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Biomedical subjects

Z Chen

Publications and source records attributed to Z Chen.

At least 19 recordsLinked to original sources
PubMed2025

HLA-E and NKG2A Mediate Resistance to BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) is the first-line therapy for high-grade non-muscle-invasive bladder cancer (NMIBC), yet many patients experience recurrence due to immune evasion. We identify HLA-E and NKG2A as mediators of adaptive resistance involving chronic activation of NK and T cells in BCG-unresponsive tumors. Prolonged IFN-γ exposure enhances HLA-E and PD-L1 expression on recurrent tumors, accompanied by the accumulation of NKG2A+ NK and CD8 T cells. HLA-Ehigh tumor cells preferentially cluster near CXCL12-rich stromal regions with dense effector cell presence, underscoring a spatially segregated tumor architecture. Although cytotoxic lymphocytes retain effector potential, their activity is restrained by HLA-E/NKG2A and PD-L1/PD-1 pathways located in their immediate neighborhood within the bladder tumor microenvironment. These data reveal a spatially organized immune escape program that limits anti-tumor immunity. Our findings support dually targeting NKG2A and PD-L1 checkpoint blockade as a rational, bladder-sparing strategy for patients with BCG-unresponsive NMIBC.

BCG-unresponsive↗
PubMed2007

DNA repair capacity as a possible biomarker of breast cancer risk in female BRCA1 mutation carriers.

The BRCA1 gene product helps to maintain genomic integrity through its participation in the cellular response to DNA damage: specifically, the repair of double-stranded DNA breaks. An impaired cellular response to DNA damage is a plausible mechanism whereby BRCA1 mutation carriers are at increased risk of breast cancer. Hence, an individual's capacity to repair DNA may serve as a useful biomarker of breast cancer risk. The overall aim of the current study was to identify a biomarker of DNA repair capacity that could distinguish between BRCA1 mutation carriers and non-carriers. DNA repair capacity was assessed using three validated assays: the single-cell alkaline gel electrophoresis (comet) assay, the micronucleus test, and the enumeration of gamma-H2AX nuclear foci. DNA repair capacity of peripheral blood lymphocytes from 25 cancer-free female heterozygous BRCA1 mutation carriers and 25 non-carrier controls was assessed at baseline and following cell exposure to gamma-irradiation (2 Gy). We found no significant differences in the mean tail moment, in the number of micronuclei or in the number of gamma-H2AX nuclear foci between the carriers and non-carriers at baseline, and following gamma-irradiation. These data suggest that these assays are not likely to be useful in the identification of women at a high risk for breast cancer.

Adult↗
PubMed2007

Arsenic trioxide and acute promyelocytic leukemia: clinical and biological.

Arsenic has recently been identified as an effective drug in the treatment of newly diagnosed and relapsed acute promyelocytic leukemia. Indeed, arsenic trioxide combined with all-trans retinoic acid shows a synergistic effect. Mechanistically, arsenic targets the key leukemogenic protein PML-RARalpha, setting up a new example of molecular target-based cancer therapy.

Antineoplastic Agents↗
PubMed2007

Anomalous intracranial venous drainage associated with basal ganglia calcification.

We describe the neuroradiologic findings in a 7-year-old boy with anomalous intracranial venous drainage and cerebral calcification. CT scans demonstrated that his scalp mass was a plexus of scalp veins filled through the emissary foramen, and there were cerebral calcifications. Angiography revealed bilateral sigmoid sinus atresia with most of the intracranial venous drainage via the prominent mastoid emissary veins into dilated scalp vein. The possible relationship between cerebral calcification and anomalous intracranial venous drainage is discussed.

Basal Ganglia Diseases↗
PubMed2006

The optimal structure-conductivity relation in epoxy-phthalocyanine nanocomposites.

Phthalcon-11 (aquocyanophthalocyaninatocobalt (III)) forms semiconducting nanocrystals that can be dispersed in epoxy coatings to obtain a semiconducting material with a low percolation threshold. We investigated the structure-conductivity relation in this composite and the deviation from its optimal realization by combining two techniques. The real parts of the electrical conductivity of a Phthalcon-11/epoxy coating and of Phthalcon-11 powder were measured by dielectric spectroscopy as a function of frequency and temperature. Conducting atomic force microscopy (C-AFM) was applied to quantify the conductivity through the coating locally along the surface. This combination gives an excellent tool to visualize the particle network. We found that a large fraction of the crystals is organized in conducting channels of fractal building blocks. In this picture, a low percolation threshold automatically leads to a conductivity that is much lower than that of the filler. Since the structure-conductivity relation for the found network is almost optimal, a drastic increase in the conductivity of the coating cannot be achieved by changing the particle network, but only by using a filler with a higher conductivity level.

Journal Article↗
PubMed2006

Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target.

Glioblastoma is the most common primary malignant brain tumor of adults and one of the most lethal of all cancers. Patients with this disease have a median survival of 15 months from the time of diagnosis despite surgery, radiation, and chemotherapy. New treatment approaches are needed. Recent works suggest that glioblastoma patients may benefit from molecularly targeted therapies. Here, we address the compelling need for identification of new molecular targets. Leveraging global gene expression data from two independent sets of clinical tumor samples (n = 55 and n = 65), we identify a gene coexpression module in glioblastoma that is also present in breast cancer and significantly overlaps with the "metasignature" for undifferentiated cancer. Studies in an isogenic model system demonstrate that this module is downstream of the mutant epidermal growth factor receptor, EGFRvIII, and that it can be inhibited by the epidermal growth factor receptor tyrosine kinase inhibitor Erlotinib. We identify ASPM (abnormal spindle-like microcephaly associated) as a key gene within this module and demonstrate its overexpression in glioblastoma relative to normal brain (or body tissues). Finally, we show that ASPM inhibition by siRNA-mediated knockdown inhibits tumor cell proliferation and neural stem cell proliferation, supporting ASPM as a potential molecular target in glioblastoma. Our weighted gene coexpression network analysis provides a blueprint for leveraging genomic data to identify key control networks and molecular targets for glioblastoma, and the principle eluted from our work can be applied to other cancers.

Animals↗
PubMed2006

Protective efficacy of a targeted anti-caries DNA plasmid against cariogenic bacteria infections.

We have previously reported that a targeted anti-caries DNA plasmid pGJA-P/VAX which was constructed against the antigenic determinants of Streptococcus mutans (S. mutans) successfully induced antibody responses in mice and monkeys. The present study explored the protective efficacy of pGJA-P/VAX against cariogenic bacterial challenge. Groups of rats were orally challenged with S. mutans or Streptococcus sobrinus (S. sobrinus) and then immunized with pGJA-P/VAX or the vector pVAX1 intranasally. Serum IgG and salivary IgA antibody levels were assessed by an enzyme-linked immunosorbent assay and caries activity was evaluated by the Keyes method. The results showed that specific salivary IgA antibody responses were induced following intranasal vaccination with pGJA-P/VAX. Moreover, immunization with pGJA-P/VAX resulted in significantly reduced enamel and dentinal caries lesions in rats after S. mutans infection and significantly reduced enamel caries lesions after S. sobrinus infection. Thus, pGJA-P/VAX was not only protective toward S. mutans infection, but also provided cross-strain protection against S. sobrinus infection in rats.

Administration, Intranasal↗
PubMed2006

Combined therapy of transcatheter arterial chemoembolisation and three-dimensional conformal radiotherapy for hepatocellular carcinoma.

To evaluate the toxicity and efficacy of combined therapy of three-dimensional conformal radiotherapy (3DCRT) and transcatheter arterial chemoembolisation (TACE) for hepatocellular carcinoma (HCC). 50 HCC patients treated by combined TACE and 3DCRT were selected from a patient database. Sequence of treatments was that TACE was performed first, followed by 3DCRT with an interval of about 4 weeks between. TACE was administered by 5-Fu 500-600 mg m(-2), cis-platinum 30-40 mg m(-2), epi-adriamycin 40-60 mg m(-2) mixed with iodized oil and Gelfoam embolisation. A median of two courses of TACE was given. 3DCRT was delivered by 4-6 coplanar or non-coplanar fields. The mean tumour dose was 43.0+/-6.3 Gy by conventional fractionation (2 Gy per fraction, five fractions a week), and mean dose to normal liver, 19.1+/-6.3 Gy. Acute hepatic toxicities were notable in five patients (10%) with Common Toxicity Criteria (CTC) grade 1 in two cases and grade 3 in three patients, but all recovered eventually. Two patients developed radiation-induced liver disease (RILD) and died soon after the onset of RILD. Four patients had Radiation Therapy Oncology Group (RTOG) grade 1 acute gastrointestinal complication and one patient had acute gastrointestinal bleeding. Five patients experienced RTOG Grade 1 leukopenia and Grade 2 in five cases. Nine patients achieved have partial response, and 37 patients were in stable disease. Four patients were observed to have progressive disease. The overall survival rates at 1 year, 2 years and 3 years were 60%, 38% and 28%, respectively, with a median survival period of 17 months. Irradiation dose, T-stage and hepatic cirrhosis were identified as independent predictors for overall survival by Cox proportional regression analysis. The 1 year, 2 years and 3 years local progression-free rates were 74%, 57% and 38%, and the 1 year, 2 years and 3 years distant metastasis rates were 15%, 21% and 40%, respectively. The combined modality of TACE and 3DCRT was tolerable for the majority of HCC patients, resulted in good outcome and warrants for further prospective trial.

Adult↗
PubMed2006

Optical measurement and control of spin diffusion in n-doped GaAs quantum wells.

Transient spin gratings are used to study spin diffusion in lightly n-doped GaAs quantum wells at low temperatures. The spin grating is shown to form in the excess electrons from doping, providing spin relaxation and transport properties of the carriers most relevant to spintronic applications. We demonstrate that spin diffusion of the these carriers is accelerated by increasing the density or energy of the optically excited carriers. These results can be used to better understand and even control spin transport in experiments that optically excite spin-polarized carriers.

Journal Article↗
PubMed2006

A prospective, blinded analysis of thymidylate synthase and p53 expression as prognostic markers in the adjuvant treatment of colorectal cancer.

BACKGROUND: Despite previous studies, uncertainty has persisted about the role of thymidylate synthase (TS) and p53 status as markers of prognosis in colorectal cancer (CRC). PATIENTS AND METHODS: A total of 967 patients accrued to a large adjuvant trial in CRC were included in a prospectively planned molecular substudy, and of them, 59% had rectal cancer and about 90% received adjuvant chemotherapy (either systemically or randomly allocated to intraportal 5-fluorouracil infusion or both). TS and p53 status were determined, blinded to any clinical data, by immunohistochemistry using a validated polyclonal antibody or the DO-7 clone, respectively, and their relationships with overall survival were examined. RESULTS: High TS expression was observed in 58% and overexpression of p53 in 60% of tumours. TS expression correlated with tumour stage, and p53 overexpression, with rectal cancers. There was no evidence that either marker was significantly associated with survival by either univariate (TS hazard ratio (HR) = 0.94, 95% CI 0.76-1.18 and P = 0.6 and p53 HR = 0.98, 95% CI 0.78-1.23 and P = 0.9) or multivariate analyses (TS HR = 0.99, 95% CI 0.79-1.25 and P = 0.9 and p53 HR = 0.98, 95% CI 0.78-1.23 and P = 0.8). CONCLUSIONS: Neither TS nor p53 expression has significant prognostic value in the adjuvant setting of CRC.

Antimetabolites, Antineoplastic↗
PubMed2006

Antisense Smo under the control of the PTCH1 promoter delivered by an adenoviral vector inhibits the growth of human pancreatic cancer.

Hedgehog (Hh) signaling pathway is crucial in growth and patterning during embryonic development. Recent data have shown an association of its activation with cancer formation and maintenance. A ligand-dependent activation, where Hh components (SHH, PTCH1, Smo and GLi1) are aberrantly expressed with PTCH1 being a negative feedback regulator, is a newly identified mechanism for pancreatic carcinogenesis. In this study, we developed a cell-specific cytotoxic model for the treatment of human pancreatic cancer (HPC) in which expression of antisense Smo (SAS) was under the control of the PTCH1 promoter (ptch/p) delivered by an adenoviral vector (Ad-ptch/p-SAS). We observed that the cell-specific cytotoxicity in HPC cells depended on the expressions of inherent PTCH1, Smo and GLi1 in the target cells in which the Hh pathway was presumed to be activated. Fluorescence-activated cell sorting analysis indicated that the cell death was apoptosis. Western blot showed that Smo protein in the infected cells significantly decreased. Furthermore, an in vivo experiment demonstrated that such Hh activity-cell-specific cytotoxicity was achieved by daily intratumoral injection of Ad-ptch/p-SAS (10(9) plaque-forming unit) for 5 days. Our study suggests that targeting at the Hh signaling pathway may be an effective novel gene therapeutic strategy alone or in combination with other agents for the treatment of pancreatic cancer.

Adenoviridae↗
PubMed2006

Functional duality of merlin: a conundrum of proteome complexity.

Merlin and ezrin proteins belong to the same gene family, i.e., MERM containing merlin, ezrin radixin and moesin. Members of this family possess an extensive homology in their amino acid sequences. It has been shown that merlin is a tumor suppressor, while ezrin is a promoter in tumor progression. The expression of these two proteins is commonly found inversely proportional to each other in cancer cells, i.e. down-regulation of merlin concomitant with over-expression of ezrin and vice versa. However, when determining merlin and ezrin in ovarian carcinoma cells, we have observed that both merlin and ezrin could be over-expressed simultaneously in some ovarian cancer (OVCA) cell lines and OVCA ascites cells, suggesting that merlin could be an oncoprotein rather than a tumor suppressor protein in certain OVCA cells. The functional duality of merlin might represent a paradigm in proteome complexity and is especially important in investigating multifactorial diseases such as cancer.

Cell Line, Tumor↗
PubMed2006

The inhibitory effect of magnolol from Magnolia officinalis on glucosyltransferase.

Dental caries has been an intractable disease in spite of intense dental research. Glucosyltransferase (GTF) enzyme plays the most important role in the development of dental caries. In our previous studies, magnolol, a compound from Magnolia officinalis Rehder et Wilson (Magnoliaceae), was shown to possess a strong anti-GTF activity. The purpose of the present study was to examine the effect of magnolol on the functional domains of GTF for the purpose of defining its anti-GTF activity mechanism. GTF-I which was prepared from Streptococcus milleri transformant KSB8 cells expressing the gtfB gene was used. The results demonstrated magnolol reduced total glucan synthesis, depending on the magnolol concentration. There were no significant differences in Michaelis constant (K(m)) values between the presence and absence of magnolol as determined by Lineweaver-Burk plot, and maximum velocity (V(m)) in the presence of magnolol was lower than that in its absence. Magnolol significantly inhibited both sucrose hydrolysis and glucosyl transfer to glucan by GTF-I. Free glucose in the presence of magnolol was reduced by 33-48% as compared to in its absence, while the quantity of glucan was reduced by 75-82%. These findings suggested that magnolol inhibited both two sequential reaction phases of GTF non-competitively by operating on the glucan-binding domain, but not on the catalytic domain. Magnolol could be a valuable resource for the exploration of novel bioactive compounds in natural products.

Biphenyl Compounds↗
PubMed2006

Eriocalyxin B induces apoptosis of t(8;21) leukemia cells through NF-kappaB and MAPK signaling pathways and triggers degradation of AML1-ETO oncoprotein in a caspase-3-dependent manner.

Diterpenoids isolated from Labiatae family herbs have strong antitumor activities with low toxicity. In this study, Eriocalyxin B (EriB), a diterpenoid extracted from Isodon eriocalyx, was tested on human leukemia/lymphoma cells and murine leukemia models. Acute myeloid leukemia cell line Kasumi-1 was most sensitive to EriB. Significant apoptosis was observed, concomitant with Bcl-2/Bcl-XL downregulation, mitochondrial instability and caspase-3 activation. AML1-ETO oncoprotein was degraded in parallel to caspase-3 activation. EriB-mediated apoptosis was associated with NF-kappaB inactivation by preventing NF-kappaB nuclear translocation and inducing IkappaBalpha cleavage, and disturbance of MAPK pathway by downregulating ERK1/2 phosphorylation and activating AP-1. Without affecting normal hematopoietic progenitor cells proliferation, EriB was effective on primary t(8;21) leukemia blasts and caused AML1-ETO degradation. In murine t(8;21) leukemia models, EriB remarkably prolonged the survival time or decreased the xenograft tumor size. Together, EriB might be a potential treatment for t(8;21) leukemia by targeting AML1-ETO oncoprotein and activating apoptosis pathways.

Animals↗
PubMed2006

Segmental uniparental isodisomy on 5q32-qter in a patient with childhood-onset schizophrenia.

Schizophrenia is a severe mental disorder affecting approximately 1% of the world's population. Although the aetiology of schizophrenia is complex and multifactorial, with estimated heritabilities as high as 80%, genetic factors are the most compelling. Childhood-onset schizophrenia (COS), defined as onset of schizophrenia before the age of 13 years, is a rare and malignant form of the illness that may have more salient genetic influence. The first known case of paternal segmental uniparental isodisomy (iUPD) on 5q32-qter in a patient with COS is described, which adds to the previously known high rates of chromosomal abnormalities reported in this sample. iUPD is a rare genetic condition in which the offspring receives two chromosomal homologues from one parent. Segmental UPD is defined as UPD on a portion of a chromosome with biparental inheritance seen in the rest of the homologous pair. Complications owing to this abnormality may arise from malfunctioning imprinted genes or homozygosity of recessive disease-causing mutations. This aberration became apparent during whole-genomic screening of a COS cohort and is of particular interest because 5q has been implicated in schizophrenia by several genomewide linkage studies and positive gene associations. This report, therefore, presents more evidence that schizophrenia susceptibility gene, or genes, may be found on distal 5q.

Adolescent↗
PubMed2006

Molecular response in acute promyelocytic leukemia: a direct comparison of regular and real-time RT-PCR.

Evaluation of molecular response is important for the diagnosis and monitoring of minimal residual disease in patients with acute promyelocytic leukemia (APL). In this study, we analyzed the molecular response by regular reverse transcription-polymerase chain reaction (RT-PCR) and quantitative real-time RT-PCR in 31 newly diagnosed patients. The real-time RT-PCR results are reported as normalized DoseN and log-reduction (3.0-4.9 log-reduction as minor and > or =5.0 log-reduction as major molecular response). After induction therapy and completion of consolidation, minor molecular response was documented in 35.5 and 96.8% patients, respectively, which was equivalent to the regular RT-PCR (22.6 and 96.8%), whereas the major molecular response rate was significantly lower (12.9 and 90.3%, respectively). All patients achieved major molecular response during and after maintenance therapy. During the follow-up study, loss of major molecular response was observed in two patients, which was associated with subsequent loss of minor molecular response, positive RT-PCR and then documentation of central nervous system leukemia or clinical relapse in 3-6 months. For summary, we demonstrated that the real-time RT-PCR is potentially superior to regular RT-PCR in evaluation of molecular response in APL patients and that reporting real-time RT-PCR data by log-reduction is feasible and clinically relevant.

Follow-Up Studies↗
PubMed2006

Increased expression of cysteinyl leukotriene receptor-1 in the brain mediates neuronal damage and astrogliosis after focal cerebral ischemia in rats.

Cysteinyl leukotrienes are potent pro-inflammatory mediators. Cysteinyl leukotriene receptor 1 is one of the two cysteinyl leukotriene receptors cloned. We recently reported that cysteinyl leukotriene receptor 1 antagonists protected against cerebral ischemic injury, and an inducible expression of cysteinyl leukotriene receptor 1 was found in neuron- and glial-appearing cells after traumatic injury in human brain. To determine the role of cysteinyl leukotriene receptor 1 in ischemic brain injury, we investigated the temporal and spatial profile of cysteinyl leukotriene receptor 1 expression in rat brain from 3 h to 14 days after 30 min of middle cerebral artery occlusion, and observed the effect of pranlukast, a cysteinyl leukotriene receptor 1 antagonist, on the ischemic injury. We found that cysteinyl leukotriene receptor 1 mRNA expression was up-regulated in the ischemic core both 3-12 h and 7-14 days, and in the boundary zone 7-14 days after reperfusion. In the ischemic core, cysteinyl leukotriene receptor 1 was primarily localized in neurons 24 h, and in macrophage/microglia 14 days after reperfusion; while in the boundary zone it was localized in proliferated astrocytes 14 days after reperfusion. Pranlukast attenuated neurological deficits, reduced infarct volume and ameliorated neuron loss in the ischemic core 24 h after reperfusion; it reduced infarct volume, ameliorated neuron loss and inhibited astrocyte proliferation in the boundary zone 14 days after reperfusion. Thus, we conclude that cysteinyl leukotriene receptor 1 mediates acute neuronal damage and subacute/chronic astrogliosis after focal cerebral ischemia.

Animals↗