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Biomedical subjects

J K Wu

Publications and source records attributed to J K Wu.

At least 37 records · Page 2Linked to original sources
PubMed1998

Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-beta-lactamase.

BACKGROUND: High level resistance to carbapenem antibiotics in gram negative bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co-administration of metallo-beta-lactamase inhibitors to resistant bacteria is expected to restore the antibacterial activity of carbapenems. RESULTS: Biphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-lactamase identified through screening and predicted using molecular modeling of the enzyme structure. The X-ray crystal structure of the enzyme bound to the BPT L-159,061 shows that the tetrazole moiety of the inhibitor interacts directly with one of the two zinc atoms in the active site, replacing a metal-bound water molecule. Inhibition of metallo-beta-lactamase by BPTs in vitro correlates well with antibiotic sensitization of resistant B. fragilis. CONCLUSIONS: BPT inhibitors can sensitize a resistant B. fragilis clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem or penicillin G but not to rifampicin.

Bacteroides fragilis↗
PubMed1997

A technique for accurate planning of stereotactic brain implants prior to head ring fixation.

PURPOSE: A two-step procedure is described for accurate planning of stereotactic brain implants prior to head-ring fixation. METHODS AND MATERIALS: Approximately 2 weeks prior to implant a CT scan without the head ring is performed for treatment-planning purposes. An entry point and a reference point, both marked with barium and later tattooed, facilitate planning and permit correlation of the images with a later CT scan. A plan is generated using a conventional treatment-planning system to determine the number and activity of I-125 seeds required and the position of each catheter. I-125 seed anisotropy is taken into account by means of a modification to the treatment planning program. On the day of the implant a second CT scan is performed with the head ring affixed to the skull and with the same points marked as in the previous scan. The planned catheter coordinates are then mapped into the coordinate system of the second CT scan by means of a manual translational correction and a computer-calculated rotational correction derived from the reference point coordinates in the two scans. RESULTS: The rotational correction algorithm was verified experimentally in a Rando phantom before it was used clinically. For analysis of the results with individual patients a third CT scan is performed 1 day following the implant and is used for calculating the final dosimetry. CONCLUSION: The technique that is described has two important advantages: 1) the number and activity of seeds required can be accurately determined in advance; and 2) sufficient time is allowed to derive the best possible plan.

Brachytherapy↗
PubMed1997

Response of intracranial melanoma metastases to stereotactic radiosurgery.

We analyzed our recent stereotactic radiosurgery (SRS) experience to determine the radiographic response of intracranial metastatic melanomas to SRS. Twelve patients with 21 intracranial melanoma metastases treated with SRS were evaluated. Fifteen (72%) metastases were hemispheric, 3 (14%) were cerebellar, and 3 (14%) were in the basal ganglion or thalamus. All lesions were 2.5 cm or less in maximum diameter. Eleven patients also had whole brain external beam radiotherapy. Mean SRS dosage was 1,800 cGy to the 85% isodose surface and median dose was 1,800 cGy to the 80% isodose surface (range 1,100-3, 100 cGy at the 80-95% isodose surface). Overall, 12 (57%) lesions showed decrease or stabilization of tumor volume (i.e., local control), while 9 (43%) showed enlargement. Division of metastases into small (< or = 1.0 cm diameter) and large (> 1.0 cm diameter) tumors showed that the small tumors were more likely to regress than the large tumors (chi-square test; P < 0.03). Only 1 of 9 (11%) large lesions regressed as opposed to 7 of 12 (58%) small lesions regressed with SRS. We conclude that SRS is suited for small melanoma brain metastases, but lesions between 1.0 and 2.5 cm in diameter, while still generally considered appropriate for SRS, may not be as responsive to SRS at currently employed dosages.

Adult↗
PubMed1997

High-yield expression, purification, and characterization of active, soluble Bacteroides fragilis metallo-beta-lactamase, CcrA.

The gene from Bacteroides fragilis encoding a metallo-beta-lactamase, ccrA, was expressed in Escherichia coli BL21(DE3) containing the wild-type disulfide bond-catalyzing system dsb as an active, soluble enzyme in quantities exceeding 100 mg/liter using both rich and minimal media. Both the nonfusion and a glutathione S-transferase fusion enzyme lacking the periplasmic signal sequence were purified to homogeneity. Characteristics of the purified nonfusion enzyme are shown to be similar to those of the renatured enzyme previously reported. Thermal denaturation studies using circular dichroism and fluorescence spectroscopy show that CcrA undergoes a transition at approximately 50 degrees C which corresponds to the transition temperature of catalytic activity. The secondary structure of the protein and the catalytic apparatus are thus intimately linked.

Bacterial Proteins↗
PubMed1997

The bystander effect exerted by tumor cells expressing the herpes simplex virus thymidine kinase (HSVtk) gene is dependent on connexin expression and cell communication via gap junctions.

To elucidate the role gap junctions play in the bystander effect, we examined the cytotoxic effect of herpes simplex virus thymidine kinase (HSVtk) modified tumor cells on gap junction communication-deficient tumor cells and their connexin transfectants. Communication competent Walker 256 tumor cells engineered to express the HSVtk gene (Walker-tk+) when cocultured with N2A mouse neuroblastoma and PC12 rat pheochromocytoma cells with absent endogenous junctional conductance showed no bystander cytotoxicity. Transfection of N2A cells with the rat connexin37 gene (5Q) and PC12 cells with the human connexin43 gene rendered them susceptible to bystander cell death. Additionally, communication-deficient N2A cells transfected with the HSVtk gene failed to exert a bystander effect, whereas N2A transfectants coexpressing the connexin37 and HSVtk genes (5Qtk+ cells) exerted bystander cytotoxicity on gap junction communication-competent 5Q but not on communication-deficient N2A cells in vitro. In vivo experiments also showed tumor growth inhibition of communication-competent 5Q but not communication-incompetent N2A cells by 5Qtk+ cells. In conclusion, these results indicate that in several cellular environments the bystander effect is dependent on connexin expression and gap junctional communication between HSVtk-positive and HSVtk-negative cells.

Animals↗
PubMed1997

Evidence for clonal origin of neoplastic neuronal and glial cells in gangliogliomas.

Gangliogliomas are rare tumors of the central nervous system that account for approximately 1% of all brain tumors. Histologically, gangliogliomas are composed of intimately admixed glial and neuronal components, the pathological origins of which remain to be characterized. Clonal analysis through examination of the pattern of the X chromosome inactivation allows one to distinguish monoclonal differentiation of a genetically abnormal progenitor cell from parallel, but independent, clonal expansion of two different cell types during tumorigenesis in biphasic neoplasms, such as gangliogliomas. In the present study, we investigated the clonality of eight gangliogliomas from female patients using both methylation- and transcription-based clonality assays at the androgen receptor locus (HUMARA) on the X chromosome. Among tumors from seven patients who were heterozygous at the HUMARA locus, five were identified as monoclonal with the methylation-based clonality assay, and the results were confirmed by the transcription-based method, whereas two were shown to be polyclonal by the methylation-based clonality assay but monoclonal by transcription-based clonality analysis. We conclude that the predominant cell types in most gangliogliomas are monoclonal in origin and derive from a common precursor cell that subsequently differentiates to form neoplastic glial and neuronal elements.

Adult↗
PubMed1997

[Clinical study of effect of yinji capsule on left ventricular systolic function of angina pectoris patients with blood stasis syndrome].

OBJECTIVE: To explore the Yinji Capsule (YJC) in improving the left ventricular systolic function of angina pectoris patients with Blood Stasis Syndrome. METHODS: The systolic function of left ventricle (LV) in cardiac cycle of 28 angina pectoris patients with Blood Stasis Syndrome was examined with three-dimensional echocardiograph (3-DE) before and after treatment with YJC. RESULTS: The total symptomatic effective rate was 85.7%. The changes of LV systolic function were those: left ventricle ejection fraction (LVEF) increased from 45.0 +/- 4.9% to 48.2 +/- 3.5% (P < 0.05); EF on early stage and late stage increased from 22.6 +/- 2.1%, 8.3 +/- 1.2% to 28.1 +/- 3.0% and 10.3 +/- 0.9% respectively (P < 0.01, P < 0.05), myocardial region with segment systole (SS) < 5% decreased significantly (P < 0.01). CONCLUSION: YJC could improve LV systolic function on early stage and late stage in cardiac cycles, and mainly improve the systolic function of the region with low SS of LV.

Aged↗
PubMed1996

CTL lysis: there is a hyperbolic relation of killing rate to exocytosable granzyme A for highly cytotoxic murine cytotoxic T lymphocytes.

The lysis of susceptible targets by efficient cytotoxic T lymphocytes (CTL) increases both with time and with the ratio of CTL to target. Simple methods for calculating a killing rate constant from the time dependence of killing and for calculating the relation of the killing rate constant to the concentration of exocytosable granzyme A are given. Application of these methods to the killing of target cells by the highly efficient mouse CTL AR1 is presented. AR1 needed granzyme A for efficient killing. AR1 contained sufficient exocytosable granzyme A to kill at about 80% of the rate possible at infinite exocytosable granzyme A.

Animals↗
PubMed1996

Microsatellite instability analysis of primary human brain tumors.

Microsatellite instability, as shown by the presence of additional alleles or shifts of electrophoretic mobility at simple sequence tandem repeat loci, has been demonstrated in hereditary and sporadic colorectal tumors and many other tumor types. To study microsatellite instability in human brain tumors, we examined a total of 144 sporadic neoplasms. These included 33 astrocytic tumors, 23 oligodendrogliomas, six gangliogliomas, 41 meningiomas, 10 vestibular schwannomas and 31 pituitary adenomas. Di-, tri- and tetranucleotide repeat microsatellite markers localized on chromosome 4 and 9, X, 13 and 22, respectively, were used to assess whether instability was a significant aspect of their abnormal chromosomal pattern. Instability of microsatellite markers was detected in four oligodendrogliomas (17.4%), one pituitary adenoma (3.2%), one meningioma (2.4%), one astrocytic tumor (3.0%) and not at all in gangliogliomas and schwannomas. Therefore, our results suggest that the microsatellite instability which occurs in colorectal cancers with defective mismatch repair is infrequent in many types of human brain tumors and that the lower level of instability observed in brain tumors may be reflective of other mechanisms of genetic instability.

Base Sequence↗
PubMed1996

Olfactory neuroblastoma is a peripheral primitive neuroectodermal tumor related to Ewing sarcoma.

Olfactory neuroblastoma (ONB) is a malignant tumor of the nasal mucosa whose histogenesis is unclear. A relationship to neuroblastoma (NB), a pediatric tumor of the sympathetic nervous system, is based on morphologic similarities and the expression of similar neural antigens. However, the clinical presentation of ONB differs from that of NB, and MYCN amplification characteristic of NB is not observed. We have therefore examined the relationship of this malignancy to other classes of neural tumors. In previous studies, two ONB cell lines demonstrated cytogenetic features and patterns of protooncogene expression suggestive of a relationship to the Ewing sarcoma family of childhood peripheral primitive neuroectodermal tumors (pPNETs). The pPNETs show t(11;22)(q24;q12) or t(21;22)(q22;q12) chromosomal translocations fusing the EWS gene from 22q12 with either the FL11 gene on 11q24 or the ERG gene on 21q22. We therefore analyzed ONBs for the presence of pPNET-associated gene fusions. Both cell lines showed rearrangement of the EWS gene, and fluorescence in situ hybridization (FISH) of each case demonstrated fusion of EWS and FL11 genomic sequences. Moreover, both lines expressed EWS/FL11 fusion transcripts with in-frame junctions between exon 7 of EWS and exon 6 of FL11 as described for pPNETs. We identified similar gene fusions in four of six primary ONB cases. None of the cases expressed tyrosine hydroxylase, a catecholamine biosynthetic enzyme widely expressed in NB. Our studies indicate that ONB is not a NB but is a member of the pPNET family.

Adult↗
PubMed1996

Errors involving pediatric patients receiving chemotherapy: a literature review.

A review of mishaps involving pediatric patients receiving anticancer chemotherapy was undertaken in order to assist intervention. Although the case literature is too sparse to provide definite recommendations, suggestions for management are made in the event of an error with a high risk (based on the case literature) of life-threatening toxicities. It is recommended that all incidents be reported in the literature in order to provide a basis for devising standard treatment protocols. It is also suggested that studies using animal models continue to be done in order to provide more experimental data about toxicities and potentially beneficial rescue therapies.

Antineoplastic Agents↗
PubMed1996

Preservation of the bystander cytocidal effect of irradiated herpes simplex virus thymidine kinase (HSV-tk) modified tumor cells.

In vitro and animal experiments have demonstrated the potential efficacy of using the bystander effect alone in the treatment of brain tumors. A known problem in some in vitro and in vivo experiments is that a fraction of cells engineered to express the herpes simplex virus thymidine kinase (HSV-tk) gene survive ganciclovir (GCV) treatment and undergo cell division. To prevent the recurrent growth of HSV-tk+ cells in the presence of GCV we examined the potential use of lethal or sublethal irradiation of Walker 256 carcinosarcoma cells selected for expression of the HSV-tk gene (Walker-tk+). Western blot analysis of Walter-tk+ cells showed similar levels of HSV-tk protein expression at 0, 1, 3, 6 and 9 days after lethal gamma-irradiation. In vitro, there was no difference in the bystander effect exerted by non-irradiated, sublethally irradiated or lethally irradiated Walker-tk+ cells on wild-type Walker cells in the presence of GCV. In vivo experiments demonstrated long-term survival (100 days) in rats implanted intrathecally with sublethally or lethally irradiated Walker-tk+ cells with GCV treatments. Intrathecal implantation of irradiated Walker-tk+ cells either pre-mixed with Walker cells or used in in situ treatment of established Walker tumors resulted in prolonged animal survival compared to controls (p < 0.05). These experiments suggest that the bystander tumoricidal effect is preserved despite gamma-irradiation of the HSV-tk modified tumor cells and that irradiation could be an effective method to prevent long-term resistance to GCV in HSV-tk+ tumor cells.

Animals↗
PubMed1996

Clonal analysis of meningiomas.

Meningiomas are primary brain tumors arising from meningothelial cells. They usually grow slowly and are surgically easy to separate from the brain. A recent clonal analysis of meningiomas, using methylation-sensitive restriction fragment length polymorphisms, suggested a monoclonal origin. Using the same technique but with a highly informative X chromosome probe (M27 beta), we found that 17 (85%) of the 20 meningiomas analyzed were informative. Of the 17 informative tumors, 8 (47%) were monoclonal, 3 (18%) had loss of heterozygosity on the X chromosome, and, unexpectedly, 6 (35%) had a polyclonal pattern. Samples from two areas of one tumor showed a monoclonal pattern and loss of heterozygosity, respectively, on the X chromosome. A review of the histopathological and radiological features of the 17 informative tumors did not help to distinguish the clonal from the polyclonal tumors. We conclude that meningiomas are heterogeneous in clonal composition.

Adult↗
PubMed1996

Tumor cells expressing the herpes simplex virus-thymidine kinase gene in the treatment of Walker 256 meningeal neoplasia in rats.

A promising strategy in the treatment of neoplastic meningitis involves the use of herpes simplex virus-thymidine kinase (HSV-tk)-modified cells. In these experiments the authors used cells expressing HSV-tk to treat meningeal carcinomatosis in the rat Walker 256 model. Intrathecal injection of 2 x 10(5) Walker cells resulted in a median survival time of 15 days. Up to 80% of animals implanted with HSV-tk-modified Walker cells (Walker-tk+) and treated with ganciclovir showed long-term survival (120 days or more), whereas the remaining animals died from tumor growth between 37 and 44 days after implantation. Tumor cells from an animal in which the treatment failed were cultured in vitro and were shown to be still sensitive to ganciclovir. However, continuous ganciclovir administration for 6 weeks rather than 2 weeks did not improve survival. Histopathological studies confirmed leptomeningeal infiltration in the untreated Walker or Walker-tk+ animals. Walker-tk+ cells were mixed with Walker cells in 1:1, 10:1, or 50:1 ratios, respectively, and implanted intrathecally; the animals were treated with ganciclovir. All groups of treated animals had long-term survivors, with 40% of the rats in the 10:1 and 50:1 groups demonstrating long-term survival and absence of microscopic tumors in the brain or spinal cord. Similarly, murine fibroblast HSV-tk virus-producer cells improved survival. Walker-tk+ cells were better than fibroblast-producer cells in improving the survival of animals with Walker tumors at low (1:1) but not at high (10:1) effector-to-target cell ratios. Repeated intrathecal administration of Walker-tk+ cells resulted in inhibition of established Walker tumors. The authors conclude that Walker-tk+ cells are at least as effective as murine virus-producer cells and could be used in the treatment of meningeal neoplasia.

3T3 Cells↗
PubMed1995

Blunt gastrointestinal injury in trauma patients.

The evaluation, management, and final outcome of 34 patients with blunt gastrointestinal injury (BGI) were reviewed. Initial absence of symptoms and signs led to two delayed diagnoses. Sonography provided 80% (12/15) positive-predictive value, and three false-negative patients were subsequently detected by diagnostic peritoneal lavage (DPL). Besides repeated clinical surveillance, screening by sonography complemented with DPL provided early detection of blunt bowel injury in trauma patients. In the outcome analysis, BGI patients with high injury-severity scores, intraoperative hypotension, or accompanying major medical diseases were associated significantly with increased risk of infectious complications (P < .05).

Adolescent↗
PubMed1995

Urgent laparotomy versus emergency craniotomy for multiple trauma with head injury patients.

In blunt multiple trauma (MT) with head injury (HI) patients, it is difficult to decide whether to proceed with immediate laparotomy or craniotomy. In August 1989, abdominal ultrasonography (US) using a simple US scoring system was introduced for MT and HI patients as an initial rapid screening procedure. In MT and HI patients with a US score > or = 3 (n = 14), urgent laparotomy was the procedure of first choice. However, immediate head CT scan, then emergency craniotomy, may be justified in hemodynamically stable MT and HI patients with a US score < 3 (n = 98). Appropriate decision making can be applied to decide which procedure is most exigent.

Abdomen↗