PubMed Health⌕ Search

Biomedical subjects

I Vorechovsky

Publications and source records attributed to I Vorechovsky.

30 records · Page 2Linked to original sources
PubMed1996

Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. NBCCS maps to chromosome 9q22.3. Familial and sporadic BCCs display loss of heterozygosity in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region. Mutation analysis revealed alterations of PTC in NBCCS patients and in related tumors. We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types.

Alleles↗
PubMed1996

A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities.

Drosophila patched is a segment polarity gene required for the correct patterning of larval segments and imaginal discs during fly development and has a close functional relationship with hedgehog. We have isolated a complete human PATCHED cDNA sequence, which encodes a putative protein of 1296 amino acids, and displays 39% identity and 60% similarity to the Drosophila PATCHED protein. Hydropathy analysis suggests that human PATCHED is an integral membrane protein with a pattern of hydrophobic and hydrophilic stretches nearly identical to that of Drosophila patched. In the developing mouse embryo, patched is initially detected within the ventral neural tube and later in the somites and limb buds. Expression in the limb buds is restricted to the posterior ectoderm surrounding the zone of polarizing activity. The results show that patched is expressed in target tissues of sonic hedgehog, a murine homolog of Drosophila hedgehog suggesting that patched/hedgehog interactions have been conserved during evolution. Human PATCHED maps to human chromosome 9q22.3, the candidate region for the nevoid basal cell carcinoma syndrome. Patched expression is compatible with the congenital defects observed in the nevoid basal cell carcinoma syndrome.

Amino Acid Sequence↗
PubMed1995

Identification of Btk mutations in 20 unrelated patients with X-linked agammaglobulinaemia (XLA).

X-linked agammaglobulinaemia (XLA) is an inherited immunodeficiency resulting from mutations in the gene for a cytoplasmic protein tyrosine kinase (Btk). We have utilised reverse-transcription-based PCR in combination with the chemical cleavage and mismatch technique (CCM) to screen for Btk mutations in 42 unrelated patients having classical XLA or 'leaky' XLA-like phenotypes. A variety of mutations, including point mutations, large deletions and splicing defects were detected using this strategy. In total, 20 mutations were found in these patients. All the mutations were different with the exception of three unrelated patients who all showed the same Arg-->His amino acid substitution (R641H) at a highly-conserved residue in the kinase domain. We have also used structural modelling of the Btk kinase domain to predict how two different amino acid substitution mutations at highly-conserved residues are likely to affect the Btk kinase activity.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1994

Identification of deletions in the btk gene allows unambiguous assessment of carrier status in families with X-linked agammaglobulinaemia.

Mutations within the btk gene have recently been shown to cause X-linked agammaglobulinaemia (XLA). Altered patterns of DNA restriction fragments are seen by Southern blot analysis of DNA from affected patients with deletions in the btk gene. We have identified seven affected families in which altered restriction fragments can be used to diagnose and confirm the carrier status of female relatives of affected boys and in prenatal diagnosis.

Agammaglobulinemia↗
PubMed1990

Common variable immunodeficiency and malignancy: a report of two cases and possible explanation for the association.

Two patients with common variable immunodeficiency (CVID) and malignant tumours are reported. The first patient developed myelogenous leukaemia soon after the myelodysplastic syndrome has been diagnosed. The undifferentiated gastric lymphoma found in the second patient suggests that an increased risk of gastrointestinal malignancies in CVID could partly be due to lymphomas. We hypothesize that the tissue- or site-specific risk of lymphomas and gastrointestinal cancer can be explained by an increased chromosomal or genomic instability with a higher mutation rate and genomic disorganization, and that this instability could be related to viral carcinogenesis. The primary immunodeficiency per se may not be responsible for the cancer susceptibility in CVID patients.

Adult↗
PubMed1990

Bleomycin-induced chromosomal damage in tuberous sclerosis.

To investigate the possible involvement of mutagen-induced chromosomal instability in tuberous sclerosis the blood lymphocytes obtained from eleven patients with this disease and eleven healthy controls of comparable age and sex were exposed to bleomycin in vitro during the late S and G2 phases of the cell cycle. Neither the spontaneous aberration yields nor the bleomycin-induced chromosomal sensitivity differed between the two groups. The chromosomal distribution of 578 and 478 induced breaks in patients and controls, respectively, was similar. Thus, bleomycin-induced G2 chromosomal hypersensitivity in lymphocytes of patients with tuberous sclerosis is not an intrinsic feature of this hereditary disease.

Adolescent↗
PubMed1989

Increased bleomycin-induced chromosome damage in lymphocytes of patients with common variable immunodeficiency indicates an involvement of chromosomal instability in their cancer predisposition.

To study mutagen-induced chromosome instability in cancer disposition, late S and G2 lymphocytes of 15 patients with common variable immunodeficiency and 14 healthy controls were exposed to bleomycin in vitro. The groups did not differ in the frequency of spontaneous chromosome aberrations. In bleomycin-treated samples we found higher numbers of break events per cell and increased frequency of cells with aberrations compared to the control group. A slightly reduced breakage of chromosome group D was noted in patients. These results support the hypothesis that a higher incidence of cancer in patients with genetically determined immunodeficiencies may be explained by an increased mutagen-induced chromosome instability in at least some of them.

Bleomycin↗
PubMed1989

Carcinoma in situ in testicular biopsies.

Carcinoma in situ of the testis is an abnormality of the seminiferous epithelium characterized by aneuploid cells with clear cytoplasm located along the tubular basement membrane or in the lumina of tubules. Morphological, cytogenetic, and histochemical features of this anomaly are presented. An adequate fixation of testicular tissue samples is necessary for correct diagnosis. The fact that approximately 50% of carcinoma in situ may develop into malignant germ cell tumours of the testis in 5 years and the investigations of the testicular tissue adjacent to these tumours support the malignant nature and invasive potential of testicular carcinoma in situ. The incidence of carcinoma in situ in persons at risk is reviewed.

Biopsy↗
PubMed1989

Increased breakage of chromosome 1 in lymphocytes of patients with testicular cancer after bleomycin treatment in vitro.

Chromosome damage in vitro after bleomycin treatment during the late S and G2 phases of the cell cycle was studied in the peripheral lymphocytes of 19 untreated patients with primary testicular tumours and 22 age-matched healthy men with no excess of cancer incidence in the families. The occurrence of spontaneous chromosome aberrations was not shown to be different in the studied groups. However, in the lymphocytes treated with bleomycin, cancer patients exhibited higher numbers of break events per cell (1.06 versus 0.67, P less than 0.01) and increased frequency of cells with aberrations (55.0 versus 43.0, P less than 0.05) than control group. Aberrant cells of cancer patients had more aberrations than cells of the control sample (1.79 versus 1.53, P less than 0.01). The frequency of chromosome 1 aberrations, often encountered in cancer cells of testicular and other solid tumours, was significantly higher in lymphocytes of patients with testicular cancer (15.0 versus 8.4%, P less than 0.0001), the long arm of this chromosome being predominantly affected (12.0 versus 6.3%, P less than 0.0001). These results support the view that a genome disposed to testicular cancer is less effective in the ability to repair non-specific DNA damage in this region, more susceptible to damage, or both.

Bleomycin↗