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M H Skolnick

Publications and source records attributed to M H Skolnick.

At least 19 recordsLinked to original sources
PubMed1992

Population genetics of colonic cancer.

BACKGROUND: There are several well known but rare syndromes of inherited colonic cancer. Genetic epidemiologic studies also have demonstrated that relatives of individuals with colonic cancer in general exhibit an excess risk for this malignancy. METHODS: This report reviews the literature pertinent to genetic and familial risk for colonic cancer with emphasis on the recent work that suggests that inherited susceptibility to colonic neoplasms is common. RESULTS: The adenomatous polyposis syndromes are rare inherited colonic cancer conditions caused by a mutant gene which recently has been characterized. Hereditary nonpolyposis colorectal cancer is likewise inherited and may account for up to 5% of cases. The molecular genetics of this disease remain to be clarified. The majority of colonic cancer cases are considered sporadic but are known to often cluster in families. Recent work suggests that inherited susceptibility may be the basis of this familial occurrence. Screening strategies based on inherited and familial risk are suggested. CONCLUSIONS: Knowledge of the familial and inherited risk for colonic cancer is leading to a better understanding of this disease and is suggesting more directed preventive strategies.

Adenomatous Polyposis Coli↗
PubMed1992

Genetic predisposition to breast cancer.

Breast cancer is the most common cancer among American women. Because metastatic breast cancer is an incurable disease, efforts to decrease breast cancer mortality have focused on early detection and improved treatment. Identification and analysis of a specific genetic susceptibility could permit detection of susceptible women and greatly increase the understanding of the initial step that eventually leads to cancer. Because susceptibility loci have been recognized as sites that often are altered during tumor progression, the identification and cloning of such loci could be important in developing cancer therapies. In this article, the progress being made in segregation analysis, linkage analysis, and cloning of breast cancer susceptibility loci is reviewed. The evidence for genetic inheritance is most consistent with dominant inheritance for at least three major susceptibility loci. Proliferative breast disease has been hypothesized to be an inherited lesion in breast cancer kindreds with both premenopausal and postmenopausal probands. Currently, there are many genetic markers for mapping the human genome. Technologic advances have progressed from restriction fragment length polymorphisms to highly polymorphic markers. Using this technology, breast cancer susceptibility in some kindreds with an early onset has been shown to be linked to chromosome 17q. Gene isolation eventually will follow with an increased understanding of the percentage of breast cancer cases that are a result of this genetic locus. Li-Fraumeni syndrome, which often is expressed as breast cancer, is due to mutations in the p53 gene. Characterization of the syndrome and its relationship to the altered gene should proceed rapidly. There is also a group of families exhibiting a genetic susceptibility that is not due to either of these loci. Together, these findings indicate that there are at least three separate major loci segregating for breast cancer susceptibility. With the current initiative to map and sequence the entire human genome and the advances that recently have been reported, a detailed molecular understanding of breast cancer predisposition can be envisaged.

Age Factors↗
PubMed1992

Hereditary aspects of colorectal adenomas.

BACKGROUND: Inheritance is important to the development of colonic adenomatous polyps and colon cancer. Current knowledge of inherited susceptibility to colonic neoplasms suggests that colon cancer screening strategies should consider familial and genetic risk. METHODS: This report reviews the literature pertinent to adenomatous polyp and colon cancer inheritance and suggests polyp-cancer screening procedures based on inherited or familial risk. RESULTS: Colorectal adenomas and cancer occur in several rare inherited syndromes and more commonly as sporadic cases. Intensive screening protocols have been suggested for the inherited syndromes because of the high associated cancer risk. Recent evidence suggests that inherited susceptibility also may be important in a large fraction of the so-called sporadic cases. Preliminary screening guidelines are suggested for this category based on the number of first-degree relatives affected with colon cancer. CONCLUSIONS: Inherited susceptibility appears to be more important to the pathogenesis of colorectal adenomas and cancer than previously recognized. Screening strategies which consider inherited risk may increase the effectiveness of cancer detection and prevention.

Adenoma↗
PubMed1992

Hypothalamic, dorsal raphe and external electrical stimulation modulate noxious evoked responses of habenula neurons.

Extracellular recording techniques were used to investigate the effects of focal brain stimulation and external electrical stimulation on spontaneous activity and on noxious evoked responses in the habenular nucleus of anesthetized Sprague-Dawley rats. Two hundred and forty-one habenular neurons were tested to noxious and non-noxious stimuli. The habenular neurons exhibited three cell types according to their patterns of response to the noxious stimulus: 123 neurons (51%) responded to noxious stimulus by excitation and were classified as "nociceptive-on" cells; 56 neurons (23%) responded to the same noxious stimulus by decreasing their firing rate and were classified as "nociceptive-off" cells; and 62 neurons (26%) failed to respond to noxious stimulation and were classified as "non-nociceptive" cells. None of these 241 cells responded to non-noxious stimulus. One hundred and fifty-five, 160, 142 and 241 habenular neurons were tested following focal lateral hypothalamus stimulation, dorsal raphe stimulation, cerebellar stimulation and transcranial electrical stimulation alone and concomitant with noxious stimulation, respectively. The observations demonstrate that focal lateral hypothalamic, dorsal raphe and external (transcranial) electrical stimulation suppresses habenular noxious evoked responses while cerebellar electrical stimulation elicits no effect on the nociceptive-off cells and augmenting effects on the nociceptive-on cells. In addition, it was observed that low current (below threshold) external transcranial electrical stimulation was as effective in suppression of habenular noxious evoked responses as was focal brain electrical stimulation in the lateral hypothalamus and dorsal raphe.

Acoustic Stimulation↗
PubMed1992

A screening study of prostate cancer in high risk families.

In a study of the familial risk of prostate cancer 17 sets of 2 brothers with prostate cancer were identified. A total of 34 first-degree relatives of these probands (sons and brothers, 55 to 80 years old) underwent an intensive screening examination that included prostate specific antigen, digital rectal examination, transrectal ultrasound and systematic as well as clinically directed core needle biopsies. Previously unsuspected and clinically relevant cancers were found in 8 men (24%), compared to the approximately 1 expected (p less than 0.01). Of these cancers 2 were detected by the systematic biopsies. This study emphasizes the importance of thorough screening in first-degree relatives of prostate cancer patients.

Aged↗
PubMed1991

Inheritance of nevus number and size in melanoma and dysplastic nevus syndrome kindreds.

Previous studies of the genetics of melanoma have focused on the dysplastic nevus syndrome (DNS). The variability in clinical and histopathological expression of affected individuals, however, has made definition and diagnosis of the syndrome difficult and subjective. Independent of the DNS, case-control studies have demonstrated the total number of nevi to be a significant risk factor for melanoma. In this article, we report results of genetic analyses of two quantitative nevus phenotypes that can be measured objectively in all subjects: the total number of nevi on an individual (TNN) and total nevus density (TND), a derived phenotype which incorporates both number and size of nevi. Ten kindreds ascertained for multiple cases of DNS-melanoma (multiplex ascertainment) and 16 kindreds and 19 solitary cases ascertained from a sequential list of melanoma cases without regard for family history (simplex ascertainment) were studied. Both phenotypes exhibited increased levels in relatives of probands compared with those in spouse controls. While neither TNN nor TND exhibited evidence for a major factor in the simplex pedigrees, a major factor was strongly indicated in the multiplex kindreds for TND. When both phenotypes were examined in more detail in the multiplex kindreds, the phenotype incorporating nevus size, TND, fit a mendelian pattern of inheritance better than the TNN. Significant residual familial correlations were found for both phenotypes. Parameter estimates from the best fitting genetic model indicated that a major gene may be responsible for 55% of the phenotypic variability of TND in the multiplex kindreds.

Adolescent↗
PubMed1991

High-density genetic and physical mapping of DNA markers near the X-linked Alport syndrome locus: definition and use of flanking polymorphic markers.

To refine the genetic and physical mapping of the locus for Alport syndrome (ATS), 22 X-chromosome restriction fragment length polymorphism (RFLP) markers that fall between Xq21.3 and Xq25 were tested for genetic linkage with the disease and also mapped with respect to a series of physical breakpoints in this region. The location of the COL4A5 gene, which has recently been shown to be mutated in at least some families with Alport syndrome, was determined with respect to the same physical breakpoints. Two large Utah kindreds were included in the genetic studies, kindreds P and C, with 125 and 63 potentially informative meioses, respectively. Both kindreds have essentially identical nephritis; however, kindred P has sensorineural hearing loss associated with the nephritis, while kindred C does not. A mutation in COL4A5 has been demonstrated for kindred P, but no change in this gene has yet been detected for kindred C. Twelve informative probes did not recombine with the disease locus in either kindred (theta = 0.0, with combined lod scores for the two kindreds ranging from 7.7 to 30.0). The closest markers that could be demonstrated to flank the disease locus were the same for each kindred and thus the locations of the mutations causing the two disease phenotypes are not distinguishable at the current level of genetic resolution. The flanking markers are also useful for the resolution of questionable diagnoses and allow accurate estimates for these families of the rate of sporadic hematuria in noncarrier females (7%) and the penetrance of hematuria for carrier females (93%).

Blotting, Southern↗
PubMed1991

Familial predisposition to Wilms tumor does not segregate with the WT1 gene.

Wilms tumor (WT) is one of the more common childhood cancers. A small fraction of WT occurs in association with aniridia, genitourinary abnormalities and mental retardation, the WAGR syndrome, and these cases often are accompanied by a constitutional deletion of all or part of band 11p13. Recently a WT susceptibility gene (WT1), localized to 11p13, has been isolated and shown to be inactivated in some sporadic WTs. In the present study, a highly informative CA repeat polymorphism within the gene was studied in a family with six affected members in three generations. Predisposition to WT in this large family did not segregate with this polymorphism. Furthermore, linkage analysis indicated exclusion of WT predisposition from 11p15. These results provide definitive evidence that familial predisposition to WT can be mediated by a gene other than WT1.

Alleles↗
PubMed1991

HMB-45 staining of dysplastic melanocytic nevi in melanoma risk groups.

To evaluate the hypothesis that reactivity of the intradermal component of melanocytic nevi to the monoclonal antibody HMB-45 correlates with melanoma risk, dysplastic compound melanocytic nevi were examined for expression of the HMB-45 epitope in three subject groups differing in epidemiological risk for melanoma. The study groups consisted of 10 subjects with dysplastic nevi and a personal history of melanoma, 25 subjects with dysplastic nevi and a history of melanoma in one or more first degree relatives, and 15 population control subjects with sporadic dysplastic nevi. For each case, sections from one lesion, immunohistochemically processed for HMB-45 binding, were evaluated by two pathologists without knowledge of the clinical data. Of all dysplastic nevi, 98% showed diffusely positive cytoplasmic staining of the junctional nevomelanocytes and 90% had such positive staining of those cells within the superficial dermis. Nevus cells within the deeper dermis did not stain positively in any case. Furthermore, the data showed no differences in frequency, pattern, or intensity of HMB-45 reactivity between the subject groups. These observations indicate that evaluation of dysplastic nevi with the monoclonal antibody HMB-45, an apparent marker of proliferative or otherwise stimulated melanocytes, has no discriminating value for identifying subjects at increased historical risk for melanoma. The data, however, support the concept that so-called dysplasia within nevi, as defined by histologic criteria, actually represents the active or proliferative phase of melanocytic nevi.

Antibodies, Monoclonal↗
PubMed1990

Isolation, characterization, and physical localization of 33 human X-chromosome RFLP markers.

In a search for highly polymorphic X-specific loci, the X-chromosome DOE Ch35 phage library (LAOXNL01) was screened with three oligonucleotides representative of minisatellite consensus sequences. A total of 170 clones containing human inserts were isolated by hybridization to the oligonucleotide sequences; each was tested for polymorphism on five random female DNAs with six restriction enzymes. Among the 53 clones demonstrating a polymorphic pattern, 47 were of distinct origin. Twelve of the polymorphisms (23%) were determined to be autosomal. Polymorphisms for the remaining 35 clones were characterized, These polymorphisms represent 33 new X-chromosome RFLP loci, since two pairs of clones detected partially overlapping patterns. A pattern of similar length variation with multiple enzymes ("VNTR-type") was demonstrated in 6 (50%) of the 12 non-X-polymorphic clones. However, only 3 (9%) of the 33 X polymorphic loci showed VNTR-like patterns, suggesting a decreased amount of VNTR polymorphism on the X chromosome. The 33 polymorphic X loci were physically localized with a set of rodent x human somatic cell hybrid DNAs representing nine different X-chromosome breakpoints.

Base Sequence↗
PubMed1979

Comparison of digital boundary detection and semi-automated analysis of left ventricular cine angiograms.

A technique has been developed to analyze automatically 35 mm left ventricular cine angiograms with an image dissector and digital computer. The analysis procedure detected the ventricular boundary and aortic valve position, then calculated the projected left ventricular area and estimated volume, and performed a polar wall motion analysis as a function of time. The automated method was compared to a semi-automated method using a technician-operated electronic cursor linked to a mini-computer. The two methods were used to analyze a set of idealized ventricular models as well as normal and abnormal angiographic data. The volumetric and wall motion data for the idealized models calculated by the two methods were equivalent (r greater than 0.99). Volumetric analysis of the patients' ventriculograms produced correlation coefficients of 0.88-0.99. Corresponding wall motion data produced correlation coefficients of 0.72-0.94. The time necessary to analyze 30 frames of cine ventriculogram was approximately 30 minutes for each method.

Aged↗
PubMed1978

Ancestral inference. I. The problem and the method.

A method for inferring the ancestral genotypes for the founders of a population is developed. This method uses the algorithms for the computation of probabilities on pedigrees of arbitrary complexity, developed by Cannings et al. (1978) and implemented by Thompson (1977b). When characteristics are simply determined by underlying genotypes the inference problem is simplified, and larger and more complex pedigrees may therefore be analysed. The problem of estimating the allele frequencies to be used in computing prior genotype probabilities for those founders on whom a likelihood function is not required is discussed. The same method allows us to compute extinction probabilities for any combination of original founder genes; these probabilities are interesting parameters of pedigree structure, which, since they relate to the actual genes present in a population, help to provide a clearer understanding of observed distributions of autosomal traits.

Gene Frequency↗