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At least 1,063 records · Page 59Linked to original sources
PubMed2005

IL-1-regulated responses in astrocytes: relevance to injury and recovery.

In the central nervous system (CNS), the cellular processes of astrocytes make intimate contact with essentially all areas of the brain. They have also been shown to be functionally coupled to neurons, oligodendrocytes, and other astrocytes via both contact-dependent and non-contact-dependent pathways. These observations have led to the suggestion that a major function of astrocytes in the CNS is to maintain the homeostatic environment, thus promoting the proper functioning of the neuronal network. Inflammation in the CNS disrupts this process either transiently or permanently and, as such, is thought to be tightly regulated by both astrocytes and microglia. The remarkable role that single cytokines, such as TNF and IL-1, may play in this process has now been well accepted, but the extent of the reprogramming of the transcriptional machinery initiated by these factors remains to be fully appreciated. With the advent of microarray technology, a more comprehensive analysis of this process is now available. In this report we review data obtained with this technology to provide an overview of the extent of changes induced in astrocytes by the cytokine IL-1.

Animals↗
PubMedDate not supplied

Neuroendocrine tumors of the larynx.

A review of the international literature has revealed 68 paragangliomas, 42 large cell, and 74 small cell tumors of the larynx. Paragangliomas are usually benign, although malignant cases have been reported. Large cell tumors are malignancies associated with a high incidence of early cervical metastasis. Small cell tumors are aggressive cancers characterized by early, diffuse metastatic disease. All three neoplasms demonstrate a propensity for the supraglottic larynx. While surgery remains the treatment of choice for paragangliomas and large cell cancers, small cell cancers are best treated by radiotherapy and chemotherapy. The determinate 5-year survival for patients with paragangliomas, large cell, and small cell cancers is 60%, 34%, and 14%, respectively. While representing distinct clinical entities, these neoplasms demonstrate similar ultrastructural and histochemical features and should be classified as neuroendocrine tumors of the larynx (NETL). A comprehensive analysis of these laryngeal tumors is presented herein. Their clinical behavior and management options are reviewed and a scheme for their nomenclature and classification is proposed.

Adolescent↗
PubMed2006

Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC.

Hepatocellular adenomas are benign tumors that can be difficult to diagnose. To refine their classification, we performed a comprehensive analysis of their genetic, pathological, and clinical features. A multicentric series of 96 liver tumors with a firm or possible diagnosis of hepatocellular adenoma was reviewed by liver pathologists. In all cases, the genes coding for hepatocyte nuclear factor 1alpha (HNF1alpha) and beta-catenin were sequenced. No tumors were mutated in both HNF1alpha and beta-catenin enabling tumors to be classified into 3 groups, according to genotype. Tumors with HNF1alpha mutations formed the most important group of adenomas (44 cases). They were phenotypically characterized by marked steatosis (P < 10(-4)), lack of cytological abnormalities (P < 10(-6)), and no inflammatory infiltrates (P < 10(-4)). In contrast, the group of tumors defined by beta-catenin activation included 13 lesions with frequent cytological abnormalities and pseudo-glandular formation (P < 10(-5)). The third group of tumors without mutation was divided into two subgroups based on the presence of inflammatory infiltrates. The subgroup of tumors consisting of 17 inflammatory lesions, resembled telangiectatic focal nodular hyperplasias, with frequent cytological abnormalities (P = 10(-3)), ductular reaction (P < 10(-2)), and dystrophic vessels (P = .02). In this classification, hepatocellular carcinoma associated with adenoma or borderline lesions between carcinoma and adenoma is found in 46% of the beta-catenin-mutated tumors whereas they are never observed in inflammatory lesions and are rarely found in HNF1alpha mutated tumors (P = .004). In conclusion, the molecular and pathological classification of hepatocellular adenomas permits the identification of strong genotype-phenotype correlations and suggests that adenomas with beta-catenin activation have a higher risk of malignant transformation.

Adenoma, Liver Cell↗
PubMed2007

Wnt'er in liver: expression of Wnt and frizzled genes in mouse.

UNLABELLED: The Wnt signaling pathway is essential for a wide array of developmental and physiological processes. Wnts are extracellular ligands that bind to frizzled (Fz) receptors at the membrane, canonically inducing beta-catenin nuclear translocation and activation. Although beta-catenin has been shown to be critical in liver biology, the expression of the 19 Wnt and 10 Fz genes in liver remains undetermined. We report comprehensive analysis of Wnt and Fz expression in whole liver as well as individual cell types: freshly isolated and plated hepatocytes, biliary epithelial cells, normal and activated stellate and Kupffer cells, and sinusoidal endothelial cells (SECs). Oligonucleotides for the 19 Wnt, 10 frizzled receptors genes, and secreted Frizzled-related protein-1 (sFRP or Fzb) were synthesized based on the available sequences. A total of 11 Wnts and 8 Fz genes and Fzb were expressed in normal liver. Although only 6 Wnt and 5 Fz genes were expressed in freshly isolated hepatocytes, 8 Wnt genes, 7 Fz genes, and Fzb were expressed in plated hepatocytes. Although 12 Wnt and 7 Fz genes were expressed in biliary tree, additional Fz9 and Fzb were only expressed in cultured biliary epithelial cells. The same 14 Wnt and 7 Fz genes were expressed in both activated and normal stellate and Kupffer cells; only Fzb was expressed in their activated state. Also, 11 Wnt, seven Fz, and Fzb genes were expressed in SECs. CONCLUSION: These data indicate that most Wnt and frizzled genes are expressed in the liver and might be playing important roles in liver pathobiology via canonical and noncanonical pathways.

Animals↗
PubMed2006

Neuroimaging H.M.: a 10-year follow-up examination.

In 1997, Corkin et al. described the anatomical boundaries of the amnesic patient H.M.'s surgical resection, based on a comprehensive analysis of magnetic resonance imaging (MRI) scans collected in 1992 and 1993 (Corkin et al. (1997) J Neurosci 17:3964-3979). We subsequently scanned H.M. on several occasions, employing more advanced data acquisition and analysis methods, and now describe additional details about his brain anatomy and pathology. This account combines results from high-resolution T1-weighted scans, which provide measures of cortical and subcortical morphometry, diffusion tensor images, which provide quantitative information about white matter microstructure and the anatomy of major fasciculi, and T2-weighted images, which highlight damage to deep white matter. We applied new MRI analysis techniques to these scans to assess the integrity of areas throughout H.M.'s brain. We documented a number of new changes, including cortical thinning, atrophy of deep gray matter structures, and a large volume of abnormal white matter and deep gray matter signal. Most of these alterations were not apparent in his prior scans, suggesting that they are of recent origin. Advanced age and hypertension likely contributed to these new findings.

Aged↗
PubMed1994

Hippocampus of the domestic pig: a stereological study of subdivisional volumes and neuron numbers.

With the aim of establishing a quantitative structural basis for comparative and experimental studies, the volumes of the hippocampal subdivisions and the total number of neurons in each subdivision were estimated in domestic pig brains using modern stereological techniques. In addition to a detailed description of the stereological methods used in the analysis, comprehensive descriptions of the architectonic boundaries of the subdivisions are included. The absolute and relative volumes of the subdivisions were compared to those of a number of other species and the relationship between the number of neurons and the volume of the subdivisions was compared to that in homologous subdivisions of laboratory rats and humans. The methodology used to estimate the volumes and the total number of neurons in the individual subdivisions were evaluated with regard to the sensitivity that they can provide in experimental studies.

Animals↗
PubMed2002

Highly multiplexed genotyping of coronary artery disease-associated SNPs using MALDI-TOF mass spectrometry.

Highly multiplexed genotyping methods are needed to support a comprehensive analysis of single nucleotide polymorphisms (SNPs) in coronary artery disease (CAD)-related genes. In this study we evaluated chip-based MALDI-TOF mass spectrometry for multiplexed genotyping of SNPs associated with CAD. Our analysis included 14 healthy Japanese individuals and 19 Japanese patients with myocardial infarction whose first attack occurred before age 50. We selected 29 candidate genes involved in 1) the renin-angiotensin system, 2) lipid metabolism, 3) cytokines and adhesion molecules, 4) growth factors, and 5) the coagulation-fibrinolysis system. Genotyping of candidate SNPs was performed by MALDI-TOF MS using a MassARRAY system, and 4-plex analysis was achieved at a maximum. All 39 SNPs determined by the fluorescent dye-terminator cycle sequencing method from four randomly selected patients were found to be in complete agreement with the results obtained from MassARRAY system. Significant differences were observed in the -1965delG of PAI1 (SERPINE1) with respect to allelic frequency, the G>A in the promoter region SNP in SM22 (TAGLN) for dominant genotype, and in two other SNPs (C>T in intron 1 of HGF, and -1965delG of PAI1) for recessive genotype. Three SNPs (803T>C of AGT, 677CT of MTHFR, 190T>C of ADRB3) showed weak differences in allelic frequency. MALDI-TOF-MS provided high performance with a multiplex assay design for analysis of CAD-related SNPs by increasing the throughput while maintaining a high level of accuracy.

Cell Adhesion Molecules↗
PubMed2003

Germline TP53 mutations and Li-Fraumeni syndrome.

There are now reports of nearly 250 independent germline TP53 (p53) mutations in over 100 publications. Such mutations are typically associated with Li-Fraumeni or Li-Fraumeni-like syndrome, although many have been identified in cohorts of patients with tumors considered to be typical of LFS. In general, the spectrum of mutations that has been detected in the germline reflects that found in tumors, although there are some notable exceptions in certain tumor types. Detailed knowledge of the pedigrees allows a comprehensive analysis of genotype-phenotype correlations and an understanding of the tumors that are associated with germline TP53 mutations. This review will discuss the spectrum of mutations and the methods for mutation detection, the tumors associated with inheritance of a germline mutation, and some of the ethical and clinical problems in patients with a germline TP53 mutation.

Family Health↗
PubMed2004

Context of deletions and insertions in human coding sequences.

We studied the dependence of the rate of short deletions and insertions on their contexts using the data on mutations within coding exons at 19 human loci that cause mendelian diseases. We confirm that periodic sequences consisting of three to five or more nucleotides are mutagenic. Mutability of sequences with strongly biased nucleotide composition is also elevated, even when mutations within homonucleotide runs longer than three nucleotides are ignored. In contrast, no elevated mutation rates have been detected for imperfect direct or inverted repeats. Among known candidate contexts, the indel context GTAAGT and regions with purine-pyrimidine imbalance between the two DNA strands are mutagenic in our sample, and many others are not mutagenic. Data on mutation hot spots suggest two novel contexts that increase the deletion rate. Comprehensive analysis of mutability of all possible contexts of lengths four, six, and eight indicates a substantially elevated deletion rate within YYYTG and similar sequences, which is one of the two contexts revealed by the hot spots. Possible contexts that increase the insertion rate (AT(A/C)(A/C)GCC and TACCRC) and decrease deletion (TATCGC) or insertion (GCGG) rates have also been identified. Two-thirds of deletions remove a repeat, and over 80% of insertions create a repeat, i.e., they are duplications.

Chromosome Deletion↗
PubMed1994

Non-phenylketonuria hyperphenylalaninaemia in Northern Ireland: frequent mutation allows screening and early diagnosis.

Up to 10% of newborn children with a positive Guthrie test have non-phenylketonuria hyperphenylalaninaemia, i.e., mild elevation of serum phenylalanine that does not require dietary treatment. Depending on the relative frequencies of different phenylalanine hydroxylase mutations in a particular population, non-PKU HPA is usually caused by the combined effect of a mild HPA mutation and a severe PKU mutation. Presented here is a comprehensive analysis of non-PKU HPA in Northern Ireland. Of particular interest is one prevalent HPA mutation (T380M), which is present in over 70% of non-PKU HPA patients in Northern Ireland. Screening for this mutation is easy and inexpensive and can help confirm the diagnosis of non-PKU hyperphenylalaninaemia in the majority of cases at a very early stage. This may be clinically useful and reassuring for the parents. Other mutations described are V245A, L194P, and E390G.

Adolescent↗
PubMed2002

Identification of seven novel mutations of F8C by DHPLC.

Hemophilia A is an X-linked recessive disorder resulting from deficiency of Factor VIII (F8C), an important protein in blood coagulation. A large number of disease producing mutations have been reported in the F8C gene. However, a comprehensive analysis of mutations is difficult to conduct due to the large gene size, its many scattered exons, and the high frequency of de novo mutations. In this study, we performed analysis using PCR, Conformation Sensitive Gel Electrophoresis (CSGE), Denaturing High Performance Liquid Chromatography (DHPLC) and direct sequencing. We found seven novel mutations causing severe, moderate and mild Hemophilia A: IVS14-1G>A, G458V, T1695S, L1758P, Q2311P, 1441delT, 1269-1271insA. At least four variants detected by DHPLC (IVS14-1G>A, Q2311P,_R698W and D1241Q) were not detectable by CSGE.

Amino Acid Sequence↗
PubMed2005

Altered expressions of HOX genes in human cutaneous malignant melanoma.

HOX genes act as master genes to control morphogenesis. In human, HOX genes form 4 clusters composing 9 to 11 HOX genes (39 genes in total) on different chromosomes. We hypothesized that aberrant expression of HOX genes was associated with development and subsequent progression of melanoma and that the 39 HOX gene expression pattern determined the sites where melanoma grew. The expression levels of 39 HOX genes in 15 human cutaneous melanoma specimens and 7 nevus pigmentosus specimens were quantified by a comprehensive analysis system based on the real-time RT-PCR method. We found that the expression levels of HOXA11, A13, B9, D12 and D13 in melanoma were higher than those in nevus pigmentosus and that the expression levels of HOXA11, B2 and C13 were significantly different between pT4 melanoma and pT1 to pT3 melanoma. It was most notable that the expression levels of HOXA1, A2, C4 and B13 in melanoma with distant metastasis were higher than those in melanoma without it. On the other hand, we found no relationship between HOX genes expression patterns and the growing sites of melanoma. These results indicated that the misexpressions of some specific HOX genes were implicated in melanoma genesis and metastasis but had no linkage with melanoma sites.

Adult↗
PubMed2006

Altered patterns of transcription of the septin gene, SEPT9, in ovarian tumorigenesis.

Ovarian carcinoma represents the most lethal gynaecological malignancy. A variety of morphological subtypes are recognised (e.g. serous, mucinous, endometrioid), which may be benign, borderline or malignant. While their relationship is controversial, knowledge of the molecular mechanisms of ovarian tumorigenesis may help resolve this issue and perhaps identify early markers of disease. Perturbed patterns of expression of the SEPT9 gene on chromosome 17q25.3 have been implicated in a variety of tumour types including both breast and ovarian neoplasia. In preliminary studies, we showed that SEPT9 mRNA was upregulated in a bank of ovarian tumours, which included benign, borderline and malignant tumours, and reported increased levels of one splice variant, SEPT9_v4*. We now describe a comprehensive analysis of SEPT9 expression specifically in serous and mucinous ovarian tumours (benign, borderline and malignant), using cDNA microarray, semi- and quantitative RTPCR of microdissected archival tumour material. Our data show consistent and specific overexpression of both SEPT9_v1 and SEPT9_v4* transcripts in the epithelial component of ovarian tumours. These transcripts show highest levels of expression in serous and mucinous borderline tumours. SEPT9_v1 is also upregulated in both serous and mucinous carcinomas. Interestingly, highest levels of expression are observed in serous borderline and low-grade tumours rather than high-grade in keeping with a model of progression of benign, borderline and low-grade serous tumours.

Cell Transformation, Neoplastic↗
PubMed2006

Chemokine receptors in head and neck cancer: association with metastatic spread and regulation during chemotherapy.

Head and neck carcinomas are histologically and clinically heterogeneous. While squamous cell carcinomas (SCC) are characterized by lymphogenous spread, adenoid cystic carcinomas (ACC) disseminate preferentially hematogenously. To study cellular and molecular mechanisms of organ-specific metastasis, we used SCC and ACC cell lines and tumor tissues, obtained from patients with primary or metastatic disease. Comprehensive analysis at the mRNA and protein level of human chemokine receptors showed that SCC and ACC cells exhibited distinct and nonrandom expression profiles for these receptors. SCC predominantly expressed receptors for chemokines homeostatically expressed in lymph nodes, including CC chemokine receptor (CCR) 7 and CXC chemokine receptor (CXCR)5. No difference in expression of chemokine receptors was seen in primary SCC and corresponding lymph node metastases. In contrast to SCC, ACC cells primarily expressed CXCR4. In chemotaxis assays, ACC cells were responsive to CXCL12, the ligand for CXCR4. Exposure of ACC cells to cisplatin resulted in upregulation of CXCR4 on the cell surface, which was repressed by the transcriptional inhibitor, alpha-amanitin. Treatment of ACC cells with CXCL12 resulted in the activation of Akt and ERK1/2 pathways. Furthermore, CXCL12 suppressed the rate of apoptosis induced by cisplatin in ACC cells, suggesting that signaling via CXCR4 may be part of a tumor cell survival program. Discrimination of the chemokine receptor profile in SCC and ACC in vitro and in tissues provided insights into their distinct biologic and clinical characteristics as well as indications that chemokine receptors might serve as future therapeutic targets in these malignancies.

Antineoplastic Agents↗
PubMed2006

Identification of a novel human tissue factor splice variant that is upregulated in tumor cells.

Tissue factor (TF) is a transmembrane glycoprotein that serves as the prime initiator of blood coagulation and plays a critical role in thrombosis and hemostasis. In addition, a variety of tumor cells overexpress cell-surface TF, which appears to be important for tumor angiogenesis and metastasis. To elucidate the mechanism involved in the upregulation of TF in human tumor cells, a comprehensive analysis of TF mRNA from various normal and tumor cells was performed. The results of these studies indicate that, in addition to possessing a normal full-length TF transcript and minor levels of an alternatively spliced transcript known as alternatively-spliced tissue factor (asTF), human tumor cells express additional full-length TF transcripts that are also generated by alternative splicing. Reverse transcriptase-polymerase chain reaction (RT-PCR) and 5'-rapid amplification of cDNA ends- (5'-RACE) based analyses of cytoplasmic RNA from normal and tumor cells revealed that there is alternative splicing of the first intron between exon I and exon II resulting in 2 additional TF transcripts. One of the transcripts has an extended exon I with inclusion of most of the first TF intron (955 bp), while the second transcript is formed by the insertion of a 495 bp sequence, referred to as exon IA, derived from an internal sequence of the first intron. The full length TF transcript with alternatively spliced novel exon IA, referred to as alternative exon 1A-tissue factor (TF-A), represented approximately 1% of the total TF transcripts in normal cells, but constituted 7-10% of the total TF transcript in tumor cells. Quantitative real-time RT-PCR analysis indicated that cultured human tumor cells contain 10-25-fold more copy numbers of TF-A in comparison to normal, untransformed cells. We propose that high-level expression of the novel TF-A transcript, preferentially in tumor cells, may have utility in the diagnosis and staging of a variety of solid tumors.

Adenocarcinoma↗
PubMed2006

Downregulation of the KIP family members p27(KIP1) and p57(KIP2) by SKP2 and the role of methylation in p57(KIP2) inactivation in nonsmall cell lung cancer.

Knowing the status of molecules involved in cell cycle control in cancer is vital for therapeutic approaches aiming at their restoration. The p27(KIP1) and p57(KIP2) cyclin-dependent kinase inhibitors are nodal factors controlling normal cell cycle. Their expression in normal lung raises the question whether they have a mutual exclusive or redundant role in nonsmall cell lung cancer (NSCLC). A comparative comprehensive analysis was performed in a series of 70 NSCLCs. The majority of cases showed significantly reduced expression of both members compared to normal counterparts. Low KIP protein levels correlated with increased proliferation, which seems to be histological subtype preponderant. At mechanistic level, degradation by SKP2 was demonstrated, in vivo and in vitro, by siRNA-methodology, to be the most important downregulating mechanism of both KIPs in NSCLC. Decreased p57(KIP) (2)-transcription complements the above procedure in lowering p57(KIP2)-protein levels. Methylation was the main cause of decreased p57(KIP) (2)-mRNA levels. Allelic loss and imprinting from LIT1 mRNA contribute also to decreased p57(KIP2) transcription. In vitro recapitulation of the in vivo findings, in A549 lung cells (INK4A-B((-/-))), suggested that inhibition of the SKP2-degradation mechanism restores p27(KIP1) and p57(KIP2) expression. Double siRNA treatments demonstrated that each KIP is independently capable of restraining cell growth. An additional demethylation step is required for complete reconstitution of p57(KIP2) expression in NSCLC.

Base Sequence↗
PubMed2002

Diversity in unity: the biochemical composition of the endothelial cell surface varies between the vascular beds.

The vascular endothelium represents a population of squamous epithelial cells characterized by a particular histological localization (intima of blood vessels) and by several physiological functions such as the transport of substances between blood and tissues, the modulation of the vascular tone, the control of blood coagulation and that of the leukocyte extravasation. In spite of all these elements in common and of an identical embryonic origin, endothelial cells show definite morphological and physiological variations that divide them into types and subtypes, each specifically associated to various categories of organs. Even within the vasculature of the same organ, there are clear segmental (arterial/capillary/venous) differentiations of the endothelial cells. While the morphological and physiological differences between endothelial cells are well documented, there are very few data on the biochemistry underlying this heterogeneity. This work presents several data suggesting that, at present, the domain is ripe for a comprehensive analysis of this biochemical diversity, at least in what concerns the luminal aspect of the endothelial plasmalemma, a compartment of crucial importance in the biology and pathology of the cardiovascular system.

Animals↗
PubMed2002

The crocodilian mitochondrial control region: general structure, conserved sequences, and evolutionary implications.

We present the first comprehensive analysis of the crocodilian control region. We have analyzed sequences from all three families of Crocodylia (Crocodylidae, Gavialidae, Alligatoridae), incorporating all genera except Paleosuchus and Melanosuchus. Within the control region of other vertebrates, several sequence motifs and their order appear to be conserved. Herein, we compare aligned crocodilian D-loop sequences to homologous sequences from other vertebrates ranging from fish to birds. Among other findings, we have discovered that while domain I tends to be shorter than the same region in mammals and birds, it contains sequences similar in structure to both the goose-hairpin and termination associated sequences (TAS). Domain II is highly conservative with regard to size among the taxa examined and contains several of the conserved sequence boxes characterized in other vertebrates. Domain III contains several interesting sequence motifs including tandemly repeated sequences, a long poly-A region in the Crocodylidae, and possible bidirection promoter sequences.

Alligators and Crocodiles↗