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M Xu

Publications and source records attributed to M Xu.

At least 37 records · Page 2Linked to original sources
PubMed2004

Modelling heat-induced radiosensitization: clinical implications.

Clinically achievable minimum tumour temperatures are in the order of about 41 degrees C. Therefore, it is important to evaluate mechanisms by which temperatures in this range might enhance cytotoxicity. Previous in vitro studies have demonstrated that 1-4 h (depending on the sequencing of modalities) of heating at 41 degrees C produces substantial heat-induced radiosensitization with little or no cell killing by heat alone. The increased radiation sensitivity is best modelled as a change in the single hit, alpha, parameter (with no significant effect on the two-hit parameter, beta) of the cell survival curve. The implications of heat-induced radiosensitization being mediated by a change in alpha on the traditional thermal enhancement ratio (for various radiation doses/fraction and alpha/beta) are reviewed. Response rates for a cohort of 60 patients enrolled on a prospective thermal dose escalation study are modelled assuming that the thermal dose dependence of heat-induced radiosensitization is modulated by a heat-induced delta alpha. The clinical data are fitted with delta alpha about 0.05-0.1 Gy-1. Randomized trials reported in the literature and the implication for the design of future prospective trials are reviewed in light of these observations.

Animals↗
PubMed2004

Transfection of human tumour cells with Mre11 siRNA and the increase in radiation sensitivity and the reduction in heat-induced radiosensitization.

Double-strand DNA breaks (DSBs) are potentially lethal DNA lesions induced by ionizing radiation. In eukaryotes, DSBs can be repaired by homologous recombination (HR) or non-homologous end-joining (NHEJ). DNA repair protein Mre11 participates in both the NHEJ and HR DNA repair pathways. Hyperthermia has been used clinically as a radiosensitizer. However, the mechanisms by which radiosensitization is induced by hyperthermia, especially moderate hyperthermia (41 degrees C) are not fully understood. Previous studies suggest that 41 degrees C reduces the nuclear Mre11 protein level in a manner that correlates with heat-induced changes in radiation sensitivity. Therefore, siRNA technology was used in the present study to reduce Mre11 gene expression to determine if reduced Mre11 protein levels induced radiosensitization and if such radiosensitization is similar to that induced by moderate hyperthermia. The results show that (1) the cellular level of the Mre11 protein was reduced about 60 +/- 18% by a 24-h treatment with siRNA. Results from the Mre11 protein turnover assay showed a half-life of 11.6 +/- 0.5 h for the Mre11 protein, which is consistent with reduction in protein level in 24 h after Mre11 siRNA treatment assuming a delay of 4-8 h to reduce RNA levels. After 48 h in siRNA, cellular Mre11 protein levels increased to approximately pretreatment levels. NSY cells were sensitized to ionizing radiation after 24 h of treatment with Mre11 siRNA. Two hours at 41 degrees C did not increase the radiation sensitivity of cells with a reduced Mre11 protein level following a 24-h siRNA treatment. These data support the conclusion that the DSB repair protein, Mre11, appears to be a target for radiosensitization by moderate hyperthermia.

Adenocarcinoma↗
PubMed2004

Effects of heat shock on the Mre11/Rad50/Nbs1 complex in irradiated or unirradiated cells.

The mechanism by which hyperthermia sensitizes mammalian cells to ionizing radiation remains to be elucidated, but an overwhelming amount of circumstantial evidence suggests that heat radiosensitization might be mediated by inhibition of double-strand break repair, particularly after exposure of irradiated cells to heat treatments in excess of about 43 degrees C. In mammalian cells, double-strand break repair usually occurs via two pathways, non-homologous end-joining and homologous recombination. Several reports suggest a role for non-homologous end-joining in heat radiosensitization, while others implicate homologous recombination as a target. However, cell lines that are compromised in either the non-homologous end-joining or homologous recombination pathway are still capable of being radiosensitized, suggesting that heat affects both pathways. Indeed, several of the proteins involved in one or both of these pathways have been observed to undergo alterations or translocation after unirradiated or irradiated cells are exposed to heat shock. The work summarized in this review implicates proteins of the Mre11/Rad50/Nbs1 complex as targets for heat radiosensitization.

Acid Anhydride Hydrolases↗
PubMed2004

Genetic polymorphism of the accessory gene regulator (agr) locus in Staphylococcus epidermidis and its association with pathogenicity.

Staphylococcus epidermidis has become one of the most important causes of nosocomial infections in recent years. The staphylococcal accessory gene regulator (agr) is the most important locus responsible for the regulation of virulence factors, and it has been shown to be polymorphic. The aim of this study was to investigate the agr locus and its genetic polymorphisms in different Chinese S. epidermidis isolates and the relationship between genetic polymorphisms and pathogenicity. Specific PCR was used to amplify the different agr groups. Results were confirmed by restriction enzyme digestion and sequence analysis. agr mutations were detected and three agr groups of S. epidermidis were determined. Of the isolates, 12 % were pathogenic S. epidermidis and 17 % had naturally occurring agr mutations (P > 0.05). Pathogenic S. epidermidis isolates comprised 68.2 % agr group I, 19.3 % group II and 12.5 % group III, while isolates from healthy controls comprised 39 % agr group I, 51 % group II and 10 % group III (P < 0.01). The percentages of agr locus mutants and the three agr groups in different hospitals showed no significant differences (P > 0.05). The percentage of agr group I S. epidermidis isolated from catheters and blood was higher than that isolated from the other clinical specimens. This is the first study to investigate the genetic polymorphism of agr in S. epidermidis in China. The mean percentage of agr locus mutants was 14.9 % (12 % in clinical specimens; 17.7 % in controls). Genetic polymorphism of agr in S. epidermidis was linked to its pathogenicity; group I was associated with pathogenicity, while most isolates from healthy subjects were group II. The mechanism is to be investigated.

Bacterial Proteins↗
PubMed2003

Narrowing down the region of the Vf locus for scab resistance in apple using AFLP-derived SCARs.

A narrow-down strategy to restrict the Vf region, which controls resistance to the fungal disease apple scab in apple, to a genetic distance of 0.4 cM is presented. Using 11 AFLP-derived SCARs and three RAPD-derived SCARs, all linked to the Vf gene, we subjected 1,412 scab-resistant individuals from 16 mapping populations to genotype analysis. Eleven recombinant individuals were identified within a genetic distance of 0.9 cM around the Vf gene. Using these 11 recombinants, we achieved fine-resolution of several AFLP-derived SCAR markers surrounding the Vf gene, resulting in the following genetic linkage map: ACS-6 and ACS are located left of the Vf gene at genetic distances of 0.2 cM and 0.1 cM, respectively; ACS-7 and ACS-9 are inseparable from the Vf gene; ACS-8, ACS-10, and ACS-4 are located to the right of the Vf gene at genetic distances of 0.1 cM, 0.4 cM, and 0.5 cM, respectively; the remaining five SCARs-ACS-11, ACS-5, ACS-2, ACS-1, and AL07-are inseparable and are located right of the Vf gene at a genetic distance of 0.7 cM. By integrating this linkage data with our previous physical map, we generated a revised map of the narrowed-down region of Vf.

Ascomycota↗
PubMed2003

Anomalous diffraction of light with geometrical path statistics of rays and a Gaussian ray approximation.

The anomalous-diffraction theory (ADT) of extinction of light by soft particles is shown to be determined by a statistical distribution of the geometrical paths of individual rays inside the particles. Light extinction depends on the mean and the mean-squared geometrical paths of the rays. Analytical formulas for optical efficiencies from a Gaussian distribution of the geometrical paths of rays are derived. This Gaussian ray approximation reduces to the exact ADT in the intermediate case of light scattering for an arbitrary soft particle and describes well the extinction of light from a system of randomly oriented and (or) polydisperse particles. The implications for probing of the sizes and shapes of particles by light extinction are discussed.

Journal Article↗
PubMed2003

The disposition and metabolism of 2-amino-3-methylimidazo-[4,5-f]quinoline in the F344 rat at high versus low doses of indole-3-carbinol.

Indole-3-carbinol (I3C), a compound found in cruciferous vegetables, inhibits the formation of DNA adducts, colonic aberrant crypts, and tumors in rats given heterocyclic amines, such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Previous mechanism studies indicated that I3C induces cytochromes P4501A1 (CYP1A1) and CYP1A2, as well as phase 2 pathways, leading to enhanced metabolism and excretion of IQ. However, the chemopreventive activity is dependent on the dose of I3C, and at low doses which do not induce CYP1A activity, there is evidence for increased IQ-DNA adduct formation in vivo. The present study examined the fate of IQ in the rat and the profile of urinary metabolites across a broad range of I3C doses. Male F344 rats were given a single injection of I3C by oral gavage, at a dose equivalent to that received from a single daily exposure to 0, 5, 10, 25, 50, 100, 200, 500 or 1000 ppm I3C in the diet, or they were given the 1000-ppm-equivalent dose of I3C for 14 consecutive days. Subsequently, each rat was given 14C-labeled IQ (5 mg/kg; 0.1 mCi/kg) and the animal was sacrificed 8 h later. With increasing I3C, there was a dose-dependent decrease in IQ-associated radiolabel in several systemic tissues, and an increase in the radiolabel eliminated via the feces. In the urine, there was a dose-dependent increase in IQ-5-O-glucuronide and IQ-5-O-sulfate metabolites, and a concomitant decrease in the IQ-sulfamate at intermediate and high doses of I3C. However, 5- and 10 ppm-equivalent doses of I3C enhanced the levels of IQ-sulfamate compared with controls, possibly due to the high ratio of hepatic CYP1A2 versus CYP1A1 activities at these I3C doses. The possible significance of the low versus high dose effects are discussed in the context of ongoing clinical trials with I3C and the reported chemopreventive mechanisms in vivo.

Administration, Oral↗
PubMed2003

Apoptosis modulatory activities of transiently expressed Bcl-2: roles in cytochrome C release and Bax regulation.

Bcl-2 and Bcl-X(L) are pro-survival members of the Bcl-2 family. These proteins have been shown to antagonize the pro-apoptotic activity of Bax and promote cell survival through blocking Bax translocation from the cytosol to mitochondria and by preventing the release of cytochrome c. However, it has been recently reported that transiently expressed Bcl-2 unexpectedly leads to significant cell toxicity. To study this intriguing phenomenon, we have carried out further analyses into the properties of transiently expressed Bcl-2. We found that various isoforms of human and different species of Bcl-2 were equally capable of inducing apoptosis. In addition, we discovered that transient expression of Bcl-2, unlike its pro-survival homolog Bcl-X(L), can lead to the release of cytochrome c from mitochondria and that the resulting cell death can be inhibited by caspase and calpain inhibitors. Moreover, we have shown that unlike the pro-apoptotic protein Bid, the toxicity associated with the transient expression of Bcl-2 occurs independent of the activity of the endogenous Bax. Finally, we found that in spite of its intrinsic toxicity, transiently expressed Bcl-2 is fully capable of blocking the ectopically expressed Bax from localizing to mitochondria. Taken together, these studies demonstrate that transiently expressed Bcl-2 displays opposing functional properties.

Animals↗
PubMed2003

Effects of intrathecally administered dexmedetomidine, MPV-2426 and tizanidine on EMG in rats.

BACKGROUND: When administered intrathecally, alpha-2 adrenergic agonists produce spinally mediated antinociception, but also rapidly redistribute to supraspinal sites. This investigation the compared EMG effects of intrathecally administered dexmedetomidine, MPV-2426 (fadolmidine), and tizanidine in Sprague-Dawley rats, which has not been previously described. METHODS: We studied electromyographic (EMG) responses of the head and gastrocnemius muscles, antinociception using the tail-flick test, and sedation by using observer assessment. Saline, dexmedetomidine (0.5 microg, 2.5 microg and 12.5 microg), MPV-2426 (2 microg, 10 microg and 50 microg) and tizanidine (2 microg, 10 microg and 50 microg) were administered intrathecally. RESULTS: Tizanidine 50 microg, MPV-2426 10 microg and 50 microg, and dexmedetomidine 2.5 microg and 12.5 microg, decreased EMG activity (P < 0.005). Dexmedetomidine 12.5 microg, MPV-2426 50 microg, and tizanidine 10 microg and 50 microg increased tail-flick latencies (P < 0.01). Dexmedetomidine alone significantly increased the magnitude of observer-assessed sedation (P < 0.0001). CONCLUSION: We conclude that in rats, intrathecally administered dexmedetomidine, MPV-2426 and tizanidine have dose-dependent effects on EMG. At antinociceptive doses, the EMG effects of these three alpha-2 adrenergic agonists differ (dexmedetomidine > MPV-2426 > tizanidine).

Adrenergic alpha-Agonists↗
PubMed2003

Generating MHC Class II+/Ii- phenotype after adenoviral delivery of both an expressible gene for MHC Class II inducer and an antisense Ii-RNA construct in tumor cells.

Tumor cells engineered by gene transduction to be MHC Class II+/Ii- are novel APCs capable of presenting endogenous tumor antigen epitopes to activate T helper cells. The MHC Class II+/Ii- tumor cell phenotype is created by transfecting genes for either CIITA or IFN-gamma, and inhibiting induced Ii mRNA by an Ii reverse gene construct (Ii-RGC). Adenoviral vectors are preferred for the delivery of such genes because of high infection efficiency and ubiquity of the adenoviral receptor on many cell types and tumors. Here we show that at 5 MOI (multiplicity of infection), recombinant adenoviruses with CIITA or IFN-gamma genes converted virtually all MC-38 colon adenocarcinoma cells and Renca renal carcinoma cells in culture to MHC Class II+/Ii+ cells. A single recombinant adenovirus with both genes for IFN-gamma and Ii-RGC (rAV/IFN-gamma/Ii-RGC) efficiently induced the MHC Class II+/Ii- phenotype. Injection of tumor nodules with rAV/Ii-RGC and rAV/CIITA/IFN-gamma combined with a suboptimal dose of rAV/IL-2 induced a potent antitumor immune response. The methods are adaptable for producing enhanced genetic vaccines, attenuated virus vaccines (eg, vaccinia), and ex vivo cell-based vaccines (dendritic and tumor cells).

Adenoviridae↗
PubMed2003

Engineering physiologically regulated insulin secretion in non-beta cells by expressing glucagon-like peptide 1 receptor.

Glucagon-like peptide 1 (GLP-1) is released from neuroendocrine cells in the intestine in the postprandial state and augments glucose-stimulated insulin secretion from pancreatic beta cells. To develop non-beta cells that exhibit physiologically regulated insulin secretion, we coexpressed the GLP-1 receptor and human insulin in primary rat pituitary cells using adenovirus-mediated gene transfer. The transduced cells were analyzed in a perifusion system and after transplantation into mice. Normal pituitary cells do not express the GLP-1 receptor as shown by the absence of GLP-1 receptor mRNA and the inability of GLP-1 to stimulate pituitary hormone secretion. Following transduction with an adenovirus carrying the GLP-1 receptor cDNA, the pituitary cells expressed functional GLP-1 receptors as reflected by the ability of GLP-1 to stimulate secretion of pituitary hormones. When both the GLP-1 receptor and human insulin were introduced, GLP-1 stimulated cosecretion of human insulin and endogenous pituitary hormones. GLP-1 was similar in potency to the hypothalamic-releasing hormones and stimulated hormone secretion in a dose-dependent fashion. In contrast to pancreatic beta cells, the hormone-releasing effect of GLP-1 on transduced pituitary cells was not dependent on the concentration of extracellular glucose. After transplantation of pituitary cells coexpressing human insulin and GLP-1 receptor into mice, enteral glucose stimulated insulin secretion. These results demonstrate a new approach to engineer physiologically regulated insulin secretion by non-beta cells.

Adenoviridae↗
PubMed2003

Time-dependence of SI RA neuron response to cutaneous flutter stimulation.

Spike discharge activity of RA-type SI cortical neurons was recorded extracellularly in anesthetized monkeys and cats. Multiple applications (trials) of 10-50 Hz sinusoidal vertical skin displacement stimulation ("flutter") were delivered to the receptive field (RF). Analysis revealed large and systematic temporal trends not only in SI RA neuron responsivity (measured as spikes/s and as spikes/stimulus cycle), but also in entrainment, and in phase angle of the entrained responses. In contrast to SI RA neurons, the response of RA skin afferents to comparable conditions of skin flutter stimulation exhibited little or no dynamics. The occurrence and form of the SI RA neuron response dynamics that accompany skin flutter stimulation are shown to depend on factors such as stimulus frequency and the locus of the recording site in the global cortical response pattern. Comparison of recordings obtained in near-radial vs tangential microelectrode penetrations further reveals that the SI RA neuron response dynamics that occur during skin flutter stimulation are relatively consistent within, but heterogeneous across column-sized regions. The observed SI RA neuron response dynamics are suggested to account, in part, for the improved capacity to discriminate stimulus frequency after an exposure ("adaptation") to skin flutter stimulation (Goble and Hollins, J Acoust Soc Am 96: 771-780, 1994). Parallels with recent proposals about the contributions to visual perception of short-term primary sensory cortical neuron dynamics and synchrony in multineuron spike activity patterns are identified and discussed.

Anesthesia↗
PubMed2003

Description and clinical treatment of an early outbreak of severe acute respiratory syndrome (SARS) in Guangzhou, PR China.

Severe acute respiratory syndrome (SARS), now known to be caused by a coronavirus, probably originated in Guangdong province in southern China in late 2002. The first major outbreak occurred in Guangzhou, the capital of Guangdong, between January and March 2003. This study reviews the clinical presentation, laboratory findings and response to four different treatment protocols. Case notes and laboratory findings were analysed and outcome measures were collected prospectively. The SARS outbreak in Guangdong province and the outbreak in Guangzhou associated with hospitals in the city are described, documenting clinical and laboratory features in a cohort of 190 patients randomly allocated to four treatment regimens. Patients were infected by close contact in either family or health-care settings, particularly following procedures likely to generate aerosols of respiratory secretions (e.g. administration of nebulized drugs and bronchoscopy). The earliest symptom was a high fever followed, in most patients, by dyspnoea, cough and myalgia, with 24 % of patients complaining of diarrhoea. The most frequent chest X-ray changes were patchy consolidation with progression to bilateral bronchopneumonia over 5-10 days. Thirty-six cases developed adult respiratory distress syndrome (ARDS), of whom 11 died. There was no response to antibiotics. The best response (no deaths) was seen in the group of 60 patients receiving early high-dose steroids and nasal CPAP (continuous airway positive pressure) ventilation; the other three treatment groups had significant mortality. Cross-infection to medical and nursing staff was completely prevented in one hospital by rigid adherence to barrier precautions during contact with infected patients. The use of rapid case identification and quarantine has controlled the outbreak in Guangzhou, in which more than 350 patients have been infected. Early administration of high-dose steroids and CPAP ventilation appears to offer the best supportive treatment with a reduced mortality compared with other treatment regimens.

Adult↗
PubMed2001

Cloning, expression and characterization of a novel human REPS1 gene.

Ral is a member of the small GTPase-binding protein (G protein) family, and plays an important role in the Ras-RalGDS signal transduction pathway. A series of recent findings reveal several important downstream target proteins of Ral, such as RalBP1, Reps1, and others. Here we report another binding partner for RalBP1, which we have isolated from the human fetal brain library. The human REPS1 protein shares 83% amino acid identity with the mouse Reps1 protein. Northern blot analysis shows that the REPS1 is expressed in a variety of tissues, with the strongest expression in the heart and testis.

Adult↗
PubMed2001

Generation of the mu opioid receptor (MOR-1) protein by three new splice variants of the Oprm gene.

Using 5' RACE, we have isolated four additional exons of the mu opioid receptor gene (Oprm), resulting in a gene spanning over 250 kb. The four new exons are contained within eight additional splice variants containing exon 11 at the 5' terminus. Exon 11, which is under the control of a previously unknown upstream promoter, and exon 12 are located approximately 10 kb and approximately 8 kb upstream from exon 1, respectively. Exon 13 and 14 are located between exons 1 and 2. The regional distributions of the variants, as determined by reverse transcription-PCR, varied among themselves and were distinct from that of MOR-1, implying region-specific RNA processing. Three variants (MOR-1H, MOR-1I, and MOR-1J) contained two potential translational start points, with the translational start point in exon 1 producing proteins identical to the original MOR-1 protein. When expressed, the receptor binding of these three variants was indistinguishable from that of MOR-1. The remaining eight proteins using the translation start point in exon 11 were all truncated, with three (MOR-1G, MOR-1M, and MOR-1N) predicting proteins of only six transmembrane domains and the rest giving proteins under 10 kDa. Western blots with an exon 11-specific antiserum revealed bands consistent with the six transmembrane domain proteins within the brain, but the shorter proteins were not detected. Thus, the MOR-1 protein can be generated by four different splice variants of the Oprm gene under the control of two physically distinct promoters. Although the truncated proteins are expressed in brain with a unique regional distribution, their functional significance remains unknown.

Alternative Splicing↗
PubMed2001

[Relationship between the level of plasma D-dimer and diabetic microangiopathy].

OBJECTIVE: To study the relationship between the level of plasma D-dimer and microangiopathy of the type 2 diabetes mellitus. METHODS: The level of plasma D-dimer and blood viscosity were measured in 52 cases with type 2 diabetes mellitus, and these patients were divided into three groups according to the level of urinary albumin excretion (UAE) together with 15 age-matched healthy volunteers as the control (NC group). RESULTS: In the cases with higher urinary albumin excretion rate, including 28 cases with trace albuminuria (EDN group) and 10 cases with clinical albuminuria (CDN group), plasma D-dimer and blood viscosity were increases than 14 cases without albuminuria (SDM group) and NC group. D-dimer was positively correlated with diabetic retinopathy, Serum insulin and diabetic durations, but not correlated with blood viscosity and fibrinogen. CONCLUSION: The type 2 diabetes mellitus complicated with microangiopathy had a higher level of plasma D-dimer. As a marker of thrombus formation, D-dimer may play an important role in the pathogenesis of diabetic microangiopathy.

Adult↗
PubMed2001

Well-differentiated endometrial adenocarcinomas and poorly differentiated mixed mullerian tumors have altered ER and PR isoform expression.

Both the estrogen receptor (ER) and the progesterone receptor (PR) have two subtypes: ER-alpha and beta, and PR-A and -B, respectively. These subtypes differ in function and expression, and recent reports have correlated changes in the normal proportions of these isoforms with neoplastic states. We investigated ER and PR isoform expression in normal pre- and post-menopausal endometrium, well-differentiated endometrial adenocarcinoma, and poorly differentiated malignant mixed mullerian tumors (MMMTs). Semi-quantitative RT-PCR and immunoblotting were used to measure receptor mRNA and protein expression. Estrogen receptor-alpha/beta mRNA ratios were significantly higher in postmenopausal (27.3) compared to premenopausal endometrium (4.9) mainly as a result of lower ER-beta expression in the former. Compared to age-matched postmenopausal controls, the ER-alpha/beta ratio was reduced in both grade I adenocarcinoma and MMMT specimens (3.3 and 6.8, respectively), due to a selective loss of ER-alpha. The relative abundance of PR-A and PR-B mRNA remained unchanged between all tissue subtypes. Total PR protein, however, was significantly reduced in MMMTs compared to all other groups. Thus, sex steroid receptor expression is significantly and differentially altered in well-differentiated and poorly-differentiated endometrial cancers. Both cancers exhibit decreased ER-alpha expression and the MMMTs also demonstrate a significant loss of PR protein.

Adenocarcinoma↗