Biomedical subjects

Joseph Kim

Publications and source records attributed to Joseph Kim.

33 records · Page 2Linked to original sources

PubMed2005

Epigenetic up-regulation of C-C chemokine receptor 7 and C-X-C chemokine receptor 4 expression in melanoma cells.

Histone deacetylation and DNA methylation establish epigenetic modifications, which through chromatin remodeling may result in gene silencing. We hypothesized that chemokine receptors C-C chemokine receptor 7 (CCR7) and C-X-C chemokine receptor 4 (CXCR4) on melanoma cells undergo epigenetic regulation. We investigated whether a histone deacetylase inhibitor and a demethylating agent influence CCR7 and CXCR4 expression on melanoma cells. Initially, microarray analysis was done to screen changes in chemokine receptor expression on melanoma cells after treatment with trichostatin A (TSA) and 5-Aza-2-deoxycytidine (5-Aza). CCR7 and CXCR4 mRNA expression were uniformly altered and selected for further investigation. Quantitative real-time reverse transcription-PCR assay, immunohistochemistry, and Western blot analysis were used to assess changes in mRNA and protein expression induced by TSA and 5-Aza in melanoma lines. Cell migration assays were conducted to assess the effects of altered CCR7 and CXCR4 expression on cell function. Treatment with TSA or 5-Aza increased gene expression of both CCR7 and CXCR4 in melanoma lines. TSA was the strongest enhancer. With combined treatment, CCR7 and CXCR4 mRNA expression was also up-regulated. Immunohistochemistry after combined treatment showed enhanced staining of both CCR7 and CXCR4 compared with control cells. Melanoma cell migration in TSA- and 5-Aza-treated cells was 7- and 2-fold higher than control cells for CCR7 and CXCR4, respectively. In summary, a histone deacetylase inhibitor and a demethylating agent up-regulated CCR7 and CXCR4 expression on melanoma cells. This increase in chemokine receptor expression correlated with functional activity. Most importantly, we have identified an epigenetic mechanism that may endogenously regulate chemokine receptor expression on melanoma cells.

Acetylation↗

PubMed2005

Health-related quality of life after interventional or conservative strategy in patients with unstable angina or non-ST-segment elevation myocardial infarction: one-year results of the third Randomized Intervention Trial of unstable Angina (RITA-3).

OBJECTIVES: We sought to compare the effects of an early interventional strategy (IS) versus a conservative strategy (CS) on health-related quality of life (HRQOL) in patients with non-ST-segment elevation acute coronary syndromes (ACS). BACKGROUND: The third Randomized Intervention Trial of unstable Angina (RITA-3) evaluated early IS (n = 895) versus CS (n = 915). We report one-year results of the RITA-3 trial concerning HRQOL. METHODS: The patients' HRQOL was assessed with the Short Form-36 (SF-36) and Seattle Angina Questionnaire (SAQ) at four-month and one-year follow-up, and the EuroQOL Visual Analogue Scale (EQ-VAS) and EuroQOL 5-Dimensional Classification (EQ-5D) also measured at baseline. Analysis was performed using the two-sample t test and analysis of co-variance. RESULTS: Mean changes from baseline EQ-VAS scores were better for IS than for CS at four months (treatment difference of 3.0, p < 0.001) and one year (2.3, p < 0.01). The EQ-5D utility scores were also higher for IS at four months (treatment difference: 0.036, p < 0.01) and at one year (0.016, p = 0.20). For SF-36, IS scored significantly better at four months for physical function, physical role function, emotional role function, social function, vitality, and general health. The SAQ scores for exertional capacity, anginal stability and frequency, treatment satisfaction, and disease perception were better for IS at four months. These treatment differences were present but attenuated by one-year follow-up. Improvements in HRQOL for IS could be attributed to improvements in anginal symptoms. CONCLUSIONS: In patients with non-ST-segment elevation ACS, an early IS provides greater gains in HRQOL, as compared with CS, mainly due to improvements in angina grade.

Adult↗

PubMed2004

Engineered RNase P ribozymes increase their cleavage activities and efficacies in inhibiting viral gene expression in cells by enhancing the rate of cleavage and binding of the target mRNA.

Engineered RNase P ribozymes are promising gene-targeting agents that can be used in both basic research and clinical applications. We have previously selected ribozyme variants for their activity in cleaving an mRNA substrate from a pool of ribozymes containing randomized sequences. In this study, one of the variants was used to target the mRNA encoding thymidine kinase (TK) of herpes simplex virus 1 (HSV-1). The variant exhibited enhanced cleavage and substrate binding and was at least 30 times more efficient in cleaving TK mRNA in vitro than the ribozyme derived from the wild type sequence. Our results provide the first direct evidence to suggest that a point mutation at nucleotide 95 of RNase P catalytic RNA from Escherichia coli (G(95) --> U(95)) increases the rate of cleavage, whereas another mutation at nucleotide 200 (A(200) --> C(200)) enhances substrate binding of the ribozyme. A reduction of about 99% in TK expression was observed in cells expressing the variant, whereas a 70% reduction was found in cells expressing the ribozyme derived from the wild type sequence. Thus, the RNase P ribozyme variant is highly effective in inhibiting HSV-1 gene expression. Our study demonstrates that ribozyme variants increase their cleavage activity and efficacy in blocking gene expression in cells through enhanced substrate binding and rate of cleavage. These results also provide insights into the mechanism of how RNase P ribozymes efficiently cleave an mRNA substrate and, furthermore, facilitate the development of highly active RNase P ribozymes for gene-targeting applications.

Base Sequence↗

PubMed2004

An algorithm for the accurate identification of benign liver lesions.

BACKGROUND: Benign liver lesions may be difficult to characterize preoperatively. In most instances, determination of the etiology of a hepatic mass makes its management decisions clear-cut. We present our experience using an algorithm for the management of liver masses of suspected benign or uncertain pathology and highlight this approach along with our surgical experience in benign liver lesions. METHODS: Seventy-one patients underwent hepatectomy with a preoperative diagnosis of benign disease or unknown etiology from December 1992 to February 2002. Patients were preoperatively assessed with computed tomography, along with other imaging studies, as indicated. Final pathology was reviewed to confirm the preoperative diagnosis. RESULTS: Ninety-two percent (65 of 71) were correctly characterized preoperatively. Diagnosis was inaccurate in 6 patients. Of these patients, final pathology revealed focal nodular hyperplasia in 4 patients. The remaining 2 patients, who had adenoma, were found to harbor malignancy within the surgical specimens. CONCLUSIONS: An algorithm to manage liver lesions resulted in a high diagnostic accuracy of a preoperative evaluation. Hepatic resection for benign disease can be performed with low morbidity and mortality and is highly successful in achieving relief for symptomatic patients.

Adult↗

PubMed2004

Hospitalized heart failure: rates and long-term mortality.

BACKGROUND: Heart failure has been called the "new epidemic of cardiovascular disease," but few studies have described key epidemiologic measures of the syndrome in geographically defined US populations. METHODS AND RESULTS: We obtained lists of discharge diagnosis codes in 1995 from 22 Minneapolis-St. Paul metropolitan area hospitals; identified patients 35 to 84 years old with a heart failure discharge code; and sampled and abstracted 50% of the hospital records. To identify heart failure-related hospitalizations, we applied 6 published definitions of the syndrome to the sample and selected cases that met at least 4 of the 6 definitions (n = 2887). The patient cohort was followed for 5 to 6 years to ascertain deaths. The rate of hospitalized heart failure ranged from a few dozen hospitalized patients per 100,000 residents ages 35 to 44 years to more than 2000 per 100,000 residents ages 75 to 84, and was consistently higher among men than among women (age-adjusted rate ratio 1.46; 95% CI 1.39-1.54). Within 1-year of the index admission, 37% of male patients and 30% of female patients have died-10 times the annual mortality of the source population. By the end of the follow-up, cumulative mortality reached 72% in men and 66% in women. In multivariable regression of the hazard of death on age, sex, and left ventricular ejection fraction (LVEF), age was a strong determinant of mortality and male patients had modestly higher hazard of death than female patients (adjusted hazard ratio, 1.29; 95% CI 1.18-1.41). LVEF was not a strong predictor of death. CONCLUSION: A heart failure-related hospitalization is a marker of grave prognosis: only one quarter to one third of the patients survives 5 years after admission. Both the risk of hospitalization for heart failure and the risk of subsequent death are moderately higher in men than in women. LVEF, when measured in the context of heart failure-related hospitalization, is not a strong predictor of death.

Adult↗

PubMed2004

Total sleep deprivation decreases immobility in the forced-swim test.

Sleep deprivation can exert antidepressant effects in humans in less than 24 h, making it the fastest acting antidepressant treatment. However, it is rarely used clinically because the effect disappears once the subject goes back to sleep. An understanding of the neurobiological mechanisms underlying the antidepressant effect of sleep deprivation should help to develop new rapidly acting antidepressant strategies. In the present report, an animal model of depression (the forced-swim test) was used to determine whether the effects of total sleep deprivation parallel those obtained with antidepressant drugs. Using the disk-over-water method, rats deprived of sleep for 24 h exhibited increased swimming behavior when compared to cage control rats, mimicking the effects of serotonergic antidepressants. After 48 h, sleep-deprived rats exhibited increased swimming when compared to both cage control and stimulus control rats, demonstrating that the effect is due to sleep deprivation per se, and not to extraneous factors inherent in the sleep deprivation protocol (such as stress and movement). We believe that this paradigm can be used to study the neurobiological mechanisms of rapid antidepressant effects induced by sleep deprivation.

Analysis of Variance↗

PubMed2004

Reduced morbidity following cytoreductive surgery and intraperitoneal hyperthermic chemoperfusion.

BACKGROUND: Cytoreductive surgery and intraperitoneal hyperthermic chemoperfusion (IPHC) are an aggressive treatment for patients with peritoneal based malignancies or those with peritoneal dissemination of select histology. Although promising, this therapeutic regimen has been associated with significant morbidity, long hospital stays, and, in some reports, moderate risk for perioperative mortality. Recent experience suggests that these outcomes may be improved. METHODS: Thirty-three patients underwent cytoreductive surgery and intraperitoneal hyperthermic perfusion during the period of December 1999 to July 2002. All patients underwent resection by a three-surgeon team, followed by IPHC with an open technique. Peritonectomy was performed with the goal of total gross excision of disease. RESULTS: Thirty-five procedures were performed in 33 patients (20 female) with a mean age of 49 years (range, 26-72). Complete cytoreduction was achieved in 22 cases (63%), and in 6 cases (17%) residual disease was <4 mm. There were nine major perioperative complications (27%) and no perioperative deaths. The median hospital stay was 11 days. CONCLUSIONS: These results demonstrate that cytoreductive surgery and IPHC can be performed with morbidity and mortality rates in line with those of other major oncologic operations. Employment of a three-surgeon approach, limited peritonectomy, and an open technique may help to reduce the morbidity from this aggressive treatment. Continued investigation of this promising treatment regimen is warranted.

Adult↗

PubMed2003

Engineered RNase P ribozymes are efficient in cleaving a human cytomegalovirus mRNA in vitro and are effective in inhibiting viral gene expression and growth in human cells.

By using an in vitro selection procedure, we have previously isolated RNase P ribozyme variants that efficiently cleave an mRNA sequence in vitro. In this study, a ribozyme variant was used to target the overlapping region of the mRNAs encoding human cytomegalovirus (HCMV) major transcription regulatory proteins IE1 and IE2. The variant is about 90 times more efficient in cleaving the IE1/IE2 mRNA sequence in vitro than the ribozyme derived from the wild type RNase P ribozyme. Our results provide the first direct evidence that a point mutation at nucleotide position 80 of RNase P catalytic RNA from Escherichia coli (U80--> C80) increases the rate of chemical cleavage, and another mutation at nucleotide position 188 (C188--> U188) enhances substrate binding of the ribozyme. Moreover, the variant is more effective in inhibiting viral IE1 and IE2 expression and growth in HCMV-infected cells than the wild type ribozyme. A reduction of about 99% in the expression level of IE1 and IE2 and a reduction of 10,000-fold in viral growth were observed in cells that expressed the variant. In contrast, a reduction of less than 10% in IE1/IE2 expression and viral growth was observed in cells that either did not express the ribozyme or produced a catalytically inactive ribozyme mutant. Thus, engineered RNase P ribozyme variants are highly effective in inhibiting HCMV gene expression and growth. These results also demonstrate the feasibility of engineering highly effective RNase P ribozymes for gene targeting applications, including anti-HCMV gene therapy.

Antiviral Agents↗

PubMed2003

Total pancreatectomy and autologous islet cell transplantation as a means to treat severe chronic pancreatitis.

Autologous islet cell transplantation after near-total or total pancreatic resection can alleviate pain in patients with severe chronic pancreatitis and preserve endocrine function. From February 2000 to February 2003, a total of 22 patients, whose median age was 38 years, underwent pancreatectomy and autologous islet cell transplantation. Postoperative complications, metabolic studies, insulin usage, pain scores, and quality of life were recorded for all of these patients. The average number of islet cells harvested was 245,457 (range 20,850 to 607,466). Operative data revealed a mean estimated blood loss of 635 ml, an average operative time of 9 hours, and a mean length of hospital stay of 15 days. Sixty-eight percent of the patients had either a minor or major complication. Major complications included acute respiratory distress syndrome (n=2), intra-abdominal abscess (n=1), and pulmonary embolism (n=1). There were no deaths in our series. All patients demonstrated C-peptide and insulin production indicating graft function. Forty-one percent are insulin independent, and 27% required minimal amount of insulin or a sliding scale. All patients had preoperative pain and had been taking opioid analgesics; 82% no longer required analgesics postoperatively. Pancreatectomy with autologous islet cell transplantation can alleviate pain for patients with chronic pancreatitis and preserve endocrine function.

Adolescent↗

PubMed2003

Obesity and the risk of early and late mortality after coronary artery bypass graft surgery.

BACKGROUND: Obesity is often considered to be a significant risk factor for postoperative mortality when selecting candidates for coronary artery bypass grafting (CABG). METHODS: We included all patients undergoing a first isolated CABG at the Karolinska Hospital in Stockholm, Sweden, between 1980 and 1995 (n = 6728). Patients were categorized on the basis of body mass index (BMI): non-overweight (BMI <25 kg/m2), overweight (25 kg/m2 < or = BMI <30 kg/m2), and obese (BMI > or =30 kg/m2). Multivariate Cox regression was used to assess the risk of re-operation for bleeding, deep sternal wound infection, and early (< or =30 days) and late (< or =5 years) mortality rates. RESULTS: The average length of follow-up was 6.5 years. There were 252 re-operations for bleeding, 53 deep sternal wound infections, and 628 deaths. Patients who were obese had a significantly lower risk of re-operation for bleeding (risk ratio [RR], 0.32; 95% CI, 0.19-0.53), but a greater risk of deep sternal wound infection (RR, 2.66; 95% CI, 1.21-5.88) compared with patients who were not overweight. However, patients who were obese and patients who were not overweight experienced similar 30-day (RR, 0.65; 95% CI, 0.34-1.27), 1-year (RR, 0.56; 95% CI, 0.29-1.10), and 5-year mortality rates (RR, 0.91; 95% CI, 0.66-1.25). Results for patients who were overweight were consistent with those of patients who were obese. CONCLUSION: Patients who are obese are not at a greater risk of early and late mortality after CABG compared with patients who are not overweight, although they appear to have a lower risk of re-operation for bleeding and a greater risk of deep sternal wound infection. Therefore, obesity per se is not a contraindication for CABG.

Angina Pectoris↗

PubMed2003

Increased biliary fistulas after liver resection with the harmonic scalpel.

The Harmonic Scalpel (HS) is frequently used for hepatic resection. Yet, no current study addresses its utility compared to conventional methods. We reviewed our experience with this device to determine if it decreased perioperative complications when compared to the traditional clamp crushing technique. One hundred forty-nine anatomic hepatic resections were performed at our institution from September 1992 to February 2002. Patients were divided into two groups based on the technique of resection: HS [53% (n = 79)] versus clamp crushing [47% (n = 70)]. Use of the HS was associated with a shorter mean operative time (357 +/- 15.0 vs. 404 +/- 19.1 min; p = 0.05) and a trend toward decreased blood loss (1211 +/- 125.5 vs. 1411 +/- 180.7 mL; P = NS) and transfusion requirements (2.6 +/- 0.5 vs. 1.7 +/- 0.3 units; P = 0.10). However, use of the HS was associated with a significant increase in biliary fistulas [24% (n = 19) vs. 7% (n = 5); P = 0.01]. Use of the Harmonic Scalpel was associated with decreased operative time and a trend toward decreased blood loss and transfusion requirements. Its use was also associated with a significant increase in the incidence of postoperative bile leaks, and, therefore, surgeons must be vigilant during liver parenchymal transection when using this device.

Adult↗

PubMed2002

In vitro selection of external guide sequences for directing RNase P-mediated inhibition of viral gene expression.

External guide sequences (EGSs) are small RNA molecules that bind to a target mRNA, form a complex resembling the structure of a tRNA, and render the mRNA susceptible to hydrolysis by RNase P, a tRNA processing enzyme. An in vitro selection procedure was used to select EGSs that direct human RNase P to cleave the mRNA encoding thymidine kinase (TK) of herpes simplex virus 1. One of the selected EGSs, TK17, was at least 35 times more active in directing RNase P in cleaving TK mRNA in vitro than the EGS derived from a natural tRNA sequence. TK17, when in complex with the TK mRNA sequence, resembles a portion of tRNA structure and exhibits an enhanced binding affinity to the target mRNA. Moreover, a reduction of 95 and 50% in the TK expression was found in herpes simplex virus 1-infected cells that expressed the selected EGS and the EGS derived from the natural tRNA sequence, respectively. Our study provides direct evidence that EGS molecules isolated by the selection procedure are effective in tissue culture. These results also demonstrate the potential for using the selection procedure as a general approach for the generation of highly effective EGSs for gene-targeting application.

Base Sequence↗

PubMed2002

Preliminary report on the safety of heparin for deep venous thrombosis prophylaxis after severe head injury.

BACKGROUND: Prophylaxis for venous thromboembolism (VTE) in head injured patients has avoided heparin products because of concern for exacerbating intracranial bleeding. The purpose of this study was to evaluate the safety of unfractionated heparin (UFH) for VTE prophylaxis after traumatic brain injury. METHODS: We retrospectively evaluated the early use of UFH in patients sustaining a severe closed head injury (Abbreviated Injury Scale score > 3) from January 1, 2000, through December 31, 2000. Two groups were formed on the basis of the timing of UFH administration: within 72 hours of admission (Early group), or after the third day of hospitalization (Late group), if at all. Intracranial bleeding related to UFH administration was assessed by computed tomographic scan of the head and/or clinical examination. RESULTS: Sixty-four of 76 patients with intracranial blood on admission head computed tomographic scan fulfilled study criteria. Seventy-three percent (n = 47) were in the Early group and 27% (n = 17) were in the Late group. None of the Early group had an increase in intracranial bleeding or deterioration on neurologic examination as a result of UFH administration. However, there was no statistical difference in VTE events between the two groups. CONCLUSION: Early use of UFH in the severe head injured patient does not increase bleeding complications.

Abbreviated Injury Scale↗

PubMedDate not supplied

Multiple focal nodular hyperplasia of the liver in a 21-year-old woman.

Focal nodular hyperplasia (FNH) is a relatively common condition, the diagnosis of which is now regularly made with diagnostic imaging. Cases of multiple FNH (more than four lesions) are rare, however, and the presence of numerous lesions may complicate the workup and diagnosis. We recently treated a young woman with multiple FNH. We report this case to highlight the clinical issues presented by this rare variant of a common benign hepatic disease.

Adult↗

PubMedDate not supplied

Next generation DNA vaccines for HIV-1.

We studied the effects of first generation HIV-1 plasmid vaccines in 167 individuals. The vaccines were very well tolerated and induced helper T cell responses in most vaccine recipients. However, the CTL responses were below a 20% response rate. Improvement in vaccine potency is an important goal of this technology and a central focus of our laboratory. To improve on these response rates, we used RNA optimized constructs pGag and pEnv). These vaccines express 20-100 fold better than first generation vectors. However, our studies support that additional enhancements are needed to further boost the immune response. We report that we can significantly enhance the induced CD8 effector cell response by including engineered B7 costimulatory molecules. We observed that B7.2 was more effective at driving cellular immune responses than B7.1 as a plasmid vaccine. We developed gene swaps and deletions between these two molecules. This manipulation resulted in a dramatically enhanced cellular immune response as measured by CTL, or ICC or Elispot. We have also explored the use of cytokines as plasmid vaccine adjuvants. We observed that IL-12 and IL-15 were effective as plasmid vaccine adjuvants. Interestingly, IL-15 appeared to allow T cell expansion in the absence of significant T cell help. Improvement of the immune response induced by plasmid vaccines can be engineered in multiple ways. Our studies show that both costimulation as well as cytokine signals can be harnessed for more potent vaccine development. These results have important implications for the design of vaccines for prophylaxis and therapy.

AIDS Vaccines↗