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At least 1,531 records · Page 85Linked to original sources
PubMed2005

Modified reperfusion in clinical lung transplantation: the results of 100 consecutive cases.

OBJECTIVE: Severe primary graft dysfunction occurs in 10% to 20% of lung transplant recipients and is the leading cause of early death after lung transplantation. We hypothesized that altering the content of the initial reperfusate and maintaining a low reperfusion pressure after surgical implantation would lead to a low incidence of primary graft dysfunction. METHODS: We analyzed the records of all patients who underwent lung transplantation at our institution from March 1, 2000, to August 30, 2004. The modified reperfusion technique involved the insertion of a catheter into the main or individual pulmonary artery after implantation. The recipient blood was depleted of leukocytes; supplemented with nitroglycerin; adjusted for pH and calcium level; enriched with aspartate, glutamate, and dextrose; and then administered into the pulmonary arteries of the newly transplanted lung(s) for the first 10 minutes of reperfusion. Severe primary graft dysfunction was defined as a PaO2/inspired oxygen fraction of less than 150 with diffuse infiltrate on the radiograph in absence of other causes. RESULTS: During this interval, 100 patients underwent lung transplantation with the modified reperfusion technique. Forty-two patients underwent single-lung transplantation, of which 5 patients required cardiopulmonary bypass for the procedure. Fifty-eight patients underwent double-lung transplantation; all double-lung transplantation procedures were performed with patients on cardiopulmonary bypass. There were no technical complications associated with the modified reperfusion. The mean PaO2/inspired oxygen fraction at 6 hours in this cohort was 252 +/- 123 mm Hg. The median number of days on the ventilator was 2. More importantly, the incidence of severe primary graft dysfunction in this cohort was 2.0%. The early survival (30-day or in-hospital mortality) of this group of patients was 97%. CONCLUSIONS: The technique of modified reperfusion in human lung transplantation is associated with a low incidence of severe primary graft dysfunction and favorable short-term outcomes.

Humans↗
PubMed2006

Modified and conventional ultrafiltration during pediatric cardiac surgery: clinical outcomes compared.

OBJECTIVE: This prospective study compared clinical outcomes after heart surgery between three groups of infants with congenital heart disease. One group received dilutional conventional ultrafiltration (group D), another received modified ultrafiltration (group M), and a third group received both dilutional conventional and modified ultrafiltration (group B). We hypothesized that group B patients would have the best clinical outcome. METHODS: Children younger than 1 year undergoing heart surgery for biventricular repair by the same surgeon were randomly allocated to one of the three study groups. Patient management was standardized, and intensive care staff were blinded to group allocation. Primary outcome measure was duration of postoperative mechanical ventilation. Other outcome measures recorded included total blood products transfused, duration of chest tube in situ, chest tube output, and stays in intensive care and in the hospital. RESULTS: Sixty infants completed study protocol. Mean age and weight were as follows: group D (n = 19), 61 days, 4.3 kg; group M (n = 20), 64 days, 4.5 kg; and group B (n = 21), 86 days, 4.4 kg. Preoperative and intraoperative characteristics were similar between groups. Ultrafiltrate volumes obtained were 196 +/- 93 mL/kg in group D, 105 +/- 33 mL/kg in group M, and 261 +/- 113 mL/kg in group B. There were no significant differences between groups for any outcome variable. Technical difficulties prevented completion of modified ultrafiltration in 2 of 41 infants. CONCLUSION: There was no clinical advantage in combining conventional and modified ultrafiltration. Because clinical outcomes were similar across groups, relative risks of the ultrafiltration strategies may influence choice.

Cardiopulmonary Bypass↗
PubMed2005

Immunological studies on peroxynitrite modified human DNA.

Peroxynitrite (ONOO(-)) is a strong and potent oxidizing and nitrating agent, formed by rapid reaction of two highly reactive, nitric oxide and superoxide anion. The action of peroxynitrite generated by synergistic action of diethylamine NONOate (a nitric oxide donor) and 1,4-hydroquinone (a superoxide donor), on human placental DNA was monitored by ultraviolet and fluorescence spectroscopy, melting temperature studies, S1 nuclease digestibility and alkaline agarose electrophoresis. The peroxynitrite modified human DNA (ONOO(-)-DNA) was found to be highly immunogenic in rabbits inducing high titre immunogen specific antibodies. However, the induced antibodies exhibited appreciable cross-reactivity with various polynucleotides and nucleic acids. The data demonstrate that the antibodies, though cross-reactive, preferentially bind ONOO(-)-modified epitopes on DNA. Visual detection of immune complex formation with native and ONOO(-)-DNA reiterated preferential binding with modified human DNA. DNA modified by ONOO(-) presents unique epitopes which may be one of the factors for the induction of autoantibodies in cancer patients.

Animals↗
PubMed2004

Does peroxisome proliferator-activated receptor gamma genotype (Pro12ala) modify the association of physical activity and dietary fat with fasting insulin level?

Peroxisome proliferator-activated receptor gamma (PPARgamma) has a role in controlling adipogenesis and insulin sensitivity. Previous studies have suggested that a common polymorphism (Pro12Ala) in the PPARgamma-2 isoform of this gene may be associated with markers of insulin resistance. We have previously shown that in combination, the relationships with fasting insulin of dietary polyunsaturated to saturated fatty acid ratio (P:S ratio) and physical activity are additive. We have also demonstrated that the association between P:S ratio and fasting insulin level is modified by the Pro12Ala genotype. The purpose of the present study was to investigate whether the Pro12Ala genotype modified the combined relationships of P:S ratio and physical activity level (PAL) on fasting insulin concentration. A population-based cohort of 506 Caucasian men and women aged 31 to 71 years was genotyped for the Pro12Ala polymorphism. P:S ratio was assessed by food-frequency questionnaire (FFQ) and PAL was estimated from 4 days of free-living heart rate monitoring following individual calibration of heart rate against energy expenditure during an exercise stress test. The combined associations of PAL and P:S ratio on fasting insulin level were examined stratified by Pro12Ala genotypes in a dominant model for the Ala allele. Among Pro allele homozygotes, there was no interaction between PAL and P:S ratio on fasting insulin (P =.929). However, in carriers of the Ala allele the association of P:S ratio with fasting insulin was modified by activity level (interaction P = 0.038). In those who were inactive and carried the Ala allele, the age-, sex-, and body mass-adjusted relationship between P:S ratio and log insulin was not significant (beta = -0.03, P =.93). In contrast, in physically active Ala carriers, the association of P:S ratio with log fasting insulin was highly significant (beta = -0.93, P =.004). In conclusion, this study examined the modification by PPARgamma genotype of the association between energy expenditure, P:S ratio, and fasting insulin level, a measure of insulin resistance. These data show that in Pro allele homozygotes the combined associations of P:S ratio and PAL are additive. In contrast, in Ala allele carriers, PAL modifies the association between P:S ratio and fasting insulin level in a multiplicative manner.

Adult↗
PubMed2004

Protective potential of experimental autoimmune myasthenia gravis in Lewis rats by IL-10-modified dendritic cells.

Dendritic cells (DC) are usually regarded as antigen-presenting cells (APC) involved in T cell activation, but DC also directly or indirectly affect B cell function, antibody synthesis and isotype switch. In this study, we explore potential of DC-based immunotherapy in ongoing experimental autoimmune myasthenia gravis (EAMG) in Lewis rats, which is mediated by anti-acetylcholine receptor (AChR) antibodies. Spleen DC were isolated from onset of Lewis rat EAMG on day 39 post immunization (p.i.), exposed in vitro to IL-10 and then injected intraperitoneally into ongoing EAMG Lewis rats at dose of 1 x 10(6) cells/rat on day 5 p.i. with AChR + complete Freund's adjuvant. IL-10-modified DC resulted in lower clinical scores, less body weight loss, lower numbers of anti-AChR IgG antibody-secreting cells and lower affinity of anti-AChR antibodies in rats receiving IL-10-modified DC, accompanied with lower expression of CD80 and CD86 and lower lymphocyte proliferation among lymph node mononuclear cells compared with control EAMG rats. Lower levels of IL-10 and IFN-gamma were also found in the supernatants of AChR-stimulated lymph node MNC culture in rats receiving IL-10-modified DC. These results demonstrate that IL-10-modified DC induced hypo-responsiveness by down-regulating co-stimulatory molecules, and reduced production of anti-AChR antibodies possibly by inhibiting IL-10 production. Importantly, this procedure that autologous DC from EAMG were adopted to treat ongoing EAMG is more close to clinical trial in human, encouraging future evaluation in human myasthenia gravis.

Animals↗
PubMed2004

Modified Hughes flap: division at 7 days.

PURPOSE: To report the outcome of early division of the tarsoconjunctival pedicle of a modified Hughes flap at 1 week after the primary operation. DESIGN: Noncomparative, interventional, prospective case series. PARTICIPANTS: Twenty-nine eyelids of 29 consecutive patients operated using the modified Hughes flap and full-thickness skin graft for lower eyelid reconstruction after Mohs micrographic surgery, over a 4-year period. INTERVENTION: In all patients, the pedicle of the Hughes flap was divided 1 week after the primary operation. MAIN OUTCOME MEASURES: Postoperative lower eyelid flap viability and lower eyelid contour complications. RESULTS: Twenty-nine eyelids of 29 patients (mean age: 69+/-11 years) were operated using the modified Hughes flap. The mean follow-up period was 14+/-6 months (range: 6-23). There were no cases of lower eyelid retraction, flap ischemia, or necrosis after division. Postoperative complications included lower eyelid margin erythema in 2 patients (6.9%), upper eyelid lash ptosis in 3 patients (10.3%), and upper eyelid lateral retraction in 1 patient (3.4%). CONCLUSION: Early division of the tarsoconjunctival pedicle of a modified Hughes flap at 1 week does not compromise the viability of the reconstructed lower eyelid and results in a good functional and cosmetic outcome.

Adult↗
PubMed2005

Modified functional neck dissection: a useful technique for oral cancers.

Among 60 patients with oral squamous cell carcinoma, 30 were treated by the modified functional neck dissection (preserve 8 functional tissues), 30 were treated by functional neck dissection (preserve 3 functional tissues). The recurrent rate of cervical lymph node and the sense of skin were assessed. The recurrence rates in cervical nodes was 6.67% and 10%, respectively (p > 0.05) in patients who accepted modified functional neck dissection and functional neck dissection. The sensation in skin in patients who accepted modified functional neck dissection was better than those who accepted functional neck dissection (p < 0.01). Modified functional neck dissection is helpful to decrease postoperative complications, without increasing recurrent rates of cervical lymph node.

Adult↗
PubMed2003

The endoscopic modified Lothrop procedure for salvage of chronic frontal sinusitis after osteoplastic flap failure.

OBJECTIVE: While reported results utilizing the osteoplastic flap procedure are very good, some patients fail the surgery due to recurrent or persistent frontal sinus disease. This study was performed to evaluate the utility of the endoscopic modified Lothrop sinus surgery for osteoplastic flap failure. STUDY DESIGN AND SETTING: A retrospective chart analysis and telephone survey of 10 patients from outside our institution for whom an osteoplastic flap with fat obliteration failed were salvaged using a computerized endoscopic modified Lothrop procedure. RESULTS: The main complaints were headache/pressure and recurrent infection. The usual pathology was chronic sinusitis and/or mucocele. The frontal recess and floor of the frontal sinus were the most common areas of persistent disease. Symptomatic clinical improvement was noted in more than 90% of patients. CONCLUSION: Salvage endoscopic modified Lothrop sinus surgery is recommended for a limited number of traditional osteoplastic flap failures. Computerized surgical navigation may help avoid complications in situations with abnormal anatomy and previous dissection. SIGNIFICANCE: The endoscopic modified Lothrop procedure should be considered to salvage failed osteoplastic flap sinus obliteration.

Adult↗
PubMed2006

Modified superficial parotidectomy: preserving both the great auricular nerve and the parotid gland fascia.

OBJECTIVE: To reduce the incidence of sensory deficits and Frey's syndrome by modifying the traditional superficial parotidectomy. STUDY DESIGN: After raising the skin flap, the parotid gland fascia (PGF) was elevated to form a posterior pedicle fascial flap and then was replaced after the gland removal. The great auricular nerve (GAN) that runs within the PGF was not separated, so both the GAN and the PGF were preserved. Before this modification, the GAN and PGF were examined anatomically. The complication rates in the modified and control groups were compared. RESULTS: 1) The GAN, which runs within the thick and pycnotic PGF, trifurcates into postauricular, preauricular and lobule branches. The modification could be carried out practically based on the anatomy study. 2) Long-term sensory deficit was encountered in 13.3% of the control group, but 0% in the modified one. Frey's syndrome was suffered by 66.7% and 16.7% cases in the control and modified group respectively. The incidence of other complications was not significantly different. CONCLUSION: Our modification is practical. It decreases the complications significantly. EBM RATING: B-3b.

Adenoma, Pleomorphic↗
PubMed2005

Selegiline modifies the extinction of responding following morphine self-administration, but does not alter cue-induced reinstatement, reacquisition of morphine reinforcement, or precipitated withdrawal.

Selegiline is an irreversible inhibitor of monoamine oxidase (MAO) with psychostimulant and neuroprotective effects which can prevent decreases in dopamine efflux that follow opiate withdrawal. The present study evaluated effects of selegiline treatment on morphine-seeking behavior and morphine reinforcement in Wistar rats (n = 26). In additional animals (n = 30), the ability of single doses of selegiline to modify naloxone-precipitated withdrawal was determined. After pretreatment with noncontingent morphine to establish opiate dependence, rats acquired self-administration of intravenous morphine. Daily intravenous treatment with saline or 2.0mg kg(-1) doses of selegiline was then initiated and continued over 14 days during extinction, reinstatement, and reacquisition of morphine self-administration. To reduce the potential for psychostimulant effects, selegiline was administered approximately 1h following self-administration, extinction, or reinstatement sessions. In some animals (n = 23), effects of saline or selegiline administration on locomotor activity were determined following extinction sessions. Daily selegiline treatment decreased the number of ratios completed and increased response latency during extinction, without modifying these measures during reinstatement or reacquisition of morphine self-administration. Chronic selegiline treatment increased locomotor activity recorded between 4 and 7h after selegiline administration on day 7 of extinction, but otherwise did not alter locomotor activity. Pretreatment with single, 2.0mg kg(-1) doses of selegiline did not modify naloxone-precipitated withdrawal. In conclusion, pretreatment with selegiline produced only a small decrease in responding during extinction of morphine self-administration and did not modify cue-induced reinstatement of morphine-seeking behavior, reacquisition or morphine reinforcement, or precipitated withdrawal.

Animals↗
PubMed2006

Standard and Fpg-modified comet assay in kidney cells of ochratoxin A- and fumonisin B(1)-treated rats.

The effect of ochratoxin A (OTA), fumonisin B(1) (FB(1)), and their combinations on DNA damage was studied using the standard alkaline comet assay and the Fpg-modified comet assay. Rats were orally receiving OTA (5 ng/kg b.w., 0.05 mg/kg b.w., and 0.5mg/kg b.w., respectively) for 15 days, FB(1) (200 ng/kg b.w., 0.05 mg/kg b.w., and 0.5mg/kg b.w., respectively) for 5 days, and the combinations of two lower OTA and FB(1) doses. The tail length, tail intensity, and Olive tail moment (OTM) obtained with the standard comet assay and Fpg-modified comet assay were significantly higher in treated animals than in controls, even at the lowest dose of OTA or FB(1) (p<0.01). The Fpg-modified comet assay showed significantly greater tail length, tail intensity, and OTM in all treated animal than did the standard comet assay (p<0.05), which suggests that oxidative stress is likely to be responsible for DNA damage. DNA damage detected by the standard comet assay at all OTA or FB(1) doses indicates that some other mechanism is also involved. Combined OTA+FB(1) treatment measured either by the standard comet or the Fpg-modified comet assay showed a synergistic increase in the tail intensity and OTM in kidney cells, even at doses that correspond to the daily human exposure in Europe.

Animals↗
PubMed2005

A controlled sequential evaluation of open donor nephrectomy versus classical and modified laparoscopic donor nephrectomy: an update.

This study sought to determine the procedure of choice for kidney retrieval for transplantation by comparing open donor nephrectomy to laparoscopic donor nephrectomy and modified laparoscopic donor nephrectomy and by analyzing intraoperative donor and recipient graft function parameters. In this single-center, controlled, sequential analysis, 100 consecutive donor-recipient pairs were recruited, grouped according to surgical procedure, and operated upon between 1997 to 2004, as follows: group 1, open donor nephrectomy (n = 30), performed from 1997 to 2000; group 2, laparoscopic donor nephrectomy (n = 28), performed from 2000 to 2002; and group 3, modified laparoscopic donor nephrectomy (n = 42), performed from 2002 to 2004. Data were analyzed by type of operative procedure, graft function, length of hospital stay, and donor recovery time. Operative time was similar for all three surgical approaches. Warm ischemia times for open donor nephrectomy and modified laparoscopic donor nephrectomy were similar. Acute tubular necrosis occurred in 7% of patients in all groups. Donor recovery and lengths of hospital stay were significantly shorter for laparoscopic approaches. Donor complications were similar in numbers, differing only in complication type. Graft function and survival were similar for all three surgical approaches. We conclude that modified laparoscopic donor nephrectomy is the procedure of choice for living kidney retrieval.

Adult↗
PubMed2006

Electrochemically assisted photocatalytic degradation of Acid Orange 7 with beta-PbO2 electrodes modified by TiO2.

Modification of beta-PbO(2) electrodes was carried out by TiO(2) co-deposition and characterized by scanning electron microscopy (SEM) and X-ray diffraction (XRD). The 2.0 g TiO(2) (the amount of TiO(2) used in 200 mL electrodeposition solution) modified beta-PbO(2) electrode was more compact and more uniform in comparison with the unmodified beta-PbO(2) electrode. TiO(2) particles were tightly attached on and between beta-PbO(2) crystals on modified beta-PbO(2) electrode. It was also used in electrochemically assisted photocatalytic degradation (EAPD) of Acid Orange 7. Compared with the total efficiency by a single application of ultraviolet irradiation and electrochemical procedure, application of a 1.5 V potential in EAPD improved the apparent first-order rate constant by 44.2% for 2.0 g TiO(2) modified beta-PbO(2) electrode even if it was not freshly used. A synergetic effect was significant. Within the amount of TiO(2) investigated, the more TiO(2) used in electro-deposition solution, the higher the degradation efficiencies were. Effects of initial dye concentration, initial pH values and applied potentials across the electrodes were investigated. Acidic condition and high potentials applied across the electrodes favored color or TOC removal of the dye. Decolorization rate decreased with an increase in the dye concentration in the range of 5-50mg/L. Experiments above demonstrate that TiO(2) modified beta-PbO(2) electrode, which realized TiO(2) immobilization successfully, performed well in EAPD of Acid Orange 7.

Azo Compounds↗
PubMed2005

Epistatic interactions between modifier genes confer strain-specific redundancy for Tgfb1 in developmental angiogenesis.

Tgfbm1 (chromosome 5, P = 8 x 10(-5)) and Tgfbm3 (chromosome 12, P = 6 x 10(-11)) were identified as loci that modify developmental angiogenesis of Tgfb1 -/- mice. Congenic mice validated these loci and demonstrated epistatic interaction between them. The novel locus, Tgfbm3, encompasses approximately 22 genes, colocalizes with both tumor susceptibility and atherosclerosis susceptibility loci, and is enriched in genes regulating cell growth and morphogenesis. The use of gene knockout and/or transgenic mice that predispose to a complex trait, such as vascular development/angiogenesis, facilitates the identification of modifiers by simplifying genetic analysis. Identification of genes that modify response to lack of transforming growth factor beta1 (TGFbeta1) will enhance the understanding of TGFbeta1 action in vivo and may help predict which patients would respond well to anti-TGFbeta therapy. Identification of angiogenesis-modifying genes may provide new targets for angiogenesis therapies and analysis of polymorphisms therein may contribute to assessment of risk for diseases involving angiogenesis.

Animals↗
PubMed2005

Laparoscopic modified radical hysterectomy: a strategy for a clinical dilemma.

OBJECTIVE: To investigate the role of laparoscopic modified radical (type 2) hysterectomy when cervical cancer cannot be excluded or documented preoperatively. METHODS: Between 1996 and 2004, 50 patients with cervical intraepithelial neoplasia (CIN III) or adenocarcinoma in situ (AIS) involvement of cone endocervical margins and/or endocervical curettings, who were not candidates for observation or repeat conization, underwent laparoscopy to perform a modified radical hysterectomy. RESULTS: Forty-nine (98.0%) modified radical hysterectomies were completed laparoscopically and one (2.0%) patient required a laparotomy. Of the overall group, 35 (70.0%) had residual pathology; 26 (52.0%) were precancerous lesions, and 9 (18.0%) had invasive disease (5 adenocarcinomas, 3 squamous lesions, and 1 adenosquamous carcinoma). Of the nine with cancer, one had stage IA1 disease, three had stage IA2 disease, and five had stage IB1 disease. Five (55.6%) invasive lesions were diagnosed intraoperatively (frozen section), and a laparoscopic pelvic and lower aortic lymph node dissection was performed. The median operative time was 96 min (range 58-185), blood loss 100 ml (50-450), and postoperative hospital stay 2.5 days (range 1-14). There were no incidences of prolonged urinary retention fistulas, or other serious complications. All patients with cancer remain disease-free (median follow-up 44.2 months, range 1-88.7 months). CONCLUSIONS: Laparoscopic modified radical hysterectomy is a treatment option for patients for whom cervical cancer cannot be definitively excluded, and can be completed with acceptable operative time, blood loss, and hospitalization.

Adenocarcinoma↗
PubMed2005

Difference of carboplatin clearance estimated by the Cockroft-Gault, Jelliffe, Modified-Jelliffe, Wright or Chatelut formula.

OBJECTIVE: Although the Calvert formula is the standard method to calculate the dose of carboplatin, there is no consensus how to determine the glomerular filtration rate (GFR) without using [51Cr]-ethylenediamine tetraacetic acid (51Cr-EDTA). Creatinine clearance (Ccr), calculated using the Cockroft-Gault, Jelliffe, Modified-Jelliffe or Wright formulae, has been used as a substitute for the GFR. In addition to these four formulae, the Chatelut formula has been proposed as a way to calculate carboplatin clearance. Among these formulae, Jelliffe formula does not include body surface area (BSA) or body weight to adjust the body size and thus may have greater bias than the other four formulae in estimating carboplatin clearance. The purpose of this study is to evaluate if these five formulae could equally estimate the carboplatin clearance. METHODS: : Carboplatin clearance was estimated in 253 patients with gynecologic cancer who received carboplatin-based chemotherapy between January 1996 and August 2004. Ccr was estimated using the Cockroft-Gault, Jelliffe, Modified-Jelliffe or Wright formulae. Carboplatin clearance was also calculated directly by using the Chatelut formula. The five estimations of carboplatin clearance were compared with each other using the post-hoc Wilcoxon signed rank test. The median percent error (MPE) and the median absolute percent error (MAPE) were evaluated by comparing carboplatin clearance. The relationships between BSA and ratios of estimated carboplatin clearance (Jelliffe/Cockroft-Gault, Jelliffe/Modified-Jelliffe, Jelliffe/Wright, Jelliffe/Chatelut) were evaluated by using simple regression. RESULTS: : The estimated carboplatin clearances were: Cockroft-Gault formula, 109.8 +/- 28.4; Jelliffe formula, 128.5 +/- 28.2; Modified-Jelliffe formula, 110.8 +/- 25.7; Wright formula, 112.2 +/- 24.3; Chatelut formula, 114.1 +/- 33.0. A statistically significant difference was observed between carboplatin clearance calculated using Jelliffe formula and that given by each of the other four formulae. Comparing the results of the Cockroft-Gault formula with the Jellife, Modified-Jelliffe, Wright and Chatelut formulae yielded MPEs of +19%, +2%, +3% and +3% and MAPEs of 27%, 5%, 6% and 6%, respectively. There was a significant correlation between BSA and ratio of estimated carboplatin clearance (Jelliffe/Cockroft-Gault, Jelliffe/Modified-Jelliffe, Jelliffe/Wright, Jelliffe/Chatelut), with Pearson correlation coefficients of 0.928, 0.847, 0.965 and 0.839 respectively. As the BSA of patient became smaller, the differences between the carboplatin clearance calculated by the Jelliffe formula from other four formulas became larger. CONCLUSIONS: : Estimates of carboplatin clearance calculated by the Jelliffe formula tend to have greater positive bias compared to the other four formulae, particularly when the BSA of the patient is small. In order to conduct collaborative international studies, it may be necessary to standardize the formula used to estimate carboplatin clearance to perform international collaboration studies.

Adolescent↗
PubMed2006

Modified HPV16 E7/HSP70 DNA vaccine with high safety and enhanced cellular immunity represses murine lung metastatic tumors with downregulated expression of MHC class I molecules.

OBJECTIVE: To explore whether the modified E7-HSP70, which has been introduced mutations in two zinc-binding motifs of E7, will eliminate its transformation potential and enhance the immunogenicity of fusion protein and repress E7 containing tumors with a low level of MHC-I molecules to lung metastatic in murine model. METHODS: In this study, we examined the transforming properties of mutant E7 oncoprotein by the soft agar colony-formation assays, explored the immunogenicity of modified E7-HSP70 gene by various cellular and humor immune responses and evaluated the effect of treating lung metastatic tumor with a low expressing MHC-I molecules by tumor challenge assay and therapeutic experiment. RESULTS: The mutant E7 oncoprotein has completely lost its transforming properties as measured in the soft agar colony-formation assays. Modified E7-HSP70 gene inducted stronger E7-specific cellular immune response than that induced by unmodified E7-HSP70. More importantly, the new construct significantly reduced the number of B16-HPV16E7 lung metastases. CONCLUSION: The modified E7-HSP70 gene may be as a powerful and safe DNA vaccine in controlling the hematogenous spread of HPV16E7-associated tumors with low expression of MHC-I molecules. In addition, the B16-HPV16E7 lung metastasis model can be used to test the efficacy of various E7-specific vaccines and immunotherapeutic strategies in settings more relevant to clinical requirements.

Animals↗
PubMed2004

In vivo selection of genetically modified erythroid cells using a jak2-based cell growth switch.

Cell-based therapies have potential widespread applications in clinical medicine, and methods for controlling the fate of transplanted cells are needed. We have previously described a means for directing the growth of genetically modified cells in vivo using a derivative of the thrombopoietin receptor, mpl, that is reversibly activated by a drug called a chemical inducer of dimerization (CID). Since Jak2 participates in signaling from a number of different cytokine receptors (including mpl), we tested whether direct activation of the JH1 domain of Jak2 would broaden the repertoire of hematopoietic lineages responsive to the CID. While the engineered Jak2 induced a significant rise in genetically modified red cells, as we have observed previously with mpl, it lacked mpl's ability to expand genetically modified platelets and failed to expand genetically modified granulocytes, B cells, or T cells. These findings identify a signaling molecule other than mpl that can function as a cell growth switch in vivo and demonstrate that signaling molecules used for in vivo selection need not be confined to receptors. The erythroid-restricted growth response suggests that CID-activated Jak2 may be well suited to gene therapy applications in sickle cell anemia or beta-thalassemia.

Animals↗