Recurrent germ-line BRCA1 mutations in extended African American families with early-onset breast cancer.
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Adult↗
Biomedical subjects
Q Gao
Publications and source records attributed to Q Gao.
[Ultrastructural observation on the uncinate process of chronic sinusitis].
The ultrastructures of the uncinate processes (UP) obtainel from 16 patients with clinical diagnosis of chronic sinusitis were observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The results showed that there were three main surface cell types on the UP: Most of the cilia was leaned, fractured and in disorder; Gaps of the cells increased obviously; Squamous cell metaplasia was seen; The endoplasmic reticulums and mitochondria in cytoplasm were expanded moderatly or seriously. The morphological changes indicated that mucus transportation functions in the anterior ethmoid region and the middle meatus were damaged. It is of great importance in occurrence and development of chronic sinusitis. The demaged nasal mucosa epithlial cells are repairable and reproducible.
Adult↗
The role of interleukin-4 in the induction phase of allogeneic neonatal tolerance.
We previously reported that prolonged graft survival in neonatally tolerant mice was associated with enhanced Th2/Th1 cytokines. To determine whether Th2 CD4 cells function in tolerance, we examined whether we could prevent tolerance by blocking Th2 CD4 maturation, using anti-interleukin (IL)-4 monoclonal antibody treatment during neonatal antigen exposure. Anti-IL-4 treatment restored the ability BALB/c of mice to reject A/J skin grafts and blocked the induction of tolerance through multiple mechanisms. Anti-IL-4 treatment blocked the development of donor microchimerism and recovered the ability of mice to proliferate and to generate appropriate delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte (CTL) responses against A/J in a dose-dependent manner. Low-dose anti-IL-4 recovered DTH responses and interferon (IFN)-gamma production, but failed to completely prevent IL-4 production or to recover the CTL activity. No A/J-reactive IFN-gamma-producing CD8 cells were detected in these mice. In contrast, mice treated with higher doses of anti-IL-4 generated normal CTL responses against A/J, and contained A/J-reactive IFN-gamma-producing CD8 cells. The recovery of CTL responses and IFN-gamma-producing CD8 cells was associated with a more complete blocking of Th2 cytokine production. Therefore, the presence of IL-4 may play an important role in the induction of neonatal tolerance by shifting maturation of CD4 cells toward Th2 cells and away from Th1 cells, and also by preventing maturation of alloreactive CD8 CTL cells.
Animals↗
Characterisation of acidic heteroglycans from Tremella fuciformis Berk with cytokine stimulating activity.
Four kinds of acidic heteroglycan, T3a-T3d, were isolated from the body of the fungus Tremella fuciformis Berk. The molecular weights of T3a-T3d were 550, 420, 55, and 48 kDa, respectively. Glycosidic linkage analysis showed that they had a mannan backbone consisting of 3-linked Man p, and side chains containing glucosyl, mannosyl, fucosyl, xylosyl, and glucuronic acid residues attached through O-2, O-4, or O-6 of about half of the backbone mannosyl residues. A partial acidic hydrolysate of T3a could be divided into a low-branching region (T3a-1, 2, 3, 4) mainly branched at the 2-position of 3-linked Man p in the mannan backbone, and a high-branching region (T3a-5A) branched at the 2,4- or 2,4,6-positions of 3-linked Man p in the backbone. The low-branching region, which is predominant in the backbone, was substituted with non-reducing terminal Glc pA, Fuc p and short side chains consisting of (1-->6)-linked Glc p and (1-->2)-linked Man p linked through C-2 of the mannan backbone. The high-branching region, which is a minor component of the backbone, was linked with long side chains of (1-->6)-linked Glc p and (1-->4)-linked Glc pA in their branching points. T3a-T3d were able to induce human monocytes to produce interleukin-1, interleukin-6, and tumor necrosis factor in vitro. The different fragments of the acidic hydrolysate of T3a (T3a-1, 2, 3, 4, 5A) also induced monocytes to secret interleukin-6 with high potency, indicating that the activity may be caused by a common structure, (1-->3)-mannan in the four heteroglycans and their fragments. The change of molecular weight had no obvious influence on the activity of the heteroglycans.
Basidiomycota↗
Mutant p53-induced immortalization of primary human mammary epithelial cells.
Mutations of the p53 gene are the most frequent genetic lesions in breast cancer, suggesting a critical role for p53 protein in normal mammary cell growth control. Indeed, the p53-targeting human papillomavirus oncogene E6 induces efficient immortalization of normal human mammary epithelial cells (MECs). To assess whether selective loss of p53 is sufficient for MEC immortalization, we introduced seven missense mutants and one single-amino acid deletion mutant (del239) of p53 into the 76N normal MEC strain. Although the missense mutants failed to immortalize MECs, the del239 mutant reproducibly immortalized these cells. The immortal cells were anchorage dependent and nontumorigenic, indicating a preneoplastic transformation. Gamma-irradiation of these cells failed to induce G1 cell cycle arrest and did not lead to an increase in WAF1 and mdm-2 mRNA levels, demonstrating a loss of the endogenous p53 function. These results demonstrate that selective ablation of p53 function by a dominant-negative mutant is sufficient for immortalization of MECs. Availability of an immortalizing as well as several nonimmortalizing p53 mutants should help identify functions critical for cell growth control by p53 in mammary epithelial cells.
Breast↗
Two-dimensional crystallization of rabbit C-reactive protein on lipid monolayers.
Two-dimensional (2D) crystals of rabbit C-reactive protein (CRP) have been obtained by protein binding on lipid monolayers at the air/water interface. Two different types of crystalline arrays of CRP were obtained, by specific binding and non-specific adsorption to the lipids. Electron crystallographic analysis of the negatively stained specimens showed that the unit cell parameters of the CRP 2D crystals formed by specific binding were a=81 angstroms, b=78 angstroms, gamma=118.35 degrees, and those formed by nonspecific adsorption were a=74 angstroms, b=67 angstroms, gamma=95.5 degrees, both with the layer group p1. Projection maps were obtained at a resolution of 26 angstroms and 22 angstroms respectively. They showed that only the monomers of the CRP were packed in the 2D arrays and the orientations of the monomers on the lipid monolayers were different in the two types of crystals. By comparing the two projection maps, a preliminary shape of the CRP monomer has been derived. A model of the pentameric structure of the oligomeric CRP has been proposed.
Adsorption↗
Prevention of Th1 response is critical for tolerance.
We investigated the role of Th1 ad Th2 cytokines in rejection and tolerance using the neonatal tolerance model. We reported previously that lymph nodes that drained immunogen-bearing tolerant grafts produced a 10- to 100-fold higher ratio of interleukin (IL)-4 to interferon (IFN)-gamma compared with lymph node cells from rejected grafts. Moreover, because neonatal antigen exposure triggers allospecific Th2 CD4 memory cells, whereas antigen exposure during adulthood triggers Th1 CD4 memory cells, we speculated that immunoredirection toward Th2 and away from Th1 functions as another mechanism of tolerance. To test the immunoredirection hypothesis, we examined whether recovery of Th1 cytokine responses abrogates tolerance. We now show that treatment with exogenous IFN-gamma at the time of neonatal priming recovered mixed lymphocyte reaction hypoproliferation and restored the ability of mice to reject skin grafts. Mice that received IFN-gamma at the time of neonatal priming produced more IFN-gamma and contained more A/J-reactive IFN-gamma producing CD4 cells compared with untreated neonatal primed mice, but failed to recover A/J-specific INF-gamma-producing CD8 cells or CTL responses, which suggests that graft rejection occurred via Th1 CD4 cells. Interestingly, draining lymph node cells from rejected grafts in IFN-gamma-treated neonatal primed mice also produced more IL-4, compared with cells from healthy grafts on untreated neonatal primed mice. Nonetheless, lower IL-4 to IFN-gamma ratio predicted graft rejection and higher ratios predicted acceptance. We conclude that neonatal tolerance depends on the ability to block generation of allospecific Th1 responses that lead to rejection. Thus, immunoredirection involves both the inhibition of Th1 and expansion of Th2 immune responses.
Animals↗
Binding specificity of post-activated neocarzinostatin chromophore drug-bulged DNA complex studied using electrospray ionization mass spectrometry.
Electrospray ionization mass spectrometry (ESI-MS) was employed to characterize the binding specificity of a bulged 22-mer DNA hairpin with a post-activated neocarzinostatin chromophore (NCS-Chrom) having two similar forms, where 2a has an H in a location for which 2b has it replaced by a CH2OH group. Specific binding of 2a to the bulged 22-mer DNA was observed whereas little binding was detected for 2a to non-bulged DNA 19-mer and 12-mer duplexes. The stoichiometry of the 22-mer DNA complex with 2a was determined to be predominantly 1:1. Substitution of hydrogen in 2a for the hydroxymethylene group in 2b dramatically reduced the binding strength to the 22-mer DNA. Little complex formation was observed for 2b and 22-mer DNA based upon the ESI-MS data, consistent with earlier fluorescence studies. The results indicate that ESI-MS can be a sensitive technique for probing conformational specificity in studies of biomolecular binding.
Antibiotics, Antineoplastic↗
Human acute myeloid leukemias may be etiologically associated with new human retroviral infection.
The etiology of human acute myeloid leukemias (AML) remains uncertain. In order to examine the possibility of retroviral etiology in AML, we determined retroviral antigens related to HTLV-I in leukemic cell samples from 32 AML cases and peripheral blood mononuclear cells (PBMNCs) from 20 healthy donors by D-IGSS with high sensitivity and specificity, reverse transcriptase (RT) activity by a simple and sensitive non-radioisotopic RT assay, and retroviral particles by electron microscopy. The HTLV-I-related antigens were detected in 50.0% (16/32) of fresh leukemic cell samples and 87.5% (28/32) of cultured leukemic cell samples. The HTLV-I-related antigen-positive cells in fresh and cultured leukemic samples were 10.2% and 52.8%, respectively. Both frequency and level of HTLV-I-related antigens in cultured samples were much higher than in fresh samples. In contrast, no HTLV-I-related antigens were found in normal hematopoietic cells from 20 healthy donors. Further study results show that RT activity was detected not only in HTLV-I-related antigen-positive samples, but was also well correlated with the level of HTLV-I-related antigens in these samples, and preferred Mn+2 to Mg+2 as a cation. Moreover, typical retroviral particles were localized in most cultured HTLV-I-related antigen-positive samples by immunoelectron microscope. These data suggest that human acute myeloid leukemias may be etiologically associated with new human retroviral infection.
Acute Disease↗
Orthodenticle regulation during embryonic head development in Drosophila.
The homeobox gene orthodenticle (otd) specifies anterior head development in the Drosophila embryo, otd-related genes are also found in vertebrates, with expression patterns suggesting that they are important for the development of anterior regions of the head and brain. Here, we analyze the molecular mechanisms by which otd expression is activated within its normal domain in the head and repressed outside this region. We demonstrate that, contrary to early models of embryonic pattern formation, high levels of the bicoid morphogen are not required for otd activation or for the establishment of anterior head structures. We also show that the terminal system contributes to otd activation in the head primordium. Finally, we identify a novel pathway mediated by the gap gene huckebein through which three maternal systems cooperate to repress otd expression at the anterior terminus of the embryo.
Animals↗
Fusaricide, a new cytotoxic N-hydroxypyridone from Fusarium sp.
A new cytotoxic N-hydroxypyridone, fusaricide (1), was isolated from a Fusarium sp. Its structure was solved by X-ray diffraction and spectroscopic analyses.
Antifungal Agents↗
Ordered accumulation of mutations in HIV protease confers resistance to ritonavir.
Analysis of the HIV protease gene from the plasma of HIV-infected patients revealed substitutions at nine different codons selected in response to monotherapy with the protease inhibitor ritonavir. Mutants at valine-82, although insufficient to confer resistance, appeared first in most patients. Significant phenotypic resistance required multiple mutations in HIV protease, which emerged subsequently in an ordered, stepwise fashion. The appearance of resistance mutations was delayed in patients with higher plasma levels of ritonavir. Early mutants retained susceptibility to structurally diverse protease inhibitors, suggesting that dual protease inhibitor therapy might increase the duration of viral suppression.
Codon↗
Mutational analysis of human papillomavirus type 16 E6 demonstrates that p53 degradation is necessary for immortalization of mammary epithelial cells.
We have previously demonstrated that normal human mammary epithelial cells (MECs) are efficiently immortalized by human papillomavirus type 16 (HPV16) E6. HPV16 E6 binds to and induces p53 degradation in vitro and induces a marked reduction of p53 protein in MECs. Low-risk HPV6 E6 is defective for p53 binding and degradation in vitro but immortalized MECs at low efficiency. The HPV6 E6-immortalized MECs had markedly reduced levels of p53. To directly investigate whether the ability of HPV16 E6 to stimulate p53 degradation is required for E6-induced immortalization, a series of HPV16 E6 mutants were analyzed for the ability to bind and degrade p53 in vitro, induce a reduction in p53 levels in vivo, and immortalize MECs. We observed that one set of mutants efficiently immortalized MECs, caused a reduction in p53 levels in vivo, and degraded p53 in vitro. Other mutants immortalized MECs with low efficiency and either induced p53 degradation at low levels or were unable to induce p53 degradation in vitro; however, all of the immortal clones displayed low levels of p53. A third class of mutants did not immortalize MECs and failed to induce a reduction in p53 levels in vivo or degrade p53 in vitro. These results demonstrate that a reduction in p53 protein levels due to enhanced degradation is essential for MEC immortalization by HPV16 E6.
Base Sequence↗
[Video assisted thoracoscopic major lung resection].
We report the combined experience on video assisted thoracoscopic (VAT) anatomical lung resection from two hospitals in Hong King. 60 patients successfully underwent VAT anatomical lung resections: 55 lobectomies, 2 bi-lobectomies, 2 pneumonectomies and 1 segmectomy. There was no mortality. Intraopeative complication occurred in 1 patient due to malfunctioning of a vascular stapler. Postoperative complications were few. Average postoperative hospital stay was 7.2 days. Compared with the conventional thoracotomy approach, the VAT approach was associated with the conventional thoracotomy approach, the VAT approach was associated with significantly less analgesic requirement. We conclude that VAT anatomical lung resection is technically feasible. Specific complications, however, exist. The true role of this new approach in thoracic surgery awaits further study.
Adenocarcinoma↗
[Estimation of safety and toxicity of rho-nitrophenol sodium with a physiologically based pharmacokinetics model].
The safety and toxicity of chemicals given first to animals and finally to humans are generally estimated with a method of safe coefficient, which lacks scientific ground. To change the traditional method, we designed a physiologically based pharmacokinetics model (PBPK) for the estimation of safety and toxicity of chemicals. For example, rho-nitrophenol sodium (PNP-Na) was used. The PNP-Na pharmacokinetics in bodies of rat as well as humans were studied, and possibilities of making use of the model in the estimation of safety and toxicity of chemicals were also discussed.
Animals↗
Expansion of memory Th2 cells over Th1 cells in neonatal primed mice.
BALB/c mice primed with CAF1 splenocytes during the neonatal stage developed A/J-specific tolerance with prolonged survival (> 60 days) of A/J skin grafts. Mice failed to develop A/J-specific cytotoxicity, but rejected third-party skin grafts and generated appropriate third-party cytotoxic T cell responses. We demonstrated previously that graft acceptance was associated with enhanced interleukin (IL)-4 and diminished interferon [IFN]-gamma tolerogen-specific cytokine production, whereas third-party graft rejection was associated with the opposite pattern of cytokine production. We now report that neonatal mice do not mount mixed lymphocyte reaction responses against A/J, but the mice contain a higher percentage of IL-4-producing cells that were characterized as CD4+Mel-14lo cells. Although alloantigen priming of both neonatal and adult control mice expands the CD4+Mel-14lo subset, CD4+Mel-14lo cells from neonatal primed mice produce significantly higher levels of IL-4 and IL-10 and lower IFN-gamma, whereas CD4+Mel-14lo cells from adult primed mice produce mainly IFN-gamma. Moreover, enzyme-linked spot immunosorption analysis demonstrates that, compared with adult primed mice, neonatal primed mice contain more IL-4-producing CD4 cells and less IFN-gamma-producing cells, which indicates that neonatal antigen exposure induces and expands alloreactive Th2 memory CD4 cells. The addition of neutralizing antibodies against IL-4 and IL-10 to primary MLR failed to recover IFN-gamma by CD4+Mel-14lo cells, but cells secreted IFN-gamma after a second in vitro restimulation with tolerogen, which indicates that CD4 cells from neonatal tolerant mice have the capacity to differentiate into Th1 cells. In summary, neonatal tolerant mice contain higher ratios of Th2/Th1 CD4 cells, and the Th2 cytokines function to maintain the ratio by inhibiting Th1 differentiation.
Animals↗
CD4 Th2 cells do not functionally suppress CTL generation in neonatal tolerant mice.
Injecting semiallogeneic CAF1 spleen into BALB/c newborn mice renders mice tolerant, and the majority of mice show prolonged survival of tolerogen-bearing A/J skin grafts. Moreover, graft survival is associated with enhanced Th2 cytokine responses and graft rejection with Th1 cytokine responses. To further delineate the mechanisms of tolerance, we evaluated CTL responses and found that 74% of neonatal primed mice failed to generate A/J-specific CTL responses, as determined by standard CTL assays and pTc3 frequency analyses. CTL unresponsiveness coexisted with an enhanced tolerogen-specific Th2 memory cytokine profile; spleen cells from neonatal primed mice secreted more interleukin (IL)-4 and less IL-2 and interferon (IFN)-gamma in MLR cultures compared with either adult primed or naive controls. We therefore examined the hypothesis that enhanced Th2 cytokine levels prevent the generation of tolerogen-specific CTL. Adding neutralizing antibodies to IL-4 and IL-10 recovered IFN-gamma production in vitro but not A/J-specific CTL response. In addition, CD4 cells from neonatal primed mice provided help for primary or secondary CD8 CTL generation, which suggests that the enhanced Th2 cytokine profile does not actively suppress CTL generation. Furthermore, CD4 cells from adult primed mice failed to restore the A/J-specific CD8 CTL generation of neonatal primed mice. The results show that failure to develop A/J-specific CTL reaction occurs without suppression by the enhanced Th2-type responses and imply that either deletion or anergy mechanisms block CTL generation. Therefore, neonatal alloantigen exposure not only shifts the development of alloreactive CD4 cells toward Th2, but also blocks development of alloreactive CD8 CTL in this strain combination.
Animals↗
Immortalization of distinct human mammary epithelial cell types by human papilloma virus 16 E6 or E7.
Multiple mammary epithelial cell (MEC) types are observed both in mammary ducts in vivo and in primary cultures in vitro; however, the oncogenic potential of different cell types remains unknown. Here, we used human papilloma virus 16 E6 and E7 oncogenes, which target p53 and Rb tumor suppressor proteins, respectively, to immortalize MECs present in early or late passages of human mammary tissue-derived cultures or in milk. One MEC subtype was exclusively immortalized by E6; such cells predominated in late-passage cultures but were rare at early passages and apparently absent in milk. Surprisingly, a second cell type, present only in early-passage tissue-derived cultures, was fully immortalized by E7 alone. A third cell type, observed in tissue-derived cultures and in milk, showed a substantial extension of life span with E7 but eventually senesced. Finally, both E6 and E7 were required to fully immortalize milk-derived MECs and a large proportion of MECs in early-passage tissue-derived cultures, suggesting the presence of another discrete subpopulation. Identification of MECs with distinct susceptibilities to p53- and Rb-targeting human papillomavirus oncogenes raises the possibility that these cells may serve as precursors for different forms of breast cancer.
Breast↗