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PubMed2002

Development and validation of a modified version of the Peritraumatic Dissociative Experiences Questionnaire.

This article reports results from 3 studies conducted to develop and validate a modified version of the self-administered form of the Peritraumatic Dissociative Experiences Questionnaire (PDEQ; C. R. Marmar, D. S. Weiss, & T. J. Metzler, 1997). The objective was to develop an instrument suitable for use with persons from diverse ethnic and socioeconomic backgrounds. In Study 1, the original PDEQ was administered to a small sample (N = 15) recruited from among men admitted to the hospital for physical injuries stemming from exposure to community violence. Results led to modifications aimed at improving the utility of the instrument. In Study 2, the modified PDEQ was subjected to structural equation modeling and item response theory analyses to assess its psychometric properties in a larger, primarily male, sample of community violence survivors (N = 284). In Study 3, the reliability and validity of the modified instrument were further assessed in a sample of female survivors of sexual assault (N = 90). Results attest to the psychometric properties as well as the reliability and validity of the modified 8-item PDEQ.

Adolescent↗
PubMed1977

Immunogenicity of tumour cells modified with various chemicals.

Mouse tumour cells were treated with various chemical modifiers. The number of modifying groups per cell was determined with labelled reagents. The effects of the different modifying groups on the immunogenicity of the tumour cells was tested in syngeneic mice for tumour protection using a challenge dose of viable cells at 1000 or 10,000 time LD100. Best protection was obtained after immunization of animals with tumour cells modified with dimethylsulphate or acetic anhydride, or with glutardialdehyde-fixed cells treated with a carbodiimide and methylamine. Up to 40% of the animals remained tumour-free. The other animals exhibited a greatly increased mean survival time. The post-challenge sera showed no detectable amounts of antibodies against the tumour cells.

Animals↗
PubMed1998

Vaccination with IL-7 gene-modified autologous melanoma cells can enhance the anti-melanoma lytic activity in peripheral blood of patients with a good clinical performance status: a clinical phase I study.

Recently, cytokine gene transfer into tumour cells has been shown to mediate tumour regression in animal models via immunomodulation. Consequently, a number of clinical protocols have been developed to treat cancer patients with cytokine gene-modified tumour cells. Here, we report the results of a clinical phase I trial using for the first time autologous, interleukin 7 gene-modified tumour cells for vaccination of ten patients with disseminated malignant melanoma. Melanoma cells were expanded in vitro from surgically removed metastases, transduced by a ballistic gene transfer technique and were then injected after in vitro irradiation s.c. at weekly intervals. Clinically, there was no major toxicity except for mild fever, and no major clinical response towards vaccination was observed. Eight of ten patients completed the initial three s.c. vaccinations and were eligible for immunological evaluation. Post vaccination, peripheral mononuclear cells (PBMCs) were found to contain an increased number of tumour-reactive proliferative as well as cytolytic cells, as determined by a limiting dilution analysis. In three of six patients, the frequencies of anti-melanoma cytolytic precursor cells increased between 2.6- and 28-fold. Two of these patients showed a minor clinical response. Analysis of the autologous tumour cell vaccines regarding IL-7 secretion after gene transfer, HLA class I and class II cell surface expression, secretion of immunosuppressive mediators (TGF-beta1, IL-10) and various melanoma-associated tumour antigens revealed a very diverse expression profile. In conclusion, vaccination using gene-modified autologous melanoma cells induced immunological changes in a group of advanced, terminally ill patients. These changes can be interpreted as an increased anti-tumour immune response. However, immunological modulation was most pronounced in patients in good physical condition. Therefore, patients with minimal tumour load or minimal residual disease might preferentially benefit from tumour cell vaccination in further studies. In order to evaluate the effects of the cytokine gene-modified tumour cell vaccines more precisely, an antigenically better defined vaccine is needed.

Adult↗
PubMed1995

A quantitative analysis of modifier mutations which occur in mutation accumulation lines in Drosophila melanogaster.

Seven enzyme activities were measured in Drosophila melanogaster lines in which spontaneous mutations had accumulated over about 300 generations under the minimum pressure of natural selection. These enzymes included alcohol dehydrogenase (ADH), alpha-glycerol-3-phosphate dehydrogenase (alpha GPDH), malate dehydrogenase (MDH), isocitrate dehydrogenase (IDH), glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD) and alpha-amylase (AMY). A significant genetic variance was observed for some enzyme activities. The mutations which alter the enzyme activities are called modifier mutations. The magnitudes of the genetic variance in modifier mutations differed greatly among enzymes but were often similar between two series of mutation accumulation lines (AW and JH). This may therefore indicate that the number of modifiers is specific for each enzyme system. The modifier mutation rate is suggested to be one of the clues for assessing the maintenance mechanism of protein polymorphism in natural populations.

Alcohol Dehydrogenase↗
PubMed1996

T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients.

The introduction and expression of genes in somatic cells is an innovative therapy for correcting genetic deficiency diseases and augmenting immune function. A potential obstacle to gene therapy is the elimination of such gene-modified cells by an immune response to novel protein products of the introduced genes. We are conducting an immunotherapy trial in which individuals seropositive for human immunodeficiency virus (HIV) receive CD8+ HIV-specific cytotoxic T cells modified by retroviral transduction to express a gene permitting positive and negative selection. However, five of six subjects developed cytotoxic T-lymphocyte responses specific for the novel protein and eliminated the transduced cytotoxic T cells. The rejection of genetically modified cells by these immunocompromised hosts suggests that strategies to render gene-modified cells less susceptible to host immune surveillance will be required for successful gene therapy of immunocompetent hosts.

Antigen Presentation↗
PubMed1997

The influence of 5-HT2 and 5-HT4 receptor antagonists to modify drug induced disinhibitory effects in the mouse light/dark test.

1. The ability of 5-HT2 and 5-HT4 receptor antagonists to modify the disinhibitory profile of diazepam and other agents was investigated in male BKW mice in the light/dark test box. 2. The 5-HT2A/2B/2C receptor antagonists ritanserin, MDL11939 and RP62203 and also methysergide, which failed to modify mouse behaviour when administered alone, caused dose-related enhancements (4 to 8 fold) in the potency of diazepam to disinhibit behavioural responding to the aversive situation of the test box. 3. Ritanserin was shown to enhance the disinhibitory potency of other benzodiazepines, chlordiazepoxide (4 fold), temazepam (10 fold) and lorazepam (10 fold), the 5-HT1A receptor ligands, 8-OH-DPAT (25 fold), buspirone (100 fold) and lesopitron (500 fold), the 5-HT3 receptor antagonists, ondansetron (100 fold) R(+)-zacopride (100 fold) and S(-)-zacopride (greater than a 1000 fold), the substituted benzamides, sulpiride (10 fold) and tiapride (5 to 10 fold) and the cholecystokinin (CCK)A receptor antagonist, devazepide (100 fold). It also reduced the onset of action of disinhibition following treatment with the 5-HT synthesis inhibitor parachlorophenylalanine. Ritanserin failed to enhance the disinhibitory effects of the CCKB receptor antagonist CI-988, the angiotensin AT1 receptor antagonist losarten or the angiotensin converting enzyme inhibitor ceranapril. 4. The 5-HT4 receptor antagonists SDZ205-557, GR113808 and SB204070 caused dose-related reductions in the disinhibitory effect of diazepam, returning values to those shown in vehicle treated controls. The antagonists failed to modify mouse behaviour when administered alone. 5. GR113808 was also shown to cause a dose-related antagonism of the disinhibitory effects of chlordiazepoxide, lorazepam, 8-OH-DPAT, buspirone, lesopitron, ondansetron, R(+)-zacopride, sulpiride, tiapride, devazepide, CI-988, losarten, ceranapril and parachlorophenylalanine. 6. It was concluded that in BKW mice (a) the failure of 5-HT2 and 5-HT4 receptor antagonists when administered alone to modify behaviour in the light/dark test indicates an absence of an endogenous 5-HT tone at the 5-HT2 and 5-HT4 receptors and (b) the enhancement by the 5-HT2 receptor antagonists and attenuation by the 5-HT4 receptor antagonists of drug-induced disinhibition indicates a plurality of 5-HT receptor involvement in the mediation of drug-induced disinhibitory profiles in the mouse.

Animals↗
PubMed2000

The expression of CD70 and CD80 by gene-modified tumor cells induces an antitumor response depending on the MHC status.

The expression of costimulatory molecules such as CD70 or CD80 by gene-modified tumor cells has been shown to enhance the antitumor immune response based mainly on T lymphocytes. However, most human tumors show defects of major histocompatibility complex (MHC) expression, preventing them from being recognized by MHC-restricted T cells. To investigate if coexpression of CD70 and CD80 costimulatory molecules induces comparable antitumor responses in low and high MHC-expressing tumor cells, we used two low immunogenic murine tumor models, the B16.F10 melanoma and the TS/A mammary adenocarcinoma cell lines expressing, respectively, low and high levels of MHC class I molecules. Transfection of both CD70 and CD80 genes resulted in an increased capacity of gene-modified tumor cells to costimulate in vitro the proliferation and cytokine production of optimally activated lymphoid cells. Coexpression of CD70 and CD80 by the two tumor cell lines, TS/A and B16.F10, resulted in both cases in partial regression of subcutaneous tumors. Immunochemical analysis and studies in nude mice showed that, even in the B16.F10 model, T cells had a significant role in the antitumor response induced by combining CD70 and CD80. However, rejection of the CD70/CD80-transfected tumor cells appeared more effective in the MHC class I high TS/A model, leading to a protection against parental tumor cells. B16.F10 and TS/A transfectants were then tested with fibroblasts genetically modified to secrete interleukin-12 (IL-12) as a therapeutic vaccine in mice bearing parental tumors. In the two models tested, the injections of irradiated IL-12 and CD70/CD80 gene-modified cells generated an antitumor response to established tumors leading to the slowing down of the tumor growth rate. Although the mechanisms remain to be defined, these findings suggest that the combination of several immuno-modulatory molecules could provide additional strategies for cancer immuno-gene therapy, even for MHC expression-deficient tumors.

Animals↗
PubMed2005

A "gain of function" mutation in a protein mediates production of novel modified nucleosides.

The mutation sufY204 mediates suppression of a +1 frameshift mutation in the histidine operon of Salmonella enterica serovar Typhimurium and synthesis of two novel modified nucleosides in tRNA. The sufY204 mutation, which results in an amino-acid substitution in a protein, is, surprisingly, dominant over its wild-type allele and thus it is a "gain of function" mutation. One of the new nucleosides is 5-methylaminomethyl-2-thiouridine (mnm(5)s(2)U34) modified by addition of a C(10)H(17) side chain of unknown structure. Increased amounts of both nucleosides in tRNA are correlated to gene dosage of the sufY204 allele, to an increased efficiency of frameshift suppression, and to a decreased amount of the wobble nucleoside mnm(5)s(2)U34 in tRNA. Purified tRNA(Gln)(cmnm(5)s(2)UUG) in the mutant strain contains a modified nucleoside similar to the novel nucleosides and the level of aminoacylation of tRNA(Gln)(cmnm(5)s(2)UUG) was reduced to 26% compared to that found in the wild type (86%). The results are discussed in relation to the mechanism of reading frame maintenance and the evolution of modified nucleosides in tRNA.

Amino Acid Substitution↗
PubMed2005

A modified technique of scleral fixated intraocular lenses for aphakic correction.

PURPOSE: To examine the safety and efficacy of a modified scleral fixated intraocular lens (SFIOL) technique combining a scleral tunnel for intraocular lens (IOL) insertion, horizontal passage of sutures, and performing anterior vitrectomy through self-sealing pars plana sclerostomies. METHODS: Retrospective review of all patients who underwent SFIOL for aphakic correction at the Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong (a tertiary referral centre) between October 2000 and December 2001 with either the modified or conventional techniques. RESULTS: A total of 20 eyes were identified. Eight modified (Group 1) and 12 conventional (Group 2) with a mean follow-up of 18.3 months. Postoperatively, all the eyes improved on unaided preoperative acuity and they all had a stable and well-positioned IOL. In all, 85% (7/8) of eyes in Group 1 maintained or improved best-corrected visual acuity. CONCLUSIONS: The modified SFIOL technique was found to be as safe and effective as conventional techniques. The main advantages of this technique include easy intraoperative suture management and superior globe maintenance.

Aged↗
PubMed2001

Administration of subtumor regression dosage of TNF-alpha to mice with pre-existing parental tumors augments the vaccination effect of TNF gene-modified tumor through the induction of MHC class I molecule.

One obstacle in treating pre-existing parental tumors by vaccination with cytokine gene-modified tumor cells is the impaired expression of immune-related molecules such as MHC class I. In this study, to enhance MHC class I expression on pre-inoculated parental tumors, low dose TNF (300 U, 500 U, 1000 U), that is, TNF at levels shown to cause neither tumor regression nor any severe adverse reaction, was systemically injected into parental tumors bearing mice before vaccination with TNF gene-modified Meth-A cells or B-16 cells. Since the class I expression was confirmed to continue for at least 24 h following administration of TNF, TNF was administered 6 h before vaccination. Complete regression of relatively large parental tumors (M0) (8.0-10.0 mm in diameter) was observed in five of eight mice treated with 1000 U TNF, partial regression was observed in mice treated with 500 U, and a lesser yet significant regression was observed in mice treated with only 300 U. Contrarily, in the mice which had received vaccination without the TNF pretreatment, no complete regression was observed. This effect was inhibited with the anti-class I antibody or anti-CD8 antibody. Growth of a re-established, B16 tumor was significantly suppressed with a combination of TNF preadministration and vaccination of TNF gene-modified B16. These results indicate that pre-administration of low-dose TNF may be promising for enhancing vaccination effects of TNF gene-modified tumor cells.

Animals↗
PubMed2001

Intrasplenic transplantation of IL-18 gene-modified hepatocytes: an effective approach to reverse hepatic fibrosis in schistosomiasis through induction of dominant Th1 response.

Hepatic fibrosis is a common outcome of chronic liver diseases. In schistosomiasis, chronic parasite egg-induced granuloma formation can lead to fibrosis, which is immunologically characterized by the dominant Th2 response. Recently, it has been shown that gene therapy is an attractive approach for the treatment of hepatic fibrosis. To investigate the antifibrotic effects of IL-18 gene transfer, a normal murine liver cell line BNL.CL2 was transfected with recombinant adenovirus encoding mouse IL-18, and then intrasplenically transplanted into mice infected with Schistosoma japonicum (S. japonicum). Our data show that IL-18 gene-modified hepatocytes intrasplenically transplanted into mice can effectively express IL-18 in the liver and in peripheral blood. Intrasplenic transplantation of IL-18 gene-modified hepatocytes into S. japonicum-infected mice could result in a significantly increased IFN-gamma and IL-2 but decreased IL-4 and IL-10 concentration both in the liver and in the serum, suggesting that the dominant Th2 response in mice with schistosomiasis could be reversed by this intervention. Consistent with the changes in Th1 and Th2 cytokine production, mice intrasplenically transplanted with IL-18 gene-modified hepatocytes developed much less hepatic fibrosis at 20 weeks after infection, which was evaluated by liver content of hydroxyproline, collagens, and hepatic mRNA expression of procollagens. These data indicate that intrasplenic transplantation of IL-18 gene-modified hepatocytes can be a candidate for therapeutic intervention in hepatic fibrosis through induction of a dominant Th1 response.

Adenoviridae↗
PubMed2001

A tropism-modified adenoviral vector increased the effectiveness of gene therapy for arthritis.

Adenoviral vectors (AdV) are used for anti-inflammatory cytokine therapy in experimental arthritis. Cell entry of AdV is dependent on the initial recognition of the coxsackie-adenovirus receptor (CAR) on cells. Recently, an Arg-Gly-Asp (RGD) motif was introduced in the HI loop of the fiber knob, this enables the adenovirus to bypass CAR and mediate cell entry via RGD binding integrins. In this study, we explored the transduction efficiency of the RGD-modified adenovirus in synovium and compared the RGD-modified with the conventional adenoviral vector for their effectiveness to modulate the murine collagen-induced arthritis (CIA) model when used to overexpress mIL-1Ra in the knee joint. Twenty-four hours after intra-articular injection of 10(7) fluorescent forming units (ffu) virus, luciferase (luc) activity in Ad5LucRGD-injected joints was up to 38 times higher than in AdCMVLuc-injected joints, and in arthritic joints the transduction efficiency was up to 69 times higher for the Ad5LucRGD viruses. Transduction of the synovial lining by the RGD-modified adenovirus containing the mIL-1Ra transgene, markedly improved the inhibition of CIA compared with the conventional virus in both a prophylactic and therapeutic treatment protocol. These results show that targeting integrins with the RGD-modified AdV improved the outcome of gene therapy for arthritis.

Adenoviridae↗
PubMed2006

Characterization of capsid-modified adenovirus vectors containing heterologous peptides in the fiber knob, protein IX, or hexon.

Adenovirus (Ad) vectors are widely used in gene therapy and in vitro/in vivo gene transfer because of their high transduction efficiency. However, Ad vector application in the gene therapy field is limited by poor transduction into cells not expressing the primary receptor, coxsackievirus and adenovirus receptor. To overcome this problem, several types of capsid-modified Ad vectors have been developed. The HI loop or C-terminus of the fiber knob, the C-terminus of the protein IX (pIX) and the hypervariable region 5 of the hexon are promising candidate locations for displaying foreign peptide sequences. In the present study, we constructed Ad vectors in which each of the above region was modified by a simple in vitro ligation-based method, and examined the characterization of each Ad vector containing the FLAG tag (DYKDDDDK) or RGD (CDCRGDCFC) peptide. Enzyme-linked immunosorbent assay examining the surface expression of foreign peptides on the virus suggested that foreign peptides are exposed on virion surfaces in all types vectors and that the hexon was the most efficiently reacted, reflecting the copy number of the modification. However, in the case of the transduction efficiency of Ad vectors containing the RGD peptides, the modification of pIX and the hexon showed no effect. The modification of the HI loop of the fiber knob was the most efficient, followed by the modification of the C-terminus region of the fiber knob. These comparative analyses, together with a simple construction method for each modified Ad vector, could provide basic information for the generation of capsid-modified Ad vectors.

Adenoviridae↗
PubMed2003

Mapping of genetic modifiers of thymic lymphoma development in p53-knockout mice.

The strain dependency of the spectrum and latency of tumors has been reported in p53-deficient (KO) mice, suggesting the presence of modifiers for the outcome of the p53 deficiency. The modifiers provide clues to the oncogenic pathway in cells lacking p53, the most frequently mutated gene in a wide variety of human cancers. To search the modifiers, we induced 160 lymphomas and 69 skin tumors by gamma-irradiation of p53(KO/+) backcross mice between BALB/c and MSM strains and performed genome scan. BALB/c-derived alleles at three loci on chromosome 19, Mp53D1 (modifier of p53-deficiency) at D19Mit5, Mp53D2 at D19Mit90 and Mp53D3 at D19Mit123, extended the latency of thymic lymphoma development (P values in Mantel-Cox test were 0.0007, 0.0007 and 0.0003, respectively). Mp53D3 also increased the latency of skin tumors (P value, 0.0008). The linkage of Mp53D2 was confirmed by the experiment using 94 p53-KO mice consomic for chromosome 19, providing a significant linkage. However, the linkage was not confirmed for Mp53D1 or Mp53D3, suggesting epistasis of genes involved in the tumorigenesis.

Alleles↗
PubMed2001

Effect of interfering substances on current response of recombinant peroxidase and glucose oxidase-recombinant peroxidase modified graphite electrodes.

Graphite electrodes have been modified with different forms of horseradish peroxidase (HRP). These included native HRP, wild-type recombinant HRP, and two single-point recombinant HRP mutants, N70V and N70D. The mediator-less response of these electrodes to H2O2 was studied indicating that electrodes modified with recombinant HRP forms are more stable than those modified with native HRP. Various interfering compounds were investigated for their effect on the current response to H2O2. It was found that interferences such as acetaminophen and dopamine affected the response by mediating the electron transfer (ET) between graphite and peroxidases. The mediating behaviour manifested itself as an increased current of the electrode to H2O2. The interfering effect was less pronounced for the electrodes modified with recombinant HRPs possessing better electronic coupling with the graphite surface. The interfering behaviour of acetaminophen on the response for glucose with the bienzyme electrode containing co-immobilised glucose oxidase and HRP was mainly ascribed to mediation of ET between graphite and HRP. It was experimentally proven that a high efficiency of direct ET between graphite and recombinant HRP substantially reduces the interfering effect of acetaminophen.

Journal Article↗
PubMed2002

Electrochemical behavior of the bis(2,2'-bipyridyl)copper(II) complex immobilized on a self-assembled monolayer modified electrode for L-ascorbic acid detection.

Modification of a gold electrode has been achieved by immobilizing a bis(2,2'-bipyridyl)copper(II) complex in a self-assembled monolayer (SAM) of 3-mercaptopropionic acid. The electrostatic interaction of the negatively charged SAM with a di-positive copper complex allowed the attachment. The modified electrode exhibited excellent redox behavior. The dependence of the modified electrode response was investigated in terms of pH, supporting electrolyte and ionic strength. Moreover, it showed good electrocatalytic activity for ascorbic acid oxidation, allowing convenient quantification at levels down to 8.1 x 10(-8) mol l(-1). The [Cu(bipy)2]/SAM modified electrode under optimized operational conditions (PIPES buffer 0.01 mol l(-1) at pH 6.8 and 200 mV vs. SCE) presented a linear response range between 1.0 micromol l(-1) and 100.0 micromol l(-1) for ascorbic acid. This modified electrode also presented an excellent repeatability, showing a relative standard deviation of 2.1% for a series of 12 successive measurements of a 5.0 micromol l(-1) ascorbic acid solution. Furthermore, the electroactivity was maintained over a long period (e.g., 92% after 100 determinations).

Journal Article↗
PubMed2003

Study of carbon nanotubes-HRP modified electrode and its application for novel on-line biosensors.

In this paper, multi-walled carbon nanotubes (MWCNTs) were successfully immobilized on the surface of a glassy carbon electrode by mixing with horse-radish peroxidase (HRP). The electrochemical behavior of H2O2 was also studied with the MWCNTs-HRP modified electrode as a working electrode. The MWCNTs-HRP modified electrode showed excellent response of reduction current for the determination of H2O2 at the potential of -300 mV (vs. Ag/AgCl). We assembled the MWCNTs-HRP modified electrode in a thin-layer flow cell and the H2O2 solution was continuously introduced into the cell with a syringe pump. We optimized the sensitivity of the H2O2 sensor by adjusting the working potential and the pH of the buffer solution. The peak current increased linearly with the concentration of H2O2 in the range 3.0 x 10(-7) to approximately 2.0 x 10(-4) mol L(-1). The detection limit is 1.0 x 10(-7) mol L(-1) (S/N = 3). The interferences from ascorbic acid, uric acid and other electroactive substances can be greatly excluded since the sensor can be operated at -300 mV. Stability and reproducibility of the MWCNTs-HRP chemically modified electrode were also studied in this paper. Fabricated with glucose and lactate oxidase, the MWCNTs-HRP electrode was also applied to prepare the on-line glucose and lactate biosensors because of the high sensitivity for the determination of H2O2.

Biosensing Techniques↗
PubMed2006

Modifying the liquid/liquid interface: pores, particles and deposition.

The modification of the liquid/liquid interface with solid phases is discussed in this article. Modified interfaces can be formed with molecular assemblies, but here attention is focussed on solid materials such as mesoscopic particles, or microporous and mesoporous membranes. Charge transfer across the modified liquid/liquid interface is considered in particular. The most obvious consequence of the introduction of such modifying components is their effect on the transport to, and the transfer of material across, the liquid/liquid interface, as measured voltammetrically for example. One particularly interesting reaction is interfacial metal deposition, which can also be studied under electrochemical control: the initial formation of metal nuclei at the interface transforms it from the bare, pristine state to a modified state with very different reactivity. Deposition at interfaces between liquids is compared and contrasted with the cases of metal deposition in bulk solution and conventional heterogeneous deposition on conducting solid surfaces. Comparison is also made with work on the assembly of pre-formed micron and nanometre scale solids at the liquid/liquid interface.

Electrochemistry↗