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Biomedical subjects

Y M Yang

Publications and source records attributed to Y M Yang.

At least 37 records · Page 2Linked to original sources
PubMed1998

Absence or decreased levels of the hMLH1 protein in human gastric carcinoma cell lines: implication of hMLH1 in alkylation tolerance.

Defective hMLH1 function has been increasingly associated with acquired cellular resistance to DNA alkylation damage in human colorectal and endometrial cancer cells. To investigate the relationship between the DNA alkylation tolerance and the hMLH1 status in human gastric carcinoma cells, we determined the cellular response to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), the mutational changes, and the expression of hMLH1 in 11 human gastric carcinoma cell lines. Of 11 cell lines, 4 (SNU-5, -16, -620, and -719) were sensitive, whereas 7 (SNU-1, -216, -484, -520, -601, -638, and -668) were resistant to the cytotoxic effect of MNNG. As determined by Western analysis, it was evident that all the MNNG-resistant cell lines except one (SNU-601) produced very low or undetectable levels of hMLH1 protein compared to the MNNG-sensitive cell lines. A homozygous non-sense mutation that resulted in truncated protein was found in one MNNG-resistant cell line (SNU-1). Therefore, to determine whether the sensitivity of cells to MNNG can be restored by exogenous expression of hMLH1 protein, wild-type hMLH1 cDNA was introduced into the MNNG-resistant cells (SNU-1). The cytotoxicity test showed that expression of exogenous wild-type hMLH1 protein caused an increase in sensitivity to the cytotoxic effect of MNNG. This restoration was confirmed by an increase in the cell population containing less than the G1 amount of DNA (cell death) in the wild-type hMLH1-transfected cells, as determined by flow cytometry analysis. Together our results suggest that (1) the absence or decreased level of wild-type hMLH1 protein may be a frequent event in the human gastric carcinoma cell lines, (2) such alterations in the hMLH1 protein are closely associated with the MNNG tolerance in the human gastric carcinoma cell lines, and (3) the hMLH1 protein participates not only in the repair of DNA mismatches but also in the mechanism of escape from the cytotoxic effects of DNA alkylation damage.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Mutations of the STK11 gene in sporadic gastric carcinoma.

Gastric carcinoma may occur sporadically or in association with hereditary diseases, such as Peutz-Jehgers syndrome (PJS). The PJS gene (named STK11 or LKB1) was mapped to 19p13.3 and recently cloned. Germ-line mutations of the gene have been detected in familial PJS patients and are predicted to predispose STK11 carriers to the development of a wide range of gastrointestinal and other neoplasms. To elucidate the etiological role of the STK11 gene in sporadic gastric carcinoma tumorigenesis, we analyzed 28 gastric carcinomas (22 of intestinal type and 6 of diffuse type) for STK11 gene mutations. STK11 gene mutations were detected in 3 of 28 gastric carcinomas but were not seen in the corresponding germ-line DNA sequence. In one tumor, a missense mutation, C-to-T transition, was detected at codon 324 resulting in proline to leucine substitution; in the other two, silent mutations were detected at codons 106 and 350, respectively. While these results suggest that somatic STK11 mutations are not common in sporadic gastric carcinomas, they may occur in a subset of these tumors.

Gene Expression Regulation, Neoplastic↗
PubMed1997

BFU-E colony growth in response to hydroxyurea: correlation between in vitro and in vivo fetal hemoglobin induction.

Patients with sickle-cell anemia treated with hydroxyurea may have significant reduction in frequency and severity of pain episodes. However, previous clinical trials show a variable response to hydroxyurea. Criteria which can be used to select patients who are likely to respond to hydroxyurea treatment would be useful. Our laboratory has previously demonstrated an inverse linear relationship between the total number of burst-forming unit-erythroid (BFU-E) colonies and fetal hemoglobin levels in sickle-cell patients treated with hydroxyurea. In the present report, an in vitro cell culture system was established to evaluate the effects of hydroxyurea on BFU-E colony growth and induction of fetal hemoglobin production. Five Hb SS patients who were not previously treated with hydroxyurea and three Hb SS patients who failed to respond to hydroxyurea treatment were included in the study. The results show that the number of BFU-E colonies is decreased from 153.7 to 7.2 per 3 x 10(5) mononuclear cells, whereas fetal hemoglobin levels were increased from 5.1 to 19.4% in the presence of hydroxyurea in vitro in cultured erythroid progenitors, which were derived from 5 patients before treatment. The number of BFU-E colonies decreased from 153.7 to 2.0 per 3 x 10(5) mononuclear cells in the in vitro cultures obtained from serial peripheral blood samples over a 9- to 20-week period of oral hydroxyurea therapy. A simultaneous rise in fetal hemoglobin level from 10.2 to 28.6% in the peripheral blood over the same period of hydroxyurea therapy was also observed. Our results demonstrate that the increase in fetal hemoglobin levels in cells treated with hydroxyurea in vitro is comparable to the rise of fetal hemoglobin production following hydroxyurea therapy in these patients. On the contrary, these findings were not observed in three previously non-responsive sickle-cell patients. These results suggest that the changes in number of BFU-E colonies and fetal hemoglobin levels after in vitro exposure to hydroxyurea may be a useful approach to select sickle-cell patients who will respond to hydroxyurea therapy.

Adolescent↗
PubMed1997

Cellular uptake and antitumor activity of the new anthracycline analog DA-125 in human cancer cell lines.

To predict the clinical usefulness of DA-125, a newly developed doxorubicin analog, we compared its antitumor activity against 20 different human cancer cell lines with that of doxorubicin using the MTT in vitro chemosensitivity test. We also measured and compared the cellular uptake of this drug and doxorubicin in two cancer cell lines and their doxorubicin-resistant sublines. In the MTT test, DA-125 showed lower IC50 values than doxorubicin for 14 of 20 cell lines. DA-125 was more potent than doxorubicin for hepatocellular cancer cells with high mdr 1 expression. Among cancer cells from the stomach and colon, DA-125 was more potent than doxorubicin in 12 of 14 cell lines. We also investigated the cross-resistance of this drug with doxorubicin using four doxorubicin-resistant cancer cell sublines. Except in one cell line, there was very low cross-resistance. Cellular drug-uptake experiments were performed for two gastric cancer cell lines and their doxorubicin-resistant sublines. In this experiment, DA-125 was found to be very rapidly and completely converted to its active metabolite, M1, in the culture media. After this conversion, M1 was incorporated into these cancer cells more rapidly and reached higher intracellular concentrations than doxorubicin, suggesting that DA-125 (as M1) could achieve earlier and higher levels of intracellular accumulation than doxorubicin in its target tissues from the bloodstream. As a possible alternative antineoplastic agent to doxorubicin, DA-125 awaits further evaluation for its antitumor activity and toxicity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Mental disorders in children and adolescents with sickle cell disease.

This study compares the rate of mental disorders in children and adolescents with sickle cell disease with the rate in a corresponding control population. Using the clinical interview, a diagnosis based on DSM-III-R criteria for the presence of 13 mental disorders common to childhood was considered in a sequential sample of 39 subjects with sickle cell disease and a convenience sample of 26 same-race control subjects. Thirty-one percent of the sickle cell group and 42% of the control group screened positive for one or more of the selected mental disorders. The difference was not significant. When subgroups of mental disorders were considered (anxiety disorders, depressive disorders, disruptive behavior disorders, psychotic disorders, and other selected disorders), the differences were still not significant. This study suggests that children and adolescents with sickle cell disease do not have a greater risk for clinically significant mental disorders than same-race outpatient clinic controls. This study supports other reports in the medical literature that suggest that children attending outpatient medical clinics are at a higher risk for mental disorder than is seen in epidemiologic studies of nonmedical populations.

Adolescent↗
PubMed1997

In vitro sensitivity of Plasmodium falciparum to eight antimalarials in China-Myanmar and China-Lao PDR border areas.

In 1991-1995 by using the Rieckmann in vitro micro-method, susceptibilities of Plasmodium falciparum to eight antimalarials in the China-Lao PDR and China-Myanmar border areas were tested. The resistant rates of P. falciparum to chloroquinine were 95.0%-100%; IC50 114-240nmol/l. P. falciparum resistant rates to amodiaquine resistance accounted for 83.5%-100%, IC50 52-72nmol/l. All cases were sensitive to quinine, IC50 470-608nmol/l. P. falciparum isolates from the Lao PDR frontier were highly sensitive to artesunate, dihydroartemisinin, and arteether. Resistant rates from other areas were 0-11%. P. falciparum from China-Myanmar and Lao PDR border areas were also sensitive to mefloquine, IC50 68-88nmol/l. A longitudinal survey of the sensitivity of P. falciparum in vivo on the China-Lao PDR border showed that the average defervescent time of falciparum malaria was treated by pyronaridine increased from 32.7 +/- 16.0 hours during 1984-85 to 56.2 +/- 27.4 hours in 1995; the recrudescence rate rose up from 15.2% to 37.5%. The results monitored in vitro showed that all cases assessed in 1988 for response to pyronaridine were sensitive, but 36.4% of cases had emerging resistance, IC50 increased from 13nmol/l to 40 nmol/l. The above results suggested that P. falciparum in these areas has expressed resistance to chloroquine and amodiaquine. However, the parasites are still sensitive to artemisinin, pyronaridine, mefloquine, quinine, but with a declining sensitivities.

Amodiaquine↗
PubMed1996

Expression of dominant negative CREB reduces resistance to radiation of human melanoma cells.

u.v.-responsive element (URE)-binding proteins were found to include members of the AP1 and ATF transcription factor families. To elucidate the functional contribution of URE-bound proteins to the characteristics of human melanoma, we have used a dominant negative CREB cDNA which is mutated within the DNA-binding domain and cloned into a mammalian expression vector driven by the RSV promoter (KCREB). As such, KCREB is still capable of heterodimerizing with its associated proteins, yet, due to its poor binding affinity to DNA it out competes transcriptional activity mediated by those proteins. Human melanoma cells (MeWo) were transfected with KCREB and three clones, designated K1, K2, and K10 which express KCREB transcripts were then selected for further characterization. When tested for binding activities in gel shift assays, proteins prepared from the three clones exhibited a different set of complexes than the parent MeWo and control MeWo(neo) cells (transfected with empty expression vector) under normal growth conditions, and after u.v.-irradiation. Using CAT vector, driven by a tetramer URE construct, revealed a striking decrease in transcriptional activity in each of the three clones before as well as after u.v.-irradiation. When tested for radiation resistance MeWo cells were found to exhibit 42% survival to a u.v.-dose of 16 J/m2, whereas, K1, K2 and K10 exhibited only 10.2, 3.9 and 4.2% survival, respectively. Exposure to 2 Gy of X-radiation led to 62.1% survival of MeWo as compared with 18.5% of K1 and 7.7% and 6.5% of K2 and K10, respectively. While no significant differences were noticed in their growth rate, all three clones exhibited fewer, and smaller colonies in soft agar, when compared with parent cells. These findings indicate that through their transcriptional activities, CREB and its associated proteins play an important role in the acquisition of characteristic phenotypes of human melanoma cells including resistance to u.v.-irradiation.

Base Sequence↗
PubMed1996

Tumoral calcinosis in an infant.

We report tumoral calcinosis, an uncommon disease of uncertain origin, in an infant-only the sixth instance of the disease reported in this age group. The radiologic features are typical as illustrated by three modalities. The clinical, radiologic and pathologic features are discussed along with comments concerning possible etiologies and management.

Calcinosis↗
PubMed1996

The cytotoxicity of psoralidin from Psoralea corylifolia.

A cytotoxic coumestan derivative, psoralidin (1), was isolated from the seed of Psoralea corylifolia. The IC50 values of 1 against SNU-1 and SNU-16 carcinoma cell lines were 53 and 203 micrograms/ml, respectively, indicating cytotoxic activity against stomach carcinoma cell lines.

Antineoplastic Agents, Phytogenic↗
PubMed1995

Ultraviolet light-responsive element (TGACAACA)-binding proteins in cells of xeroderma pigmentosum patients.

The ultraviolet light (UV)-responsive element (URE) is an octamer sequence, TGACAACA, that shares homology with cyclic AMP-responsive element and activator protein 1 target sequences. Because URE-binding proteins have been shown to play a role in cellular response to DNA damage, we determined their expression and DNA-binding activities in repair-deficient cells. Of the complementation groups tested, only xeroderma pigmentosum (XP)-C cells induced expression of c-jun after UV irradiation; this correlated with XP-C binding to the URE and resembled the pattern observed with normal human fibroblasts. In other cases either a decrease (XP-A) or no change (XP-D) in URE-binding activities was noticed, which may be associated with decreased c-fos and poor c-jun expression after UV irradiation. That XP-C cells were the only complementation group exhibiting URE-binding activities similar to those of repair-proficient cells points to the possible correlation between proper repair of transcriptionally active genes and the expression and activities of proteins implicated in the cellular response to UV irradiation.

Base Sequence↗
PubMed1995

Systemic lupus erythematosus in a child with sickle cell disease.

Although sickle cell disease (SCD) and systemic lupus erythematosus (SLE) are two distinct chronic diseases, many clinical features are common to both conditions. We describe a young patient who had a mild clinical course of SCD until SLE developed when he was 15 years old. His initial manifestations of SLE including fever, chest pain, and lung infiltration with pleural effusion were thought to be complications of SCD. However, a deteriorating clinical course, presence of facial and truncal rash, and persistent pleural effusion led to the diagnosis of SLE. We compare our case and the 10 previously reported cases and discuss the possible association of complement defects and the pathogenesis of SLE in patients with SCD. Our report illustrates the importance of considering other disease processes when clinical features are atypical of SCD.

Adolescent↗
PubMed1995

Toxicity of human recombinant interferon-gamma in rats and dogs.

AIM: To study the acute and chronic toxicities of human recombinant interferon-gamma (Hu-rIFN-gamma) in mice, rats, and dogs. METHOD: Twenty mice were administrated Hu-rIFN-gamma (i.m. or i.v.) 4.4 x 10(9) IU m-2 to observe the acute toxicity. In chronic studies, 1 x 10(7), 5 x 10(7), 1 x 10(8) IU m-2 d-1 were given to 80 rats and 5 x 10(5), 5 x 10(7) IU m-2 d-1 were injected to 14 dogs i.m. for 3 months, treatment-related changes were measured in the hematologic, chemical, urinalysis values, ECG and pathologic profile of organs and tissues. RESULTS: The maximal tolerance dose (MTD) i.m. or i.v. in mice was 4.4 x 10(9) IU m-2, 4400 times the recommended clinical dosage (1 x 10(6) IU m-2). No adverse effects were found in chronic toxicity studies. CONCLUSION: Human recombinant interferon-gamma did not produce toxic reaction in rats and dogs.

Animals↗
PubMed1994

Depression in children and adolescents with sickle-cell disease.

OBJECTIVE: To look at the role of a standardized screening test for assessing depression in children and adolescents with and without sickle-cell disease and to compare findings with this instrument with clinical evaluations by child psychiatrists. In addition, to suggest the prevalence of clinical depression in children and adolescents with sickle-cell disease. DESIGN: Nonrandomized, sequential sample of subjects, convenience control sample, prevalence study using the Children's Depression Rating Scale-Revised and an interview assessment by a child psychiatrist based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. SETTING: Comprehensive Sickle Cell Center outpatient clinic and ambulatory Resident Practice Clinic at the University of South Alabama Children's Medical Center, Mobile. STUDY PARTICIPANTS: Patients aged 6 through 18 years with homozygous sickle-cell disease (hemoglobin SS) served as study subjects. Subjects of the same age and race who did not have sickle-cell disease served as controls. MEASUREMENTS AND RESULTS: The mean Children's Depression Rating Scale-Revised total scores were 27.1 and 22.1 in study and control groups, respectively (P = .0073). Eleven (29%) of 38 children in the study group had scores indicating a high risk for clinical depression. Four (12%) of 34 children in the control group were in this category. The four items accounting for most of this significant difference were excessive fatigue, physical complaints, self-esteem, and morbid ideation. This contrasted with the clinical evaluation by a child psychiatrist in a clinical interview in which 13% of study subjects and 15% of control subjects had evidence of clinical depression (P = .85). CONCLUSION: Excessive fatigue and physical complaint factors contributed to a high false-positive rate when the Children's Depression Rating Scale-Revised was used to screen for depression among patients with sickle-cell disease. Based on the clinical interview by a child psychiatrist, the actual prevalence of clinical depression was not increased in children with sickle-cell disease compared with those without this chronic illness.

Adolescent↗
PubMed1994

Relationship of burst-forming-unit-erythroid progenitors and their DNA-synthesis stage to fetal hemoglobin levels in hydroxyurea-treated patients with sickle cell anemia.

DNA-synthesis stage and total number of circulating burst-forming-units-erythroid (BFU-E) have been inversely correlated with hemoglobin F levels in the peripheral blood, as well as in the cells from the BFU-E-derived colonies obtained from homozygous sickle cell anemia (SS) patients during steady state. Similar studies in SS patients treated with cytotoxic agents have not been reported. However, regeneration of the erythroid marrow that follows the cytoreduction phase of chemotherapy has been suggested as one of the mechanisms of stimulation of fetal hemoglobin synthesis. Therefore, a longitudinal study of hemopoiesis in hydroxyurea-treated SS patients was conducted. Thirty-two sets of hemopoietic studies, including total circulating BFU-E and S-phase BFU-E, were obtained from three patients treated with hydroxyurea. A dose-dependent decrease in total BFU-E colonies occurred in peripheral blood of all three patients (r = -0.58, -0.85, and -0.97, respectively, with each P < 0.05). There was a strong positive correlation between hydroxyurea dose and fetal hemoglobin levels in two of the three patients who responded clinically (r = 0.89618 and 0.88632, respectively, with each P < 0.01). When data from all patients were combined (n = 32), there was a strong, inverse, linear relationship between total number of BFU-E and percentage S-phase BFU-E with fetal hemoglobin levels (r = -0.6649 and -0.7404, respectively, with each P < 0.0001). A stronger, curvilinear, multiple relationship was detected between total BFU-E and percentage S-phase BFU-E with fetal hemoglobin levels (R = 0.8351 and 0.8602 with each P < 0.0001).

Adolescent↗
PubMed1994

UV-responsive element (TGACAACA) from rat fibroblasts to human melanomas.

When taken together, several lines of evidence suggest that the URE-bound proteins are associated with DNA replication. (1) A trans-acting factor of 60 kDa (which may include the 68-kDa URE-binding proteins) was found to be induced by UV and to mediate polyoma DNA replication; (2) the URE was able to compete for the binding of factors that promote polyoma replication in rodent cells; (3) URE-bound proteins are expressed to a higher extent at the S phase of the cell cycle; and (4) they are induced following treatment with aphidicholin. These observations may suggest that the URE may play a role in growth "release" (as opposed to growth "arrest") which would assist in restoring normal growth following DNA damage. It is clear that URE-bound proteins consist of multiple transcription factors, some of which are well characterized (i.e., jun, CREB, and fos families); however, it is likely that the growth release phenomenon we relate to is also mediated by (1) other members of these transcription factor families which have not been identified as yet and (2) a specific combination of known transcription factors which bind to this response element under certain circumstances. This hypothesis is outlined in the enclosed model (Fig. 3).

Animals↗