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Biomedical subjects

L Chin

Publications and source records attributed to L Chin.

At least 55 records · Page 3Linked to original sources
PubMed1997

Cooperative effects of INK4a and ras in melanoma susceptibility in vivo.

The familial melanoma gene (INK4a/MTS1/CDKN2) encodes potent tumor suppressor activity. Although mice null for the ink4a homolog develop a cancer-prone condition, a pathogenetic link to melanoma susceptibility has yet to be established. Here we report that mice with melanocyte-specific expression of activated H-rasG12V on an ink4a-deficient background develop spontaneous cutaneous melanomas after a short latency and with high penetrance. Consistent loss of the wild-type ink4a allele was observed in tumors arising in ink4a heterozygous transgenic mice. No homozygous deletion of the neighboring ink4b gene was detected. Moreover, as in human melanomas, the p53 gene remained in a wild-type configuration with no observed mutation or allelic loss. These results show that loss of ink4a and activation of Ras can cooperate to accelerate the development of melanoma and provide the first in vivo experimental evidence for a causal relationship between ink4a deficiency and the pathogenesis of melanoma. In addition, this mouse model affords a system in which to identify and analyze pathways involved in tumor progression against the backdrop of genetic alterations encountered in human melanomas.

Animals↗
PubMed1997

Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression.

Normal mammalian growth and development are highly dependent on the regulation of the expression and activity of the Myc family of transcription factors. Mxi1-mediated inhibition of Myc activities requires interaction with mammalian Sin3A or Sin3B proteins, which have been purported to act as scaffolds for additional co-repressor factors. The identification of two such Sin3-associated factors, the nuclear receptor co-repressor (N-CoR) and histone deacetylase (HD1), provides a basis for Mxi1/Sin3-induced transcriptional repression and tumour suppression.

3T3 Cells↗
PubMed1997

Is machine energy (4-8 MV) associated with outcome for stage I-II breast cancer patients?

PURPOSE: To assess the relationship between machine energy (4-8 MV) and treatment outcome in patients treated with conservative surgery and radiation therapy. METHODS AND MATERIALS: Between 1968 and 1985, 1624 patients were treated for clinical Stage I or II invasive breast cancer. The study population was limited to 1380 patients who underwent complete gross excision and received greater than or equal to 60 Gy to the tumor bed. Of these, 1125 were treated on a 4 MV, 153 on a 6 MV, and 102 on an 8 MV linear accelerator. Patients were selected for treatment on the 8 MV machine based on chest wall separations greater than 24 cm. Of patients treated on the 8 MV, netting was used for 42% and bolus was used for 26%. The median dose with bolus was 14 Gy in seven fractions (range: 2-34.2 Gy). Patients treated on the 8 MV accelerator were older, had a higher percentage of clinical T2 tumors, a higher percentage of pathologically positive nodes, and a lower incidence of extensive intraductal component (EIC). Median follow-up times were 130, 153, and 102 months, respectively, for survivors treated on the 4, 6, and 8 MV machines. RESULTS: We analyzed the site and 5-year crude incidence of first failure by machine energy and found the pattern of first failure site (local, nodal, or distant) to be virtually identical for each energy group. Of the local failures, 12 were in the skin of the treated breast, and these failures were evenly distributed by machine energy. We performed a multivariate analysis to adjust for factors known to predict for treatment failure. When adjusted for these other variables, machine energy was not associated with an increased (or decreased) risk of recurrence (RR for 8 MV vs. 4 MV = 0.94, p = 0.7; RR for 6 MV vs. 4 MV = 1.0, p = 0.9). We also analyzed the nature and incidence of treatment complications (rib fracture, radiation pneumonitis, soft tissue necrosis, and brachial plexopathy) and found no significant differences among the three treatment groups when stratified by treatment technique (tangents only vs. three-field). There was also no significant difference in cosmetic outcome at 5 years among the three groups. CONCLUSIONS: We conclude that machine energy over the range of 4 to 8 MV does not significantly affect treatment outcome. Specifically, it was feasible to treat patients with large chest wall separations using an 8 MV machine without an increase in skin recurrences and with the improved dose homogeneity afforded by 8 MV machines as compared with those of lower energies.

Adult↗
PubMed1996

Role of the INK4a locus in tumor suppression and cell mortality.

The cell cycle inhibitor p16INK4a is inactivated in many human tumors and in families with hereditary melanoma and pancreatic cancer. Tumor-associated alterations in the INK4a locus may also affect the overlapping gene encoding p19ARF and the adjacent gene encoding p15I1NK4b, both negative regulators of cell proliferation. We report the phenotype of mice carrying a targeted deletion of the INK4a locus that eliminates both p16INK4a and p19ARF. The mice are viable but develop spontaneous tumors at an early age and are highly sensitive to carcinogenic treatments. INK4a-deficient primary fibroblasts proliferate rapidly and have a high colony-formation efficiency. In contrast with normal cells, the introduction of activated Ha-ras into INK4a-deficient fibroblasts can result in neoplastic transformation. These findings directly demonstrate that the INK4a locus functions to suppress neoplastic growth.

Alleles↗
PubMed1996

Mouse Sin3A interacts with and can functionally substitute for the amino-terminal repression of the Myc antagonist Mxi1.

Mxi1 is a basic region helix-loop-helix leucine zipper (bHLH/LZ) protein that, in association with Max, antagonizes Myc oncogenic activities. A possible mechanistic basis for Mxi1-mediated repression was provided by the recent demonstration that the repressive potential of Mxi1 correlates with its ability to physically associate with mSin3B, one of two mammalian homologues of the yeast transcriptional repressor SIN3. Here, we sought to characterize more fully the physical properties of the second homologue, mSin3A and to determine whether the recruitment of mSin3A by Mxi1 is indeed required for anti-Myc activity. Transient transfection of mammalian cells showed that the mSin3A protein can associate with the strong repressive isoform of Mxi1 (Mxi1-SR) and that, like other Myc superfamily members, both mSin3A and Mxi1-SR localize to the nucleus. From a developmental standpoint, a comparative analysis of Myc, Mxi1-SR and Sin3A expression during postnatal mouse development and in differentiating mouse erythroleukemia (MEL) cells revealed that dramatic and reciprocal changes in Myc and Mxi1-SR mRNA levels are accompanied by minimal stage-specific changes in mSin3A gene expression. This constant expression profile, coupled with the observation that over-expression of mSin3A does not augment the anti-Myc activity of Mxi1-SR in the rat embryo fibroblast (REF) transformation assay, suggests that mSin3A is not a limiting factor in the regulation of Myc superfamily function. Finally, a mSin3A-Mxi1 fusion protein, in which the amino terminal mSin3-interacting domain of Mxi1-SR was replaced with the full-length mSin3A, exhibited a level of repression activity equivalent to, or greater than, the level of repression obtained with Mxi1-SR. Taken together, these observations directly demonstrate that the amino-terminal repression domain of Mxi1-SR functions solely to recruit mSin3A and possibly other proteins like mSin3A and this association is necessary for the anti-Myc activity of Mxi1-SR.

Amino Acid Sequence↗
PubMed1996

Expression and activity of L-Myc in normal mouse development.

To determine the role of L-Myc in normal mammalian development and its functional relationship to other members of the Myc family, we determined the normal patterns of L-myc gene expression in the developing mouse by RNA in situ hybridization and assessed the phenotypic impact of L-Myc deficiency produced through standard gene targeting methodology. L-myc transcripts were detected in the developing kidney and lung as well as in both the proliferative and the differentiative zones of the brain and neural tube. Despite significant expression of L-myc in developing mouse tissue, homozygous null L-myc mice were found to be viable, reproductively competent, and represented in expected frequencies from heterozygous matings. A detailed histological survey of embryonic and adult tissues, characterization of an embryonic neuronal marker, and measurement of cellular proliferation in situ did not reveal any congenital abnormalities. The lack of an apparent phenotype associated with L-Myc deficiency indicates that L-Myc is dispensable for gross morphological development and argues against a unique role for L-Myc in early central nervous system development as had been previously suggested. Although overlapping expression patterns among myc family members raise the possibility of complementation of L-Myc deficiency by other Myc oncoproteins, compensatory changes in the levels of c- and/or N-myc transcripts were not detected in homozygous null L-myc mice.

Animals↗
PubMed1996

Growth and radiation response of cells grown in macroporous gelatin microcarriers (CultiSpher-G).

Four cell lines have been cultured in macroporous gelatin microcarrier beads (CultiSpher-G) to test this as a new model of three-dimensional cell growth for use in experimental cancer therapy. A549, KB 3-1, KB 8-5 and V79 cells were successfully grown in CultiSphers, albeit with longer doubling times than observed for the respective cell type in monolayer cultures. MTT staining and histology demonstrated three-dimensional contact of cells in the microcarriers. A549 cells populated the microcarriers more densely than KB 3-1 cells, and with both cell types there is bead-to-bead variation in occupancy by cells. [3H]TdR autoradiography reveals labelled cells throughout A549 and KB 3-1 CultiSphers, with no proliferation gradient from edge to centre. Central necrosis has not been observed. A549 cells but not KB 3-1 cells demonstrated a radiation contact effect (i.e. resistance) when irradiated in CultiSphers, compared with monolayers. We conclude that CultiSphers may be a useful model for three-dimensional growth and cell contact when investigators want to investigate these phenomena without the microenvironmental gradients of spheroids.

Animals↗
PubMed1996

Functional interactions among members of the Myc superfamily and potential relevance to cutaneous growth and development.

Myc family oncoproteins function as sequence-specific transcription factors that are believed to regulate the expression of genes governing cellular growth, differentiation, and programmed cell death. Activities of Myc are countered by those of Mad and Mxi1, two related members of the Myc superfamily. Mad and Mxi1 compete with Myc for common elements and interact with putative transcriptional repressors. While the precise role of the Myc superfamily in cutaneous biology remains to be determined, findings from a number of organ systems suggest that the regulated expression and function of its members are intimately correlated with proper development and physiology. Reviewed here are current data on Myc superfamily function with references where relevant to cutaneous processes with the ultimate goal of providing a framework upon which these proteins can be exploited in gene therapeutic approaches for diseases of the skin, including neoplasia.

Animals↗
PubMed1995

Contrasting roles for Myc and Mad proteins in cellular growth and differentiation.

The positive effects of Myc on cellular growth and gene expression are antagonized by activities of another member of the Myc superfamily, Mad. Characterization of the mouse homolog of human mad on the structural level revealed that domains shown previously to be required in the human protein for anti-Myc repression, sequence-specific DNA-binding activity, and dimerization with its partner Max are highly conserved. Conservation is also evident on the biological level in that both human and mouse mad can antagonize the ability of c-myc to cooperate with ras in the malignant transformation of cultured cells. An analysis of c-myc and mad gene expression in the developing mouse showed contrasting patterns with respect to tissue distribution and developmental stage. Regional differences in expression were more striking on the cellular level, particularly in the mouse and human gastrointestinal system, wherein c-Myc protein was readily detected in immature proliferating cells at the base of the colonic crypts, while Mad protein distribution was restricted to the postmitotic differentiated cells in the apex of the crypts. An increasing gradient of Mad was also evident in the more differentiated subcorneal layers of the stratified squamous epithelium of the skin. Together, these observations support the view that both downregulation of Myc and accumulation of Mad may be necessary for progression of precursor cells to a growth-arrested, terminally differentiated state.

Animals↗
PubMed1995

An amino-terminal domain of Mxi1 mediates anti-Myc oncogenic activity and interacts with a homolog of the yeast transcriptional repressor SIN3.

Documented interactions among members of the Myc superfamily support a yin-yang model for the regulation of Myc-responsive genes in which transactivation-competent Myc-Max heterodimers are opposed by repressive Mxi1-Max or Mad-Max complexes. Analysis of mouse mxi1 has led to the identification of two mxi1 transcript forms possessing open reading frames that differ in their capacity to encode a short amino-terminal alpha-helical domain. The presence of this segment dramatically augments the suppressive potential of Mxi1 and allows for association with a mammalian protein that is structurally homologous to the yeast transcriptional repressor SIN3. These findings provide a mechanistic basis for the antagonistic actions of Mxi1 on Myc activity that appears to be mediated in part through the recruitment of a putative transcriptional repressor.

Amino Acid Sequence↗
PubMed1995

Toxicity, biodistribution and radioprotective capacity of L-homocysteine thiolactone in CNS tissues and tumors in rodents: comparison with prior results with phosphorothioates.

L-Homocysteine thiolactone (L-HCTL) was evaluated for its potential as an intravenously-administered central nervous system (CNS) radioprotector in C3H mice and F344 rats. Toxicity assessments in the mouse yielded a LD50 of 297 mg/kg and in the rat 389 mg/kg. Biodistribution studies in tumor-bearing mice showed that brain specimens contained more label at 10 min than the tumors but less at 30 or 60 min. Brain uptake relative to the tumors, the brain/tumor ratio, ranged between 0.5 and 3.3. The cervical spinal cord of non-tumor-bearing rats was irradiated with 32 Gy 137Cs with or without prior treatment with L-HCTL following which the time to forelimb or hindlimb paralysis was measured to determine the relative protective factors (RPFs) for this radiation dose. For forelimb paralysis the RPF was 1.9 (+/- 1.0, SD) and for hindlimb it was 2.0 (+/- 1.1, SD). 36B-10 glioma cells irradiated in vitro with or without L-HCTL and assayed for colony forming capacity demonstrated a dose modifying factor (DMF) of only 1.15 (+/- 0.16, SE). Rats bearing intracerebral 36B-10 glioma received 137Cs irradiation with or without L-HCTL after which the tumors were similarly assayed in vitro. From this the glioma DMF was 1.2 (+/- 0.30, SE). Compared to prior results with phosphorothioates our data show that the toxicity of L-HCTL is roughly the same as WR2721, WR77913 and WR3689 and that it distributes at higher levels in the CNS after systemic administration. L-HCTL may well equal these phosphorothioates at protecting normal CNS tissue without requiring administration directly into the cerebrospinal fluid-containing spaces and it does not protect the 36B-10 glioma.

Amifostine↗
PubMed1995

Hereditary adult-onset Alexander's disease with palatal myoclonus, spastic paraparesis, and cerebellar ataxia.

We describe a progressive neurologic disorder in three sisters characterized clinically by palatal myoclonus, spastic weakness, hyperreflexia, mild cerebellar dysfunction, and ocular motor abnormalities. Postmortem examination of one patient demonstrated widespread Rosenthal fiber deposition associated with demyelination. The father previously was reported to have similar pathologic findings and carried a clinical diagnosis of multiple sclerosis. These clinical and pathologic findings describe a rare familial leukodystrophy that corresponds most closely to cases reported as adult Alexander's disease. Although similar pathologically to the well-characterized infantile variant of Alexander's disease, it is not known whether this adult variant represents the same disease process.

Adult↗
PubMed1994

Immunocytochemical characterization of intrarenal adrenal tissue.

Heterotopic adrenal tissue has been reported in multiple sites, but its functionality has seldom been assessed. In this case, immunocytochemistry was used to characterize adrenocortical tissue present in the subcapsular region of a nephrectomy specimen and to determine its potential for steroidogenesis. Immunodetectable cytochrome P450scc was detectable in the adrenal gland, but not in the renal tissue, clarifying the demarcation between the two tissue types. The high level of this key enzyme in steroid synthesis in the adrenocortical cells suggested that they were capable of producing steroids.

Adrenal Cortex↗
PubMed1994

Concomitant boron-neutron capture therapy during fast-neutron irradiation of a rat glioma.

PURPOSE: Fast-neutron irradiation and boron-neutron capture therapy (BNCT) have been independently investigated as treatments for malignant disease. This study tested the feasibility of enhancing fast-neutron irradiation with concomitant BNCT. MATERIALS AND METHODS: Seventeen male Fisher rats, each weighing 180-200 g and bearing 36B10 gliomas, were irradiated with graded doses of fast-neutron radiation. Half of the animals received an L-para-boronophenylalanine (BPA) fructose complex prior to treatment. An in vitro colony-forming assay was used to measure surviving fraction. RESULTS: A significantly lower surviving fraction was noted in the tumors from the BPA group compared with those receiving neutrons alone at the three lower neutron doses (P < .005). With use of a linear quadratic curve fit of cell survival, the dose modifying factor was 1.32 at the 0.10 surviving fraction. Mean tumor boron concentration was 68.4 micrograms/g. CONCLUSIONS: BNCT enhancement of fast-neutron irradiation is feasible in an in vivo tumor system.

Animals↗
PubMed1994

CFTR expression and chloride secretion in polarized immortal human bronchial epithelial cells.

A major limitation in the study of vectorial ion transport, secretion, and differentiated function in the human airway epithelium has been the lack of suitable cell culture systems. Progress in this direction has been made through the transformation of primary cultured epithelial cells. However, these transformants tend to lose differentiated properties with increasing serial passage, particularly following crisis. The successful establishment of a postcrisis SV40 large T-antigen transformed epithelial cell line derived from human bronchial epithelium is described. This cell line, 16HBE14o-, retains differentiated epithelial morphology and functions. Cell cultures show the presence of tight junctions and cilia, and monolayers generate transepithelial resistance, as measured in Ussing chambers, and retain beta-adrenergic stimulation of cAMP-dependent chloride ion transport, measured either by 36Cl- efflux or as short-circuit current in Ussing chambers. The cells also increase chloride transport in response to bradykinin or calcium ionophore. In addition, 16HBE14o- cells express levels of both the cystic fibrosis transmembrane conductance regulator (CFTR) mRNA and protein readily detectable by Northern and Western hybridization analysis, respectively. These cells provide a valuable resource for studying the modulation of CFTR and its role in regulation of chloride ion transport in human airway epithelium as well as other aspects of human airway cell biology.

Bronchi↗
PubMed1994

Evolutionary relationships and functional conservation among vertebrate Max-associated proteins: the zebra fish homolog of Mxi1.

In mammals, current evidence supports the view that Myc-responsive activities are regulated in part through an intracellular balance between levels of transcriptionally-active Myc/Max heterodimers and those of transcriptionally-inert Max/Max, Mad/Max and Mxi1/Max complexes. To gain insight into the roles of Mad and Mxi1 in cellular growth and differentiation and to fortify key structure-function relationships from an evolutionary standpoint, low stringency hybridization screens were used to identify potential homologs of these Max-associated proteins in the zebra fish genome. A single class of cDNA clones that cross-hybridized both to human mad and mxi1 probes was shown to encode a putative protein with significantly greater homology to mammalian Mxi1 than to Mad, particularly in the basic and helix-loop-helix (bHLH) regions. The high degree of structural relatedness between vertebrate Mxi1 proteins apparent in molecular modelling studies was consistent with the findings that the HLH/leucine zipper (LZ) region of zMxi1 exhibited the same profile of dimerization specificities as its mammalian counterpart in the two-hybrid system and that zmxi1 could, like human mxi1 (Lahoz et al., 1994), suppress the oncogenic potential of mouse c-myc in a mammalian cell. Finally, a comparison of steady-state zc-myc and zmxi1 mRNA levels during zebra fish embryogenesis demonstrated (i) high levels of zc-myc relative to zmxi1 mRNA during initiation of organogenesis, a period characterized by intense growth and active differentiation and (ii) rising levels of zmxi1 mRNA during progression towards the terminally differentiated state. These contrasting patterns of developmental expression together with the capacity of zmxi1 to repress myc-induced transformation support a model for the regulation, by Max-associated proteins, of Myc functions in the control of normal cell development and neoplastic growth.

Amino Acid Sequence↗
PubMed1994

A fentanyl epidemic in Maryland 1992.

In early 1992, the Office of the Chief Medical Examiner, State of Maryland, encountered 30 cases where fentanyl was identified in the postmortem specimens. Twenty-five of the decedents were found in Baltimore City and five were found in the surrounding counties. Four of the decedents were female and eight of the victims were white. The blood fentanyl concentrations ranged from 2.2 to 100 micrograms/L. Ethanol and other abused drugs were detected in 28 of these cases. The cause of death in all cases was ethanol-, drug intoxication, or both.

Adult↗