Biomedical subjects

C Larsson

Publications and source records attributed to C Larsson.

At least 37 records · Page 2Linked to original sources

PubMed2002

Genetic analysis of lithium-associated parathyroid tumors.

OBJECTIVE: The aim of this study was to determine the primary genetic events that may underlie the formation of parathyroid tumors in patients with lithium-associated hyperparathyroidism (HPT). METHODS: Comparative genomic hybridization (CGH), loss of heterozygosity (LOH) and multiple endocrine neoplasia type 1 gene (MEN1) mutation analysis were used to analyze twelve parathyroid tumors from nine patients with lithium-associated HPT. For comparison, CGH was also carried out in a non-lithium-associated group of thirteen sporadic parathyroid tumors. RESULTS: A higher prevalence of multiglandular disease in the lithium-associated HPT patients compared with the idiopathic sporadic patients was observed (Fisher's exact test, P=0.02). CGH alterations were detected in four lithium-associated parathyroid tumors, involving loss at 1p, 11, 15q, 22q and gain of the X chromosome. In addition, one of these four cases exhibited LOH at 11q13 and was found to contain a novel somatic MEN1 mutation (c.1193insTAC). Although fewer lithium-associated parathyroid tumors were shown to contain genetic alterations compared with the sporadic parathyroid tumors, the changes detected were those frequently associated with both familial and sporadic parathyroid tumorigenesis. CONCLUSION: This is, to our knowledge, the first genetic analysis of parathyroid tumors in lithium-associated HPT patients. Our data indicated that the majority of lithium-associated parathyroid tumors do not contain gross chromosomal alterations and suggest that in most cases the tumorigenic pathway is independent of MEN1 and genes at 1p34.3-pter and 1q21-q32. It is possible that other discrete genetic alterations or epigenetic changes, not screened for in this study, could also be responsible for parathyroid tumorigenesis in lithium-associated HPT.

Adolescent↗

PubMed2002

Distinct target regions for chromosome 1p deletions in parathyroid adenomas and carcinomas.

Primary hyperparathyroidism is a common endocrine disease with a multifaceted genetic background, the elucidation of which has only begun. Among others, loss of the short arm of chromosome 1 and somatic inactivation of the multiple endocrine neoplasia type 1 gene (MEN1) in 11q13 represent significant alterations in the tumorigenesis. In the present study deletions of 1p were characterized and the findings were evaluated in relation to the loci of MEN1 and histone deacetylase 1 gene (HDAC1), a menin interacting partner in 1p, as well as to the clinical characteristics. Overall 1p LOH was detected in 18 of the 42 tumors analyzed (43%), and from the deletion patterns a main target interval of 40 cM was identified within 1p band 32.3-36.2. The mapping of HDAC1 centromeric of the main interval, and the lack of altered mRNA expression in tumors with LOH, suggest that HDAC1 is not the main target for 1p deletions in parathyroid tumors. Twenty-five of the 42 tumors (60%) showed alteration of either 1p, of the MEN1 locus, or both. Tumors with LOH at 11q13 had a significantly higher weight than tumors with 1p LOH. In conclusion, LOH in primary sporadic parathyroid adenomas occur frequently on the distal part of chromosome 1p and are thus clearly different from parathyroid carcinomas where the deletions are more proximally located. The findings support that the short arm of chromosome 1 harbors at least two different tumor suppressor genes involved in parathyroid tumorigenesis, the exact identification of which may provide a molecular basis for differential diagnosis of benign and malignant disease in the future.

Adenoma↗

PubMed2001

A PKCbeta isoform mediates phorbol ester-induced activation of Erk1/2 and expression of neuronal differentiation genes in neuroblastoma cells.

Protein kinase C (PKC) activation induces neuronal differentiation of SH-SY5Y neuroblastoma cells. This study examines the role of PKCbeta isoforms in this process. The PKCbeta-specific inhibitor LY379196 had no effect on 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced neurite outgrowth from SH-SY5Y neuroblastoma cells. On the other hand, PKCbeta inhibition suppressed the TPA-stimulated increase in neuropeptide Y mRNA, activation of neuropeptide Y gene promoter elements, and phosphorylation of Erk1/2. The TPA-induced increase in neuropeptide Y expression was also inhibited by the MEK inhibitor PD98059. These data indicate that activation of a PKCbeta isoform, through a pathway involving Erk1/2, leads to increased expression of neuronal differentiation genes in neuroblastoma cells.

Cell Differentiation↗

PubMed2001

Methylation changes in the human IGF2 p3 promoter parallel IGF2 expression in the primary tumor, established cell line, and xenograft of a human hepatoblastoma.

Hepatoblastoma (HB) is a rare malignant embryonal liver tumor. Its pathogenesis has been associated with altered regulation of the IGF2 and H19 genes, and previous studies have suggested a correlation between abnormal methylation and altered expression of these genes in hepatoblastoma. Upregulation of the activity of the IGF2 promoter P3 has previously been shown to be tightly correlated with demethylation in hepatoblastoma. Here, we have used bisulfite genomic sequencing to characterize the methylation pattern of the IGF2 promoter P3 in the hepatoblastoma-derived cell line Hep T1, in the original tumor from which Hep T1 is derived, and in nude mouse xenografts of the Hep T1 cell line. The results show a clear difference in methylation pattern of the most proximal region of the IGF2 P3 promoter between the primary tumor, the cell line, and the xenografts. RNase protection and mRNA in situ hybridization revealed that variations in methylation patterns was paralleled by the levels of IGF2 P3 mRNA, which was detectable in the primary tumor and xenografts, but not in the cell line. Furthermore, it was demonstrated that H19 was reactivated and demethylated in the HepT1 cell line by 5-azaCytidine, in contrast to IGF2 P3, which was not demethylated or reactivated. We suggest that methylation of the proximal IGF2 P3 is important for its regulation.

Animals↗

PubMed2001

Menin interacts directly with the homeobox-containing protein Pem.

The tumour suppressor gene causing multiple endocrine neoplasia type 1 (MEN1) encodes a 610 amino acid protein, menin. In order to identify menin-interacting proteins we used a yeast two-hybrid assay to screen a 12.5-dpc mouse embryo library with partial menin encompassing amino acids 278 to 476. This identified a homeobox containing protein encoded by a placenta and embryonic expression gene, referred to as Pem. GST-pull-down and coimmunoprecipitation experiments confirmed the interaction. Both proteins colocalised predominantly in the nucleus but were occasionally also found in the cytoplasm. Furthermore, in situ hybridisation studies revealed similarities in their expression patterns in mouse embryos and adult tissues. In adult mice both Men1 and Pem yielded strong signals in testis, Sertoli cells and particularly in seminiferous tubules. Thus, our study has identified that menin interacts with Pem, and the high expression of these proteins in the testis suggests a role in spermatogenesis.

Animals↗

PubMed2001

[Vibrio vulnificus. A marine bacterium with lethal potential].

Vibrio vulnificus is a halophilic gram-negative rod widespread in the aquatic environment and associated with primary septicemia and severe wound infections. The first Swedish case was reported in 1994. Ever since, sporadic cases have occurred in the south of Sweden whenever the coastal water temperature has exceeded 20 degrees C. Critical for a successful outcome in these infections has been early diagnosis with appropriate antibiotic and surgical treatment. A review of this subject was prompted by two cases of fulminant septicemia, which both presented themselves as atypical erysipelas.

Aged↗

PubMed2001

Characterization of chromosomal abnormalities in uroepithelial carcinomas by G-banding, spectral karyotyping and FISH analysis.

Chromosome analysis by G-banding, spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) was performed on 24 short-term cultured transitional cell bladder carcinomas and 5 cell lines established from bladder carcinomas. Except for one tumor with an apparently normal chromosomal constitution, clonal chromosome abnormalities were detected in all examined cases by the combined approach. The application of SKY and FISH techniques improved the karyotypic descriptions, originally based on G-banding only, by identifying 32 additional numerical changes, by establishing the chromosomal origin of 27 markers and 2 ring chromosomes, by redefining 53 aberrations and by detecting 15 hidden chromosomal rearrangements. No recurrent translocation, however, was detected. The most prominent karyotypic feature was thus the occurrence of deletions and losses of whole chromosome copies indicating the importance of tumor suppressor genes in transitional cell carcinoma pathogenesis. Invasive carcinomas were karyotypically more complex than were low grade superficial tumors. Specific losses of material from chromosome 9 and from chromosome arms 11p and 8p, and gains of 8q and 1q seem to be early changes appearing in superficial tumors, whereas losses from 4p and 17p and the formation of an isochromosome for 5p were associated with more aggressive tumor phenotypes.

Aged↗

PubMed2001

Characterization of a novel human putative mitochondrial transporter homologous to the yeast mitochondrial RNA splicing proteins 3 and 4.

We report here a novel human gene, hMRS3/4, encoding a putative mitochondrial transporter structurally and functionally homologous to the yeast mitochondrial RNA splicing proteins 3 and 4. These proteins belong to the family of mitochondrial carrier proteins (MCF) and are likely to function as solute carriers. hMRS3/4 spans approximately 10 kb of genomic DNA on chromosome 10q24 and consists of four exons that encode a 364-aa protein with six transmembrane domains. A putative splice variant, encoding a 177-aa protein with three transmembrane domains, was also identified. hMRS3/4 has a well-conserved signature sequence of MCF and is targeted into the mitochondria. When expressed in yeast, hMRS3/4 efficiently restores the mitochondrial functions in mrs3(o)mrs4(o) knock-out mutants. Ubiquitous expression in human tissues and a well-conserved structure and function suggest an important role for hMRS3/4 in human cells.

Alternative Splicing↗

PubMed2001

Aberrations of chromosome 8 in 16 breast cancer cell lines by comparative genomic hybridization, fluorescence in situ hybridization, and spectral karyotyping.

Comparative genomic hybridization (CGH) studies have shown that chromosome 8 is a frequent target for chromosomal aberrations in breast cancer. We characterized these aberrations of chromosome 8 in 16 breast cancer cell lines (BT-474, BT-549, CAMA-1, DU-4475, MCF-7, MDA-MB-134, MDA-MB-157, MDA-MB-361, MDA-MB-415, MDA-MB-436, MPE600, SK-BR-3, T-47D, UACC-812, UACC-893 and ZR-75-1) by CGH, fluorescence in situ hybridization (FISH) with arm- and locus-specific probes, and spectral karyotyping (SKY). Chromosome 8 was structurally abnormal in 13 of 16 cell lines. Loss of 8p was detected in nine cell lines, gain of entire 8q in six cell lines, 8q21-qter in three, 8q23-qter in two, and 8q12-qter and 8p21-q21 in one cell line. Extra copies of the C-MYC oncogene were found in 11 cell lines, but high-level amplification only in SK-BR-3. Derivative chromosomes including material from chromosomes 8 were complex, and the breakpoints were strikingly dissimilar. Chromosome 11 was the most frequent translocation partner with chromosome 8 (in 7 cell lines). Isochromosomes and/or isoderivative 8q were found in four cell lines. The high frequency and complexity of alterations at 8q indicate a significant pathogenetic role in breast cancer. The high-level amplification of c-myc is less common than previously thought.

Breast Neoplasms↗

PubMed2001

The epsilon isoform of protein kinase C is involved in regulation of the LTD(4)-induced calcium signal in human intestinal epithelial cells.

We investigated the potential roles of specific isoforms of protein kinase C (PKC) in the regulation of leukotriene D(4)-induced Ca(2+) signaling in the intestinal epithelial cell line Int 407. RT-PCR and Western blot analysis revealed that these cells express the PKC isoforms alpha, betaII, delta, epsilon, zeta, and mu, but not betaI, gamma, eta, or theta;. The inflammatory mediator leukotriene D(4) (LTD(4)) caused the TPA-sensitive PKC isoforms alpha, delta, and epsilon, but not betaII, to rapidly translocate to a membrane-enriched fraction. The PKC inhibitor GF109203X at 30 microM but not 2 microM significantly impaired the LTD(4)-induced Ca(2+) signal, indicating that the response involves a novel PKC isoform, such as delta or epsilon, but not alpha. LTD(4)-induced Ca(2+) signaling was significantly suppressed in cells pretreated with TPA for 15 min and was abolished when the pretreatment was prolonged to 2 h. Immunoblot analysis revealed that the reduction in the LTD(4)-induced calcium signal coincided with a reduction in the cellular content of PKCepsilon and, to a limited extent, PKCdelta. LTD(4)-induced Ca(2+) signaling was also markedly suppressed by microinjection of antibodies against PKCepsilon but not PKCdelta. These data suggest that PKCepsilon plays a unique role in regulation of the LTD(4)-dependent Ca(2+) signal in intestinal epithelial cells.

Antibodies↗

PubMed2001

Characterisation of the human APC1, the largest subunit of the anaphase-promoting complex.

Accurate segregation of sister chromatids during mitosis is necessary to avoid the aneuploidy found in many cancers. The spindle checkpoint, which monitors the metaphase to anaphase transition, has been shown to be defective in cancers with chromosomal instability. This checkpoint regulates the anaphase-promoting complex or cyclosome (APC/C), a cell cycle ubiquitin ligase regulating among other things sister chromatid separation. We have previously investigated the mouse Apc1 protein (previously also called Tsg24), the largest subunit of the APC/C. We have now sequenced a full-length human APC1 cDNA, mapped its chromosomal location, and analysed its intron-exon boundaries. We have also investigated the RNA and protein expression of the Apc1 and other APC/C components in normal and cancer cells and the relative occurrence of expressed sequence tags (ESTs) representing APC subunits from different tissues. The different APC/C subunits are expressed in most tissues and cell types at fairly constant levels relative to each other, suggesting that they perform their functions as part of a complex. A difference from this pattern is however seen for the APC6, which in some cases is more strongly expressed, suggesting a special function for this protein in certain tissues and cell types.

Amino Acid Sequence↗

PubMed2001

Gain of 1q and loss of 9q21.3-q32 are associated with a less favorable prognosis in papillary thyroid carcinoma.

In order to approach the genetic mechanisms behind initiation and progression of papillary thyroid carcinoma (PTC) tumorigenesis, we characterized numerical chromosomal imbalances in a panel of 25 PTCs with varying histopathological and clinical features using comparative genomic hybridization (CGH). The most frequently detected imbalance was gain of 9q33-qter, which was seen in close to 30% of the cases. The commonly occurring regions of loss were assigned to 22q (12%) and 9q21.3-q32 (12%), while gains preferentially involved the entire X chromosome (20%), 1q (16%), 17q (16%), and 22q (12%). The distribution of CGH alterations supports the idea of a progression of genetic events in the development of PTC, where gain of 9q33-qter would represent a relatively early event that is followed by loss of 22q and gain of X, 1q, 17q, and 22q. When the detected CGH alterations were compared with the clinical outcome and the histopathological features of the 25 PTC cases, several statistically significant correlations were revealed. The total number of genetic alterations was higher in tumors from patients with aggressive disease as compared to those without signs of aggressiveness. Gain of 1q and loss of 9q21.3-q32 were exclusively seen in tumors from patients with aggressive disease, and the presence of distant metastases was associated with gain of 1q. A sex-dependent distribution was also evident for one of the common alterations, with gain of X exclusively seen in male cases. Taken together, the findings identify several candidate locations for tumor suppressor genes and oncogenes that are potentially involved in the establishment and progression of papillary thyroid carcinogenesis.

Adult↗

PubMed2001

Cytosolic redox metabolism in aerobic chemostat cultures of Saccharomyces cerevisiae.

Cytosolic redox balance has to be maintained in order to allow an enduring cellular metabolism. In other words, NADH generated in the cytosol has to be re-oxidized back to NAD(+). Aerobically this can be done by respiratory oxidation of cytosolic NADH. However, NADH is unable to cross the mitochondrial inner membrane and mechanisms are required for conveying cytosolic NADH to the mitochondrial electron transport chain. At least two such systems have proved to be functional in S. cerevisiae, the external NADH dehydrogenase (Luttik et al., 1998; Small and McAlister-Henn, 1998) and the G3P shuttle (Larsson et al., 1998). The aim of this investigation was to study the regulation and performance of these two systems in a wild-type strain of S. cerevisiae using aerobic glucose- and nitrogen-limited chemostat cultures. The rate of cytosolic NADH formation was calculated and as expected there was a continuous increase with increasing dilution rate. However, measurements of enzyme activities and respiratory activity on isolated mitochondria revealed a diminishing capacity at elevated dilution rates for both the external NADH dehydrogenase and the G3P shuttle. This suggests that adjustment of in vivo activities of these systems to proper levels is not achieved by changes in amount of protein but rather by, for example, activation/inhibition of existing enzymes. Adenine nucleotides are well-known allosteric regulators and both the external NADH and the G3P shuttle were sensitive to inhibition by ATP. The most severe inhibition was probably on the G3P shuttle, since one of its member proteins, Gpdp, turned out to be exceptionally sensitive to ATP. The external NADH dehydrogenase is suggested as the main system employed for oxidation of cytosolic NADH. The G3P shuttle is proposed to be of some importance at low growth rates and perhaps its real significance is only expressed during starvation conditions.

Adenosine Triphosphate↗

PubMed2001

The catabolic capacity of Saccharomyces cerevisiae is preserved to a higher extent during carbon compared to nitrogen starvation.

A comparison of catabolic capacity was made between S. cerevisiae cells subjected to 24 h carbon or nitrogen starvation. The cells were shifted to starvation conditions at the onset of respiratory growth on ethanol in aerobic batch cultures, using glucose as the carbon and energy source. The results showed that the catabolic capacity was preserved to a much larger extent during carbon compared to nitrogen starvation. Nitrogen starvation experiments were made in the presence of ethanol (not glucose) to exclude the effect of glucose transport inactivation (Busturia and Lagunas, 1986). Hence, the difference in catabolic capacity could not be attributed to differences in glucose transport capacity during these conditions. In order to understand the reason for this difference in starvation response, measurement of protein composition, adenine nucleotides, inorganic phosphate, polyphosphate and storage carbohydrates were performed. No clear correlation between any of these variables and catabolic capacity after starvation could be obtained. However, there was a positive correlation between total catabolic activity and intracellular ATP concentration when glucose was added to starved cells. The possible mechanism for this correlation, as well as what determines the ATP level, is discussed.

Adenosine Diphosphate↗

PubMed2001

Genetic background of adrenocortical tumor development.

The increasing occurrence of incidentally discovered benign adrenocortical tumors has become a clinical dilemma because of the difficulties in differentiating them from their malignant counterpart. Adrenocortical tumors are associated with familial cancer syndromes such as the Beckwith-Wiedemann syndrome, the Li-Fraumeni syndrome, the Carney complex, multiple endocrine neoplasia type 1, congenital adrenal hyperplasia, and the McCune-Albright syndrome. Genetic events are known to take place on the chromosomal and gene level in sporadic adrenocortical tumors.

Adrenal Cortex↗

PubMed2001

Comparative genomic hybridization identifies loss of 18q22-qter as an early and specific event in tumorigenesis of midgut carcinoids.

Carcinoid tumors are rare neuroendocrine tumors occurring in the lung or in the digestive tract where they are further subclassified as foregut, midgut, or hindgut carcinoids. To gain a better understanding of the genetic basis of the different types of carcinoid tumors, we have characterized numerical imbalances in a series of midgut carcinoids, and compared the results to previous findings in carcinoids from the lung. Numerical imbalances were revealed in 16 of the 18 tumors, and the most commonly detected aberrations were losses of 18q22-qter (67%), 11q22-q23 (33%), and 16q21-qter (22%), and gain of 4p14-qter (22%). The total number of alterations found in the metastases was significantly higher than in the primary tumors, indicating the accumulation of acquired genetic changes in the tumor progression. Losses of 18q and 11q were present both in primary tumors and metastases, whereas loss of 16q and gain of 4 were only detected in metastases. Furthermore, the pattern of comparative genomic hybridization alterations varied depending on the total number of detected alterations. Taken together, the findings would suggest a progression of numerical imbalances, in which loss of 18q and 11q represent early events, and loss of 16q and gain of 4p are late events in the tumor progression of midgut carcinoids. When compared to previously published comparative genomic hybridization abnormalities in lung carcinoids, loss of 11q was found to occur in both tumor types, whereas loss of 18q and 16q and gain of 4 were not revealed in lung carcinoids. The results indicate that inactivation of a putative tumor suppressor gene in 18q22-qter represents a frequent and early event that is specific for the development of midgut carcinoids.

Adult↗

PubMed2001

A highly aggressive primitive mesenchymal tumor with a translocation (1;19)(q12;q13.2).

Soft tissue sarcomas constitute a heterogeneous group of malignant tumors of mesenchymal origin, the classification of which may present a diagnostic challenge. We present here the cytological, histopathological, immunohistochemical, and cytogenetic findings of an unusual case of a highly aggressive sarcoma. Based on the morphology and the immunohistochemical profile, this primitive tumor and its metastases could not be conclusively classified as any of the defined subtypes of sarcomas, although the findings were suggestive of a variant of rhabdomyosarcoma. Cytogenetic characterization using G-banding, SKY, FISH, and CGH revealed almost identical chromosomal compositions of the primary tumor and the metastasis. The hypertetraploid karyotype was characterized by numerical imbalances as well as by an unbalanced translocation t(1;19)(q12;q13.2), which has not been previously reported.

Amputation, Surgical↗

PubMed2001

Identification of numerical and structural chromosome aberrations in 15 high hyperdiploid childhood acute lymphoblastic leukemias using spectral karyotyping.

Spectral karyotyping (SKY) on metaphase spreads from 15 high hyperdiploid (>51 chromosomes) childhood acute lymphoblastic leukemias (ALL), which typically display a poor chromosome morphology, was performed in order to investigate the pattern of numerical abnormalities, reveal the chromosomal origin of marker chromosomes, and identify translocations and other interchromosomal rearrangements not detected by G-banding analysis. In all cases the numerical changes could be fully characterized, and a non-random pattern of chromosomal gain was identified, with chromosomes X, 21, 14, 17, 6, 18, 4, and 10 being most frequently gained. The numerical changes had been partly misinterpreted in 12 of the 15 ALL patients using G-banding, and the present study hence emphasizes the importance of SKY in identifying such anomalies, some of which, i.e. +4 and +10, have been suggested to be prognostically important. The chromosomal origin of all marker chromosomes and of seven structural rearrangements, one of which was the prognostically important Philadelphia chromosome, could be identified. Five rearrangements [der(1)t(1;14)(q32;q21), der(2)t(2;8)(q36;?), der(3)t(2;3)(q21;?), der(8)t(8;14)(?;?), and t(9;21)(q12;q22)] have previously not been reported in ALL, emphasizing the value of SKY in identifying novel chromosomal rearrangements.

Child↗