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Qiang Yu

Publications and source records attributed to Qiang Yu.

At least 19 recordsLinked to original sources
PubMed2026

Hepatocyte-derived LRG1 primes the liver for metastasis and impairs immunotherapy.

The liver undergoes active remodeling by the primary tumor prior to metastatic spread. However, the mechanisms by which hepatocytes dictate the liver-specific tropism of tumors remain elusive. Here, we identify hepatocyte-derived leucine-rich alpha-2-glycoprotein 1 (LRG1) as a key mediator of liver premetastatic niche (PMN) formation. Clinically, elevated serum LRG1 levels are correlated with an increased risk of liver metastasis in patients and multiple mouse models. Mechanistically, LRG1 remodels the hepatic microenvironment by driving immunosuppressive neutrophil accumulation, impairing the function of effector T cells and dendritic cells, and enhancing angiogenesis in the liver, thereby fostering a prometastatic landscape. Hepatocyte-specific ablation of LRG1 dampens premetastatic niche formation and significantly reduces the metastatic burden in vivo. Hepatic LRG1 induced by tumor-associated inflammation via IL-6/STAT3 signaling promotes liver metastasis through the formation of TGFBR/PI3K/AKT axis-driven neutrophil extracellular traps (NETs). Importantly, therapeutic blockade of LRG1 not only suppressed liver metastasis but also reprogrammed the hepatic niche toward an immune-activated state, sensitizing tumors to anti-PD-1 therapy. Collectively, our findings reveal a hepatocyte-LRG1 axis that drives liver premetastatic niche remodeling and highlight LRG1 as a promising target for the prevention and treatment of liver metastasis.

Animals↗
PubMed2006

4'-Alkoxyl substitution enhancing the anti-mitotic effect of 5-(3',4',5'-substituted)anilino-4-hydroxy-8-nitroquinazolines as a novel class of anti-microtubule agents.

Mitosis inhibitors are powerful anticancer drugs. Based on a novel anti-microtubule agent of 5-(4'-methoxy)anilino-4-hydroxy-8-nitroquinazoline, a series of 5-(3',4',5'-substituted)anilino-4-hydroxy-8- nitroquinazolines were designed and synthesized to investigate the effect of the substitution on the inhibitory activity against mitotic progression of tumor cells. The large alkoxyl substitution on the 4'-position of 5-anilino ring is beneficial for the potency. The 5-(3',4',5'-trimethoxy)anilino-8-nitroquinazoline (1h) displays an overwhelming activity in arresting the cells at the G2/M phase, providing a promising new template for further development of potent microtubule-targeted anti-mitotic drugs.

Alcohols↗
PubMed2006

Apoptosis signal-regulating kinase 1 is a direct target of E2F1 and contributes to histone deacetylase inhibitor-induced apoptosis through positive feedback regulation of E2F1 apoptotic activity.

The oncogenic retinoblastoma protein (Rb)/E2F pathway links cellular proliferation control to apoptosis as a fail-safe mechanism to protect aberrant oncogenic transformation. We have previously shown that histone deacetylase inhibitors (HDACIs) activate the E2F1-Bim apoptotic pathway, leading to efficient cell killing in cancer cells with deregulated E2F1 activity. To identify additional gene cassettes that might contribute HDACI-induced apoptosis upon E2F1 activation, we investigated the apoptotic transcriptional network affected by HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) in cancer cells with inducible E2F1. Data analysis focusing on 220 apoptosis-related genes identified apoptosis signal-regulating kinase 1 (ASK1) as one of a few genes in addition to Bim that are substantially up-regulated by SAHA upon E2F1 activation. We show that ASK1 is directly regulated by E2F1 and that prevention of ASK1 induction by RNA interference decreases SAHA-induced apoptosis. We further show that the role of ASK1 in the SAHA apoptotic response is not associated with its downstream effectors p38 or JNK. Instead, ASK1 knockdown results in reduced E2F1 transcriptional activity, leading to decreased Bim induction by SAHA. Moreover, ASK1 expression reverses the negative effect of Rb on E2F1 activity. These results indicate that ASK1 induction by E2F1 provides positive feedback regulation of E2F1 activity via Rb inhibition, which allows an efficient E2F1-Bim activation. Thus, the concomitant induction of E2F1 targets ASK1 and Bim by HDACIs warrants an effective activation of E2F1-dependent apoptosis in response to SAHA.

Adenoviridae↗
PubMed2006

A global map of p53 transcription-factor binding sites in the human genome.

The ability to derive a whole-genome map of transcription-factor binding sites (TFBS) is crucial for elucidating gene regulatory networks. Herein, we describe a robust approach that couples chromatin immunoprecipitation (ChIP) with the paired-end ditag (PET) sequencing strategy for unbiased and precise global localization of TFBS. We have applied this strategy to map p53 targets in the human genome. From a saturated sampling of over half a million PET sequences, we characterized 65,572 unique p53 ChIP DNA fragments and established overlapping PET clusters as a readout to define p53 binding loci with remarkable specificity. Based on this information, we refined the consensus p53 binding motif, identified at least 542 binding loci with high confidence, discovered 98 previously unidentified p53 target genes that were implicated in novel aspects of p53 functions, and showed their clinical relevance to p53-dependent tumorigenesis in primary cancer samples.

Binding Sites↗
PubMed2006

Topotecan is a substrate for multidrug resistance associated protein 4.

Topotecan (TPT) is a semisynthetic water-soluble derivative of camptothecin (CPT) used as second-line therapy in patients with metastatic ovarian carcinoma, small cell lung cancer, and other malignancies. However, both dose-limiting toxicity and tumor resistance hinder the clinical use of TPT. The mechanisms for resistance to TPT are not fully defined, but increased efflux of the drug by multiple drug transporters including P-glycoprotein (PgP), multidrug resistance associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) from tumor cells has been highly implicated. This study aimed to investigate whether overexpression of human MRP4 rendered resistance to TPT by examining the cytotoxicity profiles using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) assay and cellular accumulation of TPT in HepG2 cells stably overexpressing MRP4. Two kinds of cell lines, HepG2 with insertion of an empty vector plasmid (V/HepG2), HepG2 cells stably expressing MRP4 (MRP4/HepG2), were exposed to TPT for 4 or 48 hr in the absence or presence of various MRP4 inhibitors including DL-buthionine-(S,R)-sulphoximine (BSO), diclofenac, celecoxib, or MK-571. The intracellular accumulation of TPT and paclitaxel (a PgP substrate) by V/HepG2 and MRP4/HepG2 cells was determined by incubation of TPT with the cells and the amounts of the drug in cells were determined by validated HPLC methods. The study demonstrated that MRP4 conferred a 12.03- and 6.86-fold resistance to TPT in the 4- and 48-hr drug-exposure MTT assay, respectively. BSO, MK-571, celecoxib, or diclofenac sensitised MRP4/HepG2 cells to TPT cytotoxicity and partially reversed MRP4-mediated resistance to TPT. In addition, the accumulation of TPT was significantly reduced in MRP4/HepG2 cells compared to V/HepG2 cells, and one-binding site model was found the best fit for the MRP4-mediated efflux of TPT, with an estimated K(m) of 1.66 microM and V(max) of 0.341 ng/min/106 cells. Preincubation of MRP4/HepG2 cells with BSO (200 microM) for 24 hr, celecoxib (50 microM), or MK-571 (100 microM) for 2 hr significantly increased the accumulation of TPT over 10 min in MRP4/HepG2 cells by 28.0%, 37.3% and 32.5% (P < 0.05), respectively. By contrast, there was no significant difference in intracellular accumulation of paclitaxel in V/HepG2 and MRP4/HepG2 cells over 120 min. MRP4 also rendered resistance to adefovir dipivoxil (bis-POM-PMEA) and methotrexate, two reported MRP4 substrates. MRP4 did not exhibit any significant resistance to other model drugs including vinblastine, vincristine, etoposide, carboplatin, cyclosporine and paclitaxel in both long (48 hr) and short (4 hr) drug-exposure MTT assays. These findings indicate that MRP4 confers resistance to TPT and TPT is the substrate for MRP4. Further studies are needed to explore the role of MRP4 in resistance to, toxicity and pharmacokinetics of TPT in cancer patients.

Antineoplastic Agents↗
PubMed2006

[Evaluation of the accuracy of 16 slices spiral CT in diagnosing maxillary sinus diseases].

PURPOSE: To investigate the diagnostic value of 16 slices spiral CT in maxillary sinus diseases. METHODS: 16 slices spiral CT findings of 58 cases with maxillary sinus diseases confirmed clinically were analyzed, postprocessing of images was performed by using the software package at the workstation. All the cases were proved by surgery. RESULTS: Among 58 cases, there were 30 cases with inflammatory diseases; 6 cases with benign tumors; 8 cases with malignant tumors and 14 cases with fractures. The correct rate of CT diagnosis for location was 100%, and for the nature of the disease was 91.38%. CONCLUSIONS: 16 slices spiral CT was proved to be a good way to show the range of maxillary sinus diseases, the degree of bony change and the relation to surrounding tissues, but determination of the nature of the diseases should be incorporated with clinical and pathological findings.

Humans↗
PubMed2005

Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim.

Inhibitors of histone deacetylases (HDACIs) are a new generation of anticancer agents that selectively kill tumor cells. However, the molecular basis for their tumor selectivity is not well understood. We investigated the effects of HDACIs on the oncogenic Rb-E2F1 pathway, which is frequently deregulated in human cancers. Here, we report that cancer cells with elevated E2F1 activity, caused either by enforced E2F1 expression, or by E1A oncogene expression, are highly susceptible to HDACI-induced cell death. This E2F1-mediated apoptosis is neither p53- nor p73-dependent but proceeds through selective induction of proapoptotic BH3-only protein Bim. We show that Bim is a direct target of E2F1 and that HDAC inhibition promotes the recruitment of E2F1 to the Bim promoter. Moreover, silencing of Bim by specific small interfering RNA (siRNA) effectively abolishes the E2F1-mediated cell death sensitization to HDACIs. These findings suggest that the oncogenic E2F1 pathway participates in HDACIs-induced apoptosis in cancer cells and underscore the importance of Bim as a key mediator of oncogene-induced apoptosis. Our study provides an important insight into the molecular mechanism of tumor selectivity of HDACIs and predicts that, clinically, HDACIs will be more effective in tumors with high E2F1 activity.

Antineoplastic Agents↗
PubMed2005

[Interventional radiological techniques in management of early hepatic artery thrombosis after liver transplantation].

OBJECTIVE: To evaluate the safety and efficacy of interventional radiological techniques in management of early hepatic artery thrombosis (HAT) after orthotopic liver transplantation (OLT). METHODS: Nine patients with HAT after OLT, 8 males and 1 female, aged 47.6 (32-63), presenting elevation of liver enzymes and bilirubin, whose diagnosis was suggested by Doppler ultrasonography and confirmed by angiography 16 hours to 10 days after the OLT, underwent interventional radiological techniques, including indwelling transcatheter hepatic artery (HA) thrombolysis with a low dose of urokinase, and stent placement into the stenotic segment of HA. Contemporaneous systemic low dose of heparin was given intravenously. Ultrasonography was performed every 12 hours during the intra-arterial (IA) thrombolysis. RESULTS: HA flow was established in 7 of the 9 patients (78%) 12 hours to 9 days (on average 4.8 days) after the IA thrombolysis with significant improvement of liver functions. HA stenosis (HAS) at the anastomotic stoma was found in 6 of these 7 patients, and stent placement at the stenotic segment was performed successfully in 6 of them with a degree of stenosis over 90%. IA thrombolysis failed in 2 cases. One patient with intraperitoneal hemorrhage 12 hours after the treatment underwent emergent graft revision and the bleeding place was found at the HA anastomotic stoma. One patient remained completely occluded of the HA 7 days after the treatment; however, the collateral flow to the liver was identified. His liver function was improved without further intervention. Follow-up of 6 months (2-14 months) showed that the 7 patients with successful HA recanalization had a good clinical course with normal graft function. CONCLUSION: Transcatheter endovascular interventional techniques are effective on treatment of early HAT after OLT.

Adult↗
PubMed2005

Pharmacologic modulation of glycogen synthase kinase-3beta promotes p53-dependent apoptosis through a direct Bax-mediated mitochondrial pathway in colorectal cancer cells.

Activation of p53 tumor suppressor induces either cell cycle arrest or apoptosis through transcription-dependent and independent pathways; however, their relative roles in apoptosis induction and how these pathways are regulated remains elusive. Here, we report a unique role for glycogen synthesis kinase-3beta (GSK-3beta) in regulating p53 functions in human colorectal cancer cells. Pharmacologic modulation of GSK-3beta markedly impaired p53-dependent transactivation of targets including p21 and Puma but promoted p53-dependent conformational activation of Bax, resulting in cytochrome c release, loss of mitochondrial membrane potential, and caspase-9 processing. Thus, p53-mediated damage response is converted from cell cycle arrest to apoptosis following exposure to a variety of chemotherapeutic agents. We found that this effect is associated with the modulation of inhibitory Ser(9) phosphorylation of GSK-3beta but not with the activating tyrosine phosphorylation. We further show that the induction of apoptosis is through a direct mitochondrial pathway that requires Bax but not Puma. Our results underscore the importance of transcription-independent mechanism in p53-induced apoptosis and indicate that GSK-3beta plays distinct dual roles in regulating p53 pathways: promoting p53 transcriptional activity in the nucleus but suppressing p53-mediated direct apoptotic function at the mitochondria. Importantly, our data suggest that small-molecule inhibition of GSK-3beta might represent a novel approach for modulating chemotherapy.

Aminophenols↗
PubMed2005

Triterpenoids from Sanguisorba officinalis.

Seven triterpenoids, i.e., 3beta-[(alpha-L-arabinopyranosyl)oxy]-19beta-hydroxyurs-12,20(30)-dien-28-oic acid (1), 3beta-[(alpha-L-arabinopyranosyl)oxy]-urs-11,13(18)-dien-28-oic acid beta-D-glucopyranosyl ester (2), 2alpha,3alpha,23-trihydroxyurs-12-en-24,28-dioic acid 28-beta-D-glucopyranosyl ester (3), 3beta-[(alpha-L-arabinopyranosyl)oxy]-urs-12,19(20)-dien-28-oic acid (4), 3beta-[(alpha-L-arabinopyranosyl)oxy]-urs-12,19(29)-dien-28-oic acid (5), 3beta-[(alpha-L-arabinopyranosyl)oxy]-19alpha-hydroxyolean-12-en-28-oic acid (6), 2alpha,3beta-dihydroxy-28-norurs-12,17,19(20),21-tetraen-23-oic cid (7), together with three known ones (8-10), were isolated from the roots of Sanguisorba officinalis. Their structures were determined by spectroscopic and chemical methods. Compounds 7 and 10 showed marginal inhibition activity against the growth of tumor cell lines.

Antineoplastic Agents, Phytogenic↗
PubMed2005

Modeling water and carbon fluxes above summer maize field in North China Plain with back-propagation neural networks.

In this work, datasets of water and carbon fluxes measured with eddy covariance technique above a summer maize field in the North China Plain were simulated with artificial neural networks (ANNs) to explore the fluxes responses to local environmental variables. The results showed that photosynthetically active radiation (PAR), vapor pressure deficit (VPD), air temperature (T) and leaf area index (LAI) were primary factors regulating both water vapor and carbon dioxide fluxes. Three-layer back-propagation neural networks (BP) could be applied to model fluxes exchange between cropland surface and atmosphere without using detailed physiological information or specific parameters of the plant.

Agriculture↗
PubMed2005

Application of least squares vector machines in modelling water vapor and carbon dioxide fluxes over a cropland.

Least squares support vector machines (LS-SVMs), a nonlinear kemel based machine was introduced to investigate the prospects of application of this approach in modelling water vapor and carbon dioxide fluxes above a summer maize field using the dataset obtained in the North China Plain with eddy covariance technique. The performances of the LS-SVMs were compared to the corresponding models obtained with radial basis function (RBF) neural networks. The results indicated the trained LS-SVMs with a radial basis function kernel had satisfactory performance in modelling surface fluxes; its excellent approximation and generalization property shed new light on the study on complex processes in ecosystem.

Agriculture↗
PubMed2005

[Application of X ray cephalogram in the measurement of adenoids in children].

PURPOSE: To evaluate the clinical value of X ray lateral cephalogram in the measurement of adenoids in children. METHODS: 45 cases (aged from 3 to 13 year old) with adenoid hypertrophy suspected clinically were examined with lateral cephalometric projections, of which 40 cases were examined with lateral nasopharyngeal projections at one time. Then the quality of films were appraisal and the adenoids were measured on the film. Student's X(2) test was used for statistics analysis. RESULTS: X ray lateral cephalogram can distinctly reveal the structure of nasopharynx. The method was simply and reproducible. The quality of the films were determined based on the conjunction between the base of the pterygoid plate and extracranial aspect of the occipital slope, with consideration of the mandibular margin and sphenoid saddle. The conjunction should be clearly demonstrated and the edges of the mandibular margin and sphenoid saddle should be sharp and well demarcated in qualified films. 45 cases were examined with lateral cephalometric projections, 34 cases had standard films, accounting for 76%. 40 cases were examined with lateral nasopharyngeal projections, 21 had standard films, accounting for 53%. The quality of X ray lateral cephalogram was significantly better than lateral nasopharyngeal projections (P<0.05). CONCLUSION: Compared with the routine lateral nasopharyngeal projection, lateral nasopharyngeal cephalogram has images of high quality, is better for showing the nasopharyngeal structures as well as measurement of the adenoids with parenchyma. It is the imaging method of choice for children with OSAHS.

Adenoids↗
PubMed2005

[CT evaluation of malignant tumors of upper cervical lymph nodes invading the carotid sheath].

PURPOSE: The aim of this article is to evaluate the CT findings of malignant tumors of upper cervical lymph nodes invading the carotid sheath. METHODS: Seventy-seven patients (83 lesions) with malignant tumors in the upper cervical lymph nodes shown on CT scans were collected. All lesions were certificated with pathological examination by operation or biopsy. RESULTS: The CT manifestations of malignant tumors of upper cervical lymph nodes invading the carotid sheath included :(1) compression and deformation of vessels in the carotid sheath in 52 lesions (ICA, one lesions; ICV, 51 lesions); (2) disappearance of vessels in the carotid sheath (ICV, 13 lesions); (3) displacement of vessels of the carotid sheath in 67 lesions (ICA, 22 lesions; ICV, 50 lesions); and (4) malignant tumors encompassing the carotid sheath in 15 lesions. CONCLUSIONS: On CT images, the most common form of malignant lymph node lesions invading the carotid sheath is displacement of ICA and ICV. It is concluded that all forms of affecting carotid sheath demonstrating on the CT images are important in diagnosing the malignant invasion of the ICA and ICV.

Head and Neck Neoplasms↗
PubMed2005

[Diagnostic value of CT perfusion for parotid gland tumors].

PURPOSE: The aim of this study was to determine whether CT perfusion was valuable in differentiating benign tumors from malignant ones in the parotid gland. METHODS: Fifty-three parotid gland tumors, 35 benign and 18 malignant, in 51 patients were included in this study. All the tumors were confirmed histopathologically and examined with CT perfusion before operations. The parameters of CT perfusion, including blood flow (BF: ml x 100g(-1) x min(-1)), blood volume (BV: ml x 100g(-1)), mean transmit time (MTT:s) and permeability surface (PS: ml x 100g(-1) x min(-1)) were evaluated. Wilcoxon sign sum test, a nonparameters test for paired data were used to determine the statistical differences of parameters between the benign and malignant tumors. RESULTS: The mean values +/- standard variations of BF, BV, MTT and PS were 139.85+/-175.13, 17.16+/-15.67, 13.27+/-4.42, and 24.38+/-14.52 respectively in benign tumors, versus 231.69+/-205.29, 32.22+/-20.56, 11.40+/-3.95 and 38.28+/-19.00 respectively in malignant tumors. Except for MTT, the differences of BF, BV and PS between benign and malignant tumors were statistically significant (P<0.01). CONCLUSIONS: On the basis of the results of this study, the parameters of CT perfusion, BF, BV and PS, were valuable in differentiating benign and malignant tumors of the parotid gland.

Humans↗
PubMed2004

Expression of inwardly rectifying potassium channels (GIRKs) and beta-adrenergic regulation of breast cancer cell lines.

BACKGROUND: Previous research has indicated that at various organ sites there is a subset of adenocarcinomas that is regulated by beta-adrenergic and arachidonic acid-mediated signal transduction pathways. We wished to determine if this regulation exists in breast adenocarcinomas. Expression of mRNA that encodes a G-protein coupled inwardly rectifying potassium channel (GIRK1) has been shown in tissue samples from approximately 40% of primary human breast cancers. Previously, GIRK channels have been associated with beta-adrenergic signaling. METHODS: Breast cancer cell lines were screened for GIRK channels by RT-PCR. Cell cultures of breast cancer cells were treated with beta-adrenergic agonists and antagonists, and changes in gene expression were determined by both relative competitive and real time PCR. Potassium flux was determined by flow cytometry and cell signaling was determined by western blotting. RESULTS: Breast cancer cell lines MCF-7, MDA-MB-361 MDA-MB 453, and ZR-75-1 expressed mRNA for the GIRK1 channel, while MDA-MB-468 and MDA-MB-435S did not. GIRK4 was expressed in all six breast cancer cell lines, and GIRK2 was expressed in all but ZR-75-1 and MDA-MB-435. Exposure of MDA-MB-453 cells for 6 days to the beta-blocker propranolol (1 microM) increased the GIRK1 mRNA levels and decreased beta2-adrenergic mRNA levels, while treatment for 30 minutes daily for 7 days had no effect. Exposure to a beta-adrenergic agonist and antagonist for 24 hours had no effect on gene expression. The beta adrenergic agonist, formoterol hemifumarate, led to increases in K+ flux into MDA-MB-453 cells, and this increase was inhibited by the GIRK channel inhibitor clozapine. The tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a high affinity agonist for beta-adrenergic receptors stimulated activation of Erk 1/2 in MDA-MB-453 cells. CONCLUSIONS: Our data suggests beta-adrenergic receptors and GIRK channels may play a role in breast cancer.

Adenocarcinoma↗
PubMed2004

Altered regulation of Src upon cell detachment protects human lung adenocarcinoma cells from anoikis.

Src plays an important role in cell proliferation, differentiation, adhesion, and migration. Altered Src activity has been strongly implicated in the development, growth, progression, and metastasis of human cancers. We have analysed the change and regulation of Src upon cell detachment in anoikis-resistant human lung adenocarcinoma cells and compared with that of relatively normal and anoikis-sensitive epithelial cells. We found that Src activity was increased in the anoikis-resistant lung tumor cells when they were detached and cultured in suspension. The detachment-induced Src activation in the tumor cells compensates for the loss of cell survival signals caused by disruption of cell--matrix interactions and contributes to anoikis resistance of the tumor cells. Pyk2, rather than PI 3K/Akt or Erk, appears to be the key downstream effecter of Src in mediating the cell survival signals. The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells. The increased Src activity upon cell detachment may contribute to the metastasis potential of malignant tumors.

Adenocarcinoma↗