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PubMed1999

Intraspinal delivery of neurotrophin-3 using neural stem cells genetically modified by recombinant retrovirus.

Neural stem cells have been shown to participate in the repair of experimental CNS disorders. To examine their potential in spinal cord repair, we used retroviral vectors to genetically modify a clone of neural stem cells, C17, to overproduce neurotrophin-3 (NT-3). The cells were infected with a retrovirus construct containing the NT-3.IRES.lacZ/neo sequence and cloned by limiting dilution and selection for lacZ expression. We studied the characteristics of the modified neural stem cells in vitro and after transplantation into the intact spinal cord of immunosuppressed adult rats. Our results show that: (i) most of the genetically modified cells express both NT-3 and lacZ genes with a high coexpression ratio in vitro and after transplantation; and (ii) large numbers of the xenografted cells survive in the spinal cord of adult rats for at least 2 months, differentiate into neuronal and glial phenotypes, and migrate for long distances. We conclude that genetically modified neural stem cells, acting as a source of neurotrophic factors, have the potential to participate in spinal cord repair.

Animals↗
PubMed1997

Modified radical vulvectomy without lymphadenectomy under local anesthesia in medically compromised patients.

INTRODUCTION: Our objective was to review our experience with vulvar cancer treated with modified radical vulvectomy without lymphadenectomy under local anesthesia and sedation. METHODS: A retrospective review of surgical case lists revealed five patients who underwent modified radical vulvectomy without lymphadenectomy under local anesthesia with sedation. All patients had significant medical diseases which precluded regional or general anesthesia. Modified radical vulvectomy was performed in standard fashion under sedation and local anesthesia. Inguinal lymphadenectomy was not performed. RESULTS: Median operative time was 1.5 h and median blood loss was 100 cc. Median diameter of tissue resected was 5 cm and median depth was 5 cm. Median length of hospital stay was 4 days. No patient complained of pain during the operative procedure. At a median follow-up of 2.5 years, there has been one local recurrence. CONCLUSION: Five patients with symptomatic vulvar cancer who were not candidates for regional or general anesthesia underwent modified radical vulvectomy without lymphadenectomy under local anesthesia with sedation. The procedure was well-tolerated and produced minimal morbidity and adequate short-term local control.

Aged↗
PubMed1998

Primary squamous cell cancer of the vulva: radical versus modified radical vulvar surgery.

OBJECTIVE: To evaluate the results of surgical therapy and to specifically compare radical and modified radical vulvar surgery relative to survival, recurrence, metastasis, and complications. METHODS: A retrospective review of 225 patients with primary squamous cell cancer of the vulva was performed. Clinical, pathologic, surgical, and follow-up data were collected from the patient records. All pathology slides were reviewed with a pathologist. Radical surgery included 134 patients treated by the Basset operation. Modified radical surgery accounted for 91 patients with vulvar excision alone (65) or with lymphadenectomy (26) via separate groin incisions. RESULTS: The 5-year recurrence rate was 14%. The overall and disease-free survival rates at 5 years were 76. 1 and 83.4%, respectively. There were no statistically significant differences between the two procedures regarding overall survival, disease-free survival, or the development of recurrence, even after adjusting for stage (P > 0.05). Patients undergoing radical vulvar surgery were more likely to develop surgical complications and sequelae than patients having modified radical surgery, even after adjusting for stage. CONCLUSIONS: Modified radical vulvar surgery is associated with decreased complications and 5-year overall and disease-free survival and recurrence rates similar to those of radical vulvar surgery.

Adult↗
PubMed1998

Surface Structure and Properties of Calcium Hydroxyapatite Modified by Hexamethyldisilazane.

The surface of synthetic calcium hydroxyapatite Ca10(PO4)6(OH)2 (CaHAP) particles was treated by repeated modification with hexamethyldisilazane [(CH3)3Si]2NH (HMDS) in hexane and thermal treatment and the surface of the modified CaHAP was characterized by various means. No remarkable change in XRD patterns or in particle shape by the modification was observed. The width of the CaHAP particles gradually increased with repeating the modification. FTIR results indicated that HMDS reacted with surface P-OH groups of CaHAP to yield surface Si-(CH3)3 groups. The surface of the modified CaHAP was hydrophobic. The surface Si-(CH3)3 groups turned to three kinds of surface Si-OH groups by treating the modified materials at 500 degreesC in air. These formed surface Si-OH groups and the remaining surface P-OH groups reacted with HMDS by repeating the modification, resulted in the increase of the surface Si atoms. The modified material having surface Si-(CH3)3 or Si-OH groups adsorbed much less CO2 than the unmodified one. Copyright 1998 Academic Press.

Journal Article↗
PubMed1999

Adsorption of Hydrophobically Modified Polyacrylic Acid on a Hydrophobic Surface: Hysteresis Caused by an Electrostatic Adsorption Barrier.

The adsorption of hydrophobically modified polyacrylic acid (HM-PAAc) has been compared to the adsorption of unmodified polymers by means of reflectometry. The polymers were adsorbed onto a noncharged hydrophobic polystyrene surface. The adsorption kinetics of both types of polymer is the same until a certain surface coverage. Then the unmodified sample shows a saturation while the hydrophobically modified polyacrylic acid continues to adsorb. The adsorption behavior of the polyelectrolyte can be controlled by the pH and the ionic strength of the solution. For ionic strengths of 0.001 M NaCl the hydrophobically modified polymer shows a larger adsorbed amount at pH 3 to 4 compared to the unmodified polymer. At pH higher than 4 the differences are less significant. At higher ionic strength the amount of adsorbed material increases for both polymers. While doing adsorption-desorption cycles a hysteresis-effect was detected. At the same pH the hydrophobically modified polymer sticks to the surface while the unmodified polymer is already desorbing completely. The hysteresis vanishes when the ionic strength of the solution is increased. Copyright 1999 Academic Press.

Journal Article↗
PubMed1999

TPD, FTIR, and Molecular Adsorption Studies of Calcium Hydroxyapatite Surface Modified with Hexanoic and Decanoic Acids.

The surface of synthetic calcium hydroxyapatite Ca10(PO4)6 (OH)2 (CaHAP) particles was modified with hexanoic CH3(CH2)4 COOH (HA) and decanoic CH3(CH2)8COOH (DA) acids in hexane and the resulting materials were characterized by various means. XRD pattern, specific surface area, and morphology of the CaHAP particles were essentially not altered by the modification. FTIR and TPD results indicated that HA and DA molecules are hydrogen-bonded to the surface P-OH groups of CaHAP in three adsorption types. The surface of modified particles became hydrophobic. When the modified samples were outgassed at 500 degrees C, HA and DA were removed and the surface P-OH groups were revived. The modified material adsorbed much less H2O and CO2 than the unmodified one. Copyright 1999 Academic Press.

Journal Article↗
PubMed2000

Photoluminescence Properties of Surface-Modified Nanocrystalline ZnS : Mn.

DBS surface-modified nanocrystalline ZnS : Mn was prepared by a precipitation method. Photoluminescence spectra and decay curves were measured and compared to those of unmodified samples. For both kinds of samples, luminescence decay curves of 600 nm emission consist of two components with nanosecond (ns) and millisecond (ms) lifetimes. The nanosecond component is attributed to zinc vacancies luminescence, with peak located at 440 nm. While the millisecond component is attributed to Mn(2+) luminescence and its decay time changes with Mn(2+) concentration and surface modification. The surface-modified sample has a longer lifetime compared to unmodified samples. The photoaging of surface-modified samples is slow. Particle size effects on photoaging were also examined. For nanocrystalline ZnS : Mn photoaging is more noticeable than that of bulk material. After UV irradiation, photoluminescence intensity of the modified sample is several times larger than that of the unmodified sample, because the surface-active reagent decreases surface defects and depresses radiationless transitions. XPS yields direct evidence of the surface-modification effect on the surface structure. Copyright 2000 Academic Press.

Journal Article↗
PubMed1996

Enzymatic formation of modified nucleosides in tRNA: dependence on tRNA architecture.

Information is still quite limited concerning the structural requirements in tRNA molecules for their post-transcriptional maturation by base and ribose modification enzymes. To address this question, we have chosen as the model system yeast tRNAAsp that has a known three-dimensional structure and the in vivo modifying machinery of the Xenopus laevis oocyte able to act on microinjected tRNA precursors. We have systematically compared the modification pattern of wild-type tRNAAsp with that of a series of structural mutants (21 altogether) altered at single or multiple positions in the D-, T-and the anticodon branch, as well as in the variable region. The experimental system allowed us to analyze the effects of structural perturbations in tRNA on the enzymatic formation of modified nucleosides at 12 locations scattered over the tRNA cloverleaf. We found that the formation of m1G37 and psi 40 in the anticodon loop and stem and psi 13 in the D-stem, were extremely sensitive to 3D perturbations. In contrast, the formation of T54, psi 55 and m1A58 in the T-loop, m5C49 in the T-stem and m2G6 in the amino acid accepting stem were essentially insensitive to change in the overall tRNA architecture; these modified nucleosides were also formed in appropriate minimalist (stems and loops) tRNA domains. The formation of m2G26 at the junction between the anticodon and the D-stem, of Q34 and manQ34 in the anticodon loop were sensitive only to drastic structural perturbation of the tRNA. Altogether, these results reflect the existence of different modes of tRNA recognition by the many different modifying enzymes. A classification of this family of maturation enzymes into two major groups, according to their sensitivities to structural perturbations in tRNA, is proposed.

Animals↗
PubMed1996

Incorrect base insertion and prematurely terminated transcripts during T7 RNA polymerase transcription elongation past benzo[a]pyrenediol epoxide-modified DNA.

DNA replication and transcription are affected adversely by the presence of bulky adducts that are generated by the covalent binding of a variety of metabolically activated environmental pollutants to cellular DNA. When these lesions are not cleared by cellular repair enzymes prior to replication, mutations and ultimately tumor initiation can occur. Transcription and DNA repair appear to be intimately connected, since certain adducts are more efficiently removed from the transcribed strands of active loci than from non-transcribed strands and other quiescent domains in the genome. The mechanism by which RNA polymerases deal with bulky adducts during DNA transcription is therefore of great interest. The availability of site-specifically modified and stereochemically defined oligodeoxyribonucleotides derived from the covalent reaction of 7r, 8t-dihydroxy-9, 10t-epoxy- 7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) with guanine residues prompted us to study the efficiencies of transcription past these lesions using bacteriophage T7 RNA polymerase. We show here that T7 RNA polymerase can bypass such lesions in a DNA template, providing that a cytosine residue is incorporated opposite anti-BPDE-modified guanine. However, when an incorrect base (most frequently a purine) is inserted opposite the modified site, the RNA polymerase stalls, and the complex dissociates, resulting in a truncated transcript. The ability of the T7 RNA polymerase to discriminate between a correct and an incorrect inserted base and, accordingly, to continue or terminate transcription, might constitute an important mechanism that ensures the fidelity of transcription past a modified base present on the transcribed strand of the DNA template.

Bacteriophage T7↗
PubMed2000

A Modified Vibron Model for Anharmonic Vibrations: Application to Rovibrational Levels of Linear XYZ and XY(2) Molecules.

The vibron model for anharmonic vibrations of simple polyatomic molecules has been modified by explicit inclusion of the bending energy in the vibron hamiltonian, and by incorporating vibrationally and rotationally dependent terms into the main parameters of the model. These modifications keep the simple form of the basic vibron energy expressions unchanged but make them far more flexible and capable of much higher precision than those of the pure algebraic vibron model, even one with all squares and binary products of the Casimir operators included. Applications of the modified equations to the vibrational levels and rovibrational energies of the linear molecules HCN, CO(2), and some of their isotopomers show that this modified model yields precision of fitting which is better by one to two orders of magnitude than that provided by the strict algebraic model. This suggests that the modified vibron model can provide a simple but useful alternative to the much more elaborate global treatments of the rovibrational data. Copyright 2000 Academic Press.

Journal Article↗
PubMed1999

Achieving antisense inhibition by oligodeoxynucleotides containing N(7)-modified 2'-deoxyguanosine using tumor necrosis factor receptor type 1.

Antisense oligodeoxynucleotides (ODNs) are being explored as therapeutic agents for the treatment of many disorders including viral infections, cancers, and inflammatory disorders. In addition, antisense technology can be of great benefit to those attempting to assign function to the multitude of new genes being uncovered in the genomics initiative. However, the demonstration that the gene-regulating effects produced by antisense-designed ODNs are attributable to an antisense mechanism of action requires carefully designed experimentation. Critical to the assignment of an antisense mechanism of action is the availability of nuclease-stable ODNs, inside cells, that have a high binding affinity with the target mRNA and modulate gene functions in a sequence-dependent manner. To help us achieve a goal of sequence-specific antisense activity we designed antisense ODNs containing C(5)-propyne-modified 2'-deoxyuracil and N(7)-propyne-modified 7-deaza-2'-deoxyguanosine bases and partially modified (phosphorothioate) internucleoside linkages. These modified ODNs were found to have enhanced binding affinity to their target mRNA sequences as well as reduced sequence-independent side effects. We used these ODNs to specifically inhibit p55 tumor necrosis factor receptor type 1 expression and tumor necrosis factor alpha-mediated functions in culture assays.

Antigens, CD↗
PubMed1994

Somatic gene transfer to the adult primate central nervous system: in vitro and in vivo characterization of cells genetically modified to secrete nerve growth factor.

Somatic gene transfer offers a means of delivering substances to the central nervous system (CNS) in a regionally specific, high-dose, chronic and well-tolerated manner. Studies in rats have shown that genetically modified cell grafts can prevent neuronal degeneration and promote functional recovery after injury and can improve cognitive function in aged subjects. To assess the potential utility of somatic gene transfer techniques in primate models, retroviral vectors were used to modify genetically monkey and human primary skin fibroblasts to produce and secrete human nerve growth factor (NGF). In vitro, all cell types produced NGF and sustained this production through cell growth to confluency, as determined by both Northern blot analysis and ELISA. Adult human fibroblasts produced as much NGF as did young human fibroblasts. Monkey fibroblasts genetically modified to produce NGF were then grafted to intact adult rhesus and cynomolgous monkey brains. Among nine primates that received a total of 76 grafts, surviving cells were found in all subjects up to the maximal experimental timepoint of 6 months. Cholinergic fibres from the host brain penetrated NGF-secreting grafts up to 6 months after grafting, but showed little penetration in control grafts lacking the NGF gene. Autografts survived better than allografts. These findings indicate that both human and primate fibroblasts can be transduced to produce and secrete NGF, can maintain this production whether in a growing or quiescent state and can elicit robust sprouting responses when primate fibroblasts are grafted to the adult brain. Cells genetically modified to produce trophic factors are a useful model for studying in vitro and in vivo CNS plasticity and for testing potential therapies for neurodegenerative conditions.

Animals↗
PubMed1993

Responsiveness of cardiac Na+ channels to a site-directed antiserum against the cytosolic linker between domains III and IV and their sensitivity to other modifying agents.

Elementary Na+ currents were recorded in inside-out patches from neonatal rat heart cardiocytes to analyze the influence of a site-directed polyclonal anti-serum against the linker region between the domains III and IV (amino acids 1489-1507 of the cardiac Na+ channel protein) on Na+ channel gating and to test whether this part of the alpha-subunit may be considered as a target for modifying agents such as the (-)-enantiomer of DPI 201-106. Anti-SLP 1 serum (directed against amino acids 1490-1507) evoked, usually within 10-15 min after cytosolic administration, modified Na+ channel activity. Antiserum-modified Na+ channels retain a single open state but leave, at -60 mV for example, their conducting configuration consistently with an about threefold lower rate than normal Na+ channels. Another outstanding property of noninactivating Na+ channels, enhanced burst activity, may be quite individually pronounced, a surprising result which is difficult to interpret in terms of structure-function relations. Removal of inactivation led to an increase of reconstructed peak INa (indicating a rise in NPo) and changed INa decay to obey second-order kinetics, i.e., open probability declined slowly but progressively during membrane depolarization. The underlying deactivation process is voltage dependent and responds to a positive voltage shift with a deceleration but may operate even at the same membrane potential with different rates. Iodate-modified Na+ channels exhibit very similar properties including a conserved conductance. They are likewise controlled by an efficient, voltage-dependent deactivation process.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1991

Inactivation modifiers of Na+ currents and the gating of rat brain Na+ channels in planar lipid membranes.

Rat brain Na+ channels whose inactivation process had been removed either by batrachotoxin (BTX) or veratridine (VT) were reconstituted into planar lipid membranes. The voltage dependence of the open probability (Po) of the channel, of the opening and closing rate constants, and the conductance and relative permeability for Na+ and K+ were studied in voltage-clamp conditions in the presence of agents known to modify the inactivation of Na+ currents. In relation to alkaloids (BTX, VT, and aconitine), it was found that once a Na+ channel was modified by BTX or VT, the addition of another alkaloid did not change further the gating and permeation properties of the channel over a period of about 1 h. Once the inactivation process of the channels is removed by BTX, the addition of a proteolytic enzyme (trypsin) or an halogenated compound (chloramine-T, CT) induced profound and specific modifications on the opening and closing events of Na+ channels: (1) the voltage dependence of the channel Po shifted to more hyperpolarized potentials; (2) this voltage shift can be explained by equal hyperpolarizing voltage shifts of the opening and closing rate constants of the channel; (3) although the gating properties of the channel were modified by these compounds, the permeation properties of the channel, as evaluated by the conductance and the selectivity to Na+ and K+ ions, were unaltered; (4) trypsin and CT were active only in the intracellular side of the channel and were irreversible within the time course of the experiments, suggesting covalent modifications of the channel. Inactivation modifiers also affected the gating of toxin-activated single Na+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed1984

Excretion of modified nucleosides during development of malignant lymphomas in mice after whole body irradiation.

During x-ray-induced development of malignant lymphomas in mice their urinary excretion of eight modified nucleosides was monitored and the values were compared to the results of the histological examination of the animals at time of their sacrifice. It was found that the pathologically augmented excretion of modified nucleosides begins as much as several weeks before the malignant lymphomas can be diagnosed clinically. Thus some mice had increased levels of modified nucleosides even 10 weeks before sacrifice, though at the time of sacrifice the histological investigation revealed only some small foci of reticulum cell neoplasm in their spleen. It is therefore stressed that the usefulness of the determination of urinary modified nucleosides as an early noninvasive screening test for cancer in man and as an in vivo carcinogenicity test should be evaluated.

Animals↗
PubMed1989

Temperature-dependent subconducting states and kinetics of deltamethrin-modified sodium channels of neuroblastoma cells.

The effects of temperature on the properties of sodium channels from mouse neuroblastoma cells modified by the pyrethroid insecticide deltamethrin were investigated using the patch-clamp technique. The study was aimed at determining various states of modified channels which were expected to be revealed by raising the temperature as a result of an increase in channel activity. After exposure to 10 microM deltamethrin, the decay of whole cell sodium current at -30 mV was drastically slowed. It is expressed by two exponential functions at 11 degrees C and by three exponential functions at room temperature (22 +/- 1 degree C). Thus, raising the temperature reveals a new process. Whole cell sodium tail currents associated with step repolarization from -30 mV to -100 mV were best fit by the sum of two exponential functions both at 11 degrees C and at room temperature. The decay of the summed modified single sodium channel currents at -30 mV was expressed by a single exponential function at 11 degrees C, and by two exponential functions at room temperature. In keeping with these results, the open time histograms show the single (11 degrees C) and double (room temperature) exponential distributions. Thus, raising the temperature allows a new single channel process to be revealed. Other modified open states observed previously at 11 degrees C were also found at room temperature including a flickering state and a subconducting state. In addition, several new subconducting states were found at room temperature.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Scleral damage: comparison of standard and modified diathermy electrodes.

Full-thickness scleral diathermy using a standard electrode causes significant scleral damage and necrosis. Use of a modified (Jabbour's) diathermy electrode appears to cause minimal scleral damage. We evaluated the scleral changes following transscleral diathermy application using standard and modified diathermy electrodes to the peripheral retina and ciliary body. Twelve Dutch belted pigment rabbits were used in our experiment. Three eyes each were subjected to transscleral diathermy using standard and modified electrodes to produce chorioretinal scars and cyclodestruction. Eyes were examined with the slit lamp and indirect ophthalmoscope at weekly intervals for 4 weeks. Light and transmission electron microscopy was performed 1 hour after diathermy application in 4 animals and in the remaining 8 animals at 4 weeks. Chorioretinal scarring and ciliary body atrophy were successfully induced with both types of electrodes. However, scleral damage was less severe in eyes treated with the modified electrode as compared with the standard electrode.

Animals↗
PubMed1993

Induction of cell-mediated immunity against B16-BL6 melanoma in mice vaccinated with cells modified by hydrostatic pressure and chemical crosslinking.

In the preceding paper we have demonstrated an increase in presentation of both major histocompatibility complex antigens (MHC) and a tumor-associated antigen of the weakly immunogenic B16 melanoma by a straight-forward technique. The method consists in modulating the tumor cell membrane by hydrostatic pressure and simultaneous chemical crosslinking of the cell-surface proteins. In B16-BL6 melanoma, the induced antigenic modulation was found to persist for over 48 h, which permitted the evaluation of the ability of modified B16-BL6 cells to induce immunity against unmodified B16-BL6 cells. In the present study, we have shown that a significant systemic immunity was induced only in mice that were immunized with modified B16-BL6 melanoma cells, whereas immunization with unmodified B16-BL6 cells had only a marginal effect when compared to the results in control sham-immunized mice. The induced immunity was specific since a single immunization affected the growth of B16-BL6 tumors but had no effect on MCA 106, an antigenically unrelated tumor. The addition of interleukin-2 to the immunization regimen had no effect on the antitumor responses induced by the modified B16-BL6 cells. The cell-mediated immunity conferred by immunization with treated B16-BL6 cells was confirmed in experiments in vitro where splenocytes from immunized mice could be sensitized to proliferate by the presence of B16-BL6 cells. In addition, the altered antigenicity of these melanoma cells appeared to correlate with their increased susceptibility to specific effectors. Thus, 51Cr-labeled B16-BL6 target cells, modified by pressure and crosslinking, in comparison to control labeled target cells, were lysed in much greater numbers by effectors such as lymphokine-activated killer cells and allogeneic cytotoxic lymphocytes (anti-H-2b), while such cells remained resistant to lysis by natural killer cells. Our findings indicate that the physical and chemical modifications of the tumor cells that are described here may be considered as a simple yet effective method for the preparation of tumor vaccines, which could be applied in tumor-bearing hosts.

Animals↗