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Biomedical subjects

W H Clark

Publications and source records attributed to W H Clark.

At least 37 records · Page 2Linked to original sources
PubMed1995

Prospectives for cutaneous malignant melanoma. Considerations of the precursor state and heritability.

Each of the discoveries through the years has begotten a series of Gordian knots. We must patiently inspect our new collection of mysteries and focus on those where our efforts may well change the course of the disease to the benefit of affected patients. The proper management of the precursor state, the beginning of the disease, and the patient exploration of the complexities of heritability would seem to be appropriate beginnings.

Disease Susceptibility↗
PubMed1995

The nature of cancer: morphogenesis and progressive (self)-disorganization in neoplastic development and progression.

The aberrant forms of life, neoplasia and cancer, are discussed under the events at the beginning of neoplasia and under five classes of neoplastic lesions. The lesional classes are: 1) The precursor state; 2) Intermediate lesions; 3) Primary cancer; 4) Metastasis; and 5) Metastasis from metastasis. The events at the beginning are a diverse group of agents and mechanisms that induce the lesions of the precursor state, not cancer. The lesions and events produced by induction are similar regardless of the agent. Thus, there must be similar biological principles and mechanisms operative in different neoplastic systems. The classes of neoplastic lesions and cancer are described and a theory derived therefrom. The theory is: Any perturbation that alters a cell or group of cells and their stroma so that they no longer respond appropriately to the forces of tissue, organ, and organismal maintenance, may induce a neoplastic system. The sequential progression of lesions of the induced neoplastic system is the result of a successive series of flaws in the continuum of reciprocal interactions between a group of cells and their stroma. The flaws, appearing seriatim, produce progressive (self)-disorganization of the lesions and progressive loss of response to the forces of tissue and organ maintenance.

Animals↗
PubMed1995

Parenchymal-stromal interactions in neoplasia. Theoretical considerations and observations in melanocytic neoplasia.

The paper briefly reviews the reciprocal and continuous reciprocal interactions between epithelia, mesenchyme, and extracellular matrix in the development and maintenance of organismal form in multicellular organisms in the animal kingdom and describes the progressive changes in parenchymalstromal interactions in melanocytic neoplastic development and progression. In addition to the parenchymal stromal form in non-lesional skin seven different and unique stromal patterns are described. These have been termed: 1) The stroma (diff-regress) of programmed differentiation leading to lesional regression characteristic of common nevi; 2) concentric eosinophilic fibroplasia (cef), the hallmark of precursor nevi (dyplastic nevi) with and without melanocytic nuclear atypia; 3) Fibroplasia with angiogenesis (fa) commonly seen in superficial spreading melanoma without metastic competence (SSM); 4) Lamellar fibroplasia (lf) seen in precursor nevi and melanomas with and without metastatic competence; 5) Diffuse fibroplasia with angiogenesis (dfa), 6) Narrow, uniform concentric eosinophilic fibroplasia (nucef), 7) No parenchymal-stromal interaction (nopsi); the last three being seen in the heterogeneous stroma of melanomas of the superficial spreading type with metastatic competence. The changes in neoplastic stroma proceed in concert with the changes in the parenchyma characteristic of melanocytic tumor progression.

Animals↗
PubMed1994

Age at diagnosis and transmission of invasive melanoma in 23 families with cutaneous malignant melanoma/dysplastic nevi.

BACKGROUND: Familial melanoma patients tend to have an earlier age at first melanoma diagnosis, thinner lesions, a different histologic distribution, and a higher frequency of multiple primary melanomas than patients with nonfamilial melanoma. Previous examination of a large melanoma kindred from Texas suggested that although cutaneous malignant melanoma (CMM) was transmitted in an autosomal dominant fashion, there were sex differences in penetrance and disease expression. PURPOSE: This study further evaluated the age at diagnosis, sex difference in penetrance and disease expression, and segregation of familial CMM. METHODS: We evaluated the age at diagnosis and transmission of CMM in 23 U.S. white families with CMM/dysplastic nevi who had been followed 5-17 years. We estimated the median and mean ages at diagnosis of invasive melanoma for all individuals, for men and women separately, and by generation. Using the computer program BMDP1L, we also estimated the cumulative probability of an offspring developing CMM as a function of age according to whether the mother or father had melanoma. In addition, we used a life-table approach to estimate the probability that offspring of CMM parents were affected with CMM (penetrance). RESULTS: The median age at diagnosis in the 23 kindreds (n = 106) was 33 years, substantially less than that of patients with sporadic melanomas in the U.S. white population. For females, the median age at diagnosis was 29 years; for males, it was 36 years. Nine percent of the case patients developed CMM before age 20 compared with 2% in the general population. There was little difference in the transmission pattern of melanoma between males and females in the 23 families, although sons of CMM parents had a higher risk of CMM than daughters of CMM parents. This difference was, however, based on small numbers and was not statistically significant. The penetrance estimates for CMM were high. They rose rapidly from 6% at age 18 to 85% by age 48. The median age at diagnosis of invasive melanoma decreased dramatically in successive generations; the reduction was 11-16 years per generation and was statistically significant (P < .0001). CONCLUSIONS AND IMPLICATIONS: Although this reduction in median age at diagnosis may result partly from increased surveillance in hereditary melanoma families and the fact that individuals in the younger generations have not yet reached the highest at-risk ages for developing melanoma, the possibility of changes in melanoma risk and risk factors, genetic and/or environmental, across generations should be considered.

Adolescent↗
PubMed1994

Mesendoderm cell and archenteron formation in isolated blastomeres from the shrimp Sicyonia ingentis.

The fate map of 2- and 4-cell-stage Sicyonia ingentis embryos was determined by microinjection of lysyl-rhodamine-dextran into single blastomeres. Microinjected embryos were cultured to the limb bud stage, when the body plan of the nauplius larva was evident. The animal blastomere, AB, gave rise to anterior ectoderm, while the vegetal blastomere, CD, gave rise to posterior structures, including the invagination site during gastrulation. The A blastomere gave rise to mirror-image patterns of dorsal-lateral ectoderm, while the B blastomere gave rise to anterior, ventral ectoderm. The C blastomere gave rise to posterior, dorsal-lateral ectoderm, complementary to the A pattern, as well as some naupliar mesoderm. The D blastomere gave rise to mesendoderm, naupliar mesoderm, and some posterior ectoderm. To study the specification of the early blastomeres, they were microsurgically separated and cultured in isolation. Two mesendoderm cells formed in 1/2, 1/4, 1/8, and 1/16 blastomeres in embryos dissociated at the 2-, 4-, 8-, and 16-cell stages, respectively. CD and D blastomeres could be distinguished by their larger size and gave rise to the mesendoderm cells. Archenteron formation and elongation of the embryo occurred in CD but not in AB isolates. Isolated blastomeres were recombined in various ways to determine whether their state of commitment could be altered in different cellular environments. Duplicated mesendoderm cells and archenterons formed in CD + CD recombinations, while AB + AB recombinations formed blastulae but did not produce mesendoderm cells and did not invaginate. The normal number of mesendoderm cells and a single archenteron formed in D + AB recombinations, while C + AB recombinations remained as blastulae and did not form mesendoderm cells. The results suggest that the mesendoderm cells are autonomously specified, possibly by cytoplasmic localization at the vegetal pole. The mesendoderm may also function as a signaling region to organize other developmental events.

Animals↗
PubMed1994

Inter-observer variability among pathologists' evaluation of malignant melanoma: effects upon an analytic study.

This study examined whether inter-observer variability in rating tumor characteristics affected results of an investigation of surveillance bias and malignant melanoma at the Lawrence Livermore National Laboratory. The 20 cases from the Laboratory and their 36 non-Laboratory controls belonged to the same pre-paid health plan and were diagnosed with melanoma between 1970 and 1984. Tumors were independently and then jointly rated by three dermatopathologists blind to the subjects' Laboratory status. The mean difference between the reviewers and the consensus reading for tumor thickness was small, ranging from -0.06 mm (95% confidence interval [CI]--0.12, 0.00) to 0.00 mm (95% CI--0.07, 0.07). Agreement was much lower for histologic type (kappa = 0.48, 95% CI 0.37, 0.58). Because the inter-observer variability, the study's hypothesis was rejected by analyses based on data from the consensus reading and two reviewers, but not on data from the third reviewer. These findings suggest that epidemiologists using data subject to inter-observer variability may want to employ consensus instead of individual ratings.

Dermatology↗
PubMed1994

Germline p16 mutations in familial melanoma.

The p16 gene is located in chromosome 9p21, a region that is linked to familial melanoma and homozygously deleted in many tumour cell lines. We describe eight p16 germline substitutions (one nonsense, one splice donor site and six missense) in 13/18 familial melanoma kindreds. Six of these mutations were identified in 33/36 melanoma cases in nine families, whereas two were detected in normal controls and are not disease-related. The melanoma-specific mutations were detected in 9p21-linked, but not in 1p36-linked, families, thereby confirming previous reports of genetic heterogeneity. Functional analyses of these mutations will confirm those causally related to the development of familial melanoma.

Base Sequence↗
PubMed1994

Linkage of cutaneous malignant melanoma/dysplastic nevi to chromosome 9p, and evidence for genetic heterogeneity.

We examined the relationship between cutaneous malignant melanoma/dysplastic nevi (CMM/DN) and chromosome 9p in 13 pedigrees with two or more living cases of invasive melanoma. We used two highly informative (CA)n repeats, D9S126 and IFNA, previously implicated in familial malignant melanoma (MLM), to conduct linkage analysis. Three analyses were performed: (1) CMM alone--all individuals without either confirmed melanoma or borderline lesions were considered unaffected (model A); (2) CMM/DN with both variable age at onset and sporadics (model B); and (3) CMM affecteds only--all individuals either without confirmed melanoma or with borderline lesions were designated "unknown" (model C). There was significant evidence for linkage to IFNA in all three models. For CMM alone, the maximum lod score (Zmax) was 4.36 at theta = .10 for model A and 3.39 at theta = .10 for model C. For CMM/DN (model B), Zmax = 3.05 at theta = .20. There was no significant evidence for linkage between CMM alone or CMM/DN and chromosome 9p marker D9S126. In addition, there was significant evidence for heterogeneity when a homogeneity test allowing for linkage to chromosome 9p or chromosome 1p or neither region was used. These results suggest that there is an MLM susceptibility locus on chromosome 9p but that familial melanoma is heterogeneous and not all families with CMM/DN are linked to a locus in this region.

Adolescent↗
PubMed1993

The late events of fertilisation in the penaeoidean shrimp Sicyonia ingentis.

Antibodies to sea urchin beta-tubulin and mammalian heavy neurofilaments were used to study the late events of fertilisation in the penaeoidean shrimp Sicyonia ingentis. The neurofilament antibody fortuitously stained centrosomes in eggs, as well as the subacrosomal region and acrosomal filament in sperm. The neurofilament antibody also stained a cortical site in eggs which was associated with the positioning of the mitotic spindle. During pronuclear migration, a large maternal microtubule aster formed in addition to the sperm aster. The activity of the maternal centrosome disappeared during syngamy, while the sperm centrosomes formed the poles of the first mitotic spindle. Colcemid treatment modulated the size of the mitotic spindle and blocked pronuclear migration.

Animals↗
PubMed1993

Surveillance bias and the excess risk of malignant melanoma among employees of the Lawrence Livermore National Laboratory.

To assess the role of surveillance bias in the observed three-fold excess of cutaneous malignant melanoma (CMM) at the Lawrence Livermore National Laboratory (LLNL) in California, we examined the thickness of CMMs among all 20 laboratory employees who were members of a large prepaid health plan and whose CMM was diagnosed from 1970 through 1984. For comparison, we reviewed slides of 36 other members of the same health plan matched (usually 2:1) to the laboratory case by age, sex, facility, and year of diagnosis. Three expert dermatopathologists read the slides using a multiheaded microscope to reach a consensus; they were blind to the laboratory employment status of the subjects. We found that from 1970 to 1976, before there was widespread publicity about the excess incidence of CMM at LLNL, lesion thickness was greater for non-LLNL employees (mean difference = 1.5 mm; 95% confidence interval 0.1-2.9). From 1977 through 1984, however, there was no appreciable difference [mean difference = -0.3 mm; 95% confidence limits (CL) = -1.4, 0.9]. Dropping the matching to adjust for histologic type of melanoma as well as gender, year, and age at diagnosis yielded substantially the same results. These data are compatible with an effect of surveillance bias up to around 1976, but in this health plan population, they do not support a role for surveillance bias in the continuing excess incidence observed since that time.

Bias↗
PubMed1993

Further evidence for a locus for cutaneous malignant melanoma-dysplastic nevus (CMM/DN) on chromosome 1p, and evidence for genetic heterogeneity.

Assignment of a susceptibility locus for cutaneous malignant melanoma-dysplastic nevus (CMM/DN) to chromosome 1p remains controversial. We examined the relationship between CMM/DN and markers D1S47, PND, and D1S160 on seven new families (set B) plus updated versions of six previously reported families (set A). Three linkage analyses were performed: (1) CMM alone--all individuals without confirmed melanoma or borderline lesions were considered unaffected (model I); (2) CMM/DN with variable age at onset and sporadics (model II); and (3) CMM/DN using the model of Bale et al. (model III). For CMM alone and D1S47, Zmax = 3.12 at theta = .10. For D1S160 and CMM alone, Zmax = 1.76 at theta = .10. PND showed no evidence for linkage to CMM alone. Models II and III showed strong evidence for linkage to D1S47, D1S160, and PND in the set A pedigrees but not in the set B families. We tested for homogeneity of CMM/DN (model II) by splitting families into two groups on the basis of (1) the proportion of CMM/DN cases and (2) the occurrence of immune-related tumors. In group 1 there was significant evidence of heterogeneity with both D1S47 and D1S160, and in group 2 there was significant evidence of heterogeneity with D1S160. Thus, diagnostic, clinical, and genetic heterogeneity are the likely reasons that previous studies have failed to confirm linkage of CMM/DN to chromosome 1p. The results showed significant evidence for a CMM locus linked to D1S47, as well as significant evidence for heterogeneity with only a subset of the families appearing linked to chromosome 1p.

Adult↗
PubMed1993

The early and intermediate precursor lesions of tumor progression in the melanocytic system: common acquired nevi and atypical (dysplastic) nevi.

Intermediate lesions of melanocytic tumor progression are potential precursors, simulants, and risk markers of melanoma. The clinical, public health, and biologic significance of intermediate lesions warrants their continued recognition and study, although improved schemata for their clinical and histological coding are needed. Blurred boundaries are inherently problematic to the categorization of lesions occurring along a stepwise pathway of increasing clinical and histological atypia. Nevertheless, the concepts of melanocytic dysplasia and of radial growth phase (in situ and microinvasive) melanoma are important to the classification of intermediate lesions of melanocytic tumor progression. Conceptually, these lesions are clearly separable from early and late lesions and from one another, and there is evidence that criteria distinguishing them can be reproducibly applied. Analysis of these intermediate lesions suggests that they represent responses to events (perhaps mutational) induced by ultraviolet light in constitutionally hypersensitive individuals, supporting epidemiological data that implicate sunlight as an etiologic agent for most melanomas. The continuing rigorous application of the methodologies of epidemiology and basic science to the study of these lesional steps will likely lead to the recognition of biologic markers to better distinguish benign from malignant melanocytic lesions.

Adult↗
PubMed1992

Preloading of micromolar intracellular Ca2+ during capacitation of Sicyonia ingentis sperm, and the role of the pHi decrease during the acrosome reaction.

In studying the mechanism controlling the sperm acrosome reaction (AR) in the marine shrimp Sicyonia ingentis, intracellular Ca2+ and pH were measured using the fluorescent indicators Fura-2 and Fluo-3 for Ca2+, and SNARF-1 for pH. Capacitated sperm possessed an apparent resting Ca2+ concentration of 1-2 microM which remained constant upon induction of the AR with egg water. Uncapacitated sperm had extremely low Ca2+ levels and did not respond to egg water. These results suggest that, while in other species the Ca2+ is elevated to micromolar levels during initiation of the AR, S. ingentis sperm are preloaded with Ca2+ during capacitation and the trigger for the AR is downstream of the Ca2+ increase. The notion that Ca2+ influx is not involved at the actual time of the AR in capacitated S. ingentis sperm is supported by the inability of Ca2+ ionophore A23187 to induce the AR and the ineffectiveness of Ca2+ channel antagonists to block egg water-induced AR. Measurements of capacitated sperm pH showed a significant decrease during the first 10-15 min of the AR, which did not correlate temporally to either acrosomal exocytosis (at 5 min post-induction) or filament formation (after 45 min). Inhibition of egg protease activity required for induction of filament formation did not inhibit the pH drop, indicating that intracellular acidification is not the final trigger for filament formation, although it may be required prior to action of the protease.

Acrosome↗
PubMed1992

Extracellular Mg2+ induces an intracellular Ca2+ wave during oocyte activation in the marine shrimp Sicyonia ingentis.

In contrast to most systems in which oocyte activation is triggered by the fertilizing sperm, Sicyonia ingentis oocytes are activated by seawater Mg2+ during spawning. S. ingentis oocytes were spawned into Mg(2+)-free seawater and microinjected with the fluorescent Ca2+ indicator Fluo-3 to study the effects of added Mg2+ on intracellular Ca2+ levels. The Mg2+ induced a wave of fluorescence across the oocyte that traveled at a speed of 13 +/- 3 microns/sec. Extracellular Ca2+ was not required for induction of the wave. Treatment with Ca2+ ionophore in Mg(2+)-free medium or a localized injection (0.3% oocyte volume) of 3-5 microM Ca2+ also initiated the wave; injection of 250 mM Mg2+ (up to 1.5% oocyte volume) had no effect. Microinjection of 750 microM EGTA (final) suppressed the Mg(2+)-induced wave, while an identical concentration of EDTA had no inhibitory effect. Subsequent to the initial Mg(2+)-induced intracellular Ca2+ increase, a second Ca2+ increase was observed at approximately 15 min postspawning; the timing of this second increase appeared to be independent of when the Mg(2+)-induced wave was initiated, thus an event associated with spawning may be involved. While oocytes in normal seawater were monospermic, those in Mg(2+)-free seawater were polyspermic, suggesting a role for the Mg(2+)-induced Ca2+ wave in regulating sperm entry into the oocyte.

Animals↗
PubMed1992

Cleavage and gastrulation in the shrimp Sicyonia ingentis: invagination is accompanied by oriented cell division.

Embryos of the penaeoidean shrimp Sicyonia ingentis were examined at intervals during cleavage and gastrulation using antibodies to beta-tubulin and DNA and laser scanning confocal microscopy. Cleavage occurred in a regular pattern within four domains corresponding to the 4-cell-stage blastomeres and resulted in two interlocking bands of cells, each with similar spindle orientations, around a central blastocoel. Right-left asymmetry was evident at the 32-cell-stage, and mirror-image embryos occurred in a 50:50 ratio. Gastrulation was initiated by invagination into the blastocoel at the 62-cell-stage of two mesendoderm cells, which arrested at the 32-cell-stage. Further invagination and expansion of the archenteron during gastrulation was accompanied by rapid and oriented cell division. The archenteron was composed of presumptive naupliar mesoderm and the blastopore was located at the site of the future anus of the nauplius larva. In order to trace cell lineages and determine axial relationships, single 2- and 4-cell-stage blastomeres were microinjected with rhodamine-dextran. The results showed that the mesendoderm cells which initiated gastrulation were derived from the vegetal 2-cell-stage blastomere, which could be distinguished by its slightly larger size and the location of the polar bodies. The mesendoderm cells descended from a single vegetal blastomere of the 4-cell-stage. This investigation provides the first evidence for oriented cell division during gastrulation in a simple invertebrate system. Oriented cell division has previously been discounted as a potential morphogenetic force, and may be a common mechanism of invagination in embryos that begin gastrulation with a relatively small number of cells.

Animals↗
PubMed1991

The prognostic implications of microscopic satellites in patients with clinical stage I melanoma.

Controversy exists as to whether microscopic satellites influence prognosis or patterns of progressive disease in patients with clinical stage I melanoma. Fifty patients with clinical stage I melanoma and microscopic satellites were prospectively studied from 1972 to 1984. To allow for complete histopathology assessment, 30 patients with microscopic satellites who were prospectively seen from 1972 to 1979 were matched to a cohort of 77 patients with vertical growth-phase melanoma without microscopic satellites according to six attributes. The matched cohort study showed that the presence of microscopic satellites appeared to be associated with increased local regional cutaneous and regional nodal disease and a significantly decreased actuarial disease-free survival. A Cox multivariate regression analysis that involved 384 patients with vertical growth-phase clinical stage I melanoma showed that the presence of microscopic satellites independently predicted a poorer disease-free survival and overall survival. Therefore, this study demonstrated that the presence of microscopic satellites correlated with a significantly decreased survival.

Cohort Studies↗