results are consistent with the model of BRCA-induced tumorigenesis in which loss of checkpoint control is necessary for tumour development.

Alleles↗
PubMed1999

Epidemiology and the natural course of inflammatory bowel disease.

Ulcerative colitis and Crohn's disease are inflammatory disorders of the gastrointestinal tract that are distributed unevenly within populations and throughout the world. Although the exact causes of inflammatory bowel disease (IBD) remain unknown, study of the epidemiology of IBD has provided insight into pathogenesis. This article examines the geographic, ethnic, and other trends of IBD; risk factors (including genetic and environmental); and the natural history of IBD.

Age Distribution↗
PubMed1999

Mitotic checkpoint inactivation fosters transformation in cells lacking the breast cancer susceptibility gene, Brca2.

The murine Brca2 gene encodes a nuclear protein implicated in DNA repair. Brca2 behaves as a tumor suppressor, but paradoxically, its truncation causes proliferative arrest and spontaneous chromosomal damage. Here, we report that inactivation of cell cycle checkpoints responsive to mitotic spindle disruption, by mutant forms of p53 or Bub1, relieves growth arrest and initiates neoplastic transformation in primary cells homozygous for truncated Brca2. Tumors from Brca2-deficient animals exhibit dysfunction of the spindle assembly checkpoint, accompanied by mutations in p53, Bub1, and Mad3L. The chromosomal aberrations precipitated by Brca2 truncation can be suppressed by mutant forms of Bub1 and p53. Thus, inactivating mutations in mitotic checkpoint genes likely cooperate with BRCA2 deficiency in the pathogenesis of inherited breast cancer, with important implications for treatment.

Animals↗
PubMed1999

Adenocarcinoma of the esophagogastric junction.

Adenocarcinoma of the esophagogastric junction (EGJ) has increased rapidly in incidence in the latter half of the twentieth century. The increase in incidence has affected white men between the ages of 40 and 60 disproportionately. Understanding the etiology and improving treatment requires careful classification of EGJ tumors. A recent consensus conference recognized three types of EGJ adenocarcinomas: distal esophageal, cardia, and subcardia gastric. Distal esophageal adenocarcinomas are associated with Barrett's esophagus. Helicobacter pylori infection may play a role in some adenocarcinomas of the subcardia, but the association is unproven. Therapy for all types of EGJ tumors is surgical, but multimodal forms of treatment are commonly used because of the advanced stage at which these tumors often present. Several endoscopic options exist for primary therapy of early-stage tumors and for palliation.

Adenocarcinoma↗
PubMed1998

Thymic lymphomas in mice with a truncating mutation in Brca2.

Inherited mutations in the BRCA2 gene predispose women to breast and ovarian cancer. We created a mutation in the mouse Brca2 gene that terminates translation in exon 11 at 45% of the normal transcript length. Ninety % of Brca2(tm1Cam) homozygous mutant mice die prenatally or perinatally. The location of the Brca2(tm1Cam) mutation differs from those reported previously, and this phenotype suggests a correlation with genotype analogous to that previously reported in humans. Although heterozygote mice have remained free of tumors for 10 months, Brca2(tm1Cam) homozygous mutants that survived to adulthood died with thymic lymphomas between 12 and 14 weeks of age.

Alleles↗
PubMed1998

Involvement of Brca2 in DNA repair.

Abnormalities precipitated by a targeted truncation in the murine gene Brca2 define its involvement in DNA repair. In culture, cells harboring truncated Brca2 exhibit a proliferative impediment that worsens with successive passages. Arrest in the G1 and G2/M phases is accompanied by elevated p53 and p21 expression. Increased sensitivity to genotoxic agents, particularly ultraviolet light and methylmethanesulfonate, shows that Brca2 function is essential for the ability to survive DNA damage. But checkpoint activation and apoptotic mechanisms are largely unaffected, thereby implicating Brca2 in repair. This is substantiated by the spontaneous accumulation of chromosomal abnormalities, including breaks and aberrant chromatid exchanges. These findings define a function of Brca2 in DNA repair, whose loss precipitates replicative failure, mutagen sensitivity, and genetic instability reminiscent of Bloom syndrome and Fanconi anemia.

Animals↗
PubMed1997

Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families: evidence for additional susceptibility genes.

One hundred breast and breast-ovarian cancer families identified at the Helsinki University Central Hospital in southern Finland and previously screened for mutations in the BRCA2 gene were now analyzed for mutations in the BRCA1 gene. The coding region and splice boundaries of BRCA1 were analyzed by protein truncation test (PTT) and heteroduplex analysis (HA)/SSCP in all 100 families, and 70 were also screened by direct sequencing. Contrary to expectations based on Finnish population history and strong founder effects in several monogenic diseases in Finland, a wide spectrum of BRCA1 and BRCA2 mutations was found. In the BRCA1 gene, 10 different protein truncating mutations were found each in one family. Six of these are novel Finnish mutations and four have been previously found in other European populations. Six different BRCA2 mutations were found in 11 families. Altogether only 21% of the breast cancer families were accounted for by mutations in these two genes. Linkage to both chromosome 17q21 (BRCA1) and 13q12 (BRCA2) was also excluded in a subset of seven mutation-negative families with four or more cases of breast or ovarian cancer. These data indicate that additional breast and breast-ovarian cancer susceptibility genes are likely to be important in Finland.

Adult↗
PubMed1997

Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population.

A population-based series of 54 male breast cancer cases from Southern California were analyzed for germ-line mutations in the inherited breast/ovarian cancer genes, BRCA1 and BRCA2. Nine (17%) of the patients had a family history of breast and/or ovarian cancer in at least one first-degree relative. A further seven (13%) of the patients reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. No germ-line BRCA1 mutations were found. Two male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only one of the two male breast cancer patients carrying a BRCA2 mutation had a family history of cancer, with one case of ovarian cancer in a first-degree relative. The remaining eight cases (89%) of male breast cancer with a family history of breast/ovarian cancer in first-degree relatives remain unaccounted for by mutations in either the BRCA1 gene or the BRCA2 gene.

Aged↗
PubMed1997

A low proportion of BRCA2 mutations in Finnish breast cancer families.

One hundred breast cancer families were identified at the Helsinki University Central Hospital in Finland and were screened for germ-line mutations in the coding regions and splice boundaries of the BRCA2 gene. Eight families (8%) were found to carry five different mutations, all of which are predicted to prematurely truncate the protein product. These BRCA2 families have early-onset breast cancer (mean and median age = 49 years), with four of the eight families including ovarian cancer but with no families including male breast cancer. A wide spectrum of other cancers also is seen in these families. Three mutations were identified in more than one family, and haplotype analysis in the families suggested a common founder for each recurrent mutation. One recurrent mutation, 999del5, previously has been noted as a common mutation in Iceland. The relationship between the Icelandic 999del5 mutation and the Finnish 999del5 mutation was explored by comparison of families from both countries. A common haplotype covering a minimal region intragenic to the BRCA2 gene was shared between the Icelandic and the Finnish mutation carriers.

Adult↗