Biomedical subjects

Jae Ho Kim

Publications and source records attributed to Jae Ho Kim.

At least 55 records · Page 3Linked to original sources

PubMed2004

Image-guided radiosurgery of head and neck cancers.

OBJECTIVES: Radiosurgery precisely delivers a single high dose or a few fractionated doses of radiation to a localized tumor via the stereotactic approach. Some head and neck sites are suitable for radiosurgery since there is minimal or no organ motion. The clinical studies were carried out to determine the accuracy of stereotactic radiosurgery and to demonstrate the effectiveness of radiosurgery in head and neck cancers. MATERIALS AND METHODS: Thirteen patients were treated with either single-dose or fractionated radiosurgery to the tumor. All patients except one with cancer of the lip had received prior treatments including surgery, radiotherapy, and chemotherapy for the primary cancers. The dose ranged 12 to 18 Gy for single-dose radiosurgery and 30 Gy in 5 or 6 fractions twice a week for fractionated radiosurgery. Tumor localization was achieved via the stereotactic approach. RESULTS: Accuracy of radiosurgery was within 1.5 mm. Despite the recurrent disease from previous heavy treatments, 9 patients (70%) showed a significant response (complete or >50% tumor reduction) to radiosurgery, and 3 patients had stable disease. Complete tumor response was achieved in 6 patients. All patients had excellent pain relief with functional and cosmetic preservation. There was no acute and subacute radiation toxicity detected clinically during the minimal follow-up of 6 months. CONCLUSION: Image-guided radiosurgery is effective in achieving the local tumor control and pain relief. Radiosurgery provided excellent functional and cosmetic preservation with minimal complication. The results indicate the potential of radiosurgery in the treatment of recurrent and selected primary head and neck cancers.

Carcinoma, Squamous Cell↗

PubMed2004

Isolation and characterization of a novel angiotensin I-converting enzyme inhibitory peptide derived from the edible mushroom Tricholoma giganteum.

The fruiting body of Tricholoma giganteum has many pharmaceutical uses and has long been utilized as a home remedy in Asia. This study describes the extraction and characterization of the first angiotensin I-converting enzyme (ACE) inhibitory peptide from T. giganteum. The maximum ACE inhibitory activity (IC50: 0.31 mg) was obtained when the fruiting body of T. giganteum was extracted with distilled water at 30 degrees C for 3 h. After the purification of ACE inhibitory peptides with ultrafiltration, Sephadex G-25 column chromatography, and reverse-phase HPLC, an active fraction with an IC50 of 0.04 mg and a yield of 0.3% was obtained. The ACE inhibitory peptide was a novel tripeptide, showing very low similarity to other ACE inhibitory peptide sequences, and was sequenced as Gly-Glu-Pro. The purified ACE inhibitor from T. giganteum competitively inhibited ACE, and it maintained inhibitory activity even after incubation with proteases. ACE inhibitor from T. giganteum showed a clear antihypertensive effect in spontaneously hypertensive rats (SHR), at a dosage of 1 mg/kg.

Agaricales↗

PubMed2004

Facial nerve schwannomas: different manifestations and outcomes.

BACKGROUND: The purpose of this study was to provide data on the different clinical presentations of facial nerve schwannoma, the appropriate planning for the management of schwannoma of various origins, and the predictive outcomes of surgical management. METHODS: A retrospective study was conducted in a tertiary referral hospital. We reviewed 8 consecutive cases of facial nerve schwannoma diagnosed and managed between 1993 and 2001. RESULTS: Facial nerve schwannomas originated in the internal auditory canal (IAC) (2 cases), parotid gland (2 cases), intratemporal portion (3 cases), and stylomastoid foramen (1 case). Tumor of the stylomastoid foramen presented as an intra- and extratemporal mass. The initial presenting symptom of the 8 patients was facial nerve paralysis in 4 patients, hearing loss in 2, facial numbness in 1, and an infra-auricular mass in 1. Facial palsy occurred in 7 patients during the course of the disease. One patient with a mass in the parotid gland did not show facial palsy up to 1 year after presentation of the initial symptom (facial numbness). Facial nerve paralysis was most severe in intratemporal tumors and less severe in parotid tumors. The patients with IAC suffered from hearing loss and intermittent vertigo and showed decreased vestibular function. The patients with intratemporal tumors also complained of hearing loss. The tumors were completely removed by superficial parotidectomy for parotid tumors; the translabyrinthine approach for 1 IAC tumor and 1 intratemporal tumor; the middle fossa approach for the other IAC tumor; the transmastoid approach for mastoid tumors; and the infratemporal fossa approach for intratemporal and extratemporal tumors. End-to-end cable grafts for the facial nerve were performed in 5 out of 8 cases. In 2 cases, the facial nerve was preserved after the resection of the mass. One case showed complete loss of the peripheral branch of the facial nerve. CONCLUSIONS: Facial nerve schwannoma can present in various ways. By examining the site of origin and the presenting symptoms and signs, we were able to diagnose facial nerve schwannoma preoperatively. According to the operative management of the facial nerve, the postoperative outcome of facial function could be estimated. Our finding could be pivotal in the management of the facial nerve schwannoma.

Adult↗

PubMed2004

A quantitative method for measuring gene expression magnitude and volume delivered by gene therapy vectors.

This study describes a quantitative method to measure the magnitude and distribution of gene expression following local delivery of an adenoviral vector containing the human sodium iodide symporter (hNIS) reporter gene into the canine prostate. Following systemic administration of Na(99m)TcO(4), autoradiographs of prostate sections depicting hNIS-dependent (99m)TcO(4)(-) uptake were digitized and stacked to produce a three-dimensional reconstruction of gene expression. Frequency histograms reflecting hNIS gene expression magnitude and volume were used to quantify hNIS function. The method demonstrated submillimeter resolution allowing for precise measurements of gene expression magnitude and volume in vivo. The method developed here could be applied to other reporter gene systems in which the readout can be digitized from thin tissue sections.

Adenoviridae↗

PubMed2004

Effect of Ganoderma lucidum on the quality and functionality of Korean traditional rice wine, yakju.

The goal of this study was to develop a high value Korean traditional rice wine possessing the pharmaceutical functionality of Ganoderma lucidum. The effects of the fruiting body of G. lucidum on the alcohol fermentation of Korean traditional rice wine, yakju, were investigated. Optimal fermentation conditions for the preparation of G. lucidum-yakju consisted of the koji added at 15% and a fermentation period of 15 d at 25 degrees C. The effects of the amount of G. lucidum added on the acceptability and functionality of G. lucidum-yakju were investigated. G. lucidum GL-1 yakju brewed by adding 0.1% G. lucidum into the mash showed the best acceptability and its angiotensin I-converting enzyme (ACE) inhibitory activity and SOD-like activity were 63% and 42%, respectively, both of which are higher than those of yakju. The high ACE inhibitory activity of G. lucidum GL-1 yakju was found to result from ganoderic acid K in G. lucidum on the basis of physical and spectral data. However, the fibrinolytic activity and antioxidant activity of G. lucidum GL-1 yakju were very low, while tyrosinase inhibitory activity was not determined. From these results, G. lucidum GL-1 yakju may become a new functional Korean traditional rice wine with antihypertensive properties.

Journal Article↗

PubMed2004

NHERF2 specifically interacts with LPA2 receptor and defines the specificity and efficiency of receptor-mediated phospholipase C-beta3 activation.

Lysophosphatidic acid (LPA) activates a family of cognate G protein-coupled receptors and is involved in various pathophysiological processes. However, it is not clearly understood how these LPA receptors are specifically coupled to their downstream signaling molecules. This study found that LPA(2), but not the other LPA receptor isoforms, specifically interacts with Na(+)/H(+) exchanger regulatory factor2 (NHERF2). In addition, the interaction between them requires the C-terminal PDZ domain-binding motif of LPA(2) and the second PDZ domain of NHERF2. Moreover, the stable expression of NHERF2 potentiated LPA-induced phospholipase C-beta (PLC-beta) activation, which was markedly attenuated by either a mutation in the PDZ-binding motif of LPA(2) or by the gene silencing of NHERF2. Using its second PDZ domain, NHERF2 was found to indirectly link LPA(2) to PLC-beta3 to form a complex, and the other PLC-beta isozymes were not included in the protein complex. Consistently, LPA(2)-mediated PLC-beta activation was specifically inhibited by the gene silencing of PLC-beta3. In addition, NHERF2 increases LPA-induced ERK activation, which is followed by cyclooxygenase-2 induction via a PLC-dependent pathway. Overall, the results suggest that a ternary complex composed of LPA(2), NHERF2, and PLC-beta3 may play a key role in the LPA(2)-mediated PLC-beta signaling pathway.

Animals↗

PubMed2004

Gene therapy strategies to improve the effectiveness of cancer radiotherapy.

Having the ability to alter the genetic makeup of a cancer cell by gene transfer is a potentially powerful strategy for treating human cancer. However, a low efficiency of gene delivery in vivo and poor tumour specificity has prevented the widespread implementation of this technology in the clinic. Despite these formidable obstacles, the first successful application of gene therapy in the treatment of cancer may occur when it is combined with local modalities such as radiation therapy. A small number of gene therapy strategies have been evaluated in clinical trials in combination with external beam radiation therapy. The combined therapy has been well-tolerated and has not exacerbated the side effects of radiation therapy. Gene transfer and tumour cell destruction has been demonstrated in vivo. Although the results await confirmation in larger, prospective Phase III trials, there is suggestive evidence that the combined therapies may be demonstrating better than expected antitumour activity. Our vast knowledge of the molecular defects that drive the cancer process, coupled with our expanding understanding of the genes responsible for tumour cell radioresistance, have spawned the development of rational, targeted gene therapies designed to increase tumour cell radiosensitivity. Here, the results of the clinical trials conducted so far will be reviewed, followed by a description of new approaches under development at present.

Adenoviridae↗

PubMed2004

Modification of radiation injury by ramipril, inhibitor of angiotensin-converting enzyme, on optic neuropathy in the rat.

Inhibitors of angiotensin-converting enzyme (ACE) have been used to reduce radiation-induced normal tissue injury. The present study was carried out to determine whether ramipril, one of the inhibitors of ACE, would ameliorate radiation-induced brain damage, using a well-characterized optic neuropathy model in the rat, one of the most critical and radiosensitive structures in the brain. The brains of adult Fischer rats were irradiated stereotactically with 30 Gy using a single collimated beam. Six months after irradiation and 1.5 mg/kg day(-1) ramipril (started 2 weeks after irradiation), rats were assessed for optic nerve damage functionally, using visual evoked potential, and histologically. Results show that ramipril conferred significant modification of radiation injury, since rats receiving radiation alone showed a threefold lengthening in the mean peak latency in the visual evoked potential, whereas 75% of rats receiving radiation followed by ramipril had evoked potentials that resembled those of normal untreated control rats. The histology of irradiated and ramipril-treated optic nerves appeared nearly normal, while there was significant demyelination in both optic nerves of irradiated rats. The study represents the first demonstration of prophylaxis of radiation injury by a carboxyl-containing ACE inhibitor, providing a pharmacological strategy designed to reduce radiation-induced normal tissue damage.

Administration, Oral↗

PubMed2004

Patterns of failure after single-dose radiosurgery for spinal metastasis.

OBJECT: Single-dose radiosurgery for solitary spinal metastases can achieve rapid and durable pain control. This study was conducted to determine the patterns of failure after spinal radiosurgery. METHODS: Forty-nine patients with 61 solitary spinal metastases underwent radiosurgery between May 2001 and May 2003. Single-dose radiosurgery (10-16 Gy) was delivered only to the involved spinal segments. The authors undertook a retrospective review of clinical notes, including patient questionnaires and radiological studies (computerized tomography or magnetic resonance imaging), to analyze patterns of failure following radiosurgery with regard to the pain and tumor control. Complete and partial pain relief was achieved in 85% of the lesions treated. Relapse of pain at the treated site was noted in 7%. Radiologically, lesions progressively metastasized to the immediately adjacent spines in 5%. These patients also had progressive primary and/or other systemic metastatic diseases. CONCLUSIONS: Spine-related pain control/reduction was excellent. Tumor recurrence at the treated segment and progression to the immediately adjacent region were rare. The results support the use of spinal radiosurgery as an effective treatment option for solitary spinal metastasis.

Adult↗

PubMed2004

Image-guided procedures for intensity-modulated spinal radiosurgery. Technical note.

Radiosurgery for brain tumors has been well established in the radiation oncology and neurosurgery fields. Radiosurgery of extracranial tumors such as those involving the spine is, however, still in the early stage because of difficulties in patient immobilization and organ motion. The authors describe an image-guided procedure for intensity-modulated spinal radiosurgery that was developed at Henry Ford Hospital.

Algorithms↗

PubMed2004

Gene therapy strategies to enhance the effectiveness of cancer radiotherapy.

Altering the genetic makeup of a cancer cell by gene transfer is a potentially powerful strategy for treating human cancer. However, a low efficiency of gene delivery in vivo and poor tumor specificity has prevented the widespread implementation of this technology in the clinic. Despite these formidable obstacles, the first successful application of gene therapy in the treatment of cancer could occur when it is combined with local modalities such as radiation therapy. A small number of gene therapy strategies have been evaluated in clinical trials in combination with external-beam radiation therapy. Combined therapy has been well tolerated and has not exacerbated the side effects of radiation therapy. Gene transfer and tumor cell destruction have been demonstrated in vivo. Although the results await confirmation in larger, prospective phase III trials, there is suggestive evidence that combined therapies may be demonstrating better than expected antitumor activity. The vast knowledge of the molecular defects that drive the cancer process, coupled with expanding the understanding of the genes responsible for tumor cell radioresistance, have led to the development of rational, targeted gene therapies designed to increase tumor cell radiosensitivity. Results of the clinical trials conducted to date are reviewed, followed by a description of new approaches currently under development.

Clinical Trials as Topic↗

PubMed2003

AI-guided parameter optimization in inverse treatment planning.

An artificial intelligence (AI)-guided inverse planning system was developed to optimize the combination of parameters in the objective function for intensity-modulated radiation therapy (IMRT). In this system, the empirical knowledge of inverse planning was formulated with fuzzy if-then rules, which then guide the parameter modification based on the on-line calculated dose. Three kinds of parameters (weighting factor, dose specification, and dose prescription) were automatically modified using the fuzzy inference system (FIS). The performance of the AI-guided inverse planning system (AIGIPS) was examined using the simulated and clinical examples. Preliminary results indicate that the expected dose distribution was automatically achieved using the AI-guided inverse planning system, with the complicated compromising between different parameters accomplished by the fuzzy inference technique. The AIGIPS provides a highly promising method to replace the current trial-and-error approach.

Algorithms↗

PubMed2003

Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer.

The primary study objective was to determine the safety of intraprostatic administration of a replication-competent, oncolytic adenovirus containing a cytosine deaminase (CD)/herpes simplex virus thymidine kinase (HSV-1 TK) fusion gene concomitant with increasing durations of 5-fluorocytosine and valganciclovir prodrug therapy and conventional-dose three-dimensional conformal radiation therapy (3D-CRT) in patients with newly diagnosed, intermediate- to high-risk prostate cancer. Secondary objectives were to determine the persistence of therapeutic transgene expression in the prostate and to examine early posttreatment response. Fifteen patients in five cohorts received a single intraprostatic injection of 10(12) viral particles of the replication-competent Ad5-CD/TKrep adenovirus on day 1. Two days later, patients were administered 5-fluorocytosine and valganciclovir prodrug therapy for 1 (cohorts 1-3), 2 (cohort 4), or 3 (cohort 5) weeks along with 70-74 Gy 3D-CRT. Sextant needle biopsy of the prostate was obtained at 2 (cohort 1), 3 (cohort 2), and 4 (cohort 3) weeks for determination of the persistence of transgene expression. There were no dose-limiting toxicities and no significant treatment-related adverse events. Ninety-four percent of the adverse events observed were mild to moderate and self-limiting. Acute urinary and gastrointestinal toxicities were similar to those expected for conventional-dose 3D-CRT. Therapeutic transgene expression was found to persist in the prostate for up to 3 weeks after the adenovirus injection. As expected for patients receiving definitive radiation therapy, all patients experienced significant declines in prostate-specific antigen (PSA). The mean PSA half-life in patients administered more than 1 week of prodrug therapy was significantly shorter than that of patients receiving prodrugs for only 1 week (0.6 versus 2.0 months; P < 0.02) and markedly shorter than that reported previously for patients treated with conventional-dose 3D-CRT alone (2.4 months). With a median follow-up of only 9 months, 5 of 10 (50%) patients not treated with androgen-deprivation therapy achieved a serum PSA < or = 0.5 ng/ml. The results demonstrate that replication-competent adenovirus-mediated double-suicide gene therapy can be combined safely with conventional-dose 3D-CRT in patients with intermediate- to high-risk prostate cancer. The shorter than expected PSA half-life in patients receiving more than 1 week of prodrug therapy may suggest a possible interaction between the oncolytic adenovirus and/or double-suicide gene therapies and radiation therapy.

Adenoviruses, Human↗

PubMed2003

Ca2+-dependent inhibition of NHE3 requires PKC alpha which binds to E3KARP to decrease surface NHE3 containing plasma membrane complexes.

The intestinal brush border (BB) Na+/H+ exchanger isoform 3 (NHE3) is acutely inhibited by elevation in the concentration of free intracellular Ca2+ ([Ca2+]i) by the cholinergic agonist carbachol and Ca2+ ionophores in a protein kinase C (PKC)-dependent manner. We previously showed that elevating [Ca2+]i with ionomycin rapidly inhibited NHE3 activity and decreased the amount of NHE3 on the plasma membrane in a manner that depended on the presence of the PDZ domain-containing protein E3KARP (NHE3 kinase A regulatory protein, also called NHERF2). The current studies were performed in PS120 fibroblasts (NHE-null cell line) stably transfected with NHE3 and E3KARP to probe the mechanism of PKC involvement in Ca2+ regulation of NHE3. Pretreatment with the general PKC inhibitor, GF109203X prevented ionomycin inhibition of NHE3 without altering basal NHE3 activity. Similarly, the Ca2+-mediated inhibition of NHE3 activity was blocked after pretreatment with the conventional PKC inhibitor Gö-6976 and a specific PKCalpha pseudosubstrate-derived inhibitor peptide. [Ca2+]i elevation caused translocation of PKCalpha from cytosol to membrane. PKCalpha bound to the PDZ1 domain of GST-E3KARP in vitro in a Ca2+-dependent manner. PKCalpha and E3KARP coimmunoprecipitated from cell lysates; this occurred to a lesser extent at basal [Ca2+]i and was increased with ionomycin exposure. Biotinylation studies demonstrated that [Ca2+]i elevation induced oligomerization of NHE3 in total lysates and decreased the amount of plasma membrane NHE3. Treatment with PKC inhibitors did not affect the oligomerization of NHE3 but did prevent the decrease in surface amount of NHE3. These results suggest that PKCalpha is not necessary for the Ca2+-dependent formation of the NHE3 plasma membrane complex, although it is necessary for decreasing the membrane amounts of NHE3, probably by stimulating NHE3 endocytosis.

Animals↗

PubMed2003

Image-guided and intensity-modulated radiosurgery for patients with spinal metastasis.

BACKGROUND: Radiosurgery can deliver a single, large radiation dose to a localized tumor using a stereotactic approach and hence, requires accurate and precise delivery of radiation to the target. Of the extracranial organ targets, the spine is considered a suitable site for radiosurgery, because there is minimal or no breathing-related organ movement. The authors studied spinal radiosurgery in patients with spinal metastases to determine its accuracy and precision. METHODS: The spinal radiosurgery program was based on an image-guided and intensity-modulated, shaped-beam radiosurgical unit. It is equipped with micromultileaf collimators for beam shaping and radiation intensity modulation and with a noninvasive, frameless positioning device that uses infrared, passive marker technology together with corroborative image fusion of the digitally reconstructed image from computed tomography (CT) simulation and orthogonal X-ray imagery at the treatment position. These images were compared with the port films that were taken at the time of treatment to determine the accuracy of the isocenter position. Clinical feasibility was tested in 10 patients who had spinal metastasis with or without spinal cord compression. The patients were treated with fractionated external beam radiotherapy followed by single-dose radiosurgery as a boost (6-8 grays) to the most involved portion of the spine or to the site of spinal cord compression. RESULTS: The accuracy for the isocenter was within 1.36 mm +/- 0.11 mm, as measured by image fusion of the digitally reconstructed image from CT simulation and the port film. Clinically, the majority of patients had prompt pain relief within 2-4 weeks of treatment. Complete and partial recovery of motor function also was achieved in patients with spinal cord compression. The radiation dose to the spinal cord was minimal. The maximum dose of radiation to the anterior edge of the spinal cord within a transverse section, on average, was 50% of the prescribed dose. There was no acute radiation toxicity detected clinically during the mean follow-up of 6 months. CONCLUSIONS: Image-guided, shaped-beam spinal radiosurgery is accurate and precise. Rapid clinical improvement of pain and neurologic function also may be achieved. The results indicate the potential of spinal radiosurgery in the treatment of patients with spinal metastasis, especially those with solitary sites of spine involvement, to increase the prospects of long-term palliation.

Feasibility Studies↗

PubMed2003

Lysophosphatidic acid stimulates brush border Na+/H+ exchanger 3 (NHE3) activity by increasing its exocytosis by an NHE3 kinase A regulatory protein-dependent mechanism.

Na(+)/H(+) exchanger 3 (NHE3) kinase A regulatory protein (E3KARP) has been implicated in cAMP- and Ca(2+)-dependent inhibition of NHE3. In the current study, a new role of E3KARP is demonstrated in the stimulation of NHE3 activity. Lysophosphatidic acid (LPA) is a mediator of the restitution phase of inflammation but has not been studied for effects on sodium absorption. LPA has no effect on NHE3 activity in opossum kidney (OK) proximal tubule cells, which lack expression of endogenous E3KARP. However, in OK cells exogenously expressing E3KARP, LPA stimulated NHE3 activity. Consistent with the stimulatory effect on NHE3 activity, LPA treatment increased the surface NHE3 amount, which occurred by accelerating exocytic trafficking (endocytic recycling) to the apical plasma membrane. These LPA effects only occurred in OK cells transfected with E3KARP. The LPA-induced increases of NHE3 activity, surface NHE3 amounts, and exocytosis were completely inhibited by pretreatment with the PI 3-kinase inhibitor, LY294002. LPA stimulation of the phosphorylation of Akt was used as an assay for PI 3-kinase activity. LY294002 completely prevented the LPA-induced increase in Akt phosphorylation, which is consistent with the inhibitory effect of LY294002 on the LPA stimulation of NHE3 activity. The LPA-induced phosphorylation of Akt was the same in OK cells with and without E3KARP. These results show that LPA stimulates NHE3 in the apical surface of OK cells by a mechanism that is dependent on both E3KARP and PI 3-kinase. This is the first demonstration that rapid stimulation of NHE3 activity is dependent on an apical membrane PDZ domain protein.

Animals↗

PubMed2003

Differential roles of hydrogen peroxide and hydroxyl radical in cisplatin-induced cell death in renal proximal tubular epithelial cells.

Reactive oxygen species (ROS) have been suggested as important mediators of cisplatin-induced acute renal failure in vivo. However, our previous studies have shown that cisplatin-induced cell death in vitro could not be prevented by scavengers of hydrogen peroxide and hydroxyl radical in rabbit renal cortical slices. This discrepancy may be attributed to differential roles of ROS in necrotic and apoptotic cell death. We therefore examined, in this study, the roles of ROS in necrosis and apoptosis induced by cisplatin in primary cultured rabbit proximal tubule. Cisplatin induced necrosis at high concentrations over a few hours and apoptosis at much lower concentrations over longer periods. Necrosis induced by high concentration of cisplatin was prevented by a cell-permeable superoxide scavenger (tiron), hydrogen peroxide scavengers (catalase and pyruvate), and antioxidants (Trolox and deferoxamine), whereas hydroxyl radical scavengers (dimethythiourea and thiourea) did not affect the cisplatin-induced necrosis. However, apoptosis induced by lower concentration of cisplatin was partially prevented by tiron and hydroxyl radical scavengers but not by hydrogen peroxide scavengers and antioxidants. Cisplatin-induced apoptosis was mediated by the signaling pathway that is associated with cytochrome c release from mitochondria and caspase-3 activation. These effects were prevented by tiron and dimethylthiourea but not by catalase. Dimethylthiourea produced a significant protection against cisplatin-induced acute renal failure, and the effect was associated with an inhibition of apoptosis. These results suggest that hydrogen peroxide is involved in the cisplatin-induced necrosis, whereas hydroxyl radical is responsible for the cisplatin-induced apoptosis. The protective effects of hydroxyl radical scavengers are associated with an inhibition of cytochrome c release and caspase activation.

Acute Kidney Injury↗

PubMed2003

GENIS: gene expression of sodium iodide symporter for noninvasive imaging of gene therapy vectors and quantification of gene expression in vivo.

With the goal of optimizing adenovirus-mediated suicide gene therapy for prostate cancer, we have developed a method based on the human sodium iodide symporter (hNIS) that allows for noninvasive monitoring of adenoviral vectors and quantification of gene expression magnitude and volume within the prostate. A replication-competent adenovirus (Ad5-yCD/mutTK(SR39)rep-hNIS) coexpressing a therapeutic yeast cytosine deaminase (yCD)/mutant herpes simplex virus thymidine kinase (mutTK(SR39)) fusion gene and the hNIS gene was developed. Ad5-yCD/mutTK(SR39)rep-hNIS and a replication-defective hNIS adenovirus (rAd-CMV-FLhNIS) were injected into contralateral lobes of the dog prostate and hNIS activity was monitored in live animals following administration of Na(99m)TcO(4) using gamma camera scintigraphy. Despite the close proximity of the urinary bladder, (99m)TcO(4)(-) uptake was readily detected in the prostate using viral dose levels (10(10) to 10(12) viral particles) that have been safely administered to humans. Due to its rapid clearance and short physical half-life (6 h), it was possible to obtain daily measurements of (99m)TcO(4)(-) uptake in vivo, allowing for dynamic monitoring of reporter gene expression within the prostate as well as biodistribution throughout the body. High-resolution autoradiography of prostate sections coupled with 3D reconstruction of gene expression demonstrated that the magnitude and volume of gene expression could be quantified with submillimeter resolution. Implementation of the GENIS (gene expression of Na/I symporter) technology in the clinic will facilitate optimization of future human gene therapy trials.

Adenoviridae↗