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Biomedical subjects

L Shan

Publications and source records attributed to L Shan.

At least 55 records · Page 3Linked to original sources
PubMed1998

Overexpression of p53 protein correlates with a high risk of malignant transformation of adenomas in patients with multiple colorectal adenomas.

To assess the correlation of p53 oncoprotein expression with the high risk of developing carcinomas in patients with multiple colorectal adenomas, 25 cases with histologic carcinoma in adenoma (CIA) were examined by immunohistochemistry using a monoclonal antibody specific to human p53 protein (wild and mutant). The 25 cases were classified into multiple and single groups. The former contained 13 cases with synchronous multiple colorectal adenomas (one to six adenomas) and adenocarcinoma. The latter included 12 cases with single CIA only. This study revealed an overall incidence of 57.14% of p53 overexpression in carcinomatous lesions and 31.9% in adenomatous lesions, which was statistically significant (P < 0.05). The carcinomatous lesions showed a diffuse staining pattern, whereas the adenomatous lesions showed a focal pattern. A significant finding was that the incidence of p53 overexpression was significantly higher in multiple groups (81.25%) than in single groups (31.43%) in the carcinomatous (P < 0.01) rather than in the adenomatous (P < 0.05) lesions. There were no correlations between p53 overexpression and proliferation activity or carcinoembryonic antigen expression. The results indicate that p53 abnormality may be an important genetic factor responsible for the high risk of developing carcinomas in patients with multiple adenomas.

Adenoma↗
PubMed1998

Genetic alterations in primary and secondary hyperparathyroidism.

Hyperparathyroidism refers to a term representing a wide spectrum of parathyroid disorders that are characterized by the increased production of parathyroid hormone. Hyperparathyroidism was once thought to be rare but is now more commonly recognized, affecting 1 in 500 women over 40 years of age. Yet the interpretation of parathyroid pathology is still controversial and confusing. Over the past 10 years, genetic changes (ret and menin genes) involved in the pathogenesis of MEN 2 and MEN 1 have been discovered in succession. Different mutations of the calcium-sensing receptor gene have been identified in neonatal severe hyperparathyroidism and familial hypocalciuric hypercalcemia, respectively. The HRPT 2 gene responsible for the development of hereditary hyperparathyroidism and jaw tumors has been localized on the 1q21-31 locus. Several genetic alterations have also been characterized in primary and secondary hyperparathyroidism. Different genetic alterations appear to involve the development of different types of hyperparathyroidism. These novel advances give us new insights into the pathogenesis of hyperparathyroidism and allow better differentiation between the different types of parathyroid disorders.

Adult↗
PubMed1998

Pulmonary capillary hemangiomatosis: a unique feature of congestive vasculopathy associated with hypertrophic cardiomyopathy.

A 34-year-old man with an 18-year history of hypertrophic cardiomyopathy died of worsening right-sided heart failure. Central venous pressure was greatly increased to 25 cm H2O before death. Postmortem examination revealed features of severe congestive vasculopathy, including those of pulmonary capillary hemangiomatosis in the lungs. Marked proliferation of capillaries was seen chiefly in alveolar septa and extending into pulmonary veins and arteries, causing severe luminal occlusion with recanalization. Diffusely distributed intra-alveolar edema and hemorrhage with collections of hemosiderin-laden macrophages were also seen, which suggested that the pulmonary capillary hemangiomatosis was associated with longstanding chronic passive congestion of the lung. It is possible that severe pulmonary passive congestion may be one of the causes of development of idiopathic pulmonary capillary hemangiomatosis.

Adult↗
PubMed1998

Somatic mutations of multiple endocrine neoplasia type 1 gene in the sporadic endocrine tumors.

Endocrine tumors of the parathyroid and pancreas are encountered either as sporadic type or as part of multiple endocrine neoplasia type 1 (MEN 1). A high frequency of the loss of heterozygosity (LOH) has been observed in tumors of the sporadic type in the locus of the MEN 1 gene, which has recently been cloned and designated the menin gene. It would be of great interest to determine whether somatic mutations in the menin gene are responsible for the sporadic endocrine tumors. For this purpose, we have investigated the menin gene mutations in 21 sporadic parathyroid adenomas, 2 parathyroid carcinomas, 4 sporadic insulinomas, and 1 malignant VIP (vasoactive intestinal polypeptide)oma with WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome, using PCR-single strand conformation polymorphism analysis and DNA sequencing. In none of these cases did the patient have a family history or other possible association with MEN 1. We have discovered somatic point mutations in two parathyroid adenomas (A340T and A541T), in one insulinoma (T429K), and in the malignant VIPoma (W198X). In addition, we have found two polymorphisms (D418D and V367V) in two parathyroid carcinomas and two parathyroid adenomas. Of these mutations and polymorphisms, three (A340T, T429K, and V367V) are first reported here, in the present article. Our results indicate that somatic mutations of the menin gene are responsible for a proportion of the sporadic parathyroid adenomas and pancreatic islet cell tumors.

Adenoma↗
PubMed1997

Comparative analysis of clonality and pathology in primary and secondary hyperparathyroidism.

Parathyroid adenoma and hyperplasia are the most common causes for hyperparathyroidism, and distinction between them is controversial based on the current criteria for pathological diagnosis. We studied the clonality of hyperparathyroidism and its correlation with the pathological features, analysing 39 female patients with hyperparathyroidism. Clonality was successfully detected in 12 heterozygous cases by PCR amplification of PGK-1 gene. The 12 cases yielded 14 hypercellular glands, 8 affected by primary and 6 by secondary hyperparathyroidism. The results revealed that 7 of the 8 glands with primary hyperparathyroidism showed monoclonal proliferation. Only 1 gland pathologically diagnosed as adenoma showed a polyclonal pattern. In the 4 cases with secondary hyperparathyroidism, at least one monoclonal tumour was detected in each case. Our data indicate that monoclonal tumours are more common than expected in both primary and secondary hyperparathyroidism. Monoclonal tumours and polyclonal hyperplasia can co-exist in the same patient. Comparative study of the clonality and the pathological features showed that the clonality was consistent with the diagnosis of parathyroid adenoma, whereas it was in conflict with the diagnosis of hyperplasia with multigland involvement. One of the reasons for this is that we are ignorant of the true natures of hyperparathyroidism with multigland involvement.

Cell Line↗
PubMed1997

Allelic variants of human calcitonin receptor in the Japanese population.

Evidence from cDNA cloning has shown that calcitonin receptors (CTRs) have seven potential transmembrane domains. In this study, structural analysis of CTRs from ten cultured human tumor cell lines and 117 human blood samples demonstrated allelic variants at the 1377th nucleotide in intracellular domain 4, expressing either proline or leucine as the 463rd amino acid. It was found that the variant with proline at this site was the more prevalent type of CTR among the Japanese population.

Alleles↗
PubMed1997

Detection of Epstein-Barr virus DNA in gastric carcinoma with lymphoid stroma.

Gastric carcinoma with lymphoid stroma (GCLS) was considered to be one of the virus-associated neoplasms. However, the precise mechanism of Epstein-Barr virus (EBV) oncogenesis for GCLS remains unclear. We used polymerase chain reaction (PCR) and DNA in situ hybridization (ISH) methods to detect the presence of EBV DNA in 14 cases of gastric carcinoma, including 8 cases of GCLS. Epstein-Barr virus DNA was detected by both PCR and ISH in 3 of the 8 GCLS cases (37.5%) and was negative in the other 6 cases of non-GCLS. In situ DNA hybridization showed that the EBV DNA was in the carcinoma cells in all cases that were positive by PCR. Among the positive cases, one early gastric carcinoma showed that EBV DNA was not only in the carcinoma cells, but also in the normal epithelium. This study provides the interpretation of the finding of EBV DNA in nonneoplastic gastric epithelium. Some genetic changes may be initiated in the EBV-infected nonneoplastic cells, which would lead to oncogenesis.

DNA, Viral↗
PubMed1997

Synchronous and metachronous multicentric squamous cell carcinomas in the upper aerodigestive tract.

A rare case is presented of a 57-year-old Japanese male with synchronous and metachronous multicentric squamous cell carcinomas (SCC) in the upper aerodigestive tract. During a 9-year-period from the appearance of first primary SCC to autopsy, 14 foci of primary SCC and one severe dysplasia developed in succession in the thoracic esophagus, oral floor, soft palate, uvula, lingual radix, piriform recess, hypopharynx, cervical esophagus, trachea and lingual body. The patient died of severe bronchopneumonia due to Gram-negative bacterial infection that developed as a result of recurrent nerve paralysis. Human papilloma virus and Epstein-Barr virus, which are risk factors, were not detected by immunohistochemistry or by the polymerase chain reaction method. Genetic analysis revealed the absence of point mutations in K-ras codon 12. Heavy consumption of alcohol and excessive smoking may have been responsible for the multicentric carcinogenesis. This is the first case report in the literature of the development of so many primary SCC lesions in the upper aerodigestive tract during such a short period.

Carcinoma, Squamous Cell↗
PubMed1997

A simple approach to single-cell microdissection and molecular analysis.

OBJECTIVE: To develop a simple approach to single-cell microdissection from Papanicolaou-stained smears and to determine its usefulness in molecular diagnosis using archival cytologic material. STUDY DESIGN: Culture cells from three cell lines (TT, A549 and Lu65) were used to prepare Papanicolaou-stained smears. Mount-Quick, a mounting medium, was used to establish the method of sorting target single cells from smear slides under direct microscopic observation. Calcitonin receptor gene and codon 12 of the K-ras oncogene were amplified to check the application of single-cell genetic analysis in cytology. RESULTS: The target single cell could be simply sorted from Papanicolaou-stained smears using the Mount-Quick microdissection technique. Boiling in water was more suitable for preparing DNA from a single cell or from fewer than five cells versus other methods. Analysis of calcitonin receptor gene and K-ras codon 12 demonstrated that molecular analysis was applicable to a single cell or a few cells from archival Papanicolaou-stained smears. CONCLUSION: This approach has significant implications for cytology: (1) it circumvents the limitations of molecular analysis in cytology and makes the combination of molecular analysis and morphologic diagnosis possible in cases with limited materials; (2) the remaining part of the smear is still preserved well for additional analysis; and (3) the approach is simple, economical and practical for cytology as well as histology.

DNA, Neoplasm↗
PubMed1996

Conserved residues are functionally distinct within transketolases of different species.

Most of the amino acid residues which interact with thiamine pyrophosphate are highly conserved among enzymes which use this cofactor. The possible roles of several such residues in cofactor binding, catalysis, and/or substrate binding were examined for human transketolase. Mutations in H110 resulted in dramatic reductions to 2% or less of the normal activity. No alterations were found in the K(m)app's for the cofactor or for the donor and acceptor substrates. Alterations in Q428 resulted in a less severe loss of activity and also no changes in the K(m)app's. On the basis of the results, H110, an invariant residue, is proposed to function as a base which abstracts a proton from the protonated 4'-iminopyrimidine ring. The deprotonated 4'-imino moiety is required for generation of the C2-thiazolium carbanion which attacks the donor substrate. Interestingly, the function in the human enzyme of this invariant histidine is distinct from its role in yeast transketolase in which it aids in binding donor substrate and in subsequent catalytic events. Q428 is suggested to play a supportive role by stabilizing and orientating a water molecule which mediates the interaction between the 4'-amino group and H110. In other TPP-utilizing enzymes, the equivalent residue of Q428 is a histidine and is thought to deprotonate the 4'-amino group.

Binding Sites↗
PubMed1996

Three-dimensional structure of the alpha-conotoxin GI at 1.2 A resolution.

Predatory marine snails of the genus Conus paralyze their fish prey by injecting a potent toxin. The alpha-conotoxin GI is a 13-residue peptide isolated from venom of Conus geographus. It functions by blocking the postsynaptic nicotinic acetylcholine receptor. After crystallization in deionized water, the three-dimensional structure of the GI neurotoxin was determined to 1.2 A resolution by X-ray crystallography. This structure, which can be described as a triangular slab, shows overall similarities to those derived by NMR, CD, and predictive methods. The principal framework of the molecule is provided by two disulfide bonds, one linking Cys 2 and Cys 7 and the other Cys 3 and Cys 13. Opposite ends of the sequence are drawn together even further by hydrogen bonds between Glu 1 and Cys 13 and between Cys 2 and Ser 12. Since the C-terminus is amidated, only one negative charge is present (carboxylate of Glu 1), and this is not implicated in receptor binding. Two positively charged regions (the alpha-amino group of Glu 1 and the guanido group of Arg 9) are situated 15 A apart at the corners of the triangular face of the molecule. phi, psi angles characteristic of a 3(10) helix were observed for residues 5-7. For residues 8-11, these angles were consistent with either a type I beta-turn or a distorted 3(10) helix.

Amino Acid Sequence↗
PubMed1996

Crystallographic Analysis of Antigen-Antibody Complexes: End-on Insertion of Ligands in Antibodies-CDR3 Loops as Arbiters

As the dominant constituents of the active sites, complementarity-determining regions (CDRs) and particularly the CDR3 loops strongly influence the size and shape of this interdomain space. Six sets of CDR3 loops were extracted from our collection of crystal structures and examined for their modes of association. The CDR3 loops of the NC6.8 Fab face each other across a small crevice that is expanded further by end-on insertion of its high-affinity ligand (a trisubstituted guanidine sweet-tasting compound). This wedging event triggers a series of extensive local and transmitted conformational changes. In the 4-4-20 Fab, the CDR3 loops provide scaffolding for the high-affinity binding of fluorescein and shield the ligand from bulk solvent in the interdomain space above and below the very compact binding slot. Constituents of the CDR2 and CDR3 loops of the BV04-01 Fab interact to form "false floors" over potential cavity-type sites and thereby eliminate end-on insertion. Instead, fragments of single-stranded DNA are bound with low affinity in a groove whose course is altered on complex formation by global movements of VH relative to VL and by local shifts of HCDR3. Trafficking of even small peptide ligands between the V domains of the Pot Fv is prevented by the collapse of the large HCDR3 segment into the residual interdomain space. This protein is better suited to polyreactive binding of a variety of large protein antigens on its external surfaces. By comparison, the space available between the CDR3 loops of the Mcg light-chain dimer is very large. It has proved to be accessible for end-on insertion of peptides and other ligands ranging over seven orders of magnitude in affinity. Recently, an insect neuropeptide hormone, with pGlu as its penetrating agent, has been found to pierce the entire V dimer interface from the entrance of the traditional active site to the solvent pool between the V and C domains. In an Mcg x Hud heterodimer, the Hud CDR3 plays a role similar to that of the Pot H chain and blocks access to the interdomain space by close interactions with the CDR3 of Mcg.

Journal Article↗
PubMed1996

Burnout among Nurses in the People's Republic of China.

This study was designed to examine the burnout symptoms among nurses in different settings, differing by specialty, age, gender, number of years on the job, and place of work, in the People's Republic of China. A total of 1,100 nurses completed the Maslach Burnout Inventory. Burnout symptoms in nurses were related to setting, specialty, age, gender, place of work, and number of years on the job. The findings suggest that the physical features in clinics and in obstetrics and gynecology departments should be improved and that social and public health support systems, as well as stress management skills, should be offered to new nurses in order to improve their ability to cope with stress and to improve the quality of care for patients.

Journal Article↗
PubMed1995

Intramolecular signaling upon complexation.

Crystal habits can be used as indicators of conformational changes in their constituent proteins. As in the conversion of unliganded hemoglobin to the oxygenated form, the addition of a small hapten to a suspension of platy crystals of an unliganded Fab (NC6.8) results in the immediate disintegration of the plates and their replacement with prisms of the ligand-protein complex. Examination of the native and liganded forms by X-ray crystallography reveals that the space groups and protein structures are different. During complexation there are ligand-induced conformational changes both in the antigen combining site (local alterations) and in more distal portions of the molecule (allosteric changes). There is an extension of the light chain (10 A increase in length), a commensurate shortening of the heavy chain (by flexing), and a decrease in the "elbow bend" angle of 31 degrees (184 degrees to 153 degrees). Relative to the variable domains, the constant domain pair moves mainly as a unit in such a way that the carboxyl end of the heavy chain is displaced by 19 A. In an intact antibody this displacement may be relayed as a tug (by tensile forces) on the segment connecting the Fab to the Fc region, perhaps altering the orientations of the constituents responsible for such effector functions as complement activation.

Animals↗
PubMed1995

Quantitative analysis of stromal fat content of human parathyroid glands associated with thyroid diseases using computer image analysis.

The stromal fat content in the parathyroid glands and its significance are still controversial. Several methods have also been introduced to evaluate the content in the literature. In an attempt to better understand the significance of stromal fat content, a computer image analyzing system was applied and 62 glands were investigated using routinely processed tissue. Our study revealed that the average stromal fat content was 34.8 +/- 18.7% which was lower than that of other studies. The stromal fat content was correlated with the age, grade of obesity, area of the gland and serum parathormone level; however, no consistent patterns were obtained with other clinical parameters. These results indicate that the change of stromal fat content may be related to the general condition of the patient similar to the change of fat in other organs. However, the decrease of the content may indicate the early change of parathormone secretory activity even if the serum examination shows no evidence of hyperfunction of the glands.

Adipose Tissue↗
PubMed1995

Effects of luteinizing hormone (LH) and androgen on steady state levels of messenger ribonucleic acid for LH receptors, androgen receptors, and steroidogenic enzymes in rat Leydig cell progenitors in vivo.

Adult Leydig cells differentiate postnatally from mesenchymal-like progenitor cells. The relative scarcity of LH receptors (LHRs) in progenitor cells indicates that additional hormones may be important in the initial phases of Leydig cell differentiation. High levels of androgen receptor (AR) in progenitor cells point to a role for androgen in these cells. In the present study, an LHRH antagonist, [Ac-D2Nal1,4C1DPhe2,D3Pal3,Arg5,DGlu6(anis ole adduct), DAla10]GnRH (NalGlu; 250 micrograms/kg body weight), was used to suppress endogenous secretion of both LH and androgen during days 14 to 21 postpartum in vivo. To examine the effects of LH and androgen on regulation of Leydig cell progenitors (PLCs), exogenous LH (5 micrograms/day), testosterone (T; 30 micrograms/day), or both were administered to NalGlu-treated rats. After 7 days of treatment, we examined the effects on testis weight, Leydig cell morphology, and T production. The steady state messenger RNA (mRNA) levels for LHR, AR, cytochrome P450 17 alpha-hydroxylase, and 3 alpha-hydroxysteroid dehydrogenase in purified PLCs were measured by reverse transcription-polymerase chain reaction, with ribosomal protein S16 as the internal control. Treatment with NalGlu significantly decreased testis weight, resulted in an abundance of mesenchymal-like cells over immature Leydig cells, lowered T production, and reduced the levels of several Leydig cell mRNAs. Treatment with exogenous LH or T maintained testis weight and Leydig cell morphology in NalGlu-treated rats. The mRNA levels for LHR, AR, and 3 alpha-hydroxysteroid dehydrogenase were significantly increased by LH or T. P450 17 alpha-hydroxylase mRNA levels were elevated by LH to control level but strikingly reduced by T. Combined treatment with LH and T further increased basal T production but did not elevate mRNAs beyond the levels obtained with each hormone alone. LH and androgen act similarly in PLCs in promoting Leydig cell differentiation with respect to morphological and molecular landmarks. These findings support the hypothesis that androgen as well as LH is involved in the differentiation of immature Leydig cells from mesenchymal-like progenitors.

3-Hydroxysteroid Dehydrogenases↗
PubMed1994

Local and transmitted conformational changes on complexation of an anti-sweetener Fab.

Crystal structures of an Fab (NC6.8) from a murine IgG2b(kappa) antibody and its complex with a sweet-tasting, N-,N'-,N"-trisubstituted guanidine compound (NC174) have been determined by X-ray analysis. Both crystal forms are produced by a microseeding technique in polyethylene glycol (PEG) 8000 but the habits and space groups are very different. The native protein crystallizes as plates in the monoclinic space group C2 and the complex crystallizes as prisms in the orthorhombic space group P2(1)2(1)2. The structures were solved by molecular replacement methods, with the Fab fragments from the 4-4-20, HyHel-5 and BV04-01 antibodies as starting models. On binding of the ligand, N-(p-cyanophenyl)-N'-(diphenylmethyl)-N"-(carboxymethyl)g uan idine, the protein exhibits significant local conformational changes in the active site, particularly in the third complementarity-determining region (CDR3) of the heavy chain. The ligand enters the small crevice by end-on insertion with the cyanophenyl group in the lead and the diphenyl rings partially protruding from the entrance. No strict pi-pi stacking interactions are observed. However, tyrosine L32 (CDR1), tyrosine L96 (CDR3) and tryptophan H33 (CDR1) help immobilize the cyanophenyl ring and guanido group, and tyrosine H96 moves about 4.5 A to lie between the rings of the diphenyl group. The positive charge on the guanido group is compensated by glutamic acid H50 (CDR2) while the negative charge on acetic acid is neutralized by arginine H56 (CDR2) and by hydrogen bonding with asparagine H58 (CDR2). Water molecules participate in the binding process by hydrogen bonding with the cyano and guanido groups. The mechanism of binding is a clear example of induced fit. Like hemoglobin, the NC6.8 Fab can be classified as an allosteric protein, since its overall structure is altered by the binding of a small ligand. In crystals of the native Fab the elbow bend angle is 184 degrees while in crystals of the complex the elbow angle is 153 degrees. There is also a reciprocal push-pull type of change where the heavy chain is flexed and the light chain is extended. The tail of the heavy chain, which would be connected to the Fc in an intact antibody, is displaced 19 A relative to its position in the unliganded Fab. Within the limited series of sweetener-Fab complexes we have thus far examined, only the NC174 hapten has produced such results.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetates↗