Biomedical subjects

L Fu

Publications and source records attributed to L Fu.

At least 91 records · Page 5Linked to original sources

PubMed1998

Human galactocerebrosidase gene: promoter analysis of the 5'-flanking region and structural organization.

Galactocerebrosidase (GALC; EC 3.2.1.46) is a lysosomal enzyme which hydrolyzes several galactolipids and the deficiency of GALC is responsible for Krabbe disease. Recently, we cloned cDNAs for human and murine GALC. In this study we characterized the genomic organization and the promoter of the human gene. The gene was about 60 kb in length and consisted of 17 exons as reported by Luzi et al. DNA sequence analysis showed that the 5'-flanking region of the first exon was GC-rich and had not typical TATA-box but ten GC-box-like sequences within a 200 bp sequence upstream from the initiation codon. Another inframe ATG, which has better Kozak consensus sequence, was found at 48 bp upstream to the first ATG reported]. Promoter analysis using a luciferase assay in COS 7 cells showed that the -149 to -112 nucleotide (from the initiation codon A) region has dominant promoter activity. In this region three GC-box-like sequence and one YY1 binding site were detected. Primer extension revealed several transcription start sites within the region of -146 to -103 nucleotide. In this study we firstly demonstrated that the YY1 binding site and subsequent GC-box-like sequences could be a promoter in a housekeeping gene.

Animals↗

PubMed1998

CD44V6 expression in human colorectal carcinoma.

CD44 is an adhesion molecule involved in cell-to-cell and cell-to-matrix interactions. This transmembrane glycoprotein exists in either standard or variant forms, originated by alternative splicing. One of the isoforms (CD44V6) has been shown, in some systems, to modify the metastatic potential of tumor cells. To investigate the role of this biomarker as possible prognostic antigen in colorectal cancer, we immunohistochemically analyzed the distribution of CD44V6 expression on formalin-fixed, paraffin-embedded tissues from resected colorectal cancers of 34 patients. The monoclonal antibody VFF7 against the amino acid sequence encoded by exon CD44V6 was applied using the avidin-biotin-peroxidase method. For each resected specimen, normal (N), adenomatous (AD), and carcinomatous (CA) colonic mucosa were tested. In 68% of the resected cases, these areas were present in the same slide, and in 76% of cases, nodal or liver metastases (MT) were available for evaluation. Adenomatous polyp biopsy specimens of 10 carcinoma-free patients were also tested. In selected cases, CD44V6 expression was also determined using the Western blot immunoprecipitation technique. CD44V6 immunoreactivity was detected in 100% of the ADs, and in 91% of CAs, but was mostly weak in only 38% of MTs (n=26). In 49% (n=35) of ADs, 11% (n=34) of CAs, and 4% of MTs (n=26), the stain was moderate to strong. CD44V6 immunoreactivity was predominantly membranous in ADs and cytoplasmic in MTs. In the CAs, both staining patterns were noted. Interestingly, the normal mucosa had a weak subnuclear localization of the stain. In the cases evaluated by Western blotting immunoprecipitation analysis, the level of CD44V6 protein expression was similar to that obtained by immunohistochemistry. No correlation was found with tumor type, stage, or patient survival. The predominant CD44V6 expression in ADs and CAs, but not in MTs, suggests that, in many cases, the expression of this adhesion molecule may be lost during the acquisition of migratory function by the tumor cells.

Adenocarcinoma↗

PubMed1998

Prognostic significance of p53, bcl-2, vimentin, and S100 protein-positive Langerhans cells in endometrial carcinoma.

Immunohistochemical expression of p53, Bc12, vimentin, and S100 protein-positive Langerhans cell was evaluated in 50 endometrial carcinomas (6 stage I, 14 stage II, 20 stage III, and 10 stage IV), in an attempt to use these markers as predictors of survival. Monoclonal antibodies to p53, Bcl-2, vimentin, and S100 proteins were applied to paraffin-embedded sections of endometrial adenocarcinoma, using the avidin-biotin peroxidase complex technique (ABC). All 20 patients with stage I and II carcinomas were alive with a mean follow-up of 3 years. Of 30 patients with stage III and IV carcinomas, 13 died of tumor (3-year survival, 57%; SE, 10%), eight were alive with tumor, and nine were alive with no evidence of tumor (mean follow-up, 46 months). Strong p53 positivity was present in 11 carcinomas (22%), including nine high-stage and two low-stage tumors. Bcl-2 positivity was identified in 33 tumors (66%). These tumors were mostly low stage; however, no correlation was found between Bcl-2 expression and prognosis. Vimentin positivity (P < .001), and tumor infiltration by a large number of S100 protein-positive Langerhans cells (P < .05) were associated with low-stage tumors. Vimentin was expressed in 23 carcinomas, including 70% of low-stage tumors and 20% of high-stage tumors. Most high-grade carcinomas were Langerhans cell depleted; most low-grade carcinomas showed >50 S100 protein-positive Langerhans cells/10 high-power fields. Our results indicate that Langerhans cell infiltration and vimentin positivity of tumor cells are favorable prognostic factors in endometrial carcinomas.

Adenocarcinoma↗

PubMed1998

Imaging axonal damage of normal-appearing white matter in multiple sclerosis.

The current study was designed to determine the relative distribution of decreases of N-acetylasparate (NAA), a marker of axonal damage, between lesions and normal-appearing white matter of patients with established multiple sclerosis and to test for associations between changes in the ratio of NAA to creatine/phosphocreatine (NAA:Cr) in those compartments and changes in disability. Data were collected from a 30-month longitudinal study of 28 patients with either a relapsing course with partial remissons and no progression between attacks (relapsing/remitting) (11 patients) or a course of progressively increasing disability, following a period of relapsing/remitting disease (secondary progressive) (17 patients). Proton magnetic resonance spectroscopic imaging (MRSI) and conventional MRI examinations were performed at 6-8-month intervals with concurrent clinical assessments of disability. General linear models were used to test associations between MRSI, MRI, lesion volume and clinical data. Analysis confirmed that the NAA:Cr ratio is lower in lesions than in the normal-appearing white matter (-15.3% in relapsing/remitting multiple sclerosis and -8.8% in secondary progressive multiple sclerosis). The lower NAA:Cr ratio per unit lesion volume previously observed for secondary progressive relative to relapsing/remitting patients was found to result from a lower ratio (8.2%, P < 0.01) in the normal-appearing white matter rather than from any differences within lesions. The importance of changes in the normal-appearing white matter was emphasized further with the observation that the NAA:Cr ratio in the normal-appearing white matter accounted for most of the observed 15.6% (P < 0.001) decrease in the NAA:Cr ratio in the brains of relapsing/remitting patients over the period of study. The decrease in the NAA:Cr ratio in normal-appearing white matter correlated strongly (P < 0.001) with changes in disability in the relapsing/remitting subgroup. These results add to data suggesting that axonal damage or loss may be responsible for functional impairments in multiple sclerosis. The accumulation of secondary axonal damage in the normal-appearing white matter may be of particular significance for understanding chronic disability in this disease.

Aspartic Acid↗

PubMed1998

Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study.

It has been difficult to establish a strong correlation between total brain T2-weighted lesion volume on MRI and clinical disability in multiple sclerosis, in part because of the lack of pathological specificity of T2-weighted MRI signal changes. Proton magnetic resonance spectroscopy studies have shown that measurements of the resonance intensity of N-acetylaspartate (which is localized exclusively in neurons and neuronal processes in the mature brain) can provide a specific index of axonal damage or dysfunction. Here we report a 30-month longitudinal study of 29 patients with multiple sclerosis who had either a relapsing or a secondary progressive clinical course. Conventional brain MRI and single-voxel proton magnetic resonance spectroscopy examinations were obtained at intervals of 6-8 months with concurrent clinical evaluation. At the onset of the study, the brain N-acetylaspartate:creatine resonance intensity ratio was abnormally low for the whole group of patients (control mean = 2.93 +/- 0.2, patient mean = 2.56 +/- 0.4, P < 0.005). There were no significant differences between the relapsing and secondary progressive subgroups. Over the follow-up period, there was a trend towards a decrease (8%) in the brain N-acetylaspartate:creatine ratio for the 11 relapsing patients and a significant (P < 0.001) correlation between changes in the brain N-acetylaspartate:creatine ratio and expanded disability scale scores for the patients in this group. This correlation was even more evident for the patients who had clinically relevant relapses during the 30 months of follow-up (seven of 11 patients). Increases in T2-weighted lesion volumes (35% in 30 months for the group as a whole, P < 0.0001, without differences between the subgroups) did not correlate with disability either in the group of patients as a whole or in the different subgroups. We conclude that indices of axonal damage or loss such as brain N-acetylaspartate may provide a specific measure of pathological changes relevant to disability. Total T2-weighted lesion volumes, although more sensitive to changes with time than brain N-acetylaspartate, may be less relevant to understanding the progression of disability.

Aspartic Acid↗

PubMed1998

Clinicopathologic features and incidence of invasive lobular carcinoma in Japanese women.

Intending to clarify the true incidence of invasive lobular carcinoma of the breast in Japanese women as well as the frequency of unilateral multicentricity, 362 cases of clinically defined monocentric breast cancer without pre-operative biopsy (previously fine needle aspiration or needle biopsy were routinely carried out for every case) were examined by whole mammary gland serial sectioning. On the basis of pathology and the World Health Organization classification of breast tumors, each case was assigned to one of two main histologic types: invasive lobular carcinoma (ILC) or invasive ductal carcinoma (IDC). Invasive lobular carcinoma was further separated into classic and variant types by employing previously published criteria. Twenty-one cases of ILC (5.8%) were diagnosed, which is more than in most previous Japanese studies. Unilateral multicentric breast carcinoma was detected in 9.5% of ILC and 16.1% of IDC (the difference was found not significant). Microscopically, ILC tumors were found to be, on average, larger than IDC. Patients with classic type ILC tended to be younger than those with variant type or IDC. Estrogen receptor expression was found more frequently in variant type ILC than in classic type. These results suggest that the incidence of invasive lobular carcinoma of the breast in Japanese women is low and that unilateral multicentricity is not significantly higher in ILC than in IDC.

Adult↗

PubMed1998

Neuropeptides mediate the ozone-induced increase in the permeability of the tracheal mucosa in guinea pigs.

We examined the effects of acute exposure to ozone on the permeability of the tracheal mucosa and the contribution of neural pathways to the effects of ozone using horseradish peroxidase (HRP; mol wt 40,000) as a marker of lumen-to-blood transfer of a macromolecule in guinea pigs in vivo. Each guinea pig was anesthetized and exposed for 30 min to either ozone [0.5 or 3 parts/million (ppm)] or air. Immediately after exposure, a tracheal segment was isolated between two polyethylene cannulas in vivo and filled with HRP solution (50 mg/ml). Blood samples were drawn before and 10, 20, 30, and 40 min after the intratracheal instillation of HRP. The plasma levels of HRP in guinea pigs exposed for 30 min to 3 ppm of ozone, but not to 0.5 ppm of ozone, were significantly greater than those in guinea pigs exposed to air. Although the increased plasma HRP levels after exposure to 3 ppm of ozone were unaffected by propranolol or atropine, they were completely inhibited by pretreatment with capsaicin (50 mg/kg sc, injected in two doses). These results suggest that endogenous neuropeptides mediate the ozone-induced increase in the permeability of the tracheal mucosa in guinea pigs in vivo, but neither an adrenergic nor a cholinergic pathway appears to be involved.

Animals↗

PubMed1998

Chemokine receptors in the human brain and their relationship to HIV infection.

Chemokine receptors have been recently identified as the important co-factors which in conjunction with CD4, mediate entry of HIV into its target cells. The brain is one of the most prominent targets of HIV infection, where it leads to HIV encephalitis (HIVE) and HIV-associated dementia. Knowledge of the distribution, physiology, and pathology of chemokines and chemokine receptors in the human brain is fundamental for understanding the pathogenesis of the interaction between HIV and the central nervous system (CNS). There is also increasing evidence that chemokine receptors expression in the CNS increases during pathological, especially inflammatory, conditions. The major co-factors for HIV infection, CCR5, CCR3, and CXCR4 have been detected in the human brain in a variety of cell types including microglia, astrocytes, neurons, and vascular endothelial cells. Furthermore, antibodies to chemokine receptors can also block HIV infectivity in cultured CNS cells. This indicates that chemokine receptors are likely to have a functional role in the pathogenesis of HIVE.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Transsphenoidal microsurgical removal of large pituitary adenomas.

OBJECTIVE: To retrospectively analyze the diagnostic modes, transsphenoidal microsurgical technique and outcomes of 145 patients with pituitary macroadenoma or giant pituitary adenoma. METHODS: A total of 145 patients suffering from pituitary macroadenoma or giant pituitary adenoma with suprasellar extension were performed with transsphenoidal microsurgery in our department. Diagnoses were made by CT or MRI scanning. All adenomas had suprasellar extension (extension size: > 10 mm). Operations were performed via either sublabio-septo-sphenoidal approach or naso-vestibulo-sphenoidal approach under microscope. During operation, a subarachnoid catheter was inserted into the lumbar cistern, via the catheter saline was slowly injected to increase the intracranial pressure (ICP) and to deliver the suprasellar tumor into the operative field for easy removal. RESULTS: The gross total removal of adenoma in 102 patients (70.4%) and subtotal removal in 35 patients (24.1%) were achieved; partial removal was carried out in the remaining 8 patients (5.5%) with fibrous or dumbbell-shaped adenomas. There were no deaths after surgery. Long-term follow-up observation (median: 3.5 years) in 132 patients revealed good recovery in 93 (70.5%) and late recurrence in 39 (29.5%). Those patients with tumor recurrence underwent reoperation, drug therapy, radiotherapy, and radiosurgery either alone or in combination. CONCLUSION: Except for fibrous and dumbbell-shaped ones, microsurgical technique via transsphenoidal approach is a safe and effective way to remove large pituitary adenomas.

Adenoma↗

PubMed1998

[Pressure control system for the hermetically sealed cabin of the recoverable satellite].

There are many precision instruments and equipment for scientific researches and experiments in the hermetically sealed cabin of satellite. Appropriate pressure must be controlled in the cabin in order to ensure the instruments and equipment from the adverse space environment. This paper describes a pressure control system for the hermetically sealed cabin in the recoverable scientific detect and experimental satellite. The cabin pressure is regulated automatically into the specific levels by venting or supplying the air from or to the cabin during launch, on orbit and before reentry of the satellite. The system has low mass, low power consumption and high reliability. It was used successfully in the recoverable satellite first in September 1987 and had been used many times since then. It is the first active pressure control system for the hermetically sealed cabin of the satellite in China.

Atmospheric Pressure↗

PubMed1998

[Endovascular treatment of intracranial aneurysms with GDC: report of 8 cases].

OBJECTIVE: To assess the usefulness and practical experience in intracranial aneurysm embolization with guglielmi detachable coil (GDC) applied firstly in China. METHOD: Under general anesthesia and systematic anticoagulation, eight cases of intracranial aneurysms were embolized with GDC which was introduced by tracker micro-catheter, combined remodeling technique (RT) if necessary. RESULT: 100% occlusion was achieved in 5 cases, 95% in 2 and 90% in 1, without any complication. Among these cases, 4 failed in the previous attempts of endovascular treatment with mechanical detachable system (MDS), because MDS could not be safely and totally placed inside the aneurysms and Mag 3F/2F micro-catheter could not be navigated into the aneurysms. CONCLUSION: Embolization of intracranial aneurysms with GDC is safe, effective and reliable, and it may offer the cure opportunity to those enearysms which are very dangerous to embolize or can not be embolized with MDS.

Adult↗

PubMed1998

[Multiple dose pharmacokinetic and bioavailability studies of oral sustained release and conventional formulations of isosorbide-5-mononitrate in healthy volunteers].

The pharmacokinetics of a new sustained release tablets (40 mg, qd) of isosorbide-5-mononitrate (IS-5-MN) was investigated together with a conventional preparation (20 mg, bid) after multiple oral administration in ten healthy human subjects using an open, randomized two-way crossover experimental design. Based on three statistical analyses of the area under the plasma concentration-time curve (AUC), the two tablet formulations are judged to be bioequivalent (P > 0.1), with a relative bioavailability of 108.95% for the IS-5-MN sustained release formulation. Pharmacokinetic data showed that the sustained release formulation reached mean peak plasma levels significantly later and lower minimum plasma concentration (Cmin), compared with the conventional preparation. But no statistically significant difference was found for other pharmacokinetic parameters including peak plasma levels (Cmax), AUC, elimination constant (Ke), elimination half-life (T1/2) and fluctuation index (FI) between the two preparations (P > 0.05).

Adult↗

PubMed1998

Elevated c-Src protein expression is an early event in colonic neoplasia.

The molecular events regulating the development and progression of colonic neoplasia are currently being delineated. Recent studies have implicated c-Src protein kinase activation as an early event in the malignant transformation of colonic epithelial cells. However, increased c-Src activity has also been reported in colon carcinomas as well as in metastatic hepatic and extrahepatic colon carcinomas. To further investigate the potential role of c-Src in the progression of colonic neoplasia, we analyzed c-Src levels by immunohistochemistry in 27 colorectal resection specimens. Mouse monoclonal antibody to c-Src protein was applied to 3-micron sections from formalin-fixed, paraffin-embedded tissues using the avidin-biotin-peroxidase method. The combination of adenomatous (AD) and adjacent carcinomatous mucosa (CA) specimens were present in 20 of 27 patients. In 15 cases, synchronous metastatic (MT) lesions were available for evaluation. Strong c-Src expression was evident in 95% of AD (n = 20), in contradistinction to 32% of MT (n = 19) and 14% of CA (n = 22). Weak-to-moderate c-Src expression was seen in adjacent normal colonic mucosa (NM) in 96% of cases. Signed rank test univariate analysis revealed a statistically significant difference in c-Src expression between NM/AD (p = 0.0001), NM/CA (p = 0.0001), NM/MT (p = 0.0006), AD/CA (p = 0.0001), and AD/MT (p = 0.0002). No significant correlation between levels of c-Src expression and patient survival, tumor size, histologic grade, or tumor configuration was observed using the Cox's Regression Model. Similar results were obtained by analysis of c-Src protein levels and c-Src kinase activity as measured by Western blot and in vitro kinase assays of representative cases. Our results indicate that: (a) elevated c-Src expression is an important early event during colorectal carcinogenesis; (b) its activation may be involved in tumor progression in a subset of colonic carcinomas; and (c) additional molecular events are necessary for invasion to occur.

Adult↗

PubMed1998

Single and multiple dose pharmacokinetic studies of oral sustained release and non-sustained release formulations of isosorbide-5-mononitrate in healthy volunteers.

The pharmacokinetics of a new sustained release tablet (40 mg, "test") of isosorbide-5-mononitrate (CAS 16051-77-7, IS-5-MN) was investigated together with a reference preparation (20 mg, "reference") after single and multiple oral administration in ten healthy human subjects using an open, randomised two-way crossover experimental design. Based on the statistical evaluation of the area under the plasma concentration-time curve (AUC), the two tablet formulations are judged to be the same with regard to the amount absorbed. Pharmacokinetic data showed that with the test tablet significantly lower and delayed mean peak plasma levels (Cmax) were reached compared with the reference preparation in both single and multiple dose studies. The test formulation also produced lower minimum plasma concentration (Cmin). However, there was no statistically significant difference for other pharmacokinetic parameters, including the elimination rate constant (Kel), the elimination half-life (t1/2) and the peak-trough fluctuation constant (PTF) between the two treatments. It was demonstrated that the new sustained release formulation of isosorbide-5-mononitrate could be useful in clinical practice for the treatment of angina pectoris and congestive heart failure.

Adult↗

PubMed1997

Activation of c-Src by receptor tyrosine kinases in human colon cancer cells with high metastatic potential.

Recent data suggest that signal transduction may have a critical role in the development and regulation of the metastatic phenotype. Here, we investigated the role of c-Src activation in the process of human colon cancer metastasis to the liver. Our data, derived from two different sets of human colon cancer cell line metastatic variants, suggest that not only do highly-metastatic cells display constitutively elevated c-Src protein kinase activity when compared to poorly metastatic cells, but also that receptor tyrosine kinases participate in the ligand-activation of c-Src above basal levels. Specifically, the epidermal growth factor receptor (EGFR), p185HER2/Neu and the hepatocyte growth factor receptor (c-Met) appear to be linked to the process because they preferentially activate c-Src in highly-metastatic cells. EGFR was found to associate with c-Src in colon cancer cells and specific inhibitors of the EGFR resulted in a reduction of c-Src activity to basal levels. In addition, c-Src transfectants displayed partially-activated EGFRs, suggesting a feedback role for c-Src in the regulation of the EGFR. p185HER2/Neu was also identified in immunocomplexes of c-Src following ligand activation of the EGFR, but only in highly-metastatic cells. Collectively, these observations suggest a paradigm whereby c-Src interacts with multiple cell-surface growth factors in a catalytic fashion for the development of tumor cells with metastatic potential.

Colonic Neoplasms↗

PubMed1997

The effects of angiotensin II and specific angiotensin receptor blockers on embryonic cardiac development and looping patterns.

The role of angiotensin II (Ang II) in the early embryonic development of the heart has not been examined. We have used RT-PCR to identify mRNA for angiotensinogen, angiotensin-converting enzyme, and the Ang II AT1 and AT2 receptors in embryonic day 10.25 Sprague-Dawley rats, and have used confocal microscopy to localize the AT1 receptor to the greater curvature of the developing ventricle in these animals at embryonic days (ED) 9.25 and 10.25. The antibodies used in immunolocalization studies did not distinguish between the AT1a and AT1b receptor subtypes. In whole embryo culture, Ang II added to the culture media resulted in increased ventricular growth and myocyte hypertrophy when treated embryos were compared to cultured littermate controls. Use of Losartan and PD123,319 to block the Ang II AT1 and AT2 receptors resulted in reduced ventricular development and cardiac dilation when compared to control and Ang II-treated embryos. Addition of Ang II and PD123,319 to the culture media also resulted in cardiac loop inversions which may be associated with disruption of normal myofibrillar development. These results clearly indicate an important role for Ang II in the early embryonic development of the heart.

Actins↗

PubMed1997

Participation of the human p53 3'UTR in translational repression and activation following gamma-irradiation.

p53 protein levels have been shown to increase in a number of cells after treatment with genotoxic agents through a post-transcriptional mechanism. In gamma-irradiated human cells, the accumulation of p53 protein is accompanied by an increase in the association of p53 mRNA with large polysomes without any change in the level of p53 mRNA. This redistribution of p53 mRNA on polysomes in response to irradiation is consistent with enhanced translational activity of p53 mRNA. We demonstrate that a region of the p53 3'-untranslated region (3'UTR) inhibits translation of a chimeric reporter mRNA in vivo. Induced elevation of reporter activity after gamma-irradiation was seen in cells expressing chimeric reporter-p53 3'UTR transcripts. These data taken together demonstrate translational control of p53 gene expression after gamma-irradiation and denote a previously unsuspected and novel role for the p53 3'UTR in controlling translation.

Gamma Rays↗

PubMed1997

A hematopoietic cell L-selectin ligand exhibits sulfate-independent binding activity.

L-selectin is a leukocyte cell-surface glycoprotein that mediates adhesive interactions between circulating cells and vascular endothelium. All endothelial ligands of L-selectin characterized to date are glycoproteins that require sulfation for activity and share reactivity with MECA 79, a monoclonal antibody that recognizes a sulfate-dependent epitope involved in L-selectin attachment. We have recently identified by functional assay a glycoprotein L-selectin ligand expressed on the human hematopoietic cell line KG1a. We report here that this ligand is not recognized by MECA 79 and that it retains binding activity after metabolic inhibition of sulfation by chlorate. A native membrane L-selectin ligand exhibiting sulfate-independent function has not been described previously. Identification of this novel ligand on a nonendothelial cell type suggests that structural determinants conferring L-selectin binding may vary in a cell- and tissue-specific manner.

Animals↗