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Biomedical subjects

B Ma

Publications and source records attributed to B Ma.

At least 19 recordsLinked to original sources
PubMed2006

Gene therapy by membrane-expressed superantigen for alpha-fetoprotein-producing hepatocellular carcinoma.

Staphylococcus enterotoxin A (SEA) is a powerful immunostimulant, which can stimulate T cells bearing certain T-cell receptor beta-chain variable regions, when bound to major histocompatibility complex II molecules. In vivo administration of intact superantigen in sufficient therapeutic amounts risks unwanted cytotoxicity against normal cells. In this study, we used SEA fused with CD80 transmembrane region (named as SEAtm) driven by alpha-fetoprotein (AFP) enhancer/promoter to reduce toxicity and to improve safety and efficiency in the application of SEA. We demonstrated that SEAtm by adenovirus from the AFP enhancer/promoter (AdAFPSEA) could be expressed on the surface of AFP-producing cell line Hepa1-6 instead of non-AFP-producing cell lines. Hepa1-6 infected by recombinant adenovirus stimulated proliferation of splenocytes and activated CD4(+) and CD8(+) T cells in vitro. After AdAFPSEA was injected into the subcutaneously established hepatoma in vivo, the expression of SEA was detected in tumor tissues, which subsequently induced tumor-specific cytotoxic T cells in spleen. Moreover, hepatocellular carcinoma (HCC) xenografts were suppressed by treatment with AdAFPSEA and the survival time of treated mice was prolonged. These findings suggest that membrane-expressed SEA by adenovirus from AdAFPSEA can generate stronger local and systemic antitumor responses against HCC.

Adenoviridae↗
PubMed2006

Irofulven as first line therapy in recurrent or metastatic gastric cancer: a phase II multicenter study by the Cancer Therapeutics Research Group (CTRG).

BACKGROUND: The purpose of this study was to evaluate the tolerability and efficacy of irofulven, a DNA interacting acylfulvene analog, as first line therapy for patients with recurrent or metastatic gastric cancer. PATIENTS AND METHODS: Twenty-three patients with recurrent or metastatic gastric cancer received irofulven at a dose of 0.45 mg/kg administered intravenously over 30-min infusion (up to a maximum of 50 mg), on days 1 and 8, every 3 weeks. RESULTS: The median number of cycles delivered per patient was 2 (range 1-6). Two patients (9%) had >or= 1-week delay in administration of subsequent cycle of chemotherapy. For the day 8 chemotherapy, dose reductions were required in seven patients (30%); dose omitting occurred in five patients (22%). Grade 3/4 anemia and neutropenia occurred in 22 and 17% of patients, respectively. There was no grade 4 thrombocytopenia and no neutropenic fever was observed. Of the 20 evaluable patients, there were no responses observed, 3 patients had stable disease after 2 cycles of treatment which was not confirmed by a further assessment. Median overall survival was 6.05 months (95% CI 4.55-9.39). CONCLUSIONS: Irofulven was tolerated at the dose of 0.45 mg/kg on days 1 and 8, every 3 weeks but showed no evidence of antitumor activity in patients with advanced gastric cancer.

Adenocarcinoma↗
PubMed2006

Trabecular anisotropy and collagen fibre orientation in the mandibular condyle following experimental functional appliance treatment using sheep.

In order to study the modifying effects of functional appliances on the mechanical environment of the temporomandibular joint (TMJ), we characterised the structure of the mandibular condyle subsequent to an experimental functional appliance intervention. Eight, four-month-old, castrated male Merino sheep, were randomly allocated to experimental and control groups (n = 4 in each group). Forward mandibular displacement was induced with an intraoral appliance. The study period was 15 weeks, during which time fluorochromes were administered to all of the animals. Midsagittal sections of the TMJ were selected for analysis and trabecular anisotropy was estimated using bone histomorphometry. Only the experimental group demonstrated that the trabecular bone in the central condylar region was less anisotropic when compared to the subchondral region. Also, the variation in trabecular anisotropy of the central condylar region was found to be smaller in the experimental group. The collagen fibre orientation was analysed under polarised light as the proportion of the dark or bright fibres observed in regions which existed before, and regions which formed during the experiment, as determined by the fluorochrome labels. In the experimental group, more bright collagen fibres were found in the most superior region of the mandibular condyle when compared with the controls. These results suggested that the experimental functional appliances changed the orientation and pattern of the mechanical forces acting on the mandibular condyle, and possibly increased the magnitude of the lateral functional forces applied to the most superior part of the condyle during such treatments.

Animals↗
PubMed2005

Visual acuity in northern China in an urban and rural population: the Beijing Eye Study.

AIM: To evaluate prevalence and demographic associations of visual impairment in an urban and rural population in northern China. METHODS: In the Beijing Eye Study, a population based cohort study in northern China, visual acuity was assessed for 8876 eyes (4438 subjects) according to a response rate of 83.4%. The study was divided into a rural part (1972 subjects) and an urban part (n=2466). Mean age was 56.20 (SD 10.59) years (median 56 years; range 40-101 years). RESULTS: Mean uncorrected visual acuity measured 0.72 (0.32) (median, 0.80), and mean best corrected visual acuity measured 0.91 (0.21) (median, 1.0). In a multiple regression analysis, best corrected visual acuity was significantly correlated with age (p<0.001), degree of nuclear cataract (p<0.001), amount of cortical cataract (p=0.014), amount of subcapsular cataract (p<0.001), educational background (p<0.001), and refractive error (p<0.001). Rural region versus urban region (p=0.34) and sex (p=0.053) were not statistically significantly associated with best corrected visual acuity. CONCLUSIONS: In northern China, determinants of a low degree of best corrected visual acuity are age, cataract, low educational background, and myopia. Despite marked differences in educational background and family income, sex, and rural area versus urban area are not markedly associated with best corrected visual acuity.

Adult↗
PubMed2005

Liver resection after irinotecan, 5-fluorouracil, and folinic acid for patients with unresectable colorectal liver metastases: a multicenter phase II study by the Cancer Therapeutic Research Group.

The main objectives of this study were to assess the use of irinotecan, 5-fluorouracil (5-FU), and leucovorin (FA) as neoadjuvant chemotherapy for patients with unresectable colorectal liver metastases and to determine the response rate and proportion of patients that could be down-staged to resectable tumors. Forty patients were treated with irinotecan (180 mg/m2 over 30 min) on d 1, FA (200 mg/m2 over 30 min) followed by 5-FU (400 mg/m2 bolus and continuous infusion of 600 mg/m2 over 22 h) on d 1 and 2 every 2 wk. The overall response rate was 55% (95% CI: 39.5-70.4%). The progression-free survival was 12.1 mo (95% CI: 11.4-14.8 mo). The median overall survival was 20 mo (95% CI: 17.7-26.6 mo). Four patients (10%) have undergone liver resection after a median of eight cycles. Those patients remained alive with a median follow up period of 33 mo. The principal grade 3-4 toxicity was neutropenia in 20 patients (50%). We conclude that the regimen of irinotecan/5-FU/FA was highly active in patients with colorectal cancer and liver metastases with limited toxicity. In a subgroup of patients with initial inoperable liver metastases, this regimen was able to down-stage the disease to an operable stage.

Adenocarcinoma↗
PubMed2005

A point-selection algorithm based on spatial-stiffness analysis of rigid registration.

OBJECTIVE: We propose a model of shape-based registration that leads to a task-specific algorithm for preoperatively selecting a set of model registration points. MATERIALS AND METHODS: We performed five sets of computer simulations using registration points generated by our algorithm and two noise amplification index (NAI) algorithms on the basis of the research of Simon 20. We used several different bone surface models (distal radius, proximal femur and tibia) computed from CT images of patient volunteers. The number of registration points used varied between 6 and 30. RESULTS: Our algorithm was faster than the NAI-based algorithms by factors of approximately 4 and 200. It had equal or better performance in terms of target registration error (TRE) when compared with the other algorithms. Our simulations also showed that point selection can have a large effect on TRE behavior; in particular, poor point selection does not necessarily decrease TRE as more registration points are added. CONCLUSIONS: Our point-selection algorithm produces model registration points with similar or better TRE behavior than the NAI-based algorithms we tested, and it does so with significantly less computation time.

Algorithms↗
PubMed2005

Activation of antitumor cytotoxic T lymphocytes by fusion of patient-derived dendritic cells with autologous osteosarcoma.

BACKGROUND AND AIM: Fusion of human dendritic cells (DCs) with tumor cells is an effective approach for delivering tumor antigens to DCs, and DC/tumor fusion cells are potent stimulators of autologous T cells. However, the integration and morphology of DC/osteosarcoma fusion cells has not been examined. This study was designed to investigate the antitumor effects of tumor vaccine produced by electrofusion between human osteosarcoma cells and DCs. METHODS: In the present study, we eletrofused patient-derived DCs to autologous osteosarcoma cells. The fusion cells possessed the properties of both patient cells. After electrofusion, the cytoplasm of the two cells was integrated, whereas their nuclei remained separate entities. The intracellular structure was observed on fusion cells under the transmission electron microscope. RESULTS: Coculture of patient-derived peripheral blood mononuclear cells (PBMC) with DC/tumor fusion cells resulted in activation of T cells as assessed by standard cytotoxic T lymphocytes (CTLs) assays. CONCLUSIONS: The present study provides valid evidence on integration of human DCs and tumor cells and links their properties to T cell activation. The fusion cells may thus represent a promising strategy for DC-based immunotherapy of patients with osteosarcoma.

Cancer Vaccines↗
PubMed2005

Computer-assisted deformity correction using the ilizarov method.

The Taylor spatial frame is a fixation device used to implement the Ilizarov method of bone deformity correction to gradually distract an osteotomized bone at regular intervals, according to a prescribed schedule. We improve the accuracy of Ilizarov's method of osteogenesis by preoperatively planning the correction, intraoperatively measuring the location of the frame relative to the patient, and computing the final shape of the frame. In four of five tibial phantom experiments, we were able to achieve correction errors of less than 2 degrees of total rotation. We also demonstrate how registration uncertainty can be propagated through the planned transformation to visualize the range of possible correction outcomes. Our method is an improvement over an existing computer-assisted technique (Iyun et al.) in that the surgeon has the same flexibility as in the conventional technique when fixating the frame to the patient.

Artificial Intelligence↗
PubMed2004

Stereoselective metabolism of silybin diastereoisomers in the glucuronidation process.

A separation method for the hepatoprotective drug silybin and its metabolites by RP-HPLC was described. Based on this separation, the stereoselectivity of the metabolism of silybin was investigated by incubation of the drug and its two diastereoisomers with bovine liver microsomes. Information about the structures of these metabolites was obtained, using UV, HPLC/MS and NMR spectra. Four major metabolites (M(1), M(4) of silybin A and M(2), M(5) of silybin B), were prepared by preparative HPLC, and their configurations were accomplished by NMR spectra. A HPLC method was used to quantify the metabolites. The results showed that silybin was extensively metabolized and the major sites for glucuronidation were the C-20, C-7, at phenolic OH groups. Furthermore, the results obtained reveal that there was significant stereoselectivity in the glucuronidation process of silybin. Silybin B was glucuronidated at a more efficient rate than its diastereoisomer, and glucuronidation of silybin B was much preferred at the 20 position, while that of silybin A was similar at both 7 and 20 position.

Glucuronides↗
PubMed2004

Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy.

BACKGROUND: Cancer patients who are hepatitis B virus (HBV) carriers and undergoing chemotherapy (CT) may be complicated by HBV reactivation. Over 80% of hepatocellular carcinoma (HCC) patients are HBV carriers; however, the incidence of HBV reactivation during CT has not been well-reported. A prospective study was conducted to determine the incidence of HBV reactivation, the associated morbidity and mortality, and possible risk factors. PATIENTS AND METHODS: 102 HBsAg-positive patients with inoperable HCC underwent systemic CT. Patients received either combination cisplatin, interferon, doxorubicin and fluorouracil (PIAF) or single-agent doxorubicin. They were followed up during and for 8 weeks after CT. RESULTS: In 102 patients, 59 (58%) developed hepatitis amongst whom 37 (36%) were attributable to HBV reactivation. Twelve (30%) died of HBV reactivation. CT was interrupted in 32 patients (86%) with reactivation and 54 (83%) without reactivation (P>0.05). The median survivals were 6.00 and 5.62 months, respectively (P=0.694). Elevated baseline alanine aminotransferase (ALT) was found to be a risk factor. CONCLUSION: HBV reactivation is a common cause of liver damage during CT in HBsAg-positive HCC patients. The only identifiable associated risk factor was elevated pre-treatment ALT. Further studies into the role of antiviral and novel anticancer therapies are required to improve the prognosis of these patients.

Adult↗
PubMed2003

Robust registration for computer-integrated orthopedic surgery: laboratory validation and clinical experience.

In order to provide navigational guidance during computer-integrated orthopedic surgery, the anatomy of the patient must first be registered to a medical image or model. A common registration approach is to digitize points from the surface of a bone and then find the rigid transformation that best matches the points to the model by constrained optimization. Many optimization criteria, including a least-squares objective function, perform poorly if the data include spurious data points (outliers). This paper describes a statistically robust, surface-based registration algorithm that we have developed for orthopedic surgery. To find an initial estimate, the user digitizes points from predefined regions of bone that are large enough to reliably locate even in the absence of anatomic landmarks. Outliers are automatically detected and managed by integrating a statistically robust M-estimator with the iterative-closest-point algorithm. Our in vitro validation method simulated the registration process by drawing registration data points from several sets of densely digitized surface points. The method has been used clinically in computer-integrated surgery for high tibial osteotomy, distal radius osteotomy, and excision of osteoid osteoma.

Adolescent↗
PubMed2002

Differences in the absorption, metabolism and biliary excretion of a diastereomeric pair of alphavbeta3-antagonists in rat: limited role of P-glycoprotein.

1. The study investigated mechanisms underlying the pharmacokinetic differences of two zwitterionic diastereomers ((3S)-3-[(3R or 3S)-2-oxo-3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrrolidin-1-yl]-3-quinolin-3-ylpropanoic acid) with different lipophilicities using a combination of in vivo and in vitro approaches. 2. In rat, both isomers possessed comparable plasma clearances (CL). However, the more lipophilic diastereomer I exhibited a higher metabolic clearance (>2-fold higher than II), whereas the hydrophilic zwitterion II exhibited a higher biliary clearance (approximately 5-fold higher than I). Following oral administration, the bioavailability (F) of I (17%) was much higher than that of II (1%). 3. Consistent with these in vivo observations and the expectation based on their lipophilicity differences, the metabolism in rat liver microsomes was faster and the permeability in Caco-2 and LLC-PK1 cells and in situ rat intestinal loop was better for I than for II. 4. Only the absorption of the more lipophilic diastereomer I was subjected to an efflux system in the Caco-2 and in situ rat intestinal loop models. I was a good substrate for P-glycoprotein (P-gp) in both the human MDR1 and mouse mdr1a transfected cell lines, and in the wild-type mdr1a (-/-) mouse when compared with the P-gp-deficient mdr1a (-/-) mouse. Concomitant administration of I with verapamil in rat caused significant increases in oral AUC, F and Cmax of I without affecting its CL, further supporting the effect of P-gp in limiting the intestinal absorption of I in vivo in this animal model. 5. Since the findings that the lipophilic diastereomer I, but not II, was a good P-gp substrate were not in line with the observations that I was excreted to bile much slower than II and that I was absorbed better than II, the results suggested that P-gp played a minor role to the observed differences in the biliary excretion and intestinal absorption of the diastereomers I and II in rat.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Transition metal-catalyzed [4 + 2 + 2] cycloadditions of bicyclo[2.2.1]hepta-2,5-dienes (norbornadienes) and bicyclo[2.2.2]octa-2,5-dienes.

The transition-metal-catalyzed [4 + 2 + 2] cycloadditions of norbornadienes, bicyclo[2.2.2]octa-2,5-diene, and benzobarrelene with 1,3-butadienes proceed in excellent yields using cobalt-based catalytic systems. Two key distinctions between these [4 + 2 + 2] cycloadditions and the corresponding transition-metal-catalyzed [2 + 2 +2] reactions of norbornadiene are the requirement of a bimetal catalytic system with a bisphosphine ligand for the former and exclusive regioselectivity in the [4 + 2 + 2] reaction of 2-substituted norbornadienes to produce 1-substituted adducts. These distinctions may indicate two distinct mechanisms for the [4 + 2 + 2] and [2 + 2 + 2] reactions.

Bridged-Ring Compounds↗
PubMed2001

Structured disorder and conformational selection.

Traditionally, molecular disorder has been viewed as local or global instability. Molecules or regions displaying disorder have been considered inherently unstructured. The term has been routinely applied to cases for which no atomic coordinates can be derived from crystallized molecules. Yet, even when it appears that the molecules are disordered, prevailing conformations exist, with population times higher than those of all alternate conformations. Disordered molecules are the outcome of rugged energy landscapes away from the native state around the bottom of the funnel. Ruggedness has a biological function, creating a distribution of structured conformers that bind via conformational selection, driving association and multimolecular complex formation, whether chain-linked in folding or unlinked in binding. We classify disordered molecules into two types. The first type possesses a hydrophobic core. Here, even if the native conformation is unstable, it still has a large enough population time, enabling its experimental detection. In the second type, no such hydrophobic core exists. Hence, the native conformations of molecules belonging to this category have shorter population times, hindering their experimental detection. Although there is a continuum of distribution of hydrophobic cores in proteins, an empirical, statistically based hydrophobicity function may be used as a guideline for distinguishing the two disordered molecule types. Furthermore, the two types relate to steps in the protein folding reaction. With respect to protein design, this leads us to propose that engineering-optimized specific electrostatic interactions to avoid electrostatic repulsion would reduce the type I disordered state, driving the molten globule (MG) --> native (N) state. In contrast, for overcoming the type II disordered state, in addition to specific interactions, a stronger hydrophobic core is also indicated, leading to the denatured --> MG --> N state.

Enzyme Stability↗
PubMed2001

Use of the tetracycline-controlled transcriptional silencer (tTS) to eliminate transgene leak in inducible overexpression transgenic mice.

The doxycycline-inducible reverse tetracycline transactivator (rtTA) is frequently used to overexpress transgenes in a temporally regulated fashion in vivo. These systems are, however, often limited by the levels of transgene expression in the absence of dox administration. The tetracycline-controlled transcriptional silencer (tTS), a fusion protein containing the tet repressor and the KRAB-AB domain of the kid-1 transcriptional repressor, is inhibited by doxycycline. We hypothesized that tTS would tighten control of transgene expression in rtTA-based systems. To test this hypothesis we generated mice in which the CC10 promoter targeted tTS to the lung, bred these mice with CC10-rtTA-interleukin 13 (IL-13) mice in which IL-13 was overexpressed in an inducible lung-specific fashion, and compared the IL-13 production and phenotypes of parental mice and the triple transgenic CC10-rtTA/tTS-IL-13 progeny of these crosses. In the CC10-rtTA-IL-13 mice, IL-13, mucus metaplasia, inflammation, alveolar enlargement, and enhanced lung volumes were noted at base line and increased greatly after doxycycline administration. In the triple transgenic tTS animals, IL-13 and the IL-13-induced phenotype could not be appreciated without doxycycline. In contrast, tTS did not alter the induction of IL-13 or the generation of the IL-13 phenotype by doxycycline. Thus, tTS effectively eliminated the baseline leak without altering the inducibility of rtTA-regulated transgenes in vivo. Optimal "off/on" regulation of transgene expression can be accomplished with the combined use of tTS and rtTA.

Animals↗
PubMed2001

Effect of long-range interactions on the scaling of the noisy Kuramoto-Sivashinsky equation.

The effects of long-range interactions on the scaling properties of the noisy Kuramoto-Sivashinsky (KS) equation are studied by the dynamic renormalization-group technique. It is found that the presence of long-range nonlinearity in the KS equation can produce new stable fixed points with varying critical exponents that depend on both the long-range interaction parameter rho and the substrate dimension d.

Journal Article↗
PubMed2001

Protein functional epitopes: hot spots, dynamics and combinatorial libraries.

Recent studies increasingly point to the importance of structural flexibility and plasticity in proteins, highlighting the evolutionary advantage. There are an increasing number of cases in which given, presumably specific, binding sites have been shown to bind a range of ligands with different compositions and shapes. These studies have also revealed that evolution tends to find convergent solutions for stable intermolecular associations, largely via conservation of polar residues as hot spots of binding energy. On the other hand, the ability to bind multiple ligands at a given site is largely derived from hinge-based motions. The consideration of these two factors in functional epitopes allows more realism and robustness in the description of protein binding surfaces and, as such, in applications to mutants, modeled structures and design. Efficient multiple structure comparison and hinge-bending structure comparison tools enable the construction of combinatorial binding epitope libraries.

Combinatorial Chemistry Techniques↗