Biomedical subjects

Jae Ho Kim

Publications and source records attributed to Jae Ho Kim.

69 records · Page 4Linked to original sources

PubMed2003

Beneficial effect of pentoxifylline on cisplatin-induced acute renal failure in rabbits.

Pentoxifylline (PTX) has been reported to inhibit TNF-alpha production and prevent several types of acute renal failure. This study was undertaken to determine the effect of PTX on the cisplatin-induced acute renal failure in rabbits. Rabbits received a single injection of cisplatin (5 mg/kg, i.p.) with or without PTX pretreatment (30 mg/kg, i.v.). Alterations in renal function, apoptotic cell death, and TNF-alpha mRNA expression were measured at 24 or 48 h after cisplatin injection. Cisplatin caused an increase in BUN and serum creatinine levels, a reduction in GFR, and an increase in fractional Na+ excretion. Such changes were significantly attenuated by PTX pretreatment (30 mg/kg, i.p.) 30 min before and 24 h after cisplatin injection. Morphological evaluation showed that cisplatin injection induced diffuse proximal tubular necrosis and the effect was reduced by PTX pretreatment. Cisplatin induced apoptotic cell death in renal cortex and the effect was significantly prevented by PTX. Treatment of opossum kidney cells with cisplatin resulted in cell death, which was significantly prevented by PTX. The increase in lipid peroxidation and the decrease in renal blood flow induced by cisplatin were not affected by PTX. The expression of TNF-alpha mRNA was increased after cisplatin injection and the effect was inhibited by PTX pretreatment. These results suggest that cisplatin-induced acute renal failure in rabbits is associated with an induction of TNF-alpha-mediated apoptosis, and that PTX may exert a protective effect against cisplatin nephrotoxicity by inhibiting TNF-alpha production.

Acute Kidney Injury↗

PubMed2003

Point dose verification for intensity modulated radiosurgery using Clarkson's method.

In clinical radiation physics chart checking, the dose calculation results generated by computer treatment planning software are usually verified by an independent computerized monitor unit calculation routine, or by "hand calculation" using percent depth dose (PDD), tissue phantom ratio (TPR), scatter factors, and the machine calibration factors. For intensity-modulated radiosurgery (IMRS) or intensity-modulated radiation therapy (IMRT), the "hand calculation" becomes not feasible due to the sophisticated multileaf collimator (MLC) segments created for intensity-modulated dose delivery. Therefore, an independent computerized dose calculation routine is needed for fast and reliable dose verification. In this work, a point dose calculation routine for IMRS/IMRT plan verification is developed by directly applying Clarkson's method. The method includes preparing data table by measuring TPRs for circular fields with diameters ranging 6 to 98 mm, extrapolating TPR for the zero field size (TPR0) from measured data and generating scatter phantom ratio (SPR) for each individual circular field. The segmented MLC sequences created by IMRS/IMRT inverse planning are converted into irregular fields for Clarkson's calculation. This method has been tested using 29 IMRS/IMRT cases. The results indicate that it is reliable, fast, and accurate. The average time to calculate one field is about 2 s with a 300 Mhz CPU.

Algorithms↗

PubMed2003

Fuzzy logic guided inverse treatment planning.

A fuzzy logic technique was applied to optimize the weighting factors in the objective function of an inverse treatment planning system for intensity-modulated radiation therapy (IMRT). Based on this technique, the optimization of weighting factors is guided by the fuzzy rules while the intensity spectrum is optimized by a fast-monotonic-descent method. The resultant fuzzy logic guided inverse planning system is capable of finding the optimal combination of weighting factors for different anatomical structures involved in treatment planning. This system was tested using one simulated (but clinically relevant) case and one clinical case. The results indicate that the optimal balance between the target dose and the critical organ dose is achieved by a refined combination of weighting factors. With the help of fuzzy inference, the efficiency and effectiveness of inverse planning for IMRT are substantially improved.

Algorithms↗

PubMed2003

A phantom study on the positioning accuracy of the Novalis Body system.

A phantom study was conducted to investigate inherent positioning accuracy of an image-guided patient positioning system-the Novalis Body system for three-dimensional (3-D) conformal radiotherapy. This positioning system consists of two infrared (IR) cameras and one video camera and two kV x-ray imaging devices. The initial patient setup was guided by the IR camera system and the target localization was accomplished using the kV x-ray imaging system. In this study, the IR marker shift and phantom rotation were simulated and their effects on the positioning accuracy were examined by a Rando phantom. The effects of CT slice thickness and treatment sites on the positioning accuracy were tested. In addition, the internal target shift was simulated and its effect on the positioning accuracy was examined by a water tank. With the application of the Novalis Body system, the positioning error of the planned isocenter was significantly reduced. The experimental results with the simulated IR marker shifts indicated that the positioning errors of the planned isocenter were 0.6 +/- 0.3, 0.5 +/- 0.2, and 0.7 +/- 0.2 mm along the lateral, longitudinal, and vertical axes, respectively. The experimental results with the simulated phantom rotations indicated that the positioning errors of the planned isocenter were 0.6 +/- 0.3, 0.7 +/- 0.2, and 0.5 +/- 0.2 mm along the three axes, respectively. The experimental results with the simulated target shifts indicated that the positioning errors of the planned isocenter were 0.6 +/- 0.3, 0.7 +/- 0.2, and 0.5 +/- 0.2 mm along the three axes, respectively. On average, the positioning accuracy of 1 mm for the planned isocenter was achieved using the Novalis Body system.

Equipment Failure Analysis↗

PubMed2003

Arsenic trioxide enhances radiation response of 9L glioma in the rat brain.

Arsenic trioxide (ATO) at low doses induces leukemia cells to undergo apoptosis and at higher doses causes blood flow to solid tumors to shut down. To determine whether a potential synergistic interaction exists between ATO at the non-toxic dose level in the rat and radiation, the present study was carried out with orthotopic 9L malignant gliomas growing in the brains of rats. Animals died within 50 days of treatment when 12-day-old 9L gliomas growing in the brain of Fischer rats were treated with either the drug alone (8 mg/kg) or radiation alone (25 Gy). In contrast, the overall tumor cure rate exceeded 50% at a follow-up time of 120 days after the combined treatment with radiation and ATO. Long-term surviving animals showed no clinical or disproportionately enhanced histopathological changes in the brain parenchyma. Early changes in tumor physiology showed that the vascular leakage of FITC-dextran conjugates was apparent within 8 h of drug administration. Last, the use of diffusion magnetic resonance imaging as an early surrogate marker of therapeutic efficacy corroborated the effects of drug with and without radiation on brain histology and animal survival.

Animals↗

PubMed2002

Efficacy and toxicity of replication-competent adenovirus-mediated double suicide gene therapy in combination with radiation therapy in an orthotopic mouse prostate cancer model.

PURPOSE: The purpose of this study was to evaluate the efficacy and toxicity of replication-competent adenovirus-mediated double suicide gene therapy in an adjuvant setting with external beam radiation therapy (EBRT) in an experimental prostate cancer model in preparation for a Phase I clinical study in humans. METHODS: For efficacy studies, i.m. DU145 and intraprostatic LNCaP C4-2 tumors were established in immune-deficient mice. Tumors were injected with the lytic, replication-competent Ad5-CD/TKrep adenovirus containing a cytosine deaminase (CD)/herpes simplex virus thymidine kinase (HSV-1 TK) fusion gene. Two days later, mice were administered 1 week of 5-fluorocytosine + ganciclovir (GCV) prodrug therapy and fractionated doses of EBRT (trimodal therapy). Tumor control rate of trimodal therapy was compared to that of EBRT alone. For toxicology studies, immune-competent male mice received a single intraprostatic injection (10(10) vp) of the replication-competent Ad5-CD/TKrep adenovirus. Two days later, mice were administered 4 weeks of 5-fluorocytosine + GCV prodrug therapy and 56 Gy EBRT to the pelvic region. The toxicity of trimodal therapy was assessed by histopathologic analysis of major organs and clinical chemistries. RESULTS: In both the i.m. DU145 and intraprostatic LNCaP C4-2 tumor models, trimodal therapy significantly improved primary tumor control beyond that of EBRT alone. In the DU145 model, trimodal therapy resulted in a tumor growth delay (70 days) that was more than twice that (32 days) of EBRT alone. Whereas EBRT failed to eradicate DU145 tumors, trimodal therapy resulted in 25% tumor cure. In the LNCaP C4-2 tumor model, EBRT slowed the growth of intraprostatic tumors, but resulted in no tumor cures, and 57% of the mice developed retroperitoneal lymph node metastases at 3 months. By contrast, trimodal therapy resulted in 44% tumor cure and reduced significantly the percentage (13%) of lymph node metastases relative to EBRT alone. Overall, trimodal therapy was associated with little toxicity. A comparison of the major histopathologic findings among the treatment groups indicated that most of the locoregional (prostate, seminal vesicles, urinary bladder) pathology was attributable to the combined effects of the Ad5-CD/TKrep vector and EBRT and that the prodrugs contributed little to this effect. Importantly, trimodal therapy did not exacerbate inflammation of the rectum and intestines beyond that of EBRT alone. CONCLUSION: Together, the results support the thesis that replication-competent adenovirus-mediated double suicide gene therapy may be a safe and effective adjuvant to EBRT and provide a sound scientific rationale for human trials.

Adenoviridae↗

PubMed2002

Accuracy of inhomogeneity correction in photon radiotherapy from CT scans with different settings.

We report an investigation on the accuracy of inhomogeneity correction in photon radiotherapy from CT scans with different settings. Specifically, the dosimetric differences from different CT scan parameters (kV, mAs) to phantoms and from different Hounsfield unit versus electron density (HU-ED) curves to patients are investigated. The absolute dose per monitor units (dose/MU) is used to quantify the results. We found that only for high-density bones (cranium, femoral tube, etc) using small field 18 MV beams, the dose/MU is up to 2% higher for CT scans using 80 kV than for 130 kV at a depth just beyond the bone and is up to 1-1.5% higher for CT scans using 80 mAs than for 300 mAs. For low-density bones (such as femoral head) and lung, the difference is 1% or less with different kV or mAs settings. The dose/MU varies with different HU-ED curves by up to 2%. The HU-ED curve from the stochiometric calibration was found to be more accurate based on a real measurement. A simplified 4-point curve provides nearly the same accuracy as the stochiometric calibration and may be used as an alternative for routine clinical application.

Algorithms↗

PubMed2002

Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer.

Adenovirus-mediated suicide gene therapy may hold promise in the treatment of human cancer. We have developed a novel approach that utilizes a lytic, replication-competent adenovirus (Ad5-CD/TKrep) to deliver a cytosine deaminase/herpes simplex virus-1 thymidine kinase fusion gene to tumors. The cytosine deaminase and herpes simplex virus-1 thymidine kinase suicide genes render malignant cells sensitive to specific pharmacological agents and, importantly, sensitize them to radiation. The Phase I study described here represents the first gene therapy trial in which a replication-competent virus was used to deliver a therapeutic gene to humans. The indication is local recurrence of prostate cancer after definitive radiation therapy. An escalating dose (10(10), 10(11), and 10(12) viral particles) of the Ad5-CD/TKrep virus was injected intraprostatically under transrectal ultrasound guidance into 16 patients in four cohorts. Two days later, patients were given 5-fluorocytosine and ganciclovir prodrug therapy for 1 (cohorts 1-3) or 2 (cohort 4) weeks. There were no dose-limiting toxicities, and the maximum tolerated dose of the Ad5-CD/TKrep vector was not defined. Ninety-four percent of the adverse events observed were mild or moderate (grade 1/2) in nature. Seven of 16 (44%) patients demonstrated a >or=25% decrease in serum prostate-specific antigen, and 3 of 16 (19%) patients demonstrated a >or=50% decrease in serum prostate-specific antigen. Transgene expression and tumor destruction at the injection site were confirmed by sextant needle biopsy of the prostate at 2 weeks. Two patients were negative for adenocarcinoma at 1 year follow-up. Although Ad5-CD/TKrep viral DNA could be detected in blood as far out as day 76, no infectious adenovirus was detected in patient serum or urine. Together, the results demonstrate that intraprostatic administration of the replication-competent Ad5-CD/TKrep virus followed by 2 weeks of 5-fluorocytosine and ganciclovir prodrug therapy can be safely applied to humans and is showing signs of biological activity.

Adenoviruses, Human↗

PubMed2002

Pronounced radiosensitization of cultured human cancer cells by COX inhibitor under acidic microenvironment.

PURPOSE: To demonstrate the influence of pH on the cytotoxicity and radiosensitization by COX (cyclooxygenase) -1 and -2 inhibitors using established human cancer cells in culture. METHODS AND MATERIALS: Nonselective COX inhibitor, ibuprofen (IB), and selective COX-2 inhibitor, SC-236, were used to determine the cytotoxicity and radiosensitization at varying pH of culture media. Human colon carcinoma cell line (HT-29) was exposed to the drug alone and in combination with radiation at different pH of the cell culture media. The end point was clonogenic ability of the single-plated cells after the treatment. RESULTS: Cytotoxicity and radiosensitization of IB increased with higher drug concentration and longer exposure time. The most significant radiosensitization was seen with IB (1.5 mM) for 2-h treatment at pH 6.7 before irradiation. The dose-modifying factor as defined by the ratio of radiation doses required to achieve the same effect on cell survival was 1.8 at 10% survival level. In contrast, SC-236 (50 microM for 2-8 h) showed no pH-dependent cytotoxicity. There was modest increase in the cell killing at lower doses of radiation. CONCLUSION: An acidic pH was an important factor affecting the increased cytotoxicity and radiosensitization by ibuprofen. Radiation response was enhanced at shoulder portion of the cell survival curve by selective COX-2 inhibitor.

Cell Survival↗

PubMed2002

Synergistic interaction with arsenic trioxide and fractionated radiation in locally advanced murine tumor.

We have shown previously that arsenic trioxide (ATO) preferentially shutsdown tumor blood flow, leading to pronounced cell death in the central part of the solid tumor with a minimal effect on the surrounding normal tissues. On the basis of the histopathological and tumor perfusion studies, we hypothesized that the tumor control rate of locally advanced solid tumors would increase after the combined treatment of ATO and radiation relative to either radiation or ATO alone. The antitumor action and quantitative tumor perfusion studies were carried out with locally advanced methylcholanthrene-induced fibrosarcoma grown in BALB/c mice. The s.c. methylcholanthrene-induced fibrosarcoma leg tumors were treated with ATO alone (10 mg/kg), radiation alone (30 Gy), or drug plus radiation together. Radiation alone and drug alone delayed the growth of the tumor by a few days compared with untreated tumors. In contrast, when radiation and drug were given together, the tumor growth delay was longer than 1 month, resulting local tumor cure of 55%. The fractionated radiation combined with ATO showed a similar pronounced tumor growth delay relative to the drug alone or radiation alone. Sustained reduction in tumor blood flow after the combined treatment measured using a rubidium uptake method paralleled enhanced tumor response. There was an immediate 10-fold increase in the production of tumor necrosis factor-alpha in the tumor tissue after the drug treatment, concomitant with the onset of prompt reduction of the tumor blood flow. The present results indicate that tumor response was better with combined treatment than with either treatment alone, suggesting that ATO has potential as an adjuvant to radiotherapy.

Animals↗

PubMed2002

Ca(2+)-dependent inhibition of Na+/H+ exchanger 3 (NHE3) requires an NHE3-E3KARP-alpha-actinin-4 complex for oligomerization and endocytosis.

Two PDZ domain-containing proteins, NHERF and E3KARP are necessary for cAMP-dependent inhibition of Na(+)/H(+) exchanger 3 (NHE3). In this study, we demonstrate a specific role of E3KARP, which is not duplicated by NHERF, in Ca(2+)-dependent inhibition of NHE3 activity. NHE3 activity is inhibited by elevation of intracellular Ca(2+) ([Ca(2+)](i)) in PS120 fibroblasts stably expressing E3KARP but not those expressing NHERF. In addition, this Ca(2+)-dependent inhibition requires Ca(2+)-dependent association between alpha-actinin-4 and E3KARP. NHE3 is indirectly connected to alpha-actinin-4 in a protein complex through Ca(2+)-dependent interaction between alpha-actinin-4 and E3KARP, which occurs through the actin-binding domain plus spectrin repeat domain of alpha-actinin-4. Elevation of [Ca(2+)](i) results in oligomerization and endocytosis of NHE3 as well as in inhibition of NHE3 activity. Overexpression of alpha-actinin-4 potentiates the inhibitory effect of ionomycin on NHE3 activity by accelerating the oligomerization and endocytosis of NHE3. In contrast, overexpression of the actin-binding domain plus spectrin repeat domain acts as a dominant-negative mutant and prevents the inhibitory effect of ionomycin on NHE3 activity as well as the oligomerization and internalization of NHE3. From these results, we propose that elevated Ca(2+) inhibits NHE3 activity through oligomerization and endocytosis of NHE3, which occurs via formation of an NHE3-E3KARP-alpha-actinin-4 complex.

Actinin↗

PubMed2002

A technique of intensity-modulated radiosurgery (IMRS) for spinal tumors.

This study is to demonstrate the feasibility of spinal radiosurgery using an image-guided intensity-modulated radiosurgical (IMRS) procedure. A dedicated Novalis shaped beam surgery unit equipped with a built-in micro-multileaf collimator (mMLC) with a single 6 MV photon beam was used. Each patient was simulated in the supine position using an AcQsim CT simulator with infrared sensitive markers for localization. A variety of different treatment plans were developed, but the most common plan was the use of seven coplanar intensity-modulated beams to minimize radiation to critical organs such as the spinal cord and kidneys. An automatic localization device based on infrared and video cameras was used to guide the initial patient setup. Two keV x-ray imaging systems were used to identify potential deviations from the planned isocenter. A total of 25 patients with spinal tumors have been treated using this procedure with a single prescription dose ranging from 6 to 12 Gy. The final verification images indicated that the average isocenter deviation from the planned isocenter was within 2 mm. The phantom verification of isocenter doses indicated that the average deviation of measured isocenter doses from the planned isocenter doses for all patients treated with intensity-modulated beams was less than 2%. Film dose measurement in a phantom study demonstrated good agreement of above 50% isodose lines between the planned and measured results. Preliminary experience shows that precision delivery of high dose radiation could be administered to the planned target volume while the dose to the critical organs is kept within tolerable limits.

Computer Simulation↗

PubMed2002

Noninvasive detection of radiation-induced optic neuropathy by manganese-enhanced MRI.

Available imaging techniques have a limited ability to detect radiation-induced injury of the normal brain. In particular, there is no noninvasive method available for detection of structural or functional neuronal damage induced by radiation. This study was designed to determine whether MRI enhanced using the neuronal track tracer MnCl(2) can detect radiation-induced optic neuropathy. A single dose of radiation (35 Gy) was delivered to produce optic neuropathy in Fischer 344 rats by using a stereotactic method with a 6-mm dorsoventral secondary collimator. At 6 months after irradiation, MRI was performed in 1-mm sections using a 7-T magnetic field with the neuronal tracer MnCl(2) injected into the vitreous of the eye 24 h prior to imaging. The rats were then killed humanely for a histological study with hematoxylin and eosin, glial fibrillary acidic protein (Gfap) for the detection of astrocytic activity, Luxol Fast Blue/Periodic Acid Schiff (LFB/PAS) for the detection of myelinization status, and Bielschowski silver stain for axon status. In nonirradiated control animals, T1-weighted MRI with manganese vitreous injection revealed an optic nerve track that was brightly enhanced from the orbit to the optic chiasm. In the irradiated animals, there was clear evidence of the damage at the optic chiasm and optic nerves, with loss of axon and demyelinization within the site of irradiation upon histological examination. T1-weighted MRI with manganese vitreous injection showed an enhancing optic nerve posterior to the orbit. However, this enhancement disappeared at the site of irradiation. The area of loss of manganese contrast on the MRI scan correlated well with the area of histological abnormality showing axonal degeneration and demyelinization. Radiation-induced optic neuropathy was thus detected noninvasively by MRI with the antegrade neuronal tracer manganese, which exhibited negative contrast enhancement by causing loss of signal. This study represents the first demonstration of MR imaging of radiation-induced neuronal damage and could provide a means to explore the biological and functional integrity of neuronal pathways.

Animals↗

PubMed2001

Phosphorylation-dependent regulation of phospholipase D2 by protein kinase C delta in rat Pheochromocytoma PC12 cells.

Many studies have shown that protein kinase C (PKC) is an important physiological regulator of phospholipase D (PLD). However, the role of PKC in agonist-induced PLD activation has been mainly investigated with a focus on the PLD1, which is one of the two PLD isoenzymes (PLD1 and PLD2) cloned to date. Since the expression of PLD2 significantly enhanced phorbol 12-myristate 13-acetate (PMA)- or bradykinin-induced PLD activity in rat pheochromocytoma PC12 cells, we investigated the regulatory mechanism of PLD2 in PC12 cells. Two different PKC inhibitors, GF109203X and Ro-31-8220, completely blocked PMA-induced PLD2 activation. In addition, specific inhibition of PKC delta by rottlerin prevented PLD2 activation in PMA-stimulated PC12 cells. Concomitant with PLD2 activation, PLD2 became phosphorylated upon PMA or bradykinin treatment of PC12 cells. Moreover, rottlerin blocked PMA- or bradykinin-induced PLD2 phosphorylation in PC12 cells. Expression of a kinase-deficient mutant of PKC delta using adenovirus-mediated gene transfer inhibited the phosphorylation and activation of PLD2 induced by PMA in PC12 cells, suggesting the phosphorylation-dependent regulation of PLD2 mediated by PKC delta kinase activity in PC12 cells. PKC delta co-immunoprecipitated with PLD2 from PC12 cell extracts, and associated with PLD2 in vitro in a PMA-dependent manner. Phospho-PLD2 immunoprecipitated from PMA-treated PC12 cells and PLD2 phosphorylated in vitro by PKC delta were resolved by two-dimensional phosphopeptide mapping and compared. At least seven phosphopeptides co-migrated, indicating the direct phosphorylation of PLD2 by PKC delta inside the cells. Immunocytochemical studies of PC12 cells revealed that after treatment with PMA, PKC delta was translocated from the cytosol to the plasma membrane where PLD2 is mainly localized. These results suggest that PKC delta-dependent direct phosphorylation plays an important role in the regulation of PLD2 activity in PC12 cells.

Acetophenones↗

PubMedDate not supplied

Role of ERK activation in cisplatin-induced apoptosis in OK renal epithelial cells.

Cisplatin induces apoptosis in a variety of cell types. However, the signaling pathway of cisplatin-induced apoptosis in renal epithelial cells is poorly understood. The present study was undertaken to determine the role of the extracellular signal-regulated kinase (ERK) in cisplatin-induced apoptosis of renal epithelial cells using opossum kidney cells. Cisplatin at 50 microM induced apoptosis in a time-dependent manner. Cisplatin treatment caused sustained activation of ERK1/2, which was prevented by PD98059 and U0126, inhibitors of ERK1/2 upstream kinase MEK1/2. Transient transfection of cells with constitutive active MEK1 increased the cisplatin-induced apoptosis, whereas that with a dominant-negative mutant of MEK1 decreased it. Cisplatin induced an increase in Bax expression, mitochondrial membrane depolarization, mitochondrial cytochrome c release and caspase-3 activation, and these changes were prevented by the MEK inhibitor. These results suggested that (1) the ERK1/2 activation is required for the cisplatin-induced apoptosis of renal epithelial cells; and (2) ERK1/2 mediates the mitochondria-dependent apoptotic signaling by acting upstream of Bax expression.

Animals↗