Biomedical subjects

Hong Zhang

Publications and source records attributed to Hong Zhang.

At least 199 records · Page 11Linked to original sources

PubMed2005

Mechanism and modification of gastrointestinal soft tissue response to radiation: role of growth factors.

PURPOSE: The negative effects of radiation on the bowel critically limit the treatment doses possible for tumors in the abdomen. The purpose of the present study was to measure mRNA levels of inflammatory cytokines in abdominally irradiated mouse bowel. METHODS AND MATERIALS: Eight- to 12-week-old DBA mice were irradiated to the whole bowel in single fractions of 0 (mock irradiation), 12.5, or 13.5 Gy, and sacrificed 18-25 weeks thereafter. Gross bowel reactions were scored for bowel retraction, bowel wall thickening, mesenteric telangiectasia, and petechia. Tissues were snap frozen and processed for RNase protection assay or reverse transcription polymerase chain reaction assay, or both. Transforming growth factor beta1 (TGFbeta1), TGFbeta2, TGFbeta3, tumor necrosis factor alpha, interleukin-6, and interferon gamma mRNA were measured. RESULTS: Radiation at 12.5 Gy and at 13.5 Gy produced significant bowel damage. Levels of all cytokines in irradiated mice were significantly increased (p < 0.05). CONCLUSIONS: Late radiation-related bowel fibrovascular toxicity includes cytokine signal pathways that parallel those of many other normal tissues. These cytokine responses include elevations of tumor necrosis factor alpha, TGFbeta1, and interleukin-6. There exist approaches for lowering these cytokine levels that do not also protect tumor, and thus a therapeutic gain is expected. Opportunities to use these cytokine measurements both to predict clinical toxicity and to develop interventions are discussed.

Animals↗

PubMed2005

Cost-effectiveness of enfuvirtide in treatment-experienced patients with advanced HIV disease.

OBJECTIVE: Enfuvirtide (ENF) has been shown to improve short-term virologic responses when given to highly treatment-experienced patients with advanced HIV disease. Because of the high cost of ENF compared with other antiretroviral agents, our objectives were to determine the potential long-term clinical impact and cost-effectiveness of ENF in these patients. METHODS: We used a computer simulation model of HIV disease to project life expectancy, quality-adjusted life expectancy, cost, and cost-effectiveness of ENF in treatment-experienced patients. Input data were from the T-20 versus Optimized Regimen Only (TORO) 1 and 2 trials, 2 studies comparing ENF plus an optimized background regimen (OBR) with an OBR alone. RESULTS: ENF plus an OBR increased projected discounted quality-adjusted life expectancy from 45.4 months with an OBR alone to 54.9 months, a difference of 9.5 quality-adjusted life-months. At the current annual ENF cost of US 18,500 dollars per year (in 2001 US dollars), the incremental cost-effectiveness ratio for ENF plus an OBR was US 69,500 dollars per quality-adjusted life-year (QALY) compared with an OBR alone. When 48-week virologic suppression rates for ENF plus an OBR were varied from a 50% reduction to a 250% increase in the suppression rate attributable to ENF, gains in quality-adjusted life expectancy ranged from 4.5 to 25.9 quality-adjusted life-months compared with an OBR alone, with cost-effectiveness ratios ranging from US 97,900 dollars per QALY to US 52,300 dollars per QALY gained. If ENF is continued after the HIV RNA level returns to the pretreatment baseline, the cost-effectiveness ratio increases to US 168,200 dollars per QALY. CONCLUSIONS: In highly treatment-experienced patients, ENF plus an OBR provides substantial gains in quality-adjusted life expectancy compared with an OBR alone. Although ENF plus an OBR is less cost-effective than other commonly used interventions in HIV disease, its use may be justified, given the poor prognosis of these patients and their otherwise limited options for antiretroviral therapy.

Adult↗

PubMed2005

Femtosecond excited state studies of the two-center three-electron bond driven twisted internal charge transfer dynamics in 1,8-bis(dimethylamino)naphthalene.

Femtosecond fluorescence upconversion and transient absorption experiments have been performed to monitor the photoinduced electronic, geometry, and solvent relaxation dynamics of 1,8-bis(dimethylamino)naphthalene dissolved in methylcyclohexane or n-hexane, n-dodecane, dichloromethane, and acetonitrile. The data have been analyzed by using a sequential global analysis method that gives rise to species associated difference spectra. The spectral features in these spectra and their dynamic behavior enable us to associate them with specific processes occurring in the molecule. The experiments show that the internal charge-transfer lpi* state is populated after internal conversion from the 1La state. In the lpi state the molecule is concluded to be subject to a large-amplitude motion, thereby confirming our previous predictions that internal charge transfer in this state is accompanied by the formation of a two-center three-electron bond between the two nitrogen atoms. Solvent relaxation and vibrational cooling in the lpi* state cannot be separated in polar solvents, but in apolar solvents a distinct vibrational cooling process in the lpi* state is discerned. The spectral and dynamic characteristics of the final species created in the experiments are shown to correspond well with what has been determined before for the relaxed emissive lpi state.

1-Naphthylamine↗

PubMed2005

Identification of adipocyte adhesion molecule (ACAM), a novel CTX gene family, implicated in adipocyte maturation and development of obesity.

Few cell adhesion molecules have been reported to be expressed in mature adipocytes, and the significance of cell adhesion process in adipocyte biology is also unknown. In the present study, we identified ACAM (adipocyte adhesion molecule), a novel homologue of the CTX (cortical thymocyte marker in Xenopus) gene family. ACAM cDNA was isolated during PCR-based cDNA subtraction, and its mRNA was shown to be up-regulated in WATs (white adipose tissues) of OLETF (Otsuka Long-Evans Tokushima fatty) rats, an animal model for Type II diabetes and obesity. ACAM, 372 amino acids in total, has a signal peptide, V-type (variable) and C2-type (constant) Ig domains, a single transmembrane segment and a cytoplasmic tail. The amino acid sequence in rat is highly homologous to mouse (94%) and human (87%). ACAM mRNA was predominantly expressed in WATs in OLETF rats, and increased with the development of obesity until 30 weeks of age, which is when the peak of body mass is reached. Western blot analysis revealed that ACAM protein, approx. 45 kDa, was associated with plasma membrane fractions of mature adipocytes isolated from mesenteric and subdermal adipose deposits of OLETF rats. Up-regulation of ACAM mRNAs in obesity was also shown in WATs of genetically obese db/db mice, diet-induced obese ICR mice and human obese subjects. In primary cultured mouse and human adipocytes, ACAM mRNA expression was progressively up-regulated during differentiation. Several stably transfected Chinese-hamster ovary K1 cell lines were established, and the quantification of ACAM mRNA and cell aggregation assay revealed that the degree of homophilic aggregation correlated well with ACAM mRNA expression. In summary, ACAM may be the critical adhesion molecule in adipocyte differentiation and development of obesity.

Adipocytes↗

PubMed2005

[Acetabular retroversion in hip dysplasia].

OBJECTIVE: To study the occurrence and radiograph features of the acetabular retroversion in hip dysplasia, and to evaluate the effects on the retroversion by the traditional maneuvers in the periacetabular osteotomy. METHODS: Bernese periacetabular osteotomy was performed to 45 continuous dysplastic hips (43 patients) from December 2001 to November 2003. There were 37 female (39 hips) and 6 male (6 hips), average age was 28.9 (range, 15-45). The diagnosis of acetabular retroversion was based on the "cross-over" and "posterior wall" signs on the standard radiographs of the patients pre- or postoperatively. RESULTS: Among total 45 hips, the "cross-over" sign was positive in 8 hips, whereas including the "posterior wall" sign positive in 5 hips. The occurrence of retroversion was 17.8%. And the cross-over points were located within the superior 1/3 of the acetabulums in all cases. After the osteotomy, all the cross-over points moved to the inferior 1/3 of the acetabulums, and the "posterior wall" sign was seen in all 8 cases. CONCLUSIONS: Approximately one sixth of the patients with acetabular dysplasia have retroversion in which the superior 1/3 of the acetabulum faces posterolaterally. The retroversion can be identified with the standard AP pelvic radiographs. With the traditional maneuvers in periacetabular osteotomy, the retroversion will be aggravated in these patients.

Acetabulum↗

PubMed2005

Relationships of tumor inflammatory infiltration and necrosis with microsatellite instability in colorectal cancers.

AIM: The relationships between microsatellite instability (MSI) and survival in colorectal cancer patients are not consistent. The favorable survival of patient with MSI has been suggested to be related to pronounced inflammatory infiltration; however, the reason for non-association of MSI with survival is unclear. Our aims were to investigate the associations of inflammatory infiltration and tumor necrosis (TN) with microsatellite status and clinicopathological factors in colorectal cancer patients in whom MSI was not related to survival. METHODS: Three hundred and one colorectal adenocarcinomas were evaluated for inflammatory infiltration and 300 for TN under light microscope. RESULTS: Low infiltration at invasive margin (chi2 = 3.94, P = 0.047) and in whole tumor stroma (chi2 = 3.89, P = 0.049) was associated with MSI, but TN was not (chi2=0.10, P = 0.75). Low infiltration was related to advanced stage (chi2 = 8.67, P = 0.03), poorer differentiation (chi2 = 8.84, P = 0.03), DNA non-diploid (chi2 = 10.04, P = 0.002), higher S-phase fraction (chi2 = 11.30, P = 0.004), positive p53 expression (chi2 = 7.94, P = 0.01), and worse survival (P = 0.03 for both univariate and multivariate analyses). Abundant TN was related to advanced stage (chi2 = 17.74, P = 0.001) and worse survival (P = 0.02 for univariate, and P = 0.05 for multivariate analysis). CONCLUSION: The result that high inflammatory infiltration was not related to MSI might help explain the non-association of MSI with survival in colorectal cancer patients.

Adenocarcinoma↗

PubMed2005

The conserved Mec1/Rad53 nuclear checkpoint pathway regulates mitochondrial DNA copy number in Saccharomyces cerevisiae.

How mitochondrial DNA (mtDNA) copy number is determined and modulated according to cellular demands is largely unknown. Our previous investigations of the related DNA helicases Pif1p and Rrm3p uncovered a role for these factors and the conserved Mec1/Rad53 nuclear checkpoint pathway in mtDNA mutagenesis and stability in Saccharomyces cerevisiae. Here, we demonstrate another novel function of this pathway in the regulation of mtDNA copy number. Deletion of RRM3 or SML1, or overexpression of RNR1, which recapitulates Mec1/Rad53 pathway activation, resulted in an approximately twofold increase in mtDNA content relative to the corresponding wild-type yeast strains. In addition, deletion of RRM3 or SML1 fully rescued the approximately 50% depletion of mtDNA observed in a pif1 null strain. Furthermore, deletion of SML1 was shown to be epistatic to both a rad53 and an rrm3 null mutation, placing these three genes in the same genetic pathway of mtDNA copy number regulation. Finally, increased mtDNA copy number via the Mec1/Rad53 pathway could occur independently of Abf2p, an mtDNA-binding protein that, like its metazoan homologues, is implicated in mtDNA copy number control. Together, these results indicate that signaling through the Mec1/Rad53 pathway increases mtDNA copy number by altering deoxyribonucleoside triphosphate pools through the activity of ribonucleotide reductase. This comprises the first linkage of a conserved signaling pathway to the regulation of mitochondrial genome copy number and suggests that homologous pathways in humans may likewise regulate mtDNA content under physiological conditions.

Cell Cycle Proteins↗

PubMed2005

[Relationships between circulating matrix metalloproteinase-1, -2 and metalloproteinase-1 levels and bone biochemical markers and bone mineral density in Chinese postmenopausal women].

OBJECTIVE: To study the serum matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-2 (MMP-2), and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels, and the correlations of MMP-1, MMP-2, and TIMP-1 with bone turn-over markers and bone mineral density (BMD) in aged postmenopausal Chinese women. METHODS: The serum MMP-1, MMP-2, TIMP-1, serum bone alkaline phosphatase (BAP), serum osteocalcin (OC), serum cross-linked N-telopeptides of type I collagen (NTX) of 297 Chinese female volunteers aged 48 - 89 were measured using ELISA. BMD were measured using dual energy X-ray absorptiometry in aged postmenopausal Chinese women. RESULTS: (1) There were no significant negative relationships between MMP-1, TIMP-1 and BMD and bone biochemical markers. (2) A weak negative relationships were found between MMP-2 and BMD. Adjusted by age and body weight, the correlation of MMP-2 with BMD of neck of femur and hip disappeared. (3) Positive correlations between MMP-2 and BAP, OC, NTX was found (all r = 0.193, 0.231, 0.249, P < 0.01) (4) Serum MMP-2 concentrations were significantly higher in postmenopausal women with osteoporosis (1466 microg/L +/- 313 microg/L) than in age-matched normal controls (1222 microg/L +/- 243 microg/L) and osteopenia subjects (1282 microg/L +/- 220 microg/L). CONCLUSION: There are significant correlations between serum MMP-2 and bone metabolism, and MMP-2 may increase with increases in bone-turnover. The increases of serum MMP-2 appear possibly as a concomitant event in high bone turnover state, such as postmenopausal osteoporosis.

Aged↗

PubMed2005

A comprehensive update of the sequence and structure classification of kinases.

BACKGROUND: A comprehensive update of the classification of all available kinases was carried out. This survey presents a complete global picture of this large functional class of proteins and confirms the soundness of our initial kinase classification scheme. RESULTS: The new survey found the total number of kinase sequences in the protein database has increased more than three-fold (from 17,310 to 59,402), and the number of determined kinase structures increased two-fold (from 359 to 702) in the past three years. However, the framework of the original two-tier classification scheme (in families and fold groups) remains sufficient to describe all available kinases. Overall, the kinase sequences were classified into 25 families of homologous proteins, wherein 22 families (approximately 98.8% of all sequences) for which three-dimensional structures are known fall into 10 fold groups. These fold groups not only include some of the most widely spread proteins folds, such as the Rossmann-like fold, ferredoxin-like fold, TIM-barrel fold, and antiparallel beta-barrel fold, but also all major classes (all alpha, all beta, alpha+beta, alpha/beta) of protein structures. Fold predictions are made for remaining kinase families without a close homolog with solved structure. We also highlight two novel kinase structural folds, riboflavin kinase and dihydroxyacetone kinase, which have recently been characterized. Two protein families previously annotated as kinases are removed from the classification based on new experimental data. CONCLUSION: Structural annotations of all kinase families are now revealed, including fold descriptions for all globular kinases, making this the first large functional class of proteins with a comprehensive structural annotation. Potential uses for this classification include deduction of protein function, structural fold, or enzymatic mechanism of poorly studied or newly discovered kinases based on proteins in the same family.

Algorithms↗

PubMed2005

Activated Ras enhances insulin-like growth factor I induction of vascular endothelial growth factor in prostate epithelial cells.

Mutations in the three closely related RAS genes, HRAS, KRAS, and NRAS are among the most common mutations found in human cancer; reaching 50% in some types of cancer, such as colorectal carcinoma, and 10% in prostate cancers. The activated Ras proteins produced by these mutations can, among other cellular changes, increase vascular endothelial growth factor (VEGF) production. Moreover, tumors bearing RAS gene mutations are more vascular than tumors without RAS mutations. We find that, in prostate epithelial cells, the introduction of an activated HRAS causes cells to produce VEGF in response to insulin-like growth factor I (IGF-I). In comparison, cells lacking an activated Ras are unable to produce VEGF in response to IGF-I. This effect of Ras may occur through stabilization of a second messenger protein, insulin receptor substrate 1, that mediates PI 3-kinase-dependent signaling. Because IGF-I is a paracrine/endocrine hormone that has been associated with increased risk for several types of cancer, these results suggest a novel interrelationship between oncogenic conversion of a cellular gene such as HRAS, and IGF-I produced locally for normal tissue homeostasis.

Cell Line, Tumor↗

PubMed2005

Clinical phenotype and prevalence of hereditary nonpolyposis colorectal cancer syndrome in Chinese population.

AIM: To describe systematically the clinical characteristics and phenotype of HNPCC families and the prevalence of HNPCC in the general population of CRC patients in China. METHODS: HNPCC kindreds and CRC patients were from two sources. One was that we consecutively investigated kindreds and patients by ourselves. And the other was the published Chinese and foreign literature related to Chinese HNPCC syndrome. There were 142 HNPCC families fulfilling AC I and/or AC II including 57 families with detailed data, and 3874 general primary CRC patients in all. All statistical tests were two-sided. RESULTS: In AC I families, the number of Lynch syndrome I and II families were 25 (47.2%) and 28 (52.8%) respectively. There were 215 patients (82.4%) with CRC, 67 patients (25.7%) with extracolonic cancer and 50 patients (19.2%) with multiple primary cancers. In all CRC patients, multiple primary CRC were in 41 patients (19.1%), and the first-CRC was right-sided colorectal cancer in 143 patients (66.5%) and rectal cancer in 44 patients (20.5%). 8.8% and 19.2% of the first cancer were CRC and extracolonic cancers. Among those patients whose first cancer was CRC, 66.8% and 19.9% were right-sided colorectal cancer and rectal cancer, respectively. The similar results were found in AC II families. Normal distribution was only found in the distribution of the age of diagnosis of the first cancer in both AC I families (coefficient of skewness: u = 0.81, 0.20<0.40 0.5>0.20; coefficient of kurtosis: u = 0.84, 0.20<0.40<P<0.50, alpha = 0.20), but not found in the distribution of the age of diagnosis of the first CRC. When patients with HNPCC-associated cancer suffered from the first malignant tumor in HNPCC families diagnosed by AC I and AC II, the mean age and median age were 45.1+/-12.7 years and 44.0 years, 45.2+/-12.7 years and 44.5 years, respectively. The median age of diagnosis of the first tumor of the patients in the later generation was younger than that in the previous generation. Many extracolonic cancers were found to be associated with HNPCC syndrome. Gastric cancer was the most frequent extracolonic cancer followed by endometrial cancer and hepatocarcinoma. In general population of CRC patients, the prevalence of HNPCC diagnosed by AC I and AC II were 1.3% and 2.2%, respectively. CONCLUSION: The clinical phenotype and prevalence of Chinese HNPCC syndrome are similar to those of Europeans and Americans. Gastric cancer is the most common extracolonic malignant tumor. The age of diagnosis of the first malignant tumor tends to be increasingly younger in patients with HNPCC-related tumors.

Adolescent↗

PubMed2005

In vitro resistance to the CSalphabeta-type antimicrobial peptide ASABF-alpha is conferred by overexpression of sigma factor sigB in Staphylococcus aureus.

OBJECTIVES: ASABF (Ascaris suum antibacterial factor) is a CSalphabeta-type antimicrobial peptide isolated from nematodes. ASABF-alpha, a member of ASABF, is particularly effective against the gram-positive pathogen Staphylococcus aureus. In this study, we investigated the role of sigB expression on ASABF-resistance in S. aureus. METHODS: Based on preliminary characterization of the ASABF-resistant strain, Mu50, we speculated that the alternative sigma factor sigB may regulate resistance against antimicrobial peptides. To test this hypothesis, the ASABF susceptibility was compared between NKSB (a sigB-knockout derivative of N315) and its sigB-overexpressing derivative. In addition, similar experiments were carried out for N315ex, a deletion mutant of N315 for SCCmec (Staphylococcus cassette chromosome mec) which contains essential genes for beta-lactam resistance. RESULTS: The sigB-overexpressing NKSB acquired an increased resistance to ASABF-alpha compared with the parent strain. The sigB-induced ASABF-alpha resistance was also observed in N315ex. CONCLUSIONS: The overexpression of sigB confers resistance to the antimicrobial peptide, ASABF-alpha. SCCmec is not essential for this resistance.

Animals↗

PubMed2005

Recombinant human bone morphogenic protein-2-enhanced anterior spine fusion without bone encroachment into the spinal canal: a histomorphometric study in a thoracoscopically instrumented porcine model.

STUDY DESIGN: A thoracoscopically assisted 5-level anterior spinal fusion and instrumentation model analyzing new bone formation when using recombinant human bone morphogenic protein-2 (rhBMP-2) with a collagen hydroxyapatite-tricalcium phosphate (HA/TCP) composite sponge carrier. OBJECTIVE: To determine whether new bone formation extends beyond the posterior confines of the vertebral body encroaching into the spinal canal when rhBMP-2 is used to enhance anterior fusion. SUMMARY OF BACKGROUND DATA: A possible concern regarding the use of rhBMP-2 to enhance spinal fusion is the risk of unwanted bone formation leading to inadvertent fusion of adjacent levels or compression of neural elements. The safety of rhBMP-2 in one spinal application does not ensure similar results in other applications. Therefore, the expanded use of rhBMP-2 should occur only after carefully monitored preclinical and clinical studies for each new application. METHODS: Eighteen pigs underwent thoracoscopically-assisted instrumentation and fusion of 5 contiguous levels (T5-T10) and randomly assigned to 4 treatment groups: group 1 (n = 6): rh-BMP-2 on a HA/TCP-collagen sponge (Medtronic Sofamor Danek, Memphis, TN); group 2 (n = 4): iliac crest autograft; group 3 (n = 4): empty; group 4 (n = 4): HA/TCP-collagen sponge (Medtronic Sofamor Danek) only. In groups 1 and 4, the HA/TCP collagen sponge was morselized into small granules and pushed through a bone delivery funnel for implantation into the disc. At 4 months after surgery, spines were sectioned longitudinally through the midsagittal plane and underwent undecalcified processing. Bone formation extending beyond the margins of the original discectomy and the confines of vertebral body were evaluated histomorphometrically at each operative level. RESULTS: Recombinant human bone morphogenic protein-2 on a HA/TCP-collagen sponge induced significant new bone formation extending anterior to the confines of the vertebral body compared with the other treatment groups (P < 0.05). In addition, rhBMP-2 on a HA/TCP-collagen sponge induced significant new bone formation extending posterior to the original margins of the discectomy (P < 0.05). However, there was no new bone formation beyond the confines of the posterior vertebral body. The total bone volume in the rhBMP-2-HA/TCP-collagen sponge group was significantly greater compared with all other groups in both the discectomy fusion area and beyond the discectomy area (P < 0.05). CONCLUSIONS: Recombinant human bone morphogenic protein-2 on a HA/TCP-collagen sponge enhanced anterior spinal fusion and induced significant new bone formation extending beyond the margins of the original discectomy and anterior vertebral body, most likely secondary to migration of some morselized carrier fragments from the disc space. However, the new bone formation did not extend beyond the posterior confines of the vertebral body to encroach into the spinal canal because of the intact posterior anulus and/or posterior longitudinal ligament.

Animals↗

PubMed2005

Expanded screening for HIV in the United States--an analysis of cost-effectiveness.

BACKGROUND: Although the Centers for Disease Control and Prevention (CDC) recommend routine HIV counseling, testing, and referral (HIVCTR) in settings with at least a 1 percent prevalence of HIV, roughly 280,000 Americans are unaware of their human immunodeficiency virus (HIV) infection. The effect of expanded screening for HIV is unknown in the era of effective antiretroviral therapy. METHODS: We developed a computer simulation model of HIV screening and treatment to compare routine, voluntary HIVCTR with current practice in three target populations: "high-risk" (3.0 percent prevalence of undiagnosed HIV infection; 1.2 percent annual incidence); "CDC threshold" (1.0 percent and 0.12 percent, respectively); and "U.S. general" (0.1 percent and 0.01 percent). Input data were derived from clinical trials and observational cohorts. Outcomes included quality-adjusted survival, cost, and cost-effectiveness. RESULTS: In the high-risk population, the addition of one-time screening for HIV antibodies with an enzyme-linked immunosorbent assay (ELISA) to current practice was associated with earlier diagnosis of HIV (mean CD4 cell count at diagnosis, 210 vs. 154 per cubic millimeter). One-time screening also improved average survival time among HIV-infected patients (quality-adjusted survival, 220.7 months vs. 219.8 months). The incremental cost-effectiveness was 36,000 dollars per quality-adjusted life-year gained. Testing every five years cost 50,000 dollars per quality-adjusted life-year gained, and testing every three years cost 63,000 dollars per quality-adjusted life-year gained. In the CDC threshold population, the cost-effectiveness ratio for one-time screening with ELISA was 38,000 dollars per quality-adjusted life-year gained, whereas testing every five years cost 71,000 dollars per quality-adjusted life-year gained, and testing every three years cost 85,000 dollars per quality-adjusted life-year gained. In the U.S. general population, one-time screening cost 113,000 dollars per quality-adjusted life-year gained. CONCLUSIONS: In all but the lowest-risk populations, routine, voluntary screening for HIV once every three to five years is justified on both clinical and cost-effectiveness grounds. One-time screening in the general population may also be cost-effective.

Anti-Retroviral Agents↗

PubMed2005

A unified mode of epigenetic gene silencing: RNA meets polycomb group proteins.

Recently, an essential role for RNA in the epigenetic silencing of genes packaged within heterochromatin in animals has been recognized. The RNA appears to be involved in targeting chromatin remodeling activity to a specific locus and in later maintaining the repressed state of the gene. Epigenetic silencing of Hox cluster genes by the Polycomb group proteins also involves the formation of a stably inherited repressive chromatin structure. Recent studies of the C. elegans PcG gene sop-2 reveled an evolutionarily conserved property of PcG proteins in the binding of RNA, suggesting an important role for RNA in PcG-mediated Hox gene repression.

Animals↗

PubMed2005

EPIMHC: a curated database of MHC-binding peptides for customized computational vaccinology.

SUMMARY: EPIMHC is a relational database of MHC-binding peptides and T cell epitopes that are observed in real proteins. Currently, the database contains 4867 distinct peptide sequences from various sources, including 84 tumor-associated antigens. The EPIMHC database is accessible through a web server that has been designed to facilitate research in computational vaccinology. Importantly, peptides resulting from a query can be selected to derive specific motif-matrices. Subsequently, these motif-matrices can be used in combination with a dynamic algorithm for predicting MHC-binding peptides from user-provided protein queries. AVAILABILITY: The EPIMHC database server is hosted by the Dana-Farber Cancer Institute at the site http://immunax.dfci.harvard.edu/bioinformatics/epimhc/

Database Management Systems↗

PubMed2005

Expression profiles of Id1 and p16 proteins in all-trans-retinoic acid-induced apoptosis and cell cycle re-distribution in melanoma.

All-trans-retinoic acid (atRA) exerts its effects via apoptosis and cell cycle re-distribution. However, the mechanisms behind the effects have not been fully understood. In this study, we used a model system of matched primary and metastatic melanoma cells to investigate whether expression of Id1 and p16 proteins were involved in atRA-induced apoptosis and cell cycle re-distribution. Melanoma cells were exposed to 0.1 or 10 microM atRA for 1-96 h. Apoptosis and cell cycle were measured by flow cytometry. Expression of Id1 and p16 proteins was examined by Western blotting and immunocytochemistry. After exposure to atRA we found a marked increase in apoptosis and cell cycle re-distribution in both primary and metastatic melanoma cells. Expression level of Id1 protein was decreased and the p16 was increased in a dose- and time-dependent (P<0.05) manner after treatment with atRA. Alterations of these proteins were more pronounced in the primary melanoma cells than the matched metastases (P<0.05). These data suggested that the alterations of Id1 and/or p16 proteins were involved in atRA-induced apoptosis and cell cycle re-distribution in melanoma. These expression profiles of Id1 and p16 proteins may provide molecular evidence for better chemotherapy primarily for early stages of melanoma.

Antineoplastic Agents↗

PubMed2005

Sperm dysfunction in the Rb(6.16)- and Rb(6.15)-bearing mice revisited: involvement of Hyalp1 and Hyal5.

Earlier we showed that Sperm adhesion molecule1 (Spam1), the best studied sperm hyaluronidase, is involved in the sperm dysfunction associated with Robertsonian translocations (Rb). The dysfunction results in reduced fertility in mice homozygous for the Rb(6.16) or the Rb(6.15) translocation and transmission ratio distortion (TRD) in heterozygous males. This conclusion was based on the finding that Spam1 in the Rbs harbors multiple point mutations and a genomic alteration at the locus [in the case of Rb(6.16)]; and is accompanied by reduced steady-state levels of the RNA and protein. Here we show that closely linked family members in the hyaluronidase gene cluster on mouse chromosome 6, Hyalp1 and Hyal5, also harbor point mutations in these Rbs, leading to nonconservative substitutions in both the encoded proteins. To test if Spam1 by itself is capable of producing TRD we analyzed the transmission of wild-type and null alleles of the gene in the progeny of carriers and show that there is no significant TRD. This lack of TRD in null carriers argues for only a contributory role of Spam1 in the TRD seen in the Rb-bearing mice, and supports the involvement of Hyalp1 and/or Hyal5 in the sperm dysfunction and the resulting TRD. It is proposed that the clustering of point mutations in all three genes results from the cumulative effect of spontaneous mutations that do not disperse in the population due to suppression of recombination that occurs at Rb junctions.

Amino Acid Sequence↗