FNA biopsy diagnosis of HCC.
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Biopsy, Needle↗
Biomedical subjects
S K Chan
Publications and source records attributed to S K Chan.
Switching the in vivo specificity of a minimal Hox-responsive element.
The homeodomain proteins encoded by the Hox complex genes do not bind DNA with high specificity. In vitro, Hox specificity can be increased by binding to DNA cooperatively with the homeodomain protein extradenticle or its vertebrate homologs, the pbx proteins (together, the PBC family). Here we show that a two basepair change in a Hox-PBC binding site switches the Hox-dependent expression pattern generated in vivo, from labial to Deformed. The change in vivo correlates with an altered Hox binding specificity in vitro. Further, we identify similar Deformed-PBC binding sites in the Deformed and Hoxb-4 genes and show that they generate Deformed or Hoxb-4 expression patterns in Drosophila and mouse embryos, respectively. These results suggest a model in which Hox-PBC binding sites play an instructive role in Hox specificity by promoting the formation of different Hox-PBC heterodimers in vivo. Thus, the choice of Hox partner, and therefore Hox target genes, depends on subtle differences between Hox-PBC binding sites.
Animals↗
A structural model for a homeotic protein-extradenticle-DNA complex accounts for the choice of HOX protein in the heterodimer.
The genes of the homeotic complex (HOX) encode DNA binding homeodomain proteins that control developmental fates by differentially regulating the transcription of downstream target genes. Despite their unique in vivo functions, disparate HOX proteins often bind to very similar DNA sequences in vitro. Thus, a critical question is how HOX proteins select the correct sets of target genes in vivo. The homeodomain proteins encoded by the Drosophila extradenticle gene and its mammalian homologues, the pbx genes, contribute to HOX specificity by cooperatively binding to DNA with HOX proteins. For example, the HOX protein labial cooperatively binds with extradenticle protein to a 20-bp oligonucleotide that is sufficient to direct a labial-like expression pattern in Drosophila embryos. Here we have analyzed the protein-DNA interactions that are important for forming the labial-extradenticle-DNA complex. The data suggest a model in which labial and extradenticle, separated by only 4 bp, bind this DNA as a heterodimer in a head-to-tail orientation. We have confirmed several aspects of this model by characterizing extradenticle-HOX binding to mutant oligonucleotides. Most importantly, mutations in base pairs predicted to contact the HOX N-terminal arm resulted in a change in HOX preference in the heterodimer, from labial to Ultrabithorax. These results demonstrate that extradenticle prefers to bind cooperatively with different HOX proteins depending on subtle differences in the heterodimer binding site.
Amino Acid Sequence↗
An extradenticle-induced conformational change in a HOX protein overcomes an inhibitory function of the conserved hexapeptide motif.
HOX homeoproteins control cell identities during animal development by differentially regulating target genes. The homeoprotein encoded by the extradenticle (exd) gene can selectively modify HOX DNA binding, suggesting that it contributes to HOX specificity in vivo. HOX-EXD interactions are in part mediated by a conserved stretch of amino acids termed the hexapeptide found in many HOX proteins. Here, we demonstrate that a 20 bp oligonucleotide from the 5' region of the mouse Hoxb-1 gene, a homolog of Drosophila labial (lab), is sufficient to direct an expression pattern in Drosophila that is very similar to endogenous lab. In vivo, this expression requires lab and exd and, in vitro, LAB requires EXD to bind this oligonucleotide. In contrast, LAB proteins with mutations in the hexapeptide bind DNA even in the absence of EXD. Moreover, a hexapeptide mutant of LAB has an increased ability to activate transcription in vivo. Partial proteolysis experiments suggest that EXD can induce a conformational change in LAB. These data are consistent with a mechanism whereby the LAB hexapeptide inhibits LAB function by inhibiting DNA binding and that an EXD-induced conformational change in LAB relieves this inhibition, promoting highly specific interactions with biologically relevant binding sites.
Amino Acid Sequence↗
Extra specificity from extradenticle: the partnership between HOX and PBX/EXD homeodomain proteins.
For many DNA-binding transcription factors it is often difficult to reconcile their highly specific in vivo functions with their less specific in vitro DNA-binding properties. Cooperative DNA binding with cofactors often provides part of the answer to this paradox and recent studies have demonstrated this to be the case for the homeotic complex (HOX) family of transcription factors. However, the unique problem posed by these highly related and developmentally important transcription factors requires additional twists to the standard solution, which are beginning to become apparent from the characterization of the HOX cofactors encoded by the extradenticle and PBX genes.
Animals↗
Multiplane transesophageal echocardiographic assessment of left atrial appendage anatomy and function.
Anatomic indexes of the LAA are dependent on the plane in which the appendage is viewed. Greater LAA neck width and cross-sectional area are observed at 135 degrees than at 45 degrees or 90 degrees, consistent with the characteristic 3-dimensional ungular shape of this structure. Appendage ejection and inflow velocity measurements are independent of the imaging plane.
Adult↗
Segmental expression of Hoxb-1 is controlled by a highly conserved autoregulatory loop dependent upon exd/pbx.
Comparison of Hoxb-1 regulatory regions from different vertebrates identified three related sequence motifs critical for rhombomere 4 (r4) expression in the hindbrain. Functional analysis in transgenic mice and Drosophila embryos demonstrated that the conserved elements are involved in a positive autoregulatory loop dependent on labial (lab) family members. Binding of Hoxb-1 to these elements in vitro requires cofactors, and the motifs closely resemble the consensus binding site for pbx1, a homolog of the Drosophila extradenticle (exd) homoedomain protein. In vitro exd/pbx serves as a Hoxb-1 cofactor in cooperative binding and in Drosophila expression mediated by the r4 enhancer is dependent on both lab and exd. This provides in vivo and in vitro evidence that r4 expression involves direct autoregulation dependent on cooperative interactions of Hoxb-1 with exd/pbx proteins as cofactors.
Animals↗
Reduction of translation initiation factor 4E decreases the malignancy of ras-transformed cloned rat embryo fibroblasts.
Expression of the T24ras oncogene induces malignancy (tumor growth, invasion and metastasis) in cloned rat embryo fibroblasts (CREF T24). In CREF T24, the rate of phosphorylation of eukaryotic translation initiation factor 4E (eIF-4E) is increased, resulting in increased protein synthesis rates. We have recently shown that reducing the protein levels of eIF-4E in CREF T24 (AS4E line) markedly decreases soft-agar colonization, increases tumor latency periods and increases tumor doubling times without significantly altering monolayer growth. In this study, cells with reduced eIF-4E had delayed and reduced invasiveness and decreased experimental metastasis. Furthermore, reduced eIF-4E levels correlated with decreased expression of the metastasis-associated 92-kDa collagenase type-IV and exon-6 variants of the CD44 adhesion molecule [CD44(6v)]. Reduced eIF-4E levels correlated inversely with increased levels of the putative metastasis-suppressor protein nm23. Cell lines established from AS4E tumors and lung metastases exhibited increased levels of eIF-4E protein and protein synthesis rates compared to the AS4E line. Tumor-derived AS4E had the shortened tumor latency periods of CREF T24 but displayed the slow tumor-growth rates of AS4E. Tumor-derived AS4E exhibited the metastatic capacity of CREF T24 controls. Furthermore, tumor- and lung-nodule-derived AS4E expressed levels of CD44 (6v) and the 92-kDa collagenase type IV comparable to CREF T24 and displayed reduced levels of nm23 relative to AS4E. These results demonstrate that eIF-4E is an important effector molecule involved in oncogenic p21ras-induced malignant transformation.
Animals↗
The aetiology of heart failure in the Chinese population of Hong Kong--a prospective study of 730 consecutive patients.
Heart failure is a common and serious condition in many parts of the world and is a frequent cause for hospital admission in the Chinese population of Hong Kong. There is no published information on the epidemiology of heart failure in this community or from mainland China. Therefore, a prospective study of consecutive patients admitted with the clinical diagnosis of heart failure has been carried out to identify the main risk factors or possible causes, and other clinical data. Seven-hundred thirty consecutive patients with cardiac failure were identified and studied. Standard clinical criteria were used for diagnosis and identification of the main or most likely aetiologies and echocardiography was done in 30%. The data analysis of the 730 patients showed the following. The majority were females (56%) and the prevalence of heart failure increased with age (mean age 73.5 +/- 11.7 years) with 76% of the women > 70 years old. In contrast, the men were younger with 40% < 70 years old. The main identifiable risk factors were hypertension (37%), ischemic heart disease (31%), valvular heart disease (15%), cor pulmonale (27%), idiopathic dilated cardiomyopathy (4%), and miscellaneous (10%). In women, hypertension was the commonest cause at all ages but in men aged < 70 years ischemic heart disease was equal in frequency to hypertension (36% and 35%, respectively). Twenty-one percent had diabetes compared to a community rate of 10% for this age group (odds ratio 2.25, P < 0.0001). There was considerable overlap between diabetes, hypertension and ischemic heart disease. The estimated incidence rate was 3.8/1000 women and 3.0/1000 men aged > 45 years old.(ABSTRACT TRUNCATED AT 250 WORDS)
Age Factors↗
Acute renal failure after streptokinase therapy in a patient with acute myocardial infarction.
Cholesterol embolization syndrome (CES) usually occurs after the performance of invasive vascular procedures. With the frequent use of thrombolytic agents, an increasing number of reported cases of renal CES attributed to the use of such agents has appeared. In most of these reports, the diagnosis was made on the basis of either clinical presentations or skin biopsy. We report a patient who developed acute renal failure as a result of histologically proven renal CES occurring after the use of streptokinase for the treatment of an acute myocardial infarction. The acute renal failure later became chronic; consequently, the patient was placed on continuous ambulatory peritoneal dialysis. Although the prognosis of renal CES has been described to be poor, our patient regained enough of his renal function 8 months after the onset of renal failure to make it possible to discontinue the dialytic therapy.
Acute Kidney Injury↗
Fine-needle aspiration cytologic diagnosis of lymphoepithelioma-like carcinoma of the lung. Report of two cases with immunohistochemical study.
Lymphoepithelioma is a term used to describe an undifferentiated carcinoma with prominent lymphoid infiltration in the nasopharynx. Recently, tumors with similar histology, designated as lymphoepithelioma-like carcinomas, have been described in other sites including the lung. The authors report two cases of pulmonary lymphoepithelioma-like carcinoma that were correctly diagnosed by fine-needle aspiration cytology. The distinctive cytologic features consist of cohesive sheets and clusters of spindle tumor cells, which possess moderately pleomorphic vesicular nuclei and prominent nucleoli that are intimately intermixed with numerous small lymphocytes. Immunohistochemical study, performed on the cell block preparation, revealed strong positive staining of these tumor cells for epithelial markers. In both cases, the cytologic diagnosis were confirmed subsequently by histologic examination of the resected surgical specimens. Cytologically, the differential diagnoses include granulomatous inflammatory diseases (especially tuberculosis), malignant lymphoma, melanoma, and metastatic sarcoma. The characteristic cytology of the tumor cells, together with their pattern of immunohistochemical staining, are helpful to distinguish lymphoepithelioma-like carcinoma from the differential diagnoses. In these cases, careful examination of the nasopharynx, preferably with multiple random mucosal biopsies, is essential for the exclusion of nasopharyngeal undifferentiated carcinoma because of the obvious differences in treatment and prognosis.
Aged↗
Effect of low dose beta blockers on atrial and ventricular (B type) natriuretic factor in heart failure: a double blind, randomised comparison of metoprolol and a third generation vasodilating beta blocker.
OBJECTIVES: This study examines the acute effects of two differing beta adrenergic blocking agents (metoprolol and a third generation vasodilating beta blocker) on plasma concentrations of atrial natriuretic factor (ANF), brain (ventricular) natriuretic factor (BNF), and haemodynamic variables in patients with heart failure. SETTING: University teaching hospital. METHODS: 20 patients with impaired left ventricular systolic function [ejection fraction 32 (SEM 2.3)%] were randomised in a double blind manner to receive either oral metoprolol 6.25 mg twice daily or celiprolol 25 mg daily. Haemodynamic variables were evaluated by Swan-Ganz pulmonary artery catheter over 24 hours. ANF and BNF concentrations were measured at baseline, 5 h, and 24 h by radioimmunoassay. RESULTS: At baseline ANF and BNF concentrations were considerably raised compared to the normal range. Treatment with metoprolol caused ANF to rise further to 147% of the basal level at 5 h (P = 0.017) and 112% at 24 h (P = 0.029). This was associated with a small but non-significant rise in pulmonary capillary wedge pressure. Cardiac output and systemic vascular resistance were unchanged at 24 h. In contrast, after celiprolol ANF fell to 90% of basal levels at 5 h and to 74% of basal level at 24 h (P = 0.019), associated with a small but non-significant fall in pulmonary capillary wedge pressure [-3.3 (2.7) mm Hg] and systemic vascular resistance, and rise in cardiac output from 3.2 (0.2) to 4.0 (0.4) l/min (P = 0.04). BNF concentrations rose to 112% of baseline at 5 h (P = 0.09) after metoprolol but fell slightly, to 91% of baseline values, after celiprolol (NS). CONCLUSIONS: Metoprolol, even in very low doses (6.25 mg), produced a rise in ANF and BNF, although minimal haemodynamic changes were detected. In contrast, a vasodilating beta blocker was associated with a significant fall in ANF and BNF and a small rise in cardiac output. This study confirms both the advantages of vasodilating beta blockers over metoprolol for initial treatment of heart failure and the usefulness of ANF and BNF measurements for the assessment of drug effects in heart failure compared to traditional haemodynamic measurements.
Adrenergic beta-Antagonists↗
The DNA binding specificity of Ultrabithorax is modulated by cooperative interactions with extradenticle, another homeoprotein.
The Ultrabithorax (Ubx) and Antennapedia (Antp) genes of Drosophila encode homeodomain proteins that have very similar DNA binding specificities in vitro but specify the development of different segmental patterns in vivo. We describe cooperative interactions between Ubx protein and a divergent homeodomain protein, extradenticle (exd), that selectively increases the affinity of Ubx, but not Antp, for a particular DNA target. We also provide evidence that Ubx and exd bind to neighboring sites on this DNA and interact directly to stabilize the DNA-bound form of Ubx. Thus, the ability of different homeotic genes to specify distinct segmental patterns may depend on cooperative interactions with proteins such as exd that selectively modulate their otherwise similar DNA binding specificities.
Amino Acids↗
Inhibition of collagenolytic activity relates to quantitative reduction of invasion in vitro in a c-Ha-ras transfected glial cell line.
The function of proteases in brain tumor invasion is currently not well established. For tumors of epithelial and fibromatous origin collagenase production can enhance the invasive capacity of cells to penetrate basement membranes. We showed previously that a c-Ha-ras transformed glial cell line (CxT24neo3) invaded hamster brain tissue in vivo. These cells were also capable of invading reconstituted basement membrane and embryonic chick hearts in vitro. Since the histopathology of CxT24neo3 tumors mimics that of glioblastoma multiforme in humans, CxT24neo3 was used as the model in vitro for this type of brain tumor. Presently, we detected by zymogram analysis a gelatinase that was secreted by CxT24neo3 and that had an apparent molecular mass of 62 kD. To verify whether gelatinase affected invasion in vitro of these glial cells we determined the efficacy of a substrate specific collagenase inhibitor on invasion in vitro. GM6001 is a synthetic polypeptide that specifically occupies the substrate binding sites of metalloprotease. Since this drug did not show cytotoxicity, its specificity for metalloprotease is a valuable tool to evaluate the physiological function of these enzymes on invasion. We found that treatment of CxT24neo3 with GM6001 reduced the fraction of invading CxT24neo3 cells through reconstituted basement membrane. These data suggest that metalloproteases can stimulate brain tumor invasion.
Amides↗
Cytologic features of Kimura's disease in fine-needle aspirates. A study of eight cases.
Kimura's disease is a chronic inflammatory disorder of unknown etiology, presenting usually as painless subcutaneous swellings in the head and neck region or in the salivary glands. The cytologic features of fine-needle aspirates of eight cases of Kimura's disease were studied with reference to the histologic appearance of the subsequent surgical specimens. In the cytologic smears, the prominent feature was the presence of significant numbers of eosinophils in a background of lymphoid cells. Fragments of collagenous tissue and Warthin-Finkeldey polykaryocytes occasionally were seen. In the cell block, vascular proliferation and fibrosis were useful features, providing further support to the diagnosis. The constellation of these features is characteristic of Kimura's disease and should suggest this diagnosis in the appropriate clinical setting. For initial diagnosis, excisional biopsy is important for the exclusion of malignant lymphoma, histiocytosis X, angiolymphoid hyperplasia with eosinophilia and other reactive lymphadenopathies. Nonetheless, fine-needle aspiration cytology may be valuable in the diagnosis of recurrent lesions of Kimura's disease and may spare the patient from repeated biopsies.
Adult↗
Effect of subcutaneous recombinant human erythropoietin in cancer patients receiving radiotherapy: preliminary results of a randomized, open-labeled, phase II trial.
PURPOSE: To determine the efficacy and safety of subcutaneous administration of recombinant human erythropoietin (r-HuEPO) at a dose of 200 units/kg/day to cancer patients undergoing radiotherapy. METHODS AND MATERIALS: This is a randomized, open-labeled, Phase II study. Only patients receiving radiotherapy +/- chemotherapy are included. Eligibility is restricted to patients with lung cancer, carcinoma of the uterine cervix, prostatic adenocarcinoma, or adenocarcinoma of the breast. Patients in the control and treatment arms receive radiotherapy with similar policies, and their doses of radiotherapy and treatment volumes are determined by the site and stage of the disease. Patients in the "treatment arm" receive 200 units/kg/day of r-HuEPO, subcutaneously, five times a week with iron (Fe SO4, 325 mg. p.o., t.i.d.) supplements. Complete blood counts are obtained weekly. Quality of life is assessed weekly by the patients themselves by a few simple entries on an analog scale. RESULTS: Twenty-six patients have been entered in the study so far. Twelve patients were placed in the control arm and 14 in the treatment arm. Pre-randomization demographic and laboratory mean values in both arms were comparable, with none of 16 parameters compared reaching statistical significance. Our results can be summarized as follows: (a) Mean hemoglobin, hematocrit, and red blood cell values increased gradually in the treatment arm patients. Week-by-week comparison showed that mean values for these three parameters were significantly higher in the treatment arm than in the control arm. For example, the p values for the differences in hemoglobin mean values for weeks 1-6 were 0.015, 0.002, 0.003, 0.0002, 0.0006, and 0.007, respectively. Similar trends were observed for red blood cells and the hematocrit values. (b) No significant toxicity has been encountered. (c) No significant differences in the mean values of white blood cells and platelet counts were seen between the two arms. The values of these two parameters declined over the course of radiotherapy. (d) The mean weekly increase in hemoglobin levels in the treatment arm was 0.43 gm/dl. CONCLUSION: (a) The safety and efficacy of r-HuEPO, with 200 units/kg/day of subcutaneous administration, have been confirmed in our study group. (b) However, the rate of increase in hemoglobin levels is not very rapid with the doses used. (c) Dose escalation studies are needed for determination of the feasibility of improving hemoglobin levels by about 1 gm/dl/week. (d) The question whether improvement in hemoglobin with r-HuEPO therapy can improve outcome by improving tumor oxygenation needs to be studied in carcinoma of the uterine cervix and squamous cell carcinoma of the head and neck.
Adenocarcinoma↗
The segment identity functions of Ultrabithorax are contained within its homeo domain and carboxy-terminal sequences.
Using an in vivo assay for segment identity, the structural differences that distinguish two Drosophila homeotic selector proteins, Ultrabithorax (Ubx) and Antennapedia (Antp), have been investigated. There are at least two independent parts of Ubx and Antp that contribute to their functional specificities: (1) their homeo domains and (2) residues carboxy-terminal to their homeo domains (C-tails). In the absence of any C-tail, differences in 5 homeo domain amino acids are sufficient to distinguish between the functions of Ubx and Antp. Two of these are at the amino terminus of the homeo domain and could contact DNA directly. A three dimensional model suggests that the other 3 homeo domain residues and the C-tails are unlikely to contact DNA. In addition, we demonstrate that the assay used to measure the segment identity functions of Ubx and Antp is independent of any homeotic selector gene normally active in thoracic and abdominal segments. Therefore, it is likely that this assay measures the coordinate regulation of many downstream target genes. This expectation is confirmed for at least one Ubx target gene, Distal-less.
Amino Acid Sequence↗
Fine-needle aspiration anchor. A simple device to prevent needle-stick injury at fine-needle aspiration.
Pathologists and clinicians performing fine-needle aspiration for cytologic diagnosis are at risk of finger injury by the needle during the aspiration procedure. To prevent this occurrence and its accompanying potential for transmitting serious pathogens such as the human immunodeficiency virus and hepatitis B virus, we have designed a simple acrylic device (fine-needle aspiration anchor) consisting of two curved prongs with an attached handle, to take up the functions of the fingers for stabilization of the target lesion. Use of the fine-needle aspiration anchor on more than 1000 patients with various mass lesions has confirmed enhanced immobilization of the lesions for aspiration, safety for the person performing the procedure, and excellent patient acceptance.
Biopsy, Needle↗