Biomedical subjects

J Wong

Publications and source records attributed to J Wong.

At least 91 records · Page 5Linked to original sources

PubMed2002

Selective plasma filtration for treatment of fulminant hepatic failure induced by D-galactosamine in a pig model.

BACKGROUND: Plasma exchange may be useful for treating patients with fulminant hepatic failure but during the procedure growth factors that are important for hepatic regeneration are discarded. Addition of a selective plasma filter to the plasmapheresis circuit could eliminate protein bound toxic substances and retain growth factors for hepatic regeneration. This process is called selective plasma filtration. AIMS: To determine if selective plasma filtration could be a useful treatment modality for fulminant hepatic failure. METHODS: The system was tested in five groups of pigs with fulminant hepatic failure induced by galactosamine: group I, diseased control group (n=5); group II, sham control, (n=6); group III, plasma exchange (n=6); group IV, treatment with AC-1770 selective plasma filter (n=7); and group V, treatment with AC-1730 selective plasma filter which had a smaller pore size than AC-1770 (n=7). Fresh pig plasma was given to replace filtered plasma in pigs of groups III, IV, and V. Treatment was initiated 48 hours after administration of 0.75 g/kg galactosamine. The efficacy of selective plasma filtration was assessed by survival rate and improvement in haematological, biochemical, and immunohistological parameters. RESULTS: Pigs treated with AC-1770 or AC-1730 selective plasma filters survived longer than the other groups (group I: 55 (10) hours; group II: 68 (7) hours; group III: 91 (10) hours; group IV: 269 (156) hours; group V: 950 (555) hours). One pig in group IV survived for 50 days; one pig in group V survived for 77 days and another pig in group V is still alive (>150 days). After treatment, plasma levels of aspartate aminotransferase, bilirubin, bile acid, ammonia, lactate dehydrogenase, and alpha-glutathione-S-transferase decreased. Substantial amounts of tumour necrosis factor alpha (TNF-alpha) and endotoxin were found in the filtrate. The selective plasma filtration groups retained significantly higher amounts of hepatocyte growth factor than plasma exchange alone. Similar TNF-alpha clearance was observed in the selective plasma filtration groups and the plasma exchange group. On day 4, significant improvement in liver function, as measured by the indocyanine green clearance test, was observed in groups IV and V but not in the other groups. A higher regeneration index of hepatocytes was also observed in the groups treated with AC-1770 and AC-1730 selective plasma filters. CONCLUSION: Selective plasma filtration improved survival time and expedited liver regeneration in pigs with fulminant hepatic failure.

Animals↗

PubMed2002

Living donor liver transplantation without the use of blood products.

We report on two patients who presented with unresectable hepatocellular carcinoma complicating hepatitis B liver cirrhosis. After evaluation, both patients were accepted for liver transplantation. Being aware of the scarce availability of cadaveric liver grafts and the long waiting time, family members volunteered to be donors for the two patients. Living donor liver transplantation using right lobe liver grafts, including the middle hepatic vein, was subsequently performed without the use of blood products in both the donors and recipients. All involved recovered uneventfully from their respective operations.

Carcinoma, Hepatocellular↗

PubMed2002

Ten-year experience with liver transplantation at Queen Mary Hospital: retrospective study.

OBJECTIVE: To report the experience with liver transplantation at the Queen Mary Hospital from 1991 to 2000. DESIGN: Retrospective study. SETTING: Liver transplant centre of a University teaching hospital, Hong Kong. PATIENTS: One hundred and forty-eight patients (127 adults and 21 children) who underwent a total of 155 liver transplants using 75 cadaver grafts (full-size, 67; reduced-size, 5; split, 3) and 80 living donor grafts (left lateral segment, 15; left lobe, 6; right lobe, 59) from October 1991 to December 2000 were reviewed. MAIN OUTCOME MEASURES: Graft and patient survival rate. RESULTS: The most common disease indications for liver transplantation were chronic hepatitis B-related liver disease (n=74) in adults and biliary atresia (n=14) in children. Eighteen patients had hepatocellular carcinoma. Forty-eight (31%) liver transplants (three ABO-incompatible) were performed in high-urgency situations for patients requiring intensive care. The proportion of living donor liver transplants was 47.7% in adults and 73.9% in children. The overall 1-year and 5-year patient survival rates were 82% and 77%, respectively. The survival of high-risk recipients, such as those with fulminant hepatic failure (80%), chronic hepatitis B (81%), or hepatocellular carcinoma (94%), was not inferior to that of other patients. CONCLUSION: Over the last decade, the promotion of (cadaver) organ donation through public education coupled with innovative techniques in living donor liver transplantation have enabled a liver transplantation programme to be established in Hong Kong with gratifying results.

Adolescent↗

PubMed2002

Standards of pancreaticoduodenectomy in a tertiary referral centre in Hong Kong: retrospective case series.

OBJECTIVE: To evaluate the perioperative outcomes of pancreaticoduodenectomy in a tertiary referral centre in Hong Kong. DESIGN: Retrospective case series. SETTING: University teaching hospital, Hong Kong. PATIENTS: One hundred and forty patients who underwent pancreaticoduodenectomy from July 1989 through June 2001. MAIN OUTCOME MEASURES: Mortality and morbidity. RESULTS: Overall hospital mortality among 140 patients was 2.9% (n=4), and 30-day operative mortality was 2.1% (n=3). There was no significant difference in the hospital mortality rate between 43 elderly patients aged 70 years or older and 97 younger patients (2.3% versus 3.1%). The overall morbidity rate was 38.6% (n=54). Intra-abdominal abscess (13.6%) and pancreaticojejunal anastomotic leakage (12.9%) were the two most common complications. Presence of co-morbid illness (risk ratio, 2.823; 95% confidence interval, 1.541-4.385; P=0.01), preoperative cholangitis (risk ratio, 2.565; 95% confidence interval, 1.166-5.643; P=0.02), and intra-operative blood loss >/=1.5 L (risk ratio, 2.236; 95% confidence interval, 1.132-6.213; P=0.03) were independent risk factors for postoperative morbidity. CONCLUSIONS: Pancreaticoduodenectomy is associated with a low risk of operative death when performed in a tertiary referral setting in Hong Kong. The postoperative morbidity rate remains high, however. Further improvement by reducing intra-operative blood loss may help curtail the high postoperative morbidity.

Academic Medical Centers↗

PubMed2002

Hepatic resection for colorectal liver metastases: prospective study.

OBJECTIVE: To assess the operative and long-term survival outcomes of hepatic resection for colorectal liver metastases during an 11-year period in a tertiary referral centre in Hong Kong. DESIGN: Prospective study. SETTING: University teaching hospital, Hong Kong. SUBJECTS AND METHODS: Between January 1989 and December 1999, 72 patients underwent hepatic resection for colorectal liver metastases. Clinical, pathological, and outcome data were prospectively collected and analysed. Factors affecting long-term survival were also evaluated. RESULTS: Twenty-five (34.7%) patients were found to have synchronous hepatic metastasis at the time of colorectal resection. Fifty-two (72.2%) patients underwent major hepatic resection. The operative morbidity and hospital mortality rates were 19% and 4%, respectively. The 5-year survival rate after hepatectomy was 31.9%. The median disease-free survival and median overall cumulative survival were 18.5 months and 30.8 months, respectively. On multivariate analysis, a high preoperative serum carcinoembryonic antigen level (>200 ng/mL) and tumour involvement of the resection margin at histology were the two independent risk factors that adversely affected survival outcome. CONCLUSION: Hepatic resection for colorectal liver metastases can be performed safely, with minimal operative mortality and acceptable morbidity, and results in satisfactory survival. High preoperative serum carcinoembryonic antigen level and histological involvement of resection margin by cancer adversely affect the survival outcome.

Adult↗

PubMed2001

The influence of interpatient and intrapatient rectum variation on external beam treatment of prostate cancer.

PURPOSE: The rectal dose/volume relationship and inherent variations thereof are fundamental parameters to guide dose escalation in prostate cancer treatment. This study evaluates the effect of rectal dose/volume variation on the risk of rectal complication for different planning target volume (PTV) constructions. METHODS AND MATERIALS: Thirty prostate patients with multiple daily CT scans obtained during the treatment course were included in this retrospective study. The dose distribution was calculated based on the pretreatment CT image alone. Treatment plans were generated by applying the four-field-box beam arrangement to each of three different PTVs: PTVs with 0.5-cm and 1.0-cm uniform margins, and a patient-specific PTV constructed using treatment imaging feedback. For each of the 30 patients, the rectal wall as manifested on each of multiple CT images was delineated after image bony registration to the pretreatment CT image, and applied to the corresponding treatment plan to obtain the rectal wall dose-volume histogram (DVH). Interpatient and intrapatient rectal dose/volume variations were quantified accordingly. The corresponding uncertainty and sensitivity of the risk of rectal complication to the variations were evaluated for each of the three PTVs. Finally, the efficacy of using multiple CT images to reduce uncertainty in planning evaluation was examined. RESULTS: Sensitivity of the risk of rectal complication to rectal dose/volume variation strongly depends on the clinical target volume (CTV)-to-PTV margin or prescription dose, or both. Compared to the conventional two-dimensional (2D) prostate cancer treatment, the sensitivity for a conformal treatment can be 3 times higher or more. Due to the interpatient rectal dose/volume variation, the individual normal tissue complication probability (NTCP) was distributed from 10% to 37% when a common prescription dose was applied for all patients. The intrapatient rectal dose/volume variation introduces at least +/- 25% uncertainty in the NTCP calculation for at least 10% or 25% of the patients treated with the PTV of 1.0- or 0.5-cm margin, respectively. These uncertainties were larger for the smaller PTV, with the standard deviation up to 20%. By applying multiple CT image feedback, the NTCP uncertainty could be reduced by a factor of 2. CONCLUSIONS: Shape and position variation of rectum has less influence on treatment planning in the conventional 2D treatment of prostate cancer. However, this influence is quickly growing with high treatment dose or small CTV-to-PTV margins. To reduce the variation and uncertainties in the treatment planning evaluation associated with the inter- and intrapatient rectal dose/volume variation, the iso-NTCP model and treatment image feedback technique can be applied in dose escalation trials of prostate cancer treatment.

Algorithms↗

PubMed2001

Estimating the contributions of mobile sources of PAH to urban air using real-time PAH monitoring.

Motor vehicles are a significant source of airborne polycyclic aromatic hydrocarbons (PAH) in many urban areas. Traditional approaches used in determining the relative contributions of individual vehicle types to the total amount of PAH in air have been based on the analysis of integrated samples of airborne particles and gases for the presence of chemical tracers indicative of the vehicles from which the chemicals derived. As an alternative, we have used a photoelectric aerosol sensor (PAS) capable of measuring PAH levels in real-time in the emissions plumes from motor vehicles. We placed the PAS near a traffic-light in Kenmore Square, a busy crossroads in downtown Boston (MA, USA). A video camera co-located at the site recorded the vehicles passing the sensor, and this record was correlated with the PAS data. During a 5-day monitoring period (approximately 59 h) in the summer of 1998, over 34,000 motor vehicles were counted and classified and over 24,000 PAS readings were recorded (frequency = 1/8.6 s). The composition of the vehicle population was 94% passenger vehicles, 1.4% buses, 2.6% small trucks, 1.3% medium trucks, 0.35% large trucks, and 0.45% garbage and construction trucks. In analyzing the PAS data, it was assumed that the highest PAS measurements--those that exceeded the 95% critical level of the 5-min moving average of all the PAS measurements--were indicative of primary vehicular emissions. We found that approximately 46% of the mass of particle-bound PAH (i.e. approximately 46% of the integrated area under the PAS signal vs. time plots) was attributable to primary emissions from motor vehicles passing the sensor. Of this, 35-61% was attributable to passenger vehicles (cars, pickup trucks, and sports utility vehicles) and 39-65% was attributable to non-passenger vehicles [buses (14-23%), small trucks (12-20%), medium trucks (8.4-14%), large trucks (2.9-4.8%) and garbage and construction trucks (1.9-3.2%)]. Our results suggest that on a per vehicle basis, buses and trucks--the majority of which run on diesel fuel--emitted greater amounts of particle-bound PAH than passenger vehicles. Overall, we found that real-time photoelectric aerosol sensing (in combination with video photography) is useful for estimating the contributions of airborne PAB from different vehicle types. Due to the physical constraints of our monitoring site and the high volumes of traffic, however, it was not possible to uniquely attribute PAS signals to individual vehicles.

Aerosols↗

PubMed2001

Isolation and characterization of the activated B-cell factor 1 homolog in Caenorhabditis elegans.

Members of the basic helix-loop-helix (bHLH) family of transcription factors regulate a wide array of developmental processes in many cell types, including cell fate specification, differentiation and morphogenesis. Our studies describe the cloning of a gene from the nematode Caenorhabditis elegans that is closely related to the vertebrate-activated B-cell factor (ABF) gene. The nematode gene product CeABF-1 was detected by northern blot analysis from RNA isolated from pooled nematodes representing different developmental stages. The developmental expression profile of CeABF-1 was shown by RT-PCR analysis to be predominantly expressed in the larval stages L3 and L4, with lower levels observed in the L2 larval stage and adult. We also show that CeABF-1 is capable of forming heterodimers with E2A proteins and binding E-box target sites. Mammalian cells transfected with CeABF-1 expression plasmids were capable of blocking E2A-mediated gene transcription, but full repression activity required the presence of two conserved amino acid residues found within the first helix of the CeABF-1 bHLH domain. These results suggest a conserved mechanism of gene repression between certain class II bHLH and class I bHLH proteins found in vertebrates and invertebrates.

Amino Acid Sequence↗

PubMed2001

Identification of gene clusters differentially expressed during the cellular injury responses (CIR) to cisplatin.

The goal of this study was to identify changes in mRNA levels in tumour cells after a toxic exposure to cisplatin (IC(99)dose). Using suppression-subtractive hybridization (SSH) 2 cDNA libraries were created, an UP library (202 cDNA fragments) and a DOWN library (153 cDNA fragments). Using reversed Northern hybridization 16 and 30 fragments were truly differentially expressed in the UP and DOWN libraries, respectively. Most prominent in the UP library were the mitochondrial and injury response clusters and in the DOWN library the cytoskeletal, protein synthesis and signalling clusters. These distinct clusters potentially represent an expression profile of the cisplatin-induced cellular injury response.

Antineoplastic Agents↗

PubMed2001

Sequential recruitment of steroid receptor coactivator-1 (SRC-1) and p300 enhances progesterone receptor-dependent initiation and reinitiation of transcription from chromatin.

Employing a cell-free chromatin transcription system that recapitulates progesterone receptor (PR)-mediated transcription in vivo, we have investigated further the coactivator functions of steroid receptor coactivator-1 (SRC-1) in terms of its functional domains as well as cooperation with other coactivators in PR transactivation. By analyzing wild-type and mutant SRC-1 with liganded PR in the chromatin transcription system in vitro, the basic helix-loop-helix/Per-Arnt-Sim domain, the p300-binding domain, and the carboxyl-terminal region (containing the PR-binding site) of SRC-1 were shown to be important for PR transactivation. Although in context of a synthetic promoter its histone acetyltransferase activity was nonessential for PR-mediated transcription, SRC-1 was observed to act synergistically with p300 to enhance PR transactivation from chromatin. Moreover, SRC-1 and p300 were found to function cooperatively to increase the efficiency of productive transcription initiation and reinitiation. Further analysis of synergism between SRC-1 and p300 revealed an obligatory "sequential" recruitment of SRC-1 and p300 to liganded PR. Efficient recruitment of p300 required the presence of SRC-1. In addition, functional analysis of SRC-2 and SRC-3 coactivators indicated that the SRC family modulated PR transactivation from chromatin by a similar mechanism.

Acetyltransferases↗

PubMed2001

Impaired cardiac functional reserve and left ventricular hypertrophy in adult sheep after prenatal dexamethasone exposure.

We have shown that exposure of pregnant ewes to dexamethasone (11.5 mg/d for 2 days) at 27 days of gestation (term, 150 days) led to increased blood pressure and cardiac output in adult offspring. In this study, we hypothesized that dexamethasone-induced hypertension is associated with left ventricular hypertrophy and a reduced cardiac functional reserve (CO(max-0)). Six control animals (group C) and five dexamethasone-exposed animals (group D) were volume-loaded with Hemaccel until the wedge pressure was 13 mm Hg (baseline). The wedge pressure was held constant during an infusion of dobutamine at incremental doses (0.4 to 12 microgram/kg/min) while blood pressure and cardiac output were measured. The same protocol was repeated in each animal 5 days later under mild general anesthesia (1.5% isoflurane), when transthoracic echocardiography (M-mode) was obtained. Group D showed a reduced CO(max-0) in response to dobutamine during both conscious (89+/-22 versus 150+/-25 mL/kg/min in control; P<0.01) and anesthetized states (91+/-38 versus 156+/-56 mL/kg/min in control; P<0.05). Reduced CO(max-0) in group D was associated with higher left ventricular mass index compared with group C (2.6+/-0.67 versus 1.8+/-0.51 g/kg; P<0.05). In addition, group D showed a reduced cardiac contractility reserve (FS(max-0)) in response to dobutamine (21+/-22% versus 54+/-34% in group C; P<0.05). An impaired cardiac functional reserve in group D was associated with increased left ventricular type I collagen content. In conclusion, brief prenatal exposure to dexamethasone led to the development of hypertension, left ventricular hypertrophy, and reduced cardiac functional reserve in adult life.

Animals↗

PubMed2001

Motivations and psychosocial impact of genetic testing for HNPCC.

A type of hereditary colorectal cancer (CRC) known as hereditary nonpolyposis colorectal cancer (HNPCC) is associated with MLHI and MSH2 gene mutations. This study consists of a pilot, cross-sectional study of 50 individuals who were engaged in the genetic testing process for HNPCC. The study investigated the motivations and attitudes around genetic testing and current psychosocial functioning through the use of standardized measures, as well as obtained information on disclosure patterns associated with test results. The mean age of the sample was 44.3 years. (SD = 15.0). Twenty-three individuals were identified as "carriers" (13 had a previous history of CRC), seven were "non-carriers" and 20 individuals were still awaiting test results. The primary motivations for participating in genetic testing were similar to previous reports and included: wanting to know if more screening tests were needed, obtaining information about the risk for offspring and increasing certainty around their own risk. The psychosocial scores demonstrated that a subgroup of individuals exhibited distress, with greater distress for those individuals awaiting results or testing positive. There was a high level of satisfaction associated with the experience of testing. Individuals in this study tended to disclose their test results to a variety of family and non-family members. Disclosure was primarily associated with positive experiences however, some individuals reported regret around disclosure of their results. These preliminary findings should be further explored in a larger prospective study design over multiple time points.

Adult↗

PubMed2001

Management of spontaneous rupture of hepatocellular carcinoma: single-center experience.

PURPOSE: To report the management of patients with spontaneous rupture of hepatocellular carcinoma (HCC) in a single center over a 10-year period and to evaluate a two-stage therapeutic approach. PATIENTS AND METHODS: A retrospective study was performed on all 1,716 patients with HCC who presented from 1989 to 1998. The two-stage therapeutic approach to manage ruptured HCC consisted of initial management by conservative method, hemostasis by transarterial embolization (TAE) or surgical means, followed by second-stage hepatic resection or transarterial oily chemoembolization (TOCE). Results of definitive treatment were compared with patients with no history of rupture during the same study period. RESULTS: During the study period, 154 patients (9%) had spontaneous HCC rupture. Initial intervention to control bleeding included TAE in 42 patients, surgical hemostasis in 35 patients, and conservative management only in 53 patients. The 30-day mortality rate was 38%. Independent factors on presentation affecting 30-day mortality were shock on admission, hemoglobin, serum total bilirubin, and known diagnosis of inoperable tumor. After initial stabilization and clinical evaluation, 33 patients underwent hepatic resection and 30 patients received TOCE. Median survival of the hepatectomy patients was 25.7 months; that of the TOCE patients was 9.7 months. Compared with patients with no rupture, survival after hepatectomy (25.7 months v 49.2 months, P =.003) was inferior but still substantially long, whereas survival after TOCE was comparable (9.7 months v 8.7 months, P =.904). CONCLUSION: Early mortality of spontaneous rupture of HCC was dependent on prerupture disease state, liver function, and severity of bleeding. Although it was a catastrophic presentation, prolonged survival could be achieved in selected patients with second-stage hepatic resection or TOCE.

Adult↗

PubMed2001

Improvement in dose escalation using the process of adaptive radiotherapy combined with three-dimensional conformal or intensity-modulated beams for prostate cancer.

PURPOSE: Advances in technology allow the creation of complex treatment plans with tightly conforming doses. However, variations in positioning of the organ/patient with respect to treatment beams necessitate the use of an appreciable margin, potentially limiting dose escalation in many patients. To (1) reduce this margin and (2) test the hypothesis that the achievable level of dose escalation is patient dependent, a patient-specific, confidence-limited planning target volume (cl-PTV) was constructed using an adaptive radiotherapy (ART) process for prostate cancer treatment developed in-house. The potential dose escalation achievable with this ART process is quantified for both conformal radiotherapy (CRT) delivery and intensity-modulated radiotherapy (IMRT) delivery. MATERIAL AND METHODS: Patients with organ confined prostate cancer were entered prospectively into an ART process developed in-house. This ART process has been designed to improve accuracy and precision of dose delivery, consequently enhancing dose escalation. In this process, a cl-PTV is constructed for each patient in the second week of treatment based upon on-line portal and CT images acquired during the first week of treatment. The treatment prescription dose, defined as the minimum dose to the cl-PTV, is selected based on predefined dose-volume constraints for rectum/bladder and derived from the pretreatment planning CT image. In addition, the treatment modality (CRT or IMRT) is determined based on the level of dose escalation achievable and the risk of inaccurate targeting. The potential for both dose escalation and the application of IMRT was evaluated by comparing the prescription doses delivered using the ART process, with the cl-PTV, to those in the traditional treatment process, with a conventional generic PTV. In addition, the distributions of potential geometric target underdosing and normal tissue overdosing were also calculated to evaluate the quality of the conventional treatment plans. RESULTS: One hundred and fifty patients have been treated with the ART process. When compared to the treatment dose delivered with the conventional treatment process (generic PTV), an average 5% (2.5--10%) more dose could be delivered using the ART process with CRT, and 7.5% (2.5--15%) more dose could be delivered with IMRT. Of the 150 patients, 70% were treated to a minimum cl-PTV dose > or = 77.4 Gy (81.3 Gy ICRU isocenter dose). Dosimetric analysis revealed that 81 Gy to the cl-PTV (or 86.7 Gy ICRU) could be prescribed to at least 50% of patients if IMRT was applied using the ART process. In contrast, IMRT did not yield an obvious dose escalation gain if patients were treated using the generic PTV. Our results also demonstrate that the cl-PTV is significantly smaller than the conventional generic PTV for most patients, with a mean volume reduction of 24% (range, 5--43%). CONCLUSION: These results support our hypothesis that the achievable level of dose escalation using ART is patient dependent. By using the ART process to develop a cl-PTV, one can (1) optimize the dose level, (2) increase the applicability of IMRT, and (3) improve the quality of dose delivery. The ART process provides the foundation to identify a suitable option (CRT or IMRT) for the delivery of a safe treatment and dose escalation. It is now our standard of practice for prostate cancer treatment.

Adenocarcinoma↗

PubMed2001

X-ray fluorescence mapping and micro-XANES spectroscopic characterization of exhaust particulates emitted from auto engines burning MMT-added gasoline.

The elemental distribution and compositional homogeneity in auto exhaust particulates emitted from methylcyclopentadienyl manganese tricarbonyl-(MMT-)added gasoline engines have been investigated using a newly installed synchrotron X-ray microprobe. Two representative groups of exhaust particulate matter, as defined in a recent bulk X-ray absorption fine structure (XAFS) spectroscopic study at the Mn K-edge, were studied. The micro-X-ray absorption near-edge structure (XANES) spectra indicate a relatively homogeneous distribution of phases within a given particulate sample, down to a spatial extent of 40 microm (the resolution of microprobe). The micro-XANES also enabled analysis of several areas which displayed compositions different from the bulk sample, supporting the general theory describing manganese species formation in the exhaust. The ability to evaluate small regions also enabled direct verification of manganese sulfate from the S XANES despite the vast excess of sulfur present in other forms. The presence of a chloride compound, introduced through the sample dilution air and engine intake air, was also revealed. The study demonstrates the value of the combined X-ray microfluorescence with excitation by polychromatic radiation for elemental mapping and micro-XANES spectroscopy for chemical speciation in the study of dilute environmental materials containing low-Z constituents such as Cl, S, and P.

Air Pollutants↗

PubMed2001

Genetic locus in mice that blocks development of atherosclerosis despite extreme hyperlipidemia.

The genes contributing to the common forms of atherosclerosis are largely unknown. One approach to dissecting complex traits such as atherosclerosis is to use animal models, such as the mouse, to map and characterize the genetic loci involved. We now report the identification of a locus for aortic lesion formation on mouse chromosome 6 that exhibits a highly significant lod score of 6.7 in a genetic cross between the susceptible strain, C57BL/6J, and the resistant strain, CAST/Ei. The locus was confirmed by constructing a congenic strain in which the chromosome 6 segment from CAST/Ei was transferred to a C57BL/6J background in a series of backcrosses. The congenic strain was almost completely resistant to diet-induced atherosclerosis. The chromosome 6 segment was also transferred onto the background of an LDL receptor-null mutation and resulted again in almost complete resistance to aortic lesion formation. This locus also influenced insulin levels but did not affect plasma lipoprotein levels, blood pressure, or body fat. The chromosome 6 gene, which we call Artles (for arterial lesions), did not affect endothelial cell responses to oxidized LDL, but lesion formation was partially reduced through bone marrow transplantation. The locus contains the candidate gene peroxisome proliferator-activated receptor-gamma, and the congenic mice exhibited significantly reduced expression of peroxisome proliferator-activated receptor-gamma.

Animals↗

PubMed2001

Clinicopathologic features of long-term survivors and disease-free survivors after resection of hepatocellular carcinoma: a study of a prospective cohort.

PURPOSE: This study aims to clarify the clinicopathologic features of long-term survivors and disease-free survivors after resection of hepatocellular carcinoma (HCC). PATIENTS AND METHODS: The clinicopathologic features of 5-year survivors and disease-free survivors were elucidated in a cohort of 230 patients prospectively observed for > 5 years (64 to 192 months) after curative resection of HCC. RESULTS: The incidence of 5-year overall and disease-free survivors were 37% (85 of 230) and 20% (45 of 230), respectively. Clinicopathologic features associated with 5-year survivors included female sex (P =.024), preoperative serum albumin > or= 40 g/L (P =.033), AST < 50 u/L (P =.001), tumor < 5 cm (P =.001), solitary tumor (P =.035), encapsulated tumor (P =.021), no venous invasion (P =.001), no microsatellite nodule (P =.001), and early pathologic tumor-node-metastasis (pTNM) stage (I or II, P <.001). Features favoring 5-year disease-free survivors were preoperative serum AST < 50 u/L (P =.007), tumor < 5 cm (P =.005), encapsulated tumor (P =.007), no venous invasion (P <.001), no microsatellite nodule (P =.001), and early pTNM stage (I or II, P <.001). By multivariate analysis, pTNM stage was the only significant predictive factor for both overall and disease-free survival. CONCLUSION: This study shows that long-term disease-free survival > 5 years after resection of HCC can be achieved in patients with favorable tumor characteristics. Early pTNM stage was the most reliable predictor of both long-term overall and disease-free survivors.

Adolescent↗

PubMed2001

Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor.

Acetylation of core histone tails plays a fundamental role in transcription regulation. In addition to acetylation, other posttranslational modifications, such as phosphorylation and methylation, occur in core histone tails. Here, we report the purification, molecular identification, and functional characterization of a histone H4-specific methyltransferase PRMT1, a protein arginine methyltransferase. PRMT1 specifically methylates arginine 3 (Arg 3) of H4 in vitro and in vivo. Methylation of Arg 3 by PRMT1 facilitates subsequent acetylation of H4 tails by p300. However, acetylation of H4 inhibits its methylation by PRMT1. Most important, a mutation in the S-adenosyl-l-methionine-binding site of PRMT1 substantially crippled its nuclear receptor coactivator activity. Our finding reveals Arg 3 of H4 as a novel methylation site by PRMT1 and indicates that Arg 3 methylation plays an important role in transcriptional regulation.

Acetylation↗