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Biomedical subjects

J Kuo

Publications and source records attributed to J Kuo.

At least 19 recordsLinked to original sources
PubMed2006

Selective destruction of glioblastoma cells by interference with the activity or expression of ATF5.

Glioblastoma multifome is the most common and most aggressive primary brain tumor with no current curative therapy. We found expression of the bZip transcription factor ATF5 in all 29 human glioblastomas and eight human and rat glioma cell lines assessed. ATF5 is not detectably expressed by mature brain neurons and astrocytes, but is expressed by reactive astrocytes. Interference with ATF5 function or expression in all glioma cell lines tested causes marked apoptotic cell death. In contrast, such manipulations do not affect survival of ATF5-expressing cultured astrocytes or of several other cell types that express this protein. In a proof-of-principle experiment, retroviral delivery of a function-blocking mutant form of ATF5 into a rat glioma model evokes death of the infected tumor cells, but not of infected brain cells outside the tumors. The widespread expression of ATF5 in glioblastomas and the selective effect of interference with ATF5 function/expression on their survival suggest that ATF5 may be an attractive target for therapeutic intervention in such tumors.

Activating Transcription Factors↗
PubMed2006

Aortic root replacement in cardiac dextroversion.

Adult cardiac surgery in patients with malrotation of the heart is rare. A 60 year-old lady, with known cardiac dextroversion, presented with dyspnoea and pre-syncopal attacks. Echocardiographical and radiological investigation confirmed the dextroversion, with clockwise rotation of the heart through its longitudinal axis. This resulted in the right ventricular outflow tract and pulmonary artery being wrapped anteriorly around the aorta, with posterior displacement of the right atrium. The presence of a heavily calcified, bicuspid aortic valve and dilated ascending aorta was also demonstrated. At surgery, venous cannulation was established by rotating the heart anticlockwise and access to the aortic valve gained with a more superior oblique aortotomy. In the presence of a dilated ascending aorta with a calcified, bicuspid aortic valve, the aortic root was replaced with a valved conduit. To the authors' knowledge, this is the first report of an aortic root replacement in a patient with cardiac dextroversion.

Aorta, Thoracic↗
PubMed2005

Left ventricular wall motion analysis using real-time three-dimensional ultrasound.

This study tested the ability of real-time 3-D (RT 3-D) echocardiography to detect and delineate regions of abnormal contraction (akinesia or dyskinesia) in a canine model of regional myocardial injury and to develop methods to simplify injury assessments. Closed chest RT 3-D scans were obtained and regional left ventricular (LV) contractile function was assessed in nine animals at baseline and after myocardial cryoinjury with a 1-cm cryoprobe. Evaluation of contractile function was based on radial shortening of LV chamber cross-sections at multiple levels. Radial length changes were analyzed using color-coded circumferential maps of the LV. Seven sets of motion maps demonstrated new areas of poorly contracting myocardium in the cryoinjured region relative to baseline. Two sets of data were excluded due to insufficient LV visualization. Motion maps derived from RT 3-D echo have the ability to detect and localize regions of abnormal LV wall motion.

Animals↗
PubMed2004

Fast pollen tube growth in Conospermum species.

BACKGROUND AND AIMS: An unusual form of pollen tube growth was observed for several Conospermum species (family Proteaceae). The rate of pollen tube growth, the number of tubes to emerge and the ultrastructure of these tubes are given here. METHODS: Pollen was germinated in vitro in different sucrose concentrations and in the presence of calcium channel blockers, and tube emergence and growth were recorded on a VCR. Measurements were taken of the number of tubes to emerge and rate of tube emergence. Pollen behaviour in vivo was also observed. The ultrastructure of germinated and ungerminated pollen was observed using TEM. RESULTS: After 10 s to 3 min in germination medium, up to three pollen tubes emerged and grew at rates of up to 55 micro m s(-1); the rate then slowed to around 2 micro m s(-1), 30 s after the initial growth spurt. Tubes were observed to grow in pulses, and the pulsed growth continued in the presence of calcium channel blockers. Optimal sugar concentration for pollen germination was 300 g L(-1), in which up to 81 % of pollen grains showed fast germination. Germination and emergence of multiple tubes were observed in sucrose concentrations of 100-800 g L(-1). The vegetative and generative nuclei moved into one of the tubes. Multiple tubes from a single grain were observed on the stigma. Under light microscopy, the cytoplasm in the tube showed a clear region at the tip. The ultrastructure of C. amoenum pollen showed a bilayered exine, with the intine being very thick at the pores, and elsewhere having large intrusions into the plasma membrane. The cytoplasm was dense with vesicles packed with inner tube cell wall material. Golgi apparatus producing secretory vesicles, and mitochondria were found throughout the tube. The tube wall was bilayered; both layers being fibrous and loosely packed. CONCLUSIONS: It is proposed that, for Conospermum, initial pollen tube wall constituents are manufactured and stored prior to pollen germination, and that tube extension occurs as described in the literature for other species, but at an exceptionally fast rate.

Biological Transport↗
PubMed2004

Pregnancy outcomes with increased clomiphene citrate dose.

Our objective was to evaluate whether ovulation induction with an increased clomiphene citrate dose of 150-250 mg/day for 5 days adversely affected pregnancy outcome. A retrospective chart review of 1910 medical records yielded 119 pregnancies with sufficient information regarding domiphene dose and pregnancy outcome. Of the 84 pregnancies that followed clomiphene doses of 50-100 mg/day, 32.1% ended in spontaneous abortion, 10.7% in ectopic gestation, 1.2% with congenital malformations, 2.4% in stillbirth and 53.6% in normal gestation. Of the 35 pregnancies that followed clomiphene doses of 150-250 mg/day, 34.3% ended in spontaneous abortion, 5.7% in ectopic gestation, 2.9% with congenital malformations, 2.9% in stillbirth and 54.3% in normal gestation. These differences were not statistically significant. These data suggest that a clomiphene dose of 150-250 mg/day does not appear to increase adverse pregnancy outcomes.

Abortion, Spontaneous↗
PubMed2004

Left atrial phaeochromocytoma.

Phaeochromocytomas of the heart are very rare. This report describes the case of a 69 year old woman presenting with persistent hypertension and a left atrial phaeochromocytoma diagnosed by 131I-metaiodobenzylguanidine scintigraphy scanning. She was successfully treated by surgical excision with the aid of cardiopulmonary bypass and perioperative alpha and beta adrenergic blockade.

3-Iodobenzylguanidine↗
PubMed2002

Mannitol in cardioplegia as an oxygen free radical scavenger measured by malondialdehyde.

Oxygen free radicals (OFRs) are associated with ischaemia-reperfusion injury involving many organs, including the heart, which can lead to depressed cardiac function and abnormalities in the cardiac ultrastructure. This is seen upon the release of the aortic crossclamp when the ischaemic myocardium is reperfused in patients undergoing cardiopulmonary bypass (CPB). Various studies have shown that by adding OFR scavenging agents or antioxidants to the CPB prime or cardioplegia, cardiac performance improves. Mannitol is an osmotic diuretic with free radical scavenging properties, which has been shown to reduce the extent of ischaemic injury and improve the function of the myocardium. This study evaluated how effective mannitol is as an OFR scavenger by administering different concentrations of cardioplegia antegrade into the aortic root, thus maximising its effects directly upon the myocardium rather than being diluted in the CPB prime. Thirty-three patients undergoing primary coronary artery bypass grafting (CABG) were, by double blind random selection, allocated into one of three groups: group 1, a control group (consisting of 11 patients) receiving no mannitol; group 2 (11 patients), receiving a concentration of 4 g/l; and group 3 (11 patients), receiving 8 g/l. Three blood samples were taken directly from the coronary sinus during bypass: the first sample at the start of bypass, just prior to the crossclamp being applied; the second sample just after removal of the crossclamp; and the third sample just prior to termination of bypass. All samples were then centrifuged and the plasma analysed for malondialdehyde (MDA) using high-performance liquid chromatography (HPLC). MDA, an endproduct of lipid peroxidation, causes cellular damage and disruption of cell membranes when tissue antioxidants are exhausted. The more MDA produced, the greater the depletion of tissue antioxidants secondary to OR formation during reperfusion when the aortic crossclamp is removed. HPLC is a useful biochemical study; however, it is not a direct indicator of depressed myocardial function, such as an invasive test would be, and this should be borne in mind. Statistically, the results do not show a significant difference among the three groups or among the three samples. However, a trend can be seen, which shows lower levels of MDA in the two groups receiving mannitol and there is an indication of a rise in MDA levels upon the start of reperfusion in the two groups receiving mannitol, but not the control group. It is concluded that further samples would be needed to find a significant difference in MDA concentrations.

Adult↗
PubMed2001

Tetra-O-methyl nordihydroguaiaretic acid induces G2 arrest in mammalian cells and exhibits tumoricidal activity in vivo.

The transcription inhibitor tetra-O-methyl nordihydroguaiaretic acid (M4N) was found to arrest the proliferation of C3, C33a, CEM-T4, and TC-1 cells in culture at the G2 stage of the cell cycle. Investigation into the mechanism of arrest revealed that M4N reduces mRNA levels and subsequent protein production of the cyclin-dependent kinase CDC2, resulting in the inactivation of the CDC2/cyclin B complex (maturation promoting factor). When injected intratumorally in a C3-cell induced C57bl/6 mouse tumor model system, M4N demonstrated substantial tumoricidal activity that correlated with a reduction in tumor cell CDC2 protein levels. These findings suggest that M4N may be a useful chemotherapeutic agent for the control of unregulated cellular proliferation.

Animals↗
PubMed2001

Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia.

We identified TMPRSS2 as a gene that is down-regulated in androgen-independent prostate cancer xenograft tissue derived from a bone metastasis. Using specific monoclonal antibodies, we show that the TMPRSS2-encoded serine protease is expressed as a Mr 70,000 full-length form and a cleaved Mr 32,000 protease domain. Mutation of Ser-441 in the catalytic triad shows that the proteolytic cleavage is dependent on catalytic activity, suggesting that it occurs as a result of autocleavage. Mutational analysis reveals the cleavage site to be at Arg-255. A consequence of autocatalytic cleavage is the secretion of the protease domain into the media by TMPRSS2-expressing prostate cancer cells and into the sera of prostate tumor-bearing mice. Immunohistochemical analysis of clinical specimens demonstrates the highest expression of TMPRSS2 at the apical side of prostate and prostate cancer secretory epithelia and within the lumen of the glands. Similar luminal staining was detected in colon cancer samples. Expression was also seen in colon and pancreas, with little to no expression detected in seven additional normal tissues. These data demonstrate that TMPRSS2 is a secreted protease that is highly expressed in prostate and prostate cancer, making it a potential target for cancer therapy and diagnosis.

Androgens↗
PubMed2001

Association of serum estrogen level and ischemic neuroprotection in female rats.

Estrogen-related ischemic neuroprotection has been documented in male and ovariectomized female rats. The precise molecular mechanism underlying estrogen's neuroprotective effect remains obscure. In the present study, we examined whether endogenous estrogen levels affect post-ischemic outcomes in normal cycling female rats. Occlusion of both the common carotid arteries and the right middle cerebral artery (1.5 h) followed by reperfusion (24 h) caused cortical infarction, increased neutrophil accumulation, and elevated antioxidant enzyme and lactate dehydrogenase activities. These post-ischemic changes varied in the female rats and were inversely correlated with circulating estrogen levels. More severe post-ischemic changes and injury accompanied the decline in circulating estrogen levels in normal cycling female rats, indicating that estrogen is probably the major hormonal player in female resistance to ischemia.

Animals↗
PubMed2001

cAMP enhances Cx43 gap junction formation and function and reverses choline deficiency apoptosis.

Previously, it had been shown that acute choline deficiency (CD) induced apoptosis in cultured rat liver epithelial cells, whereas cells that are adapted to survive in low-choline-containing medium acquire resistance to CD apoptosis and undergo malignant transformation. Thus, understanding the mechanisms of action of CD could increase our understanding of the role of choline, an essential nutrient, in the process of malignant transformation. The present experiments were designed to test the hypothesis that CD might function as a pro-apoptotic trigger by altering the localization of connexin 43 gap junction protein and gap junctional intercellular communication (GJIC). Established liver epithelial cells (WB cells; Hep3B cells) were maintained in a defined, serum-free medium control (70 microM choline) or choline deficient medium (CD, 5 microM choline) and the localization of connexin 43 protein (Cx43) was studied by immunocytochemistry and Western blotting. In nontumorigenic WB cells, CD apoptosis was associated with retention of Cx43 in the golgi/ER region of the cytoplasm and decreased GJIC as measured using a preloading fluorescent dye transfer method (calcein AM/DiIC(18)). Cells maintained in CD in the presence of 8-bromoadenosine 3':5'-cyclic monophosphate exhibited restoration of Cx43 at the plasma membrane and increased GJIC and inhibition of apoptosis. These studies show that CD apoptosis in nontumorigenic liver epithelial cells is associated with alterations to Cx43 and GJIC and that an uncoupling of Cx43 localization and GJIC is related to resistance to CD apoptosis in transformed liver epithelial cells.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2001

Obesity hypertension: role of leptin and sympathetic nervous system.

Obesity may account for as much as 65% to 75% of human essential hypertension in most industrialized countries. Excess renal sodium reabsorption and a hypertensive shift of renal-pressure natriuresis play a key role in mediating obesity hypertension. Sympathetic activation contributes to obesity-induced sodium retention and hypertension because adrenergic blockade or renal denervation markedly attenuates these changes. Recent observations suggest that leptin and its multiple interactions with other neurochemical pathways in the hypothalamus may be a partial link between excess weight gain and increased sympathetic activity. Short-term administration of leptin into the cerebral ventricles increases renal sympathetic activity, and long-term intravenous leptin infusions in nonobese rodents at rates that raise plasma concentrations to the levels found in severe obesity increase arterial pressure and heart rate through adrenergic activation. Also, transgenic mice that overexpress leptin develop hypertension. Acute studies suggest that the renal sympathetic effects of leptin may depend on interactions with other neurochemical pathways in the hypothalamus, including melanocortin-4 receptors. However, it is unclear whether this pathway or others, such as neuropeptide Y, mediate the long-term effects of leptin on blood pressure. In addition, leptin has other actions, such as stimulation of nitric oxide formation and enhancement of insulin sensitivity, which may tend to reduce blood pressure in some conditions. Although the precise role of these complex interactions in human obesity has not been elucidated, this is an important area for further investigation, especially considering the current epidemic of obesity in most industrialized countries.

Animals↗
PubMed2001

The University of California, Irvine experience with tomotherapy using the Peacock system.

Our institutional experience using the Peacock system for intensity-modulated radiation therapy (IMRT) is summarized. Over 100 patients were treated using this system, which is fitted to a Clinac 600C linac. Both cranial and extracranial lesions have been treated using this modality. Immobilization is achieved either with the Talon system for cranial sites or an Aquaplast cast. Target volumes up to 500 cm3 have been treated. Multiple lesions (up to 3) were treated in one setup. The range of dose/fractionation schemes used was 15 Gy/1 fx (radiosurgical treatment) - 80 Gy/40 fx. Dose validation studies were carried out using film and ion chamber dosimetry in a specially designed phantom. Optimal dose distributions were attainable using inverse treatment planning for IMRT delivery. These were found to encompass the target volumes accurately using dose validation phantom studies. Immobilization methods used were accurate to within 1 mm, as evidenced by daily portal films. IMRT using the Peacock system offers the advantage of delivery of conformal therapy to high doses safely and accurately. This provides the opportunity for dose escalation studies, retreatment of previously treated tumors, as well as treating multiple targets in one setup. The system may be fitted to a conventional linac without major modifications.

Adenocarcinoma↗
PubMed2001

Stereotactic Radiotherapy of Central Nervous System and Head and Neck Lesions, Using a Conformal Intensity-Modulated Radiotherapy System (Peacocktrade mark System).

The objective of this article is to evaluate single-fraction or fractionated stereotactic radiotherapy of central nervous system (CNS) and head and neck lesions using intensity-modulated radiotherapy (IMRT) with a commercially available system (Peacocktrade mark, Nomos Corporation, Sewickley, PA). This system allows tomotherapeutic delivery of intensity-modulated radiation, that is, the slice-by-slice treatment of the volume of interest with an intensity-modulated beam, making the delivery of highly conformal radiation to the target possible in both single or multiple fractions mode. During an 18-month period, 43 (21 males and 22 females) patients were treated, using a removable cranial screw-fixation device. Ages ranged from 10 to 77 years (mean, 52.2; median, 53.5). Intra- and extra-axial lesions, including head and neck malignancies and spine metastases, were treated. Clinical target volume ranged from 0.77 to 195 cm(3) (mean, 47.8; median, 29.90). The dose distribution was normalized to the maximum and was prescribed, in most cases, at the 80% or 90% isodose line (range, 65 to 96%; median, 85%; mean, 83.4%) and ranged from 14 to 80 Gy (mean, 48; median, 50). The number of fractions ranged from 1 to 40 (mean, 23; median, 25). In all but one patient, 90% of the prescription isodose line covered 100% of the clinical target volume. The heterogeneity index (the ratio between the maximum radiation dose and the prescribed dose) ranged between 1.0 and 1.50, whereas the conformity index (the ratio between the volume encompassed by the prescription isodose line and the clinical target volume) ranged between 1.0 and 4.5. There were no complications related to the radiation treatment. With a median follow-up of 6 months, more than 70% of our patients showed decreased lesion size. Stereotactic IMRT of CNS and head and neck lesions can be delivered safely and accurately. The Peacock system delivers stereotactic radiation in single or multiple fractions and has no volume limitations. It has been used to treat intracranial, head and neck, and spinal lesions. The option of fractionation, the lack of volume constraint, and the capability of treating intracranial, head and neck, and spinal pathology make stereotactic IMRT a valuable adjunct to established stereotactic radiotherapy systems delivering convergent-beam irradiation using the Linac or Gamma Knife. In a clinical setting that offers Linac, Gamma Knife radiosurgery, and conformal stereotactic radiotherapy, the latter may have advantages for treating large (> 25-cm(3)) and irregular lesions, especially when fractionation is considered useful.

Journal Article↗
PubMed2001

Brain proton magnetic resonance spectroscopy and imaging in children exposed to cocaine in utero.

OBJECTIVE: The effects of prenatal cocaine exposure have been examined using neurobehavioral and brain structural evaluations; however, no study has examined the effects of prenatal cocaine on brain metabolism. Proton magnetic resonance spectroscopy ((1)H-MRS) is a noninvasive method to examine the biochemistry of various brain regions. The purpose of this study was to examine the possible neurotoxic effects of prenatal cocaine exposure on the developing brain using (1)H-MRS. METHODS: Cocaine-exposed children (n = 14) and age-matched unexposed control participants (n = 12) were evaluated with MRI and localized (1)H-MRS. Metabolite concentrations of N-acetyl-containing compounds (NA), total creatine (Cr), choline-containing compounds, myoinositol, and glutamate + glutamine were measured in the frontal white matter and striatum. RESULTS: Despite an absence of structural abnormalities in either group, children exposed to cocaine in utero had significantly higher Cr (+13%) in the frontal white matter. NA, primarily a measure of N-acetyl aspartate and neuronal content, was normal in both regions examined by (1)H-MRS. Normal NA suggests no significant neuronal loss or damage in the 2 brain regions examined in children exposed to cocaine prenatally. CONCLUSIONS: Consistent with findings in abstinent adult cocaine users, we found increased Cr in the frontal white matter, with normal NA in children exposed to cocaine. These findings suggest the need to investigate further possible abnormalities of energy metabolism in the brain of children exposed to cocaine in utero. In addition, this study demonstrates the feasibility of using (1)H-MRS to investigate the effects of prenatal drug exposure on the developing brain.

Aspartic Acid↗
PubMed2000

Longitudinal evaluation of activated protein C resistance among normal pregnancies of Hispanic women.

OBJECTIVE: This study was undertaken to describe pregnancy-associated activated protein C resistance and the presence of the factor V Leiden mutation in a sample population of pregnant Hispanic women. STUDY DESIGN: Twenty healthy Hispanic women with single intrauterine pregnancies were randomly selected. Blood samples were taken before 8 weeks' gestation, every 4 weeks during pregnancy, and at 6 weeks post partum. Samples were collected, separated, and stored at -70 degrees C until assay. Standard and modified partial thromboplastin time-based assays were used to evaluate response to activated protein C. A sensitivity ratio < or =2 indicated resistance to activated protein C. Repeated measures analysis of variance and unpaired t tests were used as appropriate. P <.05 was considered significant. RESULTS: Mean (+/-SEM) maternal age was 29 +/- 5 years, and most women were multiparous. Mean gestational age at delivery was 38 weeks' gestation, and the mean birth weight was 3000 g. According to the standard assay, 10 women (50%) acquired activated protein C resistance by 13 weeks' gestation, and this condition persisted through delivery and resolved post partum. Another two had preexisting activated protein C resistance. Results of the standard assay were significantly different for women with preexisting and pregnancy-associated activated protein C resistance (1.55 vs 2.18; P =.01). The modified assay distinguished between women with preexisting and pregnancy-associated activated protein C resistance at 8 weeks' gestation, 24 weeks' gestation, and post partum. The pregnancies of the women with preexisting activated protein C resistance were complicated by oligohydramnios at 34 weeks' gestation and required delivery at 36 weeks' gestation. One infant was small for gestational age. Allele-specific polymerase chain reaction analysis demonstrated that both patients with preexisting activated protein C resistance carried one copy of the factor V Leiden mutation. CONCLUSION: The incidences of pregnancy-associated and factor V Leiden mutation-associated activated protein C resistances in our cohort of gravid Hispanic women was higher than previously reported. Factor V Leiden-associated activated protein C resistance in two patients was associated with adverse perinatal outcome.

Adult↗