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Biomedical subjects

J Park

Publications and source records attributed to J Park.

At least 19 recordsLinked to original sources
PubMed2025

HLA-E and NKG2A Mediate Resistance to BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) is the first-line therapy for high-grade non-muscle-invasive bladder cancer (NMIBC), yet many patients experience recurrence due to immune evasion. We identify HLA-E and NKG2A as mediators of adaptive resistance involving chronic activation of NK and T cells in BCG-unresponsive tumors. Prolonged IFN-γ exposure enhances HLA-E and PD-L1 expression on recurrent tumors, accompanied by the accumulation of NKG2A+ NK and CD8 T cells. HLA-Ehigh tumor cells preferentially cluster near CXCL12-rich stromal regions with dense effector cell presence, underscoring a spatially segregated tumor architecture. Although cytotoxic lymphocytes retain effector potential, their activity is restrained by HLA-E/NKG2A and PD-L1/PD-1 pathways located in their immediate neighborhood within the bladder tumor microenvironment. These data reveal a spatially organized immune escape program that limits anti-tumor immunity. Our findings support dually targeting NKG2A and PD-L1 checkpoint blockade as a rational, bladder-sparing strategy for patients with BCG-unresponsive NMIBC.

BCG-unresponsive↗
PubMed2007

Optimizing typhoid fever case definitions by combining serological tests in a large population study in Hechi City, China.

Blood culture-based diagnosis can only detect a fraction of the total burden of Salmonella enterica subsp. enterica serovar Typhi. The objective of the study was to detect additional typhoid fever cases through serological tests. A total of 1732 prolonged fever episodes were evaluated using three serological tests, Widal, Tubex and Typhidot-M in a typhoid fever endemic area of southern China. A case definition which included a positive Widal test (TO>or=80 & TH>A), a positive Tubex test (>or=4) and a positive Typhidot-M test, increased the detection of cases by more than twofold from 13 to 28 cases. The case definition has a specificity of 100% and a sensitivity of 39%. Case definitions based on combinations of serological tests can detect additional typhoid fever cases with higher specificity than a single serological test. Improved case detection is essential to understand the true disease burden and can help to boost the power of intervention trials.

Adolescent↗
PubMed2007

Alliance and compliance in tuberculosis treatment of older Pakeha people in Auckland, New Zealand.

SETTING: A community-based ethnography of tuberculosis (TB) treatment of 'European' New Zealanders in Auckland was completed in 2003. OBJECTIVE: To document and analyse the nature of the process of care in this population where the majority of patients are older with other health and social complications. DESIGN: Data collection included repeated semi-structured interviews with all patients who were willing and able to give consent, semi-structured interviews on health and TB with matched participants without TB, discussions with health care providers, participant observation with TB patients, readings of patient records and monitoring of TB in the media. Reiterative inductive analyses were made of transcripts, field notes and textual materials. RESULTS: Eight patients from 2003 (out of a possible nine) and one patient from 1997 participated. All were aged 47-75 years. They represent a wide socio-economic range. All completed treatment. The contribution of multidimensional care, from initial acceptance through exigencies of treatment to successful recovery, is evident in the participants' narratives. The public health nurse is a key support and a lynchpin in the patients' support network. CONCLUSION: A model of care including alliances between patients and care givers as part of treatment is clearly successful in this population group. This study has implications for older cohorts in other low-incidence countries.

Aged↗
PubMed2006

Activated Notch1 interacts with p53 to inhibit its phosphorylation and transactivation.

We propose a biochemical mechanism for the negative role of Notch signaling on p53 transactivation function. Expression of the intracellular domain of human Notch1 (Notch1-IC) inhibits the expression of p53-responsive genes p21, mdm2, and bax in HCT116 p53(-/-) cells. Furthermore, Notch1-IC expression inhibits the phosphorylation of ectopically expressed p53 in HCT116 p53(-/-) cells as well as the phosphorylation of endogenous p53 in UV-treated HCT116 p53(+/+) cells. Transcriptional downregulation of p53-responsive genes by Notch1-IC was confirmed both by chromatin immunoprecipitation assay and Northern blot analysis. We found the intracellular interaction between Notch1-IC and p53 in HCT116 p53(+/+) cells and suggest that activated Notch1 interaction with p53 is an important cellular event for the inhibition of p53-dependent transactivation. The N-terminal fragment of Notch1-IC, which can interacts with p53, inhibits p53 phosphorylation and represses p53 transactivation. In addition, Notch signaling downregulated p53-dependent apoptosis induced by UV irradiation.

Apoptosis↗
PubMed2006

Attenuated pain responses in mice lacking Ca(V)3.2 T-type channels.

Although T-type Ca(2+) channels are implicated in nociception, the function of specific subtypes has not been well defined. Here, we compared pain susceptibility in mice lacking Ca(V)3.2 subtype of T-type Ca(2+) channels (Ca(V)3.2(-/-)) with wild-type littermates in various behavioral models of pain to explore the roles of Ca(V)3.2 in the processing of noxious stimuli in vivo. In acute mechanical, thermal and chemical pain tests, Ca(V)3.2(-/-) mice showed decreased pain responses compared to wild-type mice. Ca(V)3.2(-/-) mice also displayed attenuated pain responses to tonic noxious stimuli such as intraperitoneal injections of irritant agents and intradermal injections of formalin. In spinal nerve ligation-induced neuropathic pain, however, behavioral responses of Ca(V)3.2(-/-) mice were not different from those of wild-type mice. The present study reveals that the Ca(V)3.2 subtype of T-type Ca(2+) channels are important in the peripheral processing of noxious signals, regardless of modality, duration or affected tissue type.

Animals↗
PubMed2006

Evaluation of prenatal intra-amniotic LAMB3 gene delivery in a mouse model of Herlitz disease.

Prenatal gene therapy has been considered for Herlitz junctional epidermolysis bullosa (H-JEB), a lethal genodermatosis caused by the absence of any of the three subunits of laminin-5, resulting from birth in widespread blistering and erosions of skin and mucosae. To investigate this strategy in an animal model, adenovirus type 5- and adeno-associated virus (AAV) type 2-derived vectors carrying a beta-galactosidase reporter gene or LAMB3 cDNA encoding the beta3 chain of laminin-5 were generated, tested for stability in amniotic fluid and evaluated in vitro on murine H-JEB keratinocytes, and in vivo by prenatal injection into the amniotic cavities of laminin-5 beta3-deficient mice. The different vectors were administered individually or combined at maximum doses on day 14 post coitum. Adenoviral vectors infected preferentially the foetal epidermis, whereas AAV delivered the transgene mainly to mucous membranes of the airways and the upper digestive tract. The LAMB3 transgene was expressed in target epithelia of newborn laminin-5 beta3-deficient mice, and the transgenic beta3 chain was shown to assemble with its endogenous partner chains, resulting in detectable amounts of laminin-5 in the basement membranes of skin and mucosae and in a lower extent of tissue separation in the skin. However, only combined delivery of the two vector types led to a minor increase of the life span of H-JEB mice. Failure to rescue diseased animals was, at least in part, due to abandonment of any conspicuous pup by the heterozygous mother. This is the first study of a prenatal gene therapy approach to a heritable blistering disorder. Although our findings indicate that prenatal combined administration of adenoviral and adeno-associated LAMB3 vectors provides therapeutic benefit to H-JEB mice, this animal model appears unsuitable for long-term investigations of the therapeutic concept.

Adenoviridae↗
PubMed2006

Experimental and theoretical studies of the phenyl radical reaction with propene.

The kinetics for the reaction of C6H5 with propene has been measured by cavity ring-down spectrometry (CRDS) at temperatures 296-496 K under an Ar pressure of 40 Torr. The total rate constant can be given by the following Arrhenius expression (in units of cm3 mol(-1) s(-1)): k(C6H5 + C3H6) = 10(11.93+/-0.06) exp[-(1512 +/- 51)/T]. Density functional and higher level of theory calculations (up to the G2M level) have been carried out to provide additional insights about the mechanism of this reaction, and we also performed transition state theory (TST) calculation for the rate constant prediction. Our theoretical kinetic calculations predict that the C6H5 addition to the terminal =CH2 site in propene is dominant at the temperature range of our CRDS measurements. However, the H-abstraction channel forming benzene and the allyl radical becomes increasingly important at higher temperatures. The total high-pressure limiting rate constant calculated on the basis of the G2M reaction barriers is in reasonable agreement with the experimental values.

Journal Article↗
PubMed2006

Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase.

Mer (MerTK) is a receptor tyrosine kinase important in platelet aggregation, as well as macrophage cytokine secretion and clearance of apoptotic cells. Mer is not normally expressed in thymocytes or lymphocytes; however, ectopic Mer RNA transcript and protein expression is found in a subset of acute lymphoblastic leukemia cell lines and patient samples, suggesting a role in leukemogenesis. To investigate the oncogenic potential of Mer in vivo, we created a transgenic mouse line (Mer(Tg)) that expresses Mer in the hematopoietic lineage under control of the Vav promoter. Ectopic expression and activation of the transgenic Mer protein was demonstrated in lymphocytes and thymocytes of the Mer(Tg) mice. At 12-24 months of age, greater than 55% of the Mer(Tg) mice, compared to 12% of the wild type, developed adenopathy, hepatosplenomegaly, and circulating lymphoblasts. Histopathological analysis and flow cytometry were consistent with T-cell lymphoblastic leukemia/lymphoma. Mer may contribute to leukemogenesis by activation of Akt and ERK1/2 anti-apoptotic signals, which were upregulated in Mer(Tg) mice. Additionally, a significant survival advantage was noted in Mer(Tg) lymphocytes compared to wild-type lymphocytes after dexamethasone treatment. These data suggest that Mer plays a cooperative role in leukemogenesis and may be an effective target for biologically based leukemia/lymphoma therapy.

Animals↗
PubMed2006

Promoter methylation of helicase-like transcription factor is associated with the early stages of gastric cancer with family history.

BACKGROUND: To investigate the clinicopathological significance of promoter methylation of the helicase-like transcription factor (HLTF) in primary gastric cancer. PATIENTS AND METHODS: Two-hundred fifty six patients participated in this study. Methylation status of HLTF gene was evaluated in fresh-frozen tissues by the methylation-specific polymerase chain reaction. All statistical analyses were two-sided, with a 5% type I error rate. RESULTS: Aberrant methylation of HLTF was found in 98 (38%) of 256 gastric cancer patients. HLTF methylation was significantly associated with a family history in the early stages of gastric cancer, regardless of histologic types. In intestinal-type cases, HLTF methylation occurred in 15 (56%) of 27 patients with family histories, and in 26 (31%) of 85 patients without family histories (P = 0.02). In diffuse-type cases, patients with family histories were also found to exhibit a higher prevalence of HLTF methylation than those without family histories (61% vs. 34%; P = 0.009). HLTF methylation in both of the histologic types occurred in about 70-90% of the early stage cases in which the patient had a family history and in 15-30% of cases in which the patient did not have a family history. In our multivariate logistic regression analysis, the stage 1-2 cases with family histories were determined to carry a higher risk of HLTF methylation than did the stage 3-4 cases without family histories in both the intestinal-type (OR = 6.01, 95% CI = 1.20-30.01, P = 0.02) and the diffuse-type cancers (OR = 8.25, 95% CI = 1.67-40.86, P = 0.009). CONCLUSIONS: These results suggest that HLTF methylation may play a crucial role in the early stages of gastric carcinogenesis in patients with family histories and may be a valuable susceptible marker for the risk of gastric cancer in individuals with family histories.

Aged↗
PubMed2006

Quantification of process measures in laparoscopic suturing.

BACKGROUND: Process measures describing the generation of movement are useful for evaluation and performance feedback purposes. This study aimed to identify process measures that differ between novice and advanced laparoscopists while completing a suturing skill. METHODS: A group of junior and a group of senior residents and fellows in surgery (n = 6) placed 10 laparoscopic sutures in a synthetic model. Process measures were quantified using an opto-electric motion/force sensor assembly that recorded: instrument rotation, applied forces, time, and time delays between force application and instrument rotation. RESULTS: Advanced trainees showed increased instrument rotation, higher peak applied force, and faster performance compared to novices (alll p < .01). However, over trials, only novices showed adaptations for instrument rotation and total time (interactions at p < .01) with no adaptation for the force application. The difference between the moments of force application and instrument rotation was not sensitive to participant training. CONCLUSIONS: Movement process measures can enhance our understanding of early adaptation processes and how such factors might be used as feedback to facilitate skill acquisition.

Clinical Competence↗
PubMed2006

Efficacy of valganciclovir in the treatment of cytomegalovirus disease in kidney and pancreas transplant recipients.

Cytomegalovirus (CMV) disease is relatively common following solid organ transplant, particularly if a serologically negative recipient receives an organ from a serologically positive donor (D+/R-). Although valganciclovir is approved for the treatment of CMV retinitis in AIDS patients and is used for the prophylaxis against CMV infection in solid organ transplant patients, the current standard treatment for CMV disease in solid organ transplant recipients remains intravenous ganciclovir. We retrospectively reviewed our experience using valganciclovir as treatment for CMV disease in CMV D+/R- kidney and/or pancreas transplant recipients from March 2002 to June 2005. A total of 37 cases with primary CMV disease were diagnosed and treated with either intravenous ganciclovir as induction followed with valganciclovir or valganciclovir from the beginning. We compared clinical outcomes and viremia between the two groups. Our data suggest that valganciclovir is an effective treatment modality for primary CMV disease in kidney and/or pancreas transplant recipients. It led to the resolution of disease and undetectable viremia. Valganciclovir allowed for early initiation of treatment and for treatment to be given as an outpatient. These advantages of valganciclovir have both health and economic impact for patients with CMV disease.

Adult↗
PubMed2006

Mycophenolic acid induces islet apoptosis by regulating mitogen-activated protein kinase activation.

Mycophenolic acid (MPA), an inosine monophosphate dehydrogenase inhibitor, is widely used as an immunosuppressive drug after transplantations including those of pancreas islet cells. However, recent reports have indicated that MPA has apoptotic effects on islet cells in vitro. To study the effect of MPA on islet cells and determine its mechanism, we used an insulin secreting cell-line, HIT-T15. We examined mitogen-activated protein kinase (MAPK) activation after MPA treatment, and determining cell death levels using methylthiazdetetrazolium assays. The activations of extracellular signal-regulated protein kinase (ERK), c-jun N-terminal kinase (JNK), and p38 MAPK and caspase-3 cleavage were measured by Western blotting. MPA (1, 10, 30 micromol/L) increased cell death and caspase-3 cleavage within 24 hours. Exogenous 500 micromol/L guanosine reversed the MPA-induced islet cell death, but exogenous adenosine did not. MPA 10 micromol/L induced cell apoptosis and increased the activations of JNK, ERK, and p38 MAPK. Furthermore, exogenous guanosine, but not exogenous adenosine, reversed these effects induced by MPA. This study demonstrated that MPA may induce islet apoptosis in HIT-T15 cells by increasing activations of JNK, ERK, and p38 MAPK in a guanosine-dependent manner.

Apoptosis↗
PubMed2006

Estimation on the self recovery behavior of low-conductivity layer in landfill final cover by laboratory conductivity tests.

This study examined the application of a Self Recovering Sustainable Layer (SRSL) as a landfill final cover. Low-conductivity layers in landfill covers are known to have problems associated with cracking as a result of the differential settlement or climatic changes. A SRSL is defined as a layer with chemical properties that reduces the increased hydraulic conductivity resulting from cracking by forming low-conductivity precipitates of chemicals contained in the layer. In this study, the formation of precipitates was confirmed using a batch test, spectroscopic analysis and mineralogical speciation tests. The possibility of secondary contamination due to the chemicals used for recovery was evaluated using a leaching test. A laboratory conductivity test was performed on a single layer composed of each chemical as well as on a 2-layer system. The recovery performance of the SRSL was estimated by developing artificial cracks in the specimens and observing the change in hydraulic conductivity as a function of time. In the laboratory conductivity test, the hydraulic conductivity of a 2-layer system as well as those of the individual layers that comprise the 2-layer system was estimated. In addition sodium ash was found to enhance the reduction in conductivity. A significant increase in conductivity was observed after the cracks developed but this was reduced with time, which indicated that the SRSL has a proper recovering performance. In conclusion, a SRSL can be used as a landfill final cover that could maintain low-conductivity even after the serious damages due to settlement.

Calcium Compounds↗
PubMed2005

JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila.

Although recent progresses have unveiled the diverse in vivo functions of LKB1, detailed molecular mechanisms governing these processes still remain enigmatic. Here, we showed that Drosophila LKB1 negatively regulates organ growth by caspase-dependent apoptosis, without affecting cell size and cell cycle progression. Through genetic screening for LKB1 modifiers, we discovered the JNK pathway as a novel component of LKB1 signaling; the JNK pathway was activated by LKB1 and mediated the LKB1-dependent apoptosis. Consistently, LKB1-null mutant was defective in embryonic apoptosis and displayed a drastic hyperplasia in the central nervous system; these phenotypes were fully rescued by ectopic JNK activation as well as wild-type LKB1 expression. Furthermore, inhibition of LKB1 resulted in epithelial morphogenesis failure, which was associated with a decrease in JNK activity. Collectively, our studies unprecedentedly elucidate JNK as the downstream mediator of the LKB1-dependent apoptosis, and provide a new paradigm for understanding the diverse LKB1 functions in vivo.

AMP-Activated Protein Kinase Kinases↗
PubMed2005

Experimental observation of a periodically oscillating plasma sphere in a gridded inertial electrostatic confinement device.

The periodically oscillating plasma sphere (POPS) [D. C. Barnes and R. A. Nebel, Phys. Plasmas 5, 2498 (1998).] oscillation has been observed in a gridded inertial electrostatic confinement device. In these experiments, ions in the virtual cathode exhibit resonant behavior when driven at the POPS frequency. Excellent agreement between the observed POPS resonance frequency and theoretical predictions has been observed for a wide range of potential well depths and for three different ion species. The results provide the first experimental validation of the POPS concept proposed by Barnes and Nebel [R. A. Nebel and D. C. Barnes, Fusion Technol. 34, 28 (1998).].

Journal Article↗
PubMed2005

Prevention of alcohol-induced developmental delays and learning abnormalities in a model of fetal alcohol syndrome.

OBJECTIVE: Prenatal alcohol exposure results in fetal death and neurobehavioral complications including learning impairment. Previously synthetic peptides derived from activity-dependent neurotrophic factor have been shown to prevent aspects of alcohol-induced damage in pregnancy. The objective of this work was to evaluate whether activity-dependent neurotrophic factor-12 could prevent alcohol-induced damage in a model of fetal alcohol syndrome. STUDY DESIGN: Using a well-characterized model, C57Bl6/J mice on gestational day 8 were treated with placebo, alcohol (30% volume/volume alcohol 0.03 mL/kg), alcohol plus activity-dependent neurotrophic factor-12 30 minutes prior to alcohol, or activity-dependent neurotrophic factor-12 alone. Fetal death was assessed on gestational day 18 (25 litters were evaluated: alcohol, n = 5; placebo, n = 9; alcohol plus activity-dependent neurotrophic factor-12, n = 11). Neonatal behavior tests were performed on postnatal days 1 through 21 with the offspring of 12 dams (alcohol, n = 16; placebo, n = 46; alcohol plus activity-dependent neurotrophic factor-12, n = 23; and activity-dependent neurotrophic factor-12, n = 35). Adult males were tested in the Morris water maze for learning assessment and with the hole punch activity test for exploratory activity. Statistical analysis included Kruskal-Wallis and analysis of variance. RESULTS: Fetal death was greater in alcohol (67% +/- 13%) vs placebo (8.4% +/- 3%, P < .001). Pretreatment with activity-dependent neurotrophic factor-12 prevented the alcohol-induced fetal death (2.2% +/- 8.1%) with levels similar to control (P = .12). Alcohol exposure caused a delay in achieving developmental milestones, with alcohol achieving milestones later than all other groups (all P < .001). Pretreatment with activity-dependent neurotrophic factor-12 prevented the alcohol-induced milestone delays. In the Morris water maze, the placebo learned, decreasing their latency to find the hidden platform over 70% (P < .01). Alcohol plus activity-dependent neurotrophic factor-12 also significantly learned, with a learning curve not different from placebo (all P > .5) and significantly better than alcohol on days 4, 6, and 7 (all P < .05). Alcohol exposure resulted in significantly less time in hole punch activity (P < .02) than control. Activity-dependent neurotrophic factor-12 pretreatment prevented the alcohol-induced decline, with levels the same as control (P = .1). CONCLUSION: The novel peptide activity-dependent neurotrophic factor-12 prevents alcohol-induced fetal death and developmental and learning abnormalities in a model of fetal alcohol syndrome. This demonstrates that a single treatment with a peptide is efficacious and may be of value in the prevention of alcohol-induced damage.

Animals↗
PubMed2005

Effects of tautomycetin on proliferation and fibronectin secretion in vascular smooth muscle cells and glomerular mesangial cells.

Tautomycetin (TMC), a newly developed immunosuppressive agent, induces T-lymphocyte apoptosis through the inhibition of tyrosine kinase and protein phosphatase 1. We examined the effects of TMC on platelet-derived growth factor (PDGF)-induced proliferation and extracellular matrix synthesis in cultured vascular smooth muscle cells (VSMCs) and mesangial cells (MCs) of Sprague-Dawley rats, and investigated the molecular mechanisms involved. Different concentrations of TMC were administered 1 hour before the addition of 10 ng/mL PDGF into the growth-arrested and synchronized cells. Cell proliferation was assessed by methylthiazoletetrazolium (MTT) assay, fibronectin secretion, and the activation of Akt, ERK, and p38 MAPK by Western blot analysis. PDGF increased cell proliferation, fibronectin secretion, and the activation of Akt, ERK, and p38 MAPK in both VSMCs and MCs. In both cultured cells, TMC at >1 mug/mL significantly reduced basal MTT. TMC at 100 ng/mL significantly decreased the PDGF-induced VSMC and MC proliferation. However, fibronectin secretion and the activation of Akt, ERK, and p38 MAPK were not affected by this nontoxic concentration of TMC. The present data demonstrate that low-dose TMC reduced PDGF-induced VSMC and MC proliferation without affecting the fibronectin secretion and cellular kinase activation.

Animals↗