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PubMed1984

Single-step selection of unique human melanoma variants displaying unusually aggressive metastatic behavior in nude athymic mice.

Using two different approaches, variants from a pigmented human melanoma cell line called MeWo were selected in a single step which displayed an unusually aggressive ability to metastasize in adult athymic nude mice. The first set of variants was obtained by recovery, and establishment in culture, of 'spontaneous' lung metastases obtained 5-6 months after subcutaneous inoculation of the parent MeWo line. That these metastases arose by a nonrandom process, and were authentic variants, was shown by the fact that they were always highly aneuploid, having predominantly near-triploid or near-tetraploid chromosome numbers. In contrast, the parent MeWo cells had a predominant hypodiploid chromosome mode with a minor population (less than 10%) of near-tetraploid cells. A second set of variants was obtained through in vitro selection of cloned lectin-resistant (Lecr) aneuploid 'membrane mutants' from MeWo, using wheat germ agglutinin (WGA) as the selective agent. Some of these mutants manifested an extraordinary ability to disseminate widely and extensively to many extrapulmonary sites after intravenous inoculation of the cells; furthermore, the metastases, even those less than 0.5 mm in diameter ('pinhead' sized), were easily visible because of the remarkably intense pigmented nature of the mutant cells. These results provide a promising direction to take for the derivation of heterogenous sublines of human tumors which not only metastasize aggressively in nude mice, but which do so in a manner not unlike what is actually observed in their natural host.

Aneuploidy↗
PubMed1980

Carcinogenicity of tumor cell populations: origin of a putative H-2 isoantigenic loss variant tumor.

The properties of an unusual mouse tumor capable of extremely rapid and widespread spontaneous metastatic growth were recently described; this tumor, called MDAY-D2, at first appeared to be an H-2Kk loss variant of an (A X DBA/2)F1 (H-2KkDd) sarcoma called MDAY and was obtained by serial ip passage of MDAY in DBA/2 (KdDd) mice. The studies described here were concerned with the analysis of the origin of MDAY-D2; i.e., was it a true variant or a newly induced DBA/2 tumor? Several approaches were used, most of which exploited defined cell surface alloantigenic systems as natural genetic markers. The results indicated that MDAY-D2 was indeed a newly induced DBA/2 tumor and, furthermore, that MDAY was a homozygous A-strain tumor, probably a T-cell lymphoma. Thus a) MDAY was found to be Ly-1.2+, Ly-2.2+, and Thy-1.2+, but Ly-6.2-, whereas the opposite pattern was observed with MDAY-D2; b) MDAY possessed the private and public H-2 specificities associated with H-2k and H-2Dd, but not H-2Dk [i.e., it typed as an A-strain (H-2a) tumor, not as (A X DBA/2)F1]; c) MDAY-D2 possessed private and public specificities associated with H-2Kd and H-2Dd and was found to be H-2Kk-negative [i.e., it typed as a DBA/2 (H-2d) tumor]; d) serial injection of clonally derived ouabain-resistant H-2Kk-positive MDAY cells into DBA/2 hosts led to the rapid development of an MDAY-D2 (H-2d-positive) tumor that was fully ouabain-sensitive. Several findings did not support a contaminant theory to explain induction of MDAY-D2. The rapid induction of a tumor after injection of allogeneic tumor cells may have importance in relation to oncogenesis, tumor variant formation, and tumor progression. The results showed that tumor cells themselves can be potent carcinogens.

Animals↗
PubMed1996

Promoter region and alternatively spliced exons of the rat mu-opioid receptor gene.

The actions of exogenous and endogenous opioids are mediated by at least three different opioid receptors, called mu, kappa, and delta. Recently, we have detected a new variant of the rat mu-opioid receptor, which we termed rMOR1B and which differs from rMOR1 (now also called rMOR1A) in the amino acid sequence at the C-terminus. Both isoforms were proposed to be splicing variants of the same gene. To elucidate the molecular mechanism leading to the formation of the new variant, the exon/intron structure of the rat mu-opioid receptor gene in the respective area has been determined by analyzing a genomic P1 phage clone. In addition, we have investigated the putative promoter region of this gene. The present study revealed that rMOR1B is generated by an alternative splicing event whereby a previously unknown exon will be placed behind exon 3 to form rMOR1B mRNA, which is separated from the latter by an intron. Therefore, this new exon has to be called exon 4, whereas the former exon 4, which encodes the C-terminus of MOR1A, now becomes exon 5. Examination of the putative rat promoter region revealed a high degree of nucleotide sequence homology to the mouse gene. Using an RNase protection approach, one single transcription initiation site could be located at 230 bp upstream of the translation start. This is similar to the situation in the mouse, where four major transcription start sites were reported to lie close together around 270 bp upstream of the protein coding region.

Alternative Splicing↗
PubMed1996

Complementation of Ah receptor deficiency in hepatoma cells: negative feedback regulation and cell cycle control by the Ah receptor.

The Ah receptor (AhR) is a ligand-dependent transcription factor subunit that heterodimerizes with the AhR nuclear translocator (Arnt) and mediates the predominant biological effects of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD activates target genes in xenobiotica metabolism in many cell lines and, more specifically, delays G1-S progression of 5L hepatoma cells. Here we describe transient and stable AhR-expression analysis in AhR-deficient subclones of the TCDD-sensitive 5L cells. We tested the integrity of the AhR-signaling system beyond the lack of the receptor in the variant subclone and analyzed the role of AhR in cell cycle regulation. Transiently expressed AhR has a high basal activity on promoters containing AhR-binding sites, so-called XREs, when transfected into receptor-deficient variant cells compared to wild-type cells. Single- and double-hybrid analysis dissociates AhR ligand responsiveness, transactivation, and heterodimerization with Arnt from receptor binding to an XRE. Hybrid receptors also show the high basal activity in the absence of exogenous TCDD in AhR-deficient variant cells, indicating that the endogenous AhR-activating signal acts directly on the receptor rather than XRE-dependent promoters or DNA binding of the receptor. Stable expression of AhR in variant cell clones by retroviral infection fully reconstitutes TCDD responsiveness, including target-gene induction and delay of cell cycle progression. These AhR-reconstituted cells, like AhR-containing wild-type cells, show low basal activity of the transiently expressed AhR hybrid. Thus, the increased basal activity in AhR-deficient cells suggests a negative feedback control of AhR activity. In vitro ligand-binding assays are compatible with the idea that the increased basal activity is due to the accumulation of an AhR-binding endogenous ligand. In conclusion, AhR is causally responsible for TCDD-dependent cell cycle regulation and feedback control of AhR activity.

Animals↗
PubMed1977

Activity of creatine kinase isoenzyme MB in serum and red cell acetylcholinesterase variants in patients with Duchenne muscular dystrophy.

Activity of creatine kinase isoenzyme MB in serum and variants of red cell acetylcholinesterase were determined in patients with Duchenne muscular dystrophy, in other forms of Dystrophy and in family members of Duchenne patients and healthy controls. Creatine kinase isoenzyme MB was observed only in all cases of DMD as well as variants of red cell acetylcholinesterase characterized by so-called inhibitor numbers. Carriers of Duchenne muscular dystrophy can be distinguished from Duchenne patients and healthy controls by estimation of Acetylcholinesterase variants.

Acetylcholinesterase↗
PubMed2000

Intravascular large B-cell lymphoma with bone marrow involvement at presentation and haemophagocytic syndrome: two Western cases in favour of a specific variant.

AIMS: To report two cases of an unusual form of intravascular lymphoma, characterized by bone marrow involvement at presentation with haemophagocytic syndrome. METHODS AND RESULTS: We describe the clinicopathological features of two patients with intravascular lymphoma primarily involving bone marrow. Both patients complained only of fever with pancytopenia and reactive haemophagocytic syndrome. Diagnosis was made on bone marrow examination, which showed large tumour cells of B-cell lineage confined within the lumen of sinuses. CONCLUSION: These two cases and five previous reports could represent a variant of intravascular lymphoma, characterized by early involvement of bone marrow without dissemination to other organs. This form of intravascular lymphoma, called IVL-HS, seems to be an 'Asian' variant with a high prevalence in Asian people and a very low prevalence in Western countries. At a practical level, bone marrow biopsy may be useful in the diagnosis of intravascular lymphoma when the clinical presentation is restricted to fever of unknown origin with a reactive haemophagocytic syndrome.

Aged↗
PubMed2004

Clues for the differential diagnosis of hypersensitivity pneumonitis as an expectant variant of diffuse parenchymal lung disease.

Hypersensitivity pneumonitis, also called extrinsic allergic alveolitis, a type of diffuse parenchymal lung disease (DPLD), is an immunologically mediated pulmonary disease induced by inhalation of various antigens. As data on the frequency of hypersensitivity pneumonitis are lacking in Turkey, a retrospective analyses was performed in 43 patients with DPLD, followed up over seven years. The objective was to discover cases fulfilling the diagnostic criteria for hypersensitivity pneumonitis, to determine the frequency and/or the new characteristics of the disease, and to pick up clues for differentiating it from other DPLDs. The four subjects with hypersensitivity pneumonitis (9%) who lived in an urban area were studied in detail. The most common symptoms were dry cough and dyspnoea. According to the symptom duration, clinical features, radiological and pathological findings, three were diagnosed with chronic and one with subacute hypersensitivity pneumonitis. Patients with hypersensitivity pneumonitis and those with DPLD were compared by means of age, sex, smoking status, symptom duration, haematology, erythrocyte sedimentation rate, peripheral cell count, spirometric parameters, blood gases, and diffusion capacity. No statistically significant difference was detected in these parameters except for forced expiratory volume in one second (FEV(1)) and forced vital capacity (FVC). In conclusion, patients with a history of antigen exposure, with mild symptoms such as dry cough and dyspnoea, and who have diffuse interstitial lung involvement on radiology should be carefully evaluated for hypersensitivity pneumonitis. Moreover, among other DPLDs, stable FEV(1) or FVC values may be the clues for establishing the diagnosis of hypersensitivity pneumonitis. However, further studies are needed in larger series of patients.

Adult↗
PubMed2005

p53 as an immunotherapeutic target in head and neck cancer.

Squamous cell carcinomas of the head and neck (HNSCCs) are characterized by a high frequency of mutations in the p53 gene often leading to p53 protein accumulation. Since accumulation of p53 is associated with enhanced presentation of wild-type sequence (wt) p53 peptides to immune cells, the development of ' pan' vaccines against HNSCC has focused on wt p53 epitopes. We used the HLA-A2.1-restricted wt p53 264-272 epitope pulsed on autologous dendritic cells to generate cytotoxic T lymphocytes (CTLs) ex vivo from circulating precursor T cells of HLA-A2.1+ patients with HNSCC. CTLs specific for the wt p53 264-272 peptide were generated from leukocytes obtained from a cohort of patients with HNSCC (group A). Paradoxically, none of those patients had tumors which adequately presented the epitope, i.e. accumulated p53. In contrast, patients who did not generate CTLs (group B) had tumors which accumulated altered p53 and potentially could present the p53 264-272 epitope. When p53 264-272-specific T cells were directly enumerated in the peripheral circulation of patients with HNSCC using tetrameric p53 264-272/HLA-A2.1 complexes by multicolor flow cytometry, group A had high and group B low percentages of tetramer+ CD3+ CD8+ T cells. These findings suggested that in vivo p53-specific CTLs in group A might play a role in the elimination of tumor cells expressing the p53 264-272 epitope ('immunoselection'), leading to the outgrowth of 'epitope loss' tumor cells. On the other hand, precursor CTLs specific for the wt p53 264-272 peptide in group B are unresponsive to the p53 antigen. Unresponsiveness of CTLs specific for the wt p53264-272 peptide detected in group B could be reversed by using more immunogenic variant peptides of the p53 264-272 epitope. In vivo, immunoselection of tumors which become resistant to anti-p53 immune responses has important implications for future p53-based vaccination strategies. It calls for modified approaches, in which altered peptide variants of the wt sequence p53 264-272 epitope are used in a vaccine in order to overcome unresponsiveness of T lymphocytes to the native epitope.

Cancer Vaccines↗
PubMed1990

t(2;18) and t(18;22) variant chromosomal translocations and bcl-2 gene rearrangements in human malignant lymphomas.

Most human follicular lymphomas bear the specific t(14;18) translocation that juxtaposes the 3' region of bcl-2 to the IgH gene on chromosome 14q+. In some rare cases, t(2;18) and t(18;22) translocations have been observed that involve bcl-2 and either Ig kappa or lambda genes. Strikingly, in these cases all the breakpoints on chromosome 18 are located in the 5' end the bcl-2 gene. These rearrangements are very similar to those recently found in a significant proportion of CLL. Thus, bcl-2 rearrangements in malignant lymphomas cluster in at least three regions: the so-called major breakpoint region (mbr) and minor cluster region (mcr) in more than 85% of t(14;18) translocation, and the newly characterized region 5' of the gene. We propose to call this new cluster region vcr (for variant cluster region).

Chromosomes, Human, Pair 14↗
PubMed2000

Alternative splicing and gene structure of the transforming growth factor beta-activated kinase 1.

We have identified a fourth splice variant of the TGF beta-activated kinase (TAK1), called TAK1-d, and identified an error in the previously published TAK1-c sequence. Our data shows that the c and d variants encode proteins whose carboxyl ends differ markedly from those of variants a and b. Analysis of the human TAK1 gene sequence, located at 6q16.1-q16.3, shows that the coding sequence is organised in 17 exons. The four splice variants result from alternative splicing of exons 12 and 16, the reading frame of exon 17 being determined by the presence or absence of exon 16. Study of the relative levels of expression of the four splice variants showed significant variations between tissues. Our evidence suggests that the alternative splicing of the TAK1 mRNA may have important functional implications.

Alternative Splicing↗
PubMed1983

A monoclonal antibody with ability to distinguish between NH2-terminal fragments derived from fibrinogen and fibrin.

A stable hybridoma secreting homogeneous antibody (immunoglobulin class IgG2a) has been prepared by fusion using cells of immunoglobulin non-secreter myeloma (P3X63Ag8.653) and spleen cells of mice which had previously been immunized with the NH2-terminal CNBr fragment of human fibrinogen, the so-called N-DSK [(A alpha 1-51, B beta 1-118, gamma 1-78)2]. In competitive ELISA or radioimmunoassay this antibody (MAb/1-8C6) cross-reacted with intact fibrinogen, N-DSK, a des fibrinopeptide A (des FPA) variant of N-DSK, the so-called (B)N-DSK, as well as the intact B beta chain (B beta 1-118) obtained from N-DSK. Also, and mot importantly, cross-reactivity was observed with fibrinogen-free ethanol extracts of plasma obtained from patients known to contain high levels of fibrinogen or fibrin degradation products. In vitro thrombin digestion of any of these competitors resulted in complete loss of cross-reactivity. MAb/1-8C6 did not react with the A alpha or gamma-chains of N-DSK, free fibrinopeptide B(FPB), free B beta 15-42, as well as equimolar mixtures of the latter two peptides. These results suggest that MAb/1-8C6 may be to an epitope in or around the thrombin-susceptible B beta 14 Arg-25 Gly bond. Furthermore, due to its reactivity with patient plasma extracts, this antibody may be useful in clinical investigations dealing with fibrino(geno)lysis.

Antibodies, Monoclonal↗
PubMed2005

Detection of hepatitis B virus genotypes and mutants: current status.

Characterization results of the hepatitis B virus (HBV) genome before, during and after antiviral treatment have changed in the last year for a number of reasons. First of all, with the introduction of more nucleoside and nucleotide antiviral therapies, it has become clear that variants or mutants do emerge in time. Viral genomic changes in the HBV polymerase gene can result in a direct antiviral effect, but compensatory mutations can also be identified during prolonged treatment periods. Furthermore, there is an increasing number of reports suggesting that HBV genotypes can be related to, for example, disease progression or the effect of antiviral treatment itself (alpha-interferon or lamivudine). Combined with HBV DNA viral load monitoring, an increase in viral load or a limited reduction during treatment is indicative of genomic changes related to resistance. However, these genomic changes can also be present in the absence of an increase in HBV DNA. Methodologies for the detection of these variants, as well as the determination of genotypes, are rather straightforward. Sequence analysis is time-consuming and expensive, but provides the most information, particularly if not all information on mutations related to antiviral resistance is known. However, the sensitivity of direct sequencing for the presence of minor variant populations is poor, and no mixtures of variant populations are, in general, detected. The ability to detect minor populations and, if possible, even quantify them, gives more insightful information on the dynamic evolution of the virus itself. Antiviral treatment can result in the appearance of more than one population of variants, which can be present for a prolonged period of time, and even remain undetected with current technologies. However, screening specifically for these variant populations before starting treatment for so-called untreated patients (who have received no antiviral treatment for, e.g., 6 months) has already shown that the effects of treatment can be biased. Furthermore, the detection of more dynamic viral populations - including both wild-type and resistant variants - during, but also after therapy, does provide helpful information in the analysis of virological data. Technologies enabling the detection and quantification of these variant populations are presented and discussed.

Antiviral Agents↗
PubMed1997

[Accessory atrioventricular pathways with decremental conduction (Mahaim connections). 2 case reports].

The so called Mahaim connections form a relatively scarce variant of the preexcitation syndrome. Antidromic atrioventricular reentry tachycardia with wide QRS complex of LBBB morphology represents a typical clinical manifestation of the condition. Nodofascicular and nodoventricular fibres in all the probability do exist, but only rarely. Most of these accessory pathways are located on the firht free wall and conduct only antegradely and decrementally. Majority of these pathways are formed by long bundles inserting in the terminal part of the right bundle branch or in the myocardium near the right ventricular apex. In this setting traditional mapping strategy is of little use and different approaches must be employed. Only minority of these right-sided accessory pathways are short inserting in the ventricular myocardium under the tricuspid annulus. We present two case reports of patients with accessory connections exhibiting the so called Mahaim electrophysiology. In the first case, the pathway was merely an innocent bystander that, however, masked serious low intrahissian conduction disturbance. In the second case, the patient had a long-standing characteristic symptomatology due to the right anterolateral short accessory pathway which was successfully mapped and ablated.

Adult↗
PubMed1995

Characterization of the N314D allele of human galactose-1-phosphate uridylyltransferase using a yeast expression system.

Transferase-deficiency galactosemia is an inborn error of metabolism resulting from impairment of the enzyme galactose-1-phosphate uridylyltransferase (GALT), which normally catalyzes the second step of the Leloir pathway of galactose metabolism. Several recent studies have linked a previously reported substitution, N314D (asn to asp at position 314), with both the Duarte and Los Angeles (LA) variant alleles of GALT. While both variants demonstrate similar mobility shifts relative to the normal enzyme on isoelectric focusing (IEF) gels, one (Duarte) is associated with diminished activity, while the other (LA) is associated with greater than normal activity. Therefore, although the concordance rates between N314D and both of these phenotypes are compelling, the question remains as to whether N314D alone is sufficient to cause either or both variants. To address the question of precisely what properties of variant GALT can be attributed to the N314D substitution alone, we have modeled both the wildtype and N314D-GALT alleles in a previously defined yeast expression system, and characterized each with respect to activity, abundance, subunit interaction, and mobility on isoelectric focusing gels. Our results indicate that the N314D subunit dimerizes well both with wildtype GALT and with itself and that the N314D substitution is sufficient to confer the expected shift of IEF banding pattern associated with both the Duarte and LA variant proteins isolated from human cells. However, our results also suggest that N314D-GALT retains full specific activity, thereby calling into question the suggestion that N314D encodes the Duarte variant of GALT.

Alleles↗
PubMed1988

[Variant (forme fruste) forms of bronchial asthma].

The variant forms of bronchial asthma were studied. It was established that in 66.4% of the patients examined the bronchial obstructive syndrome was caused by bronchial asthma. In 50.30% of the patients bronchial asthma had an atypical course--variant (forme fruste) forms. Three types of variant forms of bronchial asthma are differentiated: allergic tracheobronchitis (47.23%), the so called "wet" asthma (3.27%) and the so called "dry" bronchial asthma (0.8%). The therapeutic conduct should take into consideration the presence of variant forms of bronchial asthma.

Adolescent↗
PubMed2006

Correlation of norovirus variants with epidemics of acute viral gastroenteritis in Hong Kong.

Norovirus (NV) (formerly called Norwalk-like virus) is the most common etiological agent of acute viral gastroenteritis outbreaks worldwide. Recent reports have shown that two new GII.4 variants caused epidemics in Europe. To investigate if it is also the case in Hong Kong, a molecular epidemiological study was undertaken between January 2002 and June 2005. During this period, there was a substantial increase in acute cases of gastroenteritis caused by NV. Phylogenetic analysis showed that GII.2 and GII.4 are the major circulating genotypes. Two new GII.4 variants (variants C and D) were identified in 2002 and 2004, which quickly became the predominant strains. They were almost identical to the variants causing epidemics in Europe recently. Since geographically distinct areas were involved within a short period of time, it is possible that GII.4 has a particular propensity for causing pandemics.

Base Sequence↗
PubMed2005

SRC regulates constitutive internalization and rapid resensitization of a cholecystokinin 2 receptor splice variant.

The third intracellular loop domain of G protein-coupled receptors regulates their desensitization, internalization, and resensitization. Colorectal and pancreatic cancers, but not the nonmalignant tissue, express a splice variant of the cholecystokinin 2 receptor (CCK2R) called CCK(2i4sv)R that, because of intron 4 retention, contains an additional 69 amino acids within its third intracellular loop domain. This structural alteration is associated with agonist-independent activation of Src kinase (Olszewska-Pazdrak, B., Townsend, C. M., Jr., and Hellmich, M. R. (2004) J. Biol. Chem. 279, 40400-40404). The purpose of the study was to determine the roles of intron 4 retention and Src kinase on CCK(2i4sv)R desensitization, internalization, and resensitization. Gastrin1-17 (G17) binds to both CCK2R and CCK(2i4sv)R and induces intracellular Ca2+ ([Ca2+]i) increases. Agonist-induced increases in [Ca2+]i were used to assess receptor activity. Src kinase activity was inhibited by transducing cells with a retrovirus containing a dominant-negative mutant Src (A430V). The subcellular location of enhanced green fluorescent protein-tagged receptors was monitored using laser scanning confocal microscopy. Both receptor variants desensitized at the same rate; however, CCK(2i4sv)R resensitized five times faster than CCK2R. Without agonist, 80% of CCK(2i4sv)R is located in an intracellular compartment. In contrast, 80% of CCK2R was located on the plasma membrane. Treatment with inverse agonist (YM022) or expression of dominant-negative Src blocked the constitutive internalization of CCK(2i4sv)R, resulting in its accumulation on the plasma membrane. Expression of dominant-negative Src slowed the rate of CCK(2i4sv)R resensitization. Inhibition of Src did not affect G17-induced internalization of either receptor variant. Constitutive internalization of CCK(2i4sv)R increases its rate of resensitization by creating an intracellular pool of receptors that can rapidly recycle back to the plasma membrane.

Alternative Splicing↗
PubMed2001

Reduction Invariance and Prelec's Weighting Functions.

Within the framework of separable utility theory, a condition, called reduction invariance, is shown to be equivalent to the 2-parameter family of weighting functions that Prelec (1998) derived from the condition called compound invariance. Reduction invariance, which is a variant on the reduction of compound gambles, is appreciably simpler and more easily testable than compound invariance, and a simpler proof is provided. Both conditions are generalized leading to more general weighting functions that include, as special cases, the families of functions that Prelec called exponential-power and hyperbolic logarithm and that he derived from two other invariance principles. However, of these various families, only Prelec's compound-invariance family includes, as a special case, the power function, which arises from the simplest probabilistic assumption of reduction of compound gambles. Copyright 2001 Academic Press.

Journal Article↗