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Biomedical subjects

Yang Yang

Publications and source records attributed to Yang Yang.

At least 145 records · Page 8Linked to original sources
PubMed2004

HIV-1 protease inhibitor, ritonavir: a potent inhibitor of CYP3A4, enhanced the anticancer effects of docetaxel in androgen-independent prostate cancer cells in vitro and in vivo.

We previously showed that HIV-1 protease inhibitors (PIs) slowed the proliferation of human myeloid leukemia cells and enhanced their differentiation in the presence of all-trans-retinoic acid. In this study, we found that PIs, including ritonavir, saquinavir, and indinavir, inhibited the growth of DU145 and PC-3 androgen-independent prostate cancer cells as measured by a clonal proliferation assay. Recent studies showed that ritonavir inhibited cytochrome P450 3A4 enzyme (CYP3A4) in liver microsomes. The CYP3A4 is involved in drug metabolism and acquisition of drug resistance. To clarify the drug interaction between ritonavir and other anticancer drugs, we cultured DU145 cells with docetaxel either alone or in combination with ritonavir. Ritonavir enhanced the antiproliferative and proapoptotic effects of docetaxel in the hormonally independent DU145 prostate cancer cells in vitro as measured by the clonogenic soft agar assay and detection of the activated form of caspase-3 and cleavage of poly(ADP-ribose) polymerase using Western blot analysis. Real-time PCR showed that docetaxel induced the expression of CYP3A4 at the transcriptional level, and ritonavir (10(-5) mol/L) completely blocked this induction. An ELISA-based assay also showed that ritonavir inhibited DNA binding activity of nuclear factor kappaB (NFkappaB) in DU145 cells, which is a contributor to drug resistance in cancer cells. Furthermore, combination treatment of docetaxel and ritonavir dramatically inhibited the growth of DU145 cells present as tumor xenografts in BNX nude mice compared with either drug alone. Importantly, docetaxel induced expression of CYP3A4 in DU145 xenografts, and ritonavir completely blocked this induction. Ritonavir also inhibited NFkappaB DNA binding activity in DU145 xenografts. Extensive histologic analyses of the liver, spleen, kidneys, bone marrow, skin, and subcutaneous fat pads from these mice showed no abnormalities. In summary, combination therapy of ritonavir and anticancer drugs holds promise for the treatment of individuals with advanced, drug resistant cancers.

Animals↗
PubMed2004

Heparanase promotes the spontaneous metastasis of myeloma cells to bone.

Although widespread skeletal dissemination is a critical step in the progression of myeloma, little is known regarding mechanisms that control metastasis of this cancer. Heparanase-1 (heparanase), an enzyme that cleaves heparan sulfate chains, is expressed at high levels in some patients with myeloma and promotes metastasis of some tumor types (eg, breast, lymphoma). Using a severe combined immunodeficient (SCID) mouse model, we demonstrate that enhanced expression of heparanase by myeloma cells dramatically up-regulates their spontaneous metastasis to bone. This occurs from primary tumors growing subcutaneously and also from primary tumors established in bone. Interestingly, tumors formed by subcutaneous injection of cells metastasize not only to bone, but also to other sites including spleen, liver, and lung. In contrast, tumors formed by injection of cells directly into bone exhibit a restricted pattern of metastasis that includes dissemination of tumor to other bones but not to extramedullary sites. In addition, expression of heparanase by myeloma cells (1) accelerates the initial growth of the primary tumor, (2) increases whole-body tumor burden as compared with controls, and (3) enhances both the number and size of microvessels within the primary tumor. These studies describe a novel experimental animal model for examining the spontaneous metastasis of bone-homing tumors and indicate that heparanase is a critical determinant of myeloma dissemination and growth in vivo.

Bone and Bones↗
PubMed2004

Sodium selenite induces apoptosis in acute promyelocytic leukemia-derived NB4 cells by a caspase-3-dependent mechanism and a redox pathway different from that of arsenic trioxide.

Two relatively recent discoveries stand behind our current effort to investigate the effects of the chemopreventive agent, selenium, on the proliferation and survival of NB4 cells. The first is that certain selenium compounds such as sodium selenite have pro-oxidant ability to catalyze the oxidation of thiols and simultaneously generate superoxide. The second lies in the exquisite susceptibility of NB4 cells to arsenic trioxide-induced, reactive oxygen species (ROS)-mediated apoptosis due to less efficiency of the cellular defense system. In this study, we demonstrated that sodium selenite could induce apoptosis in NB4 cells via the classic mitochondrial pathway involving caspase-3 activation and Bcl-2 cleavage. An increase in the basal cellular glutathione (GSH) content rendered NB4 cells resistant to arsenic trioxide, but could sensitize NB4 cells to sodium selenite. Moreover, combined treatment of NB4 cells with all- trans retinoic acid (ATRA) at low concentration and sodium selenite exhibited a synergistic effect on apoptosis induction. Together, our results suggest that selenite is a promising candidate for treatment of acute promyelocytic leukemia (APL) and the mechanism underlying its anticancer effects warrants further investigation.

Antineoplastic Agents↗
PubMed2004

[Clinical study of adjuvant individualized chemotherapy for hepatocellular carcinoma after liver transplantation].

OBJECTIVE: To investigate the effect of adjuvant individualized chemotherapy in prevention of tumor recurrence and improvement of patient survival after liver transplantation for hepatocellular carcinoma (HCC). METHODS: 21 HCC cases received orthotopic liver transplantation and treated with adjuvant individualized chemotherapy based on ATP tumor chemosensitivity assay (ex vivo) between April 2001 and January 2003 were retrospective reviewed, compared with 52 cases received orthotopic liver transplantation only. The cumulative and tumor-free survivals were compared between 2 groups. RESULTS: The 1, 2 years overall survival rates were 92.31%, 73.85% for the individualized chemotherapy group and 92.06%, 63.93% for the non-chemotherapy group, the difference was not statistically significant. The 6, 12, 18, 24 months tumor-free survival rates were 90.00%, 80.00%, 80.00%, 60.00% and 67.31%, 51.92%, 40.03%, 37.81% respectively, the difference was statistically significant (P <0.05). CONCLUSIONS: This study suggests that tumor recurrence decreases and tumor-free survival increases by adjuvant individualized chemotherapy after liver transplantation for HCC. The individualized protocol based on ATP-TCA may be effective for patients with HCC after liver transplantation.

Adult↗
PubMed2004

BetaIV spectrins are essential for membrane stability and the molecular organization of nodes of Ranvier.

High densities of sodium channels at nodes of Ranvier permit action potential conduction and depend on betaIV spectrins, a family of scaffolding proteins linked to the cortical actin cytoskeleton. To investigate the molecular organization of nodes, we analyzed qv(3J)"quivering" mice, whose betaIV spectrins have a truncated proline-rich "specific" domain (SD) and lack the pleckstrin homology (PH) domain. Central nodes of qv(3J) mice, which lack betaIV spectrins, are significantly broader and have prominent vesicle-filled nodal membrane protrusions, whereas axon shape and neurofilament density are dramatically altered. PNS qv(3J) nodes, some with detectable betaIV spectrins, are less affected. In contrast, a larger truncation of betaIV spectrins in qv(4J) mice, deleting the SD, PH, and ankyrinG binding domains, causes betaIV spectrins to be undetectable and causes dramatic changes, even in peripheral nodes. These results show that quivering mutations disrupt betaIV spectrin retention and stability at nodes and that distinct protein domains regulate nodal structural integrity and molecular organization.

Action Potentials↗
PubMed2004

Murine B7-H3 is a negative regulator of T cells.

T cell activation is regulated by the innate immune system through positive and negative costimulatory molecules. B7-H3 is a novel B7-like molecule with a putative receptor on activated T cells. Human B7-H3 was first described as a positive costimulator, most potently inducing IFN-gamma production and cellular immunity. In this study we examined the expression and function of mouse B7-H3. B7-H3 is mostly expressed on professional APCs; its expression on dendritic cells appears to be up-regulated by LPS. In contrast to human B7-H3, we found that mouse B7-H3 protein inhibited T cell activation and effector cytokine production. An antagonistic mAb to B7-H3 enhanced T cell proliferation in vitro and led to exacerbated experimental autoimmune encephalomyelitis in vivo. Therefore, mouse B7-H3 serves as a negative regulator of T cell activation and function.

Animals↗
PubMed2004

[Liver transplantation for hepatocellular carcinoma: a report of 60 cases].

OBJECTIVE: To evaluate the role of orthotopic liver transplantation (OLT) in treatment of hepatocellular carcinoma (HCC) and the selection of recipients. METHODS: OLT was performed in 60 patients with HCC at Organ Transplantation Centre of the First Affiliated Hospital of Sun Yat-sen University between September 1993 and September 2002. Medical records were retrospectively analyzed with regard to the response to OLT and survival. RESULTS: One-month, 1, 2, 3-year survival rate of 23 liver transplant performed from September 1993 to July 2002 were 73.9%, 60.9%, 43.5% and 29.0%, respectively. One-month, 1, 2-year survival rate of 37 liver transplant performed from August 2000 to September 2002 were 89.2%, 75.8% and 61.2%, respectively. One-month survival rate was significantly greater in the patients with a preoperative liver function of Child A or B than Child C (P < 0.05). One-month, 1, 2, 3-year survival rate of small HCC (single tumor 5 cm diameter, n = 41) were 84.2%, 76.6%, 65.6%, 65.6% and 82.9%, 63.1%, 46.7%, 37.4%, respectively. The median survival of large HCC was 18.0 months and mean survival of small HCC was 29.6 months, respectively. The recurrence rate of small HCC and large HCC were 15.8% and 27.7%, respectively. There was no significant difference between the cumulative survival of small HCC and large HCC. The quality of life of patients with long-term survival was good. CONCLUSIONS: HCC associated with cirrhosis can be effectively treated by OLT on condition that no extrahepatic spread and no vascular involvement. OLT is recommended for treatment of small HCC combined with liver cirrhosis, meanwhile, OLT performed in the partial large HCC still is reasonable at the present time.

Adult↗
PubMed2004

Containing pandemic influenza with antiviral agents.

For the first wave of pandemic influenza or a bioterrorist influenza attack, antiviral agents would be one of the few options to contain the epidemic in the United States until adequate supplies of vaccine were available. The authors use stochastic epidemic simulations to investigate the effectiveness of targeted antiviral prophylaxis to contain influenza. In this strategy, close contacts of suspected index influenza cases take antiviral agents prophylactically. The authors compare targeted antiviral prophylaxis with vaccination strategies. They model an influenza pandemic or bioterrorist attack for an agent similar to influenza A virus (H2N2) that caused the Asian influenza pandemic of 1957-1958. In the absence of intervention, the model predicts an influenza illness attack rate of 33% of the population (95% confidence interval (CI): 30, 37) and an influenza death rate of 0.58 deaths/1,000 persons (95% Cl: 0.4, 0.8). With the use of targeted antiviral prophylaxis, if 80% of the exposed persons maintained prophylaxis for up to 8 weeks, the epidemic would be contained, and the model predicts a reduction to an illness attack rate of 2% (95% Cl: 0.2, 16) and a death rate of 0.04 deaths/1,000 persons (95% CI: 0.0003, 0.25). Such antiviral prophylaxis is nearly as effective as vaccinating 80% of the population. Vaccinating 80% of the children aged less than 19 years is almost as effective as vaccinating 80% of the population. Targeted antiviral prophylaxis has potential as an effective measure for containing influenza until adequate quantities of vaccine are available.

Adolescent↗
PubMed2004

The E47 transcription factor negatively regulates CD5 expression during thymocyte development.

The expression of CD5 increases progressively as thymocytes mature. We have shown that CD5 expression is controlled by a tissue-specific regulatory promoter located upstream of the CD5 translation start sites. Deletion of this regulatory promoter, which contains three potential transcription factor binding sites (CCAAT, kappa E2, and ets) reduces the promoter activity to basal level. Of these sites, only ets proved essential for CD5 expression in T cell lines. Here, we introduce a role for the E47 transcription factor and the CD5 promoter kappa E2 site in regulating CD5 expression during thymocyte development. Using T cell lines, we show that (i) mutation of the kappa E2 site in the CD5 regulatory promoter results in a significant elevation of CD5 promoter activity; (ii) the E47 transcription factor binds to the kappa E2 site; and (iii) overexpression of E47 inhibits CD5 expression. We then show, in high-dimensional fluorescence-activated cell sorting studies with primary thymocytes at successive developmental stages, that (i) intracellular E47 levels decrease as surface CD5 expression increases; (ii) E47 expression is down-regulated and CD5 expression is correspondingly up-regulated in DN3 thymocytes in RAG-2-deficient mice injected with anti-CD3 to mimic pre-T cell receptor stimulation; and (iii) E47 expression is down-regulated and CD5 expression is up-regulated when double positive thymocytes are stimulated in vitro with anti-CD3. Based on these data, we propose that E47 negatively regulates CD5 expression by interacting with the kappa E2 site in the CD5 regulatory promoter and that decreases in E47 in response to developmental signals are critical to the progressive increase in CD5 expression as thymocytes mature.

Animals↗
PubMed2004

Methylenetetrahydrofolate reductase genotype does not play a role in adult T-cell leukemia/lymphoma pathogenesis among human T-lymphotrophic virus type 1 carriers.

Human T-lymphotropic virus type 1 (HTLV-1) is associated with adult T-cell leukemia/lymphoma (ATL). However, the incidence of ATL is low among HTLV-1 carriers suggesting additional mechanisms are involved in the progression of the disease. A recent study found that polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene influence the susceptibility to malignant lymphoma. We have analyzed the MTHFR genotype in 81 HTLV-1 carriers and 87 ATL patients. No statistically significant associations were found between MTHFR genotype and development of ATL. These data suggest that genetic polymorphisms in the MTHFR locus do not play a role in ATL pathogenesis among HTLV-1 carriers.

Carrier State↗
PubMed2004

Heparan sulfate proteoglycans and heparanase--partners in osteolytic tumor growth and metastasis.

This review summarizes a series of studies demonstrating that heparan sulfate proteoglycans act to promote the growth and metastasis of myeloma and breast tumors, two tumors that home to, and grow within, bone. Much of the growth-promoting effect of proteoglycans in these tumors may reside in the shed form of syndecan-1 that acts to favorably condition the tumor microenvironment. Moreover, the interplay between heparan sulfate and the extracellular enzyme heparanase-1 also has important regulatory implications. Recent studies indicate that the activity of heparanase, which likely releases heparin sulfate-bound growth factors and generates highly active heparan sulfate fragments, also promotes growth and metastasis of myeloma and breast tumors. Understanding the role of heparan sulfate and heparanase in the regulation of tumor behavior may lead to new therapeutic approaches for treating cancer.

Animals↗
PubMed2004

Identification and analysis of genes present in Leptospira interrogans serovar lai but absent in L. biflexa serovar monvalerio.

Genes present in virulent bacterial strains but absent in avirulent close relatives can be of great biologic and clinical interest. This project aimed to identify strain specific DNA sequences of Leptospira interrogans serovar lai, which is absent in the saprophytic L. biflexa serovar monvalerio, via suppression subtractive hybridization with the former as the tester while the latter as the driver. The mixture of PCR amplified DNA fragments from two subtractive hybridization experiments were cloned into pMD18-T vector and the positive clones were identified by dot blotting against the chromosome DNA of the two strains individually. After DNA sequencing and analysis, the distribution of these genomic fragment sequences in a panel of pathogenic and nonpathogenic leptospires was investigated employing dot blot analysis. Among the 188 positive clones randomly chosen, 24 contained the tester strain specific genomic regions, of which, 5 were non-coding fragments while the others contained 23 distinct protein coding sequences. Besides 9 genes encoding functional proteins, 12 genes encode unknown proteins and the rest two genes encode proteins with recognizable domain structures, one for a putative leucine-rich repeats (LRR) family protein while the other as an outer-membrane protein. Our experiment results indicated that suppression subtractive hybridization is effective for screening specific DNA sequences between two leptospiral strains, and some of these sequences might be responsible for virulence determination. Further analysis of these DNA sequences will provide important information on the pathogenesis of Leptospira.

DNA, Bacterial↗
PubMed2004

Proteasome inhibitor PS-341 down-regulates prostate-specific antigen (PSA) and induces growth arrest and apoptosis of androgen-dependent human prostate cancer LNCaP cells.

Proteasome inhibitor PS-341 induces growth arrest and apoptosis of multiple myeloma (MM) cells via inactivation of nuclear factor kappaB (NF-kappaB) in vitro. In addition, recent clinical studies of PS-341 have demonstrated some objective responses in individuals with relapsed, refractory MM. However, the activity of PS-341 against non-hematological malignancies remains to be fully elucidated. In this study, we found that PS-341 induced growth arrest and apoptosis of androgen-dependent human prostate cancer LNCaP cells in conjunction with markedly up-regulated levels of p21(waf1) and p53. In addition, we found that PS-341 down-regulated both 5alpha-dihydrotestosterone (DHT)- and interleukin-6 (IL-6)-induced expression of prostate-specific antigen (PSA) as measured by western blot analysis. PS-341 down-regulated basal levels of the androgen receptor (AR) in the nucleus; however, it did not affect DHT-induced nuclear translocation of AR in these cells. Reporter assays using a series of promoters of the PSA gene showed that down-regulation of PSA by PS-341 was caused by inhibition of the transcriptional activity of the androgen receptor response element (ARE) in these cells. Taken together, the results indicate that PS-341 induced growth arrest and apoptosis of LNCaP cells by blockade of the AR signaling pathway. The proteasome may be a molecular target for treatment of a variety of cancers including prostate cancer.

Androgens↗
PubMed2004

Proteasome inhibitor PS-341 induces growth arrest and apoptosis of non-small cell lung cancer cells via the JNK/c-Jun/AP-1 signaling.

Proteasome inhibitor PS-341 induces growth arrest and apoptosis of multiple myeloma (MM) cells via inactivation of NF-kappaB in vitro and has afforded some objective responses in individuals with relapsed, refractory MM. However, the activity of PS-341 against non-hematological malignancies remains to be fully elucidated. In this study, we found that PS-341 induced growth arrest and apoptosis of NCI-H520 and -H460 non-small cell lung cancer (NSCLC) cells in conjunction with markedly up-regulated levels of p21(waf1) and p53, and down-regulation of bcl-2 protein in these cells. Also, PS-341 caused phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and c-Jun, and enhanced AP-1/DNA binding activities in these cells as measured by western blotting and enzyme-linked immunosorbent assay (ELISA), respectively. Interestingly, when the JNK/c-Jun/AP-1 signal pathway was disrupted by the JNK inhibitor SP600125, the ability of PS-341 to inhibit the growth of NSCLC cells and to up-regulate the levels of p21(waf1) in these cells was blunted, but the expression of p53 was sustained at a high level, suggesting that the JNK/c-Jun/AP-1 signal pathway might mediate the anti-lung cancer effects of PS-341, with p21(waf1) playing the central role. Thus, PS-341 might be useful for the treatment of individuals with NSCLC.

Antineoplastic Agents↗
PubMed2004

HIV-1 protease inhibitor induces growth arrest and apoptosis of human multiple myeloma cells via inactivation of signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2.

We previously showed that HIV-1 protease inhibitors slowed the proliferation of human myeloid leukemia cells and enhanced their differentiation in the presence of all-trans retinoic acid (ATRA). In this study, we found that protease inhibitors, including ritonavir, saquinavir, and nelfinavir, but not indinavir, induced growth arrest and apoptosis of U266, RPMI8226, and ARH77 human multiple myeloma (MM) cells in association with down-regulation of antiapoptotic protein Mcl-1. Also, protease inhibitors inhibited the survival of freshly isolated MM cells from patients. In contrast, these protease inhibitors did not affect survival of normal B cells and colony formation of myeloid committed stem cells (CFU-GM) from healthy volunteers. In addition, we found that all of the protease inhibitors, except for indinavir, blocked interleukin-6 (IL-6)-stimulated phosphorylation of both signal transducer and activator of transcription 3 (STAT 3) and extracellular signal-regulated kinase 1/2 in U266 and RPMI8226 MM cells. Moreover, the protease inhibitors inhibited both the basal and IL-6-stimulated STAT 3/DNA binding activity in U266 cells as measured by an ELISA-based assay. Furthermore, ritonavir inhibited production of vascular endothelial growth factor one of the targets of STAT 3, in U266 and RPMI8226 cells as measured by ELISA. Taken together, protease inhibitors might be useful for treatment of individuals with MM.

Apoptosis↗
PubMed2004

Aberrant methylation in promoter-associated CpG islands of multiple genes in relapsed childhood acute lymphoblastic leukemia.

Methylation profile was analyzed in nine cases of relapsed childhood acute lymphoblastic leukemia (ALL) for p14, p15, p16, Rb, MGMT, APC, hMLH1, RARbeta, RIZ, DAPK, and FHIT genes by using methylation specific polymerase chain reaction (MSP) analysis. Frequency of methylation in each gene was: MGMT, 56%; RARbeta, 44%; and p16, 22%, respectively. None of the p14, p15, Rb, APC, hMLH1, RIZ, DAPK, and FHIT genes were hypermethylated. Five (56%) of 9 cases showed methylation of at least one gene. All of the samples with hypermethylation in p16 and MGMT gene at relapse, had already acquired the change at the time of initial diagnosis. Interestingly, three of 4 cases with RARbeta gene methylation at relapse did not have methylation of this gene at the time of initial presentation. These results suggest that hypermethylation might be involved in the relapse of childhood ALL.

Adolescent↗
PubMed2004

[Diagnosis and treatment of liver abscess after orthotopic liver transplantation].

OBJECTIVE: To investigate etiology, diagnosis, treatment and prophylaxis of liver abscess after orthotopic liver transplantation (OLT). METHODS: Of 274 recipients of OLT from January 1993 to June 2003 in our transplant center, liver abscess were identified in 6 recipients (2.2%). The clinical presentation included fever, shiver, abdominal pain, jaundice, hepatic dysfunction, hypoalbuminemia, anemia, leukocytosis and neutrophilia. They were diagnosed mainly according to the clinical presentation and Ultrasonography or CT scan. The treatments included aspiration and drainage of abscess, removing bile sludge, antibiotics and supportive therapy. RESULTS: Of 6 patients, 2 were cured, 3 refused liver retransplantation and 2 died of serious systemic infection. The cure rate was 33.3%. CONCLUSIONS: the etiology of liver abscess after OLT is complicated. The predisposing factors might be included hepatic artery thrombosis or stenosis, MP pulse therapy, cholangitis and biliary interventional therapy. Its prognosis seemed disappointing. Strong prophylactic measures should be recommended to reduce the liver abscess after OLT.

Adult↗