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Results for “consensus molecular subtypes”

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PubMed1996

The biologic activity and molecular characterization of a novel synthetic interferon-alpha species, consensus interferon.

Consensus interferon (Infergen) is a wholly synthetic type I interferon (IFN), developed by scanning several interferon-alpha nonallelic subtypes and assigning the most frequently observed amino acid in each position, resulting in a consensus sequence. The antiviral, antiproliferative, NK cell activation activity, cytokine induction, and interferon-stimulated gene-induction activity of consensus interferon has been compared with naturally occurring type I interferons. In all of these comparisons, consensus interferon had a higher activity when compared, on a mass basis, with IFN-alpha 2a and IFN-alpha 2b, although the activity was the same for all of these parameters on an antiviral unit basis. That a synthetic type I interferon could have higher activities than naturally occurring molecules is surprising and may be a result of the higher affinity for the array of type I interferon receptors demonstrated for consensus interferon when compared with IFN-alpha. In contrast, consensus interferon was shown to be an inferior inducer of IL-1 beta when compared with IFN-alpha. These results may reflect differential binding to multiple accessory proteins interacting with a type I interferon receptor. These unique biologic properties may lead to a favorable clinical benefit for consensus interferon when compared with the naturally occurring recombinant molecules. Ongoing clinical trials will ascertain whether consensus interferon can be used in a wide array of disease situations, such as chronic viral infections and certain malignancies.

Amino Acid Sequence↗

PubMed2026

Genomic hallmarks of depot medroxyprogesterone acetate-associated meningiomas.

BACKGROUND: Population-based studies have linked progestin exposure to increased meningioma risk. However, the molecular basis of meningiomas associated with depot medroxyprogesterone acetate (DMPA)-a common injectable contraceptive-remains undefined. METHODS: We performed an integrated clinicopathologic and genomic analysis of meningiomas from 10 women with long-term DMPA exposure. Tumors underwent histopathological analysis, targeted sequencing, and DNA methylation profiling. Data were integrated with reference cohorts (Baylor and Heidelberg) and analyzed through classifier assignment, consensus clustering, copy number analysis, differential methylation testing, and dimensionality reduction. RESULTS: Depot medroxyprogesterone acetate-associated meningiomas were all newly diagnosed, World Health Organization grade 1 tumors with a predilection for the anterior and central skull base (n = 6). Nine patients harbored multiple meningiomas. Four experienced regression of untreated meningiomas following DMPA cessation, while 5 demonstrated stabilization. Histopathology demonstrated relative overrepresentation of metaplastic morphology, an uncommon meningioma subtype. All DMPA-associated meningiomas mapped to benign molecular groups, and most exhibited low copy number alteration burden. Targeted sequencing revealed enrichment for TRAF7 mutations (n = 5), with no NF2 mutations detected. Eight tumors shared consensus cluster identity, with cohesive grouping on principal component analysis and t-distributed stochastic neighbor embedding. No differential methylation was identified at the progesterone receptor locus. CONCLUSIONS: Depot medroxyprogesterone acetate-associated meningiomas represent a recognizable phenotype within the broader NF2-wildtype/TRAF7-enriched spectrum of benign meningiomas, characterized by chromosomal stability, a shared methylation profile, tumor multiplicity, and regression or stabilization following DMPA cessation. While derived from a small single-institution cohort, these findings provide a molecular framework for understanding progestin-associated meningioma biology, reinterpreting epidemiologic literature, and informing population-level risk stratification.

Humans↗

PubMed2003

Therapeutic role of peroxisome proliferator-activated receptors in obesity, diabetes and inflammation.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family and play a significant role in regulation of lipid metabolism, hepatic peroxisomal enzyme expression, insulin sensitivity and glucose homeostasis. PPARs have been classified into three subtypes encoded by different genes: PPARalpha (NR1C1), PPARdelta (NR1C2), and PPARgamma (NR1C3). Each subtype of PPARs appears to be differently expressed in a tissue-specific manner because of their binding to specific consensus DNA sequences, known as PPREs (peroxisome proliferator response elements). Thus, PPARs have emerged as potential molecular targets for the design and synthesis of a different class of compounds, considering the conformation of receptors for the treatment of human metabolic disorders. This review covers the rapid progress made in functional analysis of PPARs and progress made towards the identification of ligands for each subtype receptor.

Animals↗

PubMed2005

Developmental mechanisms underlying the generation of cortical interneuron diversity.

GABAergic interneurons are critical components of cortical circuits. However, understanding their function has become extremely challenging because they constitute one of the most diverse groups of cells in the central nervous system. Indeed, cortical GABAergic interneurons are heterogeneous in so many different ways--morphology, molecular profiling, electrical properties--that even attempts to discern what parameters should be used to identify cortical interneuron subtypes have failed to generate broad consensus among experts in the field. The extent to which cortical interneuron diversity emerges during development is largely unknown, but it is likely that insights on how this process takes place may help us understand their role as integrative and synchronizing elements in cortical function. Here, we review recent data on how the large variety of distinct classes of cortical interneurons may arise during development.

Animals↗

PubMed1995

Identification and molecular evolution of new dynein-like protein sequences in rat brain.

RT-PCR cloning was performed to find unknown members of the dynein superfamily expressed in rat brain. Six kinds of degenerate primers designed for the dynein catalytic domain consensuses were used for extensive PCR amplifications. We have sequenced 550 plasmid clones which turned out to include 13 kinds of new dynein-like sequences (DLP1-8, 9A/B, 10-12) and cytoplasmic dynein heavy chain. In these clones, alternative splicing was detected for a 105 nt-domain containing the CFDEFNRI consensus just downstream of the most N-terminal P-loop (DLP9A and 9B). By using these obtained sequences, initial hybridization studies were performed. Genomic Southern blotting showed each sequence corresponds to a single copy of the gene, while northern blotting of adult brain presented more than one band for some subtypes. We further accomplished molecular evolutionary analysis to recognize their phylogenetic origins for the axonemal and non-axonemal (cytoplasmic) functions. Different methods (UPGMA, NJ and MP) presented well coincident phylogenetic trees from 44 partial amino acid sequences of dynein heavy chain from various eukaryotes. The trunk for all the cytoplasmic dynein heavy chain homologues diverged directly from the root of the phylogenetic tree, suggesting that the first dynein gene duplication defined two distinct functions as respective subfamilies. Of particular interest, we found a duplication event of the cytoplasmic dynein heavy chain gene giving rise to another subtype, DLP4, located between the divergence of yeast and that of Dictyostelium. Such evolutionary topology builds up an inceptive hypothesis that there are at least two non-axonemal dynein heavy chains in mammals.

Amino Acid Sequence↗

PubMed2026

Multiomics Integration Identifies a Molecular Subtype of Intrahepatic Cholangiocarcinoma With Enhanced Benefit From Adjuvant Therapy.

Intrahepatic cholangiocarcinoma (iCCA) is a molecularly heterogeneous liver cancer with a poor prognosis. Improved stratification is needed to guide postoperative therapy. In this study, we applied integrative multiomics analysis to classify iCCA and identify biomarkers predictive of adjuvant treatment benefit. Using publicly available datasets (including whole exome sequencing, RNA sequencing, proteomics, and phosphoproteomics from FU-iCCA cohort and a transcriptomic cohort GSE244807), we defined 3 robust molecular subtypes of iCCA. These subtypes exhibited distinct genomic alterations, pathway activation, and immune microenvironments, with significant differences in overall survival (OS). Through protein-protein interaction network analysis and consensus feature selection using 10 clustering algorithms, we prioritized 8 marker genes distinguishing the subtypes. A Cox proportional-hazards model constructed from these markers stratified patients into high- and low-risk groups. High-risk iCCA, characterized by elevated expression of markers such as CLDN18, MUC1, and MUC5AC, had significantly worse OS in the absence of adjuvant therapy. Notably, in an independent validation of 174 patients with iCCA who underwent resection (single-center cohort), high expression of any of these 3 markers were associated with markedly prolonged OS in patients who received adjuvant chemotherapy or chemoembolization, compared with those who did not. In contrast, marker-negative patients showed no clear benefit from adjuvant therapy. In conclusion, our multiomics approach identified a high-risk, mucin-enriched subtype of iCCA. CLDN18, MUC1, and MUC5AC emerge as candidate predictive biomarkers for adjuvant chemotherapy benefit in iCCA, warranting prospective validation to improve personalized postoperative management.

Humans↗

PubMed1997

Complete sequences of the neuraminidase genes of swine influenza viruses (H1N1) associated with the respiratory disease in pigs.

The complete nucleotide sequences of neuraminidase (NA) of two swine influenza viruses (H1N1) are presented. A/Sw/Quebec/5393/91 (SwQc91) virus, associated with the chronic respiratory disease and A/Sw/ Quebec/192/81 (SwQc81) virus, associated with the acute respiratory disease, were used. The deduced amino acid sequences of NA of SwQc91 and SwQc81 viruses showed a high degree (>95%) of similarity. The NA gene of both viruses was a single open reading frame of 1459 nucleotides coding for 469 aa with a 5' noncoding region of 21 nucleotides and a 3' noncoding region of 28 nucleotides. The comparison of two sequences showed that there were 23 differences recorded for SwQc91 strain, of which 5, 6, and 12 differences were recorded in the hydrophobic, stalk and head regions, respectively. A potential antigenic determinant changed from Ala to Thr at position 453 and there was a new potential glycosylation site present at position 88 for SwQc91 strain whereas it was absent at position 50 when compared with SwQc81 strain. Estimates of genetic distance and phylogenic tree analysis showed that SwQc91 and SwQc81 viruses were closely related with each other and with the American strain, A/Sw/Wisconsin/4754/94. However, the swine viruses represented a distinct group that was considerably divergent from the group of human viruses.

Amino Acid Sequence↗

PubMed1993

The NMDA receptor complex.

The synaptic responses elicited by glutamate and aspartate in the CNS are mediated by distinct groups of receptors which include the ionotropic NMDA receptor. The NMDA receptor is activated by high-strength synaptic input and produces relatively sustained depolarization which can lead to repetitive burst firing. These characteristics allow it to be involved in the maintainance of rhythmic neuronal activity and in the modulation of synaptic efficacy and plasticity. Overstimulation of the NMDA receptor appears to play a pivotal role in the physiopathology of ischemic brain injury. The NMDA receptor contains an integral cationic channel which is highly permeable to Ca2+ as well as to Na+ and K+. This receptor has several domains in addition to the NMDA recognition site: i) a divalent cation binding site within the channel pore, at which Mg2+ ions bind, ii) a binding site recognized by dissociative anesthetics and MK-801 within the channel; and iii) modulatory sites sensitive to glycine, Zn2+ and polyamines. The NMDA receptor is strictly controlled by Mg2+ ions in a voltage-dependent manner. Moreover, it is modulated by protons, by changes in the redox state and by endogenous physiological substances, eg NO and arachidonic acid. Selective antagonists now exist for the NMDA recognition site and glycine and polyamine modulatory sites. Molecular cloning of the NMDA receptor has identified a subunit termed NMDA-R1 and four additional subunits (NMDA-R2A through NMDA-R2D). Functionally distinct NMDA receptor subtypes are formed by heteromeric assembly of NMDA-R1 with NMDA-R2 subunits. NMDA receptor subunits contain consensus phosphorylation sites for protein kinases at the cytoplasmic domain. The high Ca2+ permeability and sensitivity to channel block by Mg2+ are imparted by asparagine residues in a putative channel-forming segment of the protein transmembrane 2. The knowledge of the molecular structure of the NMDA receptor will help to understand the molecular mechanisms responsible for its regulatory features and the molecular bases of neurotoxicity.

Amino Acids↗

PubMed1996

Molecular cloning and functional expression of the alpha1A-adrenoceptor of Medaka fish, Oryzias latipes.

A genomic DNA encoding a subtype adrenoceptor (AR) was cloned from Medaka fish, Oryzias latipes, using an oligonucleotide probe corresponding to the consensus sequence of mammalian alpha-AR and beta-AR. The gene spans at least 9kbp, and the coding region consists of two exons split by an intron of 7.2 kbp located at the same position as those of mammalian alpha1B-AR genes. The gene encodes 470 amino acid residues, the sequence of which shows the highest similarity to that of mammalian alpha1A-AR (61%) and significant but lower similarities to other alpha-AR and beta-AR proteins (31-45%), indicating that the gene encodes a Medaka homolog of alpha1A-AR. To characterize the encoded protein, the mRNA was synthesized in vitro and injected into Xenopus oocytes. As a result, the oocytes responded to 100 nM epinephrine evoking a Ca2 + -dependent C1- current in the order of microamperes, which was not observed for oocytes injected with water alone. The response was reversibly inhibited by an alpha1-selective antagonist, WB4101 (2-[2,6-dimethoxphenoxyethyl]aminomethyl)-1,4-benzodioxane). Similar experiments using several adrenergic agonists revealed that Medaka alpha1A-AR responds to the following agonists in the order: epinephrine > or = (-)norepinephrine > oxymetazoline > or = methoxamine, which is similar to the responses of rat alpha1A receptor expressed in COS cells. The results indicate that fish contains adrenoceptor systems similar to those of mammals in terms of primary structure and pharmacological properties.

Amino Acid Sequence↗

PubMed2005

Development of a three-dimensional model for the N-methyl-D-aspartate NR2A subunit.

NR2 subunits of N-methyl-d-aspartic acid (NMDA) receptors are known to bind the neurotransmitter glutamate, competitive agonists, and antagonists. Since crystallographic data of these proteins are not available, we built a homology model of the ligand binding domain of the NR2A subunit. A consensus binding mode of selected AP5-like NMDA antagonists has been ascertained using molecular docking. The present 3D model gives insights for the design of new NMDA subtype selective compounds.

Amino Acid Sequence↗

PubMed2026

Machine learning and multi-omics clustering to map cellular rewiring and immune evasion in ccRCC.

Immune checkpoint blockade (ICB) efficacy in clear cell renal cell carcinoma (ccRCC) is limited by tumor microenvironment (TME) heterogeneity. Because traditional bulk-derived models lack spatial resolution, we developed an integrated framework connecting macroscopic survival risks to microscopic TME structures. We applied ten algorithms to establish multi-omics subtypes and evaluated 101 machine-learning combinations across three independent cohorts to generate a Consensus Machine Learning-driven Signature (CMLS). The signature's spatial and cellular origins were decoded using spatial transcriptomics (ST) and a 140,000-cell scRNA-seq atlas. Expression of key genes was experimentally validated via RT-qPCR in 17 paired ccRCC clinical tissues. We identified two molecular subtypes with distinct clinical and epigenetic profiles. SuperPC optimization yielded a 24-gene CMLS serving as an independent prognostic factor. scRNA-seq and ST deconvolution revealed these signals predominantly originate from cancer-associated fibroblasts (CAFs) and malignant epithelial cells, which collaborate to drive spatial immune exclusion. RT-qPCR confirmed significant overexpression of five core CMLS genes in ccRCC versus adjacent normal tissues. Low CMLS scores correlated with enhanced ICB responsiveness, whereas high-CMLS tumors demonstrated specific vulnerability to dasatinib and dabrafenib. The CMLS translates spatial immune-exclusion dynamics into a quantifiable metric, outperforming tumor mutational burden in predicting ICB benefits, providing a robust tool for patient stratification in ccRCC.

Humans↗

PubMed1996

A study of biomarkers in cervical carcinoma and clinical correlation of the novel biomarker MN.

The MN protein is a newly described biomarker found to be overexpressed in most cervical carcinomas. This study was an effort to evaluate the prognostic importance of tumor MN expression, HPV status, and the presence of other biomarkers in cervical cancers. Tumor DNA and protein for study were extracted from archived frozen tissue. Tumor tissues and controls were evaluated by Western blot analysis for MN, intestinal alkaline phosphatase (IAP), c-myc, and p53 protein overexpression. Immunohistochemistry was performed for MN quantification and the study of expression patterns in histologic subtypes of cervical cancer. HPV data were obtained by PCR amplification of extracted DNA using consensus and type-specific primers. Clinical data were obtained from the patients' records and from the cancer registry. Clinical and molecular data were correlated by chi2, Fisher's exact test, and logistic regression. The results demonstrate that IAP is not overexpressed in clinical specimens of cervical carcinoma, although in somatic cell hybrid experiments, overexpression of IAP correlates with the malignant state. None of 47 tumors, including those which were HPV negative, overexpressed p53. c-myc protein overexpression occurred in 11 of 52 tumors, most of which contained HPV 16, but this was not significantly different from the tumors as a whole. There was no apparent association between MN protein expression and the overexpression of c-myc protein. MN was overexpressed in all cancers and quantitatively varied with the histologic subtype. Specifically, lower expression of MN correlated with adenosquamous and less-differentiated histology (P < 0.01 for grade 3 tumors). Low expression of MN protein also correlated with HPV negativity (P < 0.05). In stage IB and IIA cancers, low expression of MN was associated with deeper cervical stromal invasion (P < 0.03). Further, low expression of MN correlated with lymph node metastases in small (<3.5 cm) IB and IIA cervical cancers (P < 0.04). These data suggest that MN is emerging as a potentially important new biomarker for cervical carcinoma. The overexpression commonly seen in cervical cancer is possibly associated with loss of a critical tumor suppressor gene located on chromosome 11. Low expression of MN antigen appears to correlate with several adverse prognostic features and further prospective study is warranted.

Adult↗

PubMed2000

Fusion protein predicted amino acid sequence of the first US avian pneumovirus isolate and lack of heterogeneity among other US isolates.

Avian pneumovirus (APV) was first isolated from turkeys in the west-central US following emergence of turkey rhinotracheitis (TRT) during 1996. Subsequently, several APV isolates were obtained from the north-central US. Matrix (M) and fusion (F) protein genes of these isolates were examined for sequence heterogeneity and compared with European APV subtypes A and B. Among US isolates the M gene shared greater than 98% nucleotide sequence identity with only one nonsynonymous change occurring in a single US isolate. Although the F gene among US APV isolates shared 98% nucleotide sequence identity, nine conserved substitutions were detected in the predicted amino acid sequence. The predicted amino acid sequence of the US APV isolate's F protein had 72% sequence identity to the F protein of APV subtype A and 71% sequence identity to the F protein of APV subtype B. This compares with 83% sequence identity between the APV subtype A and B predicted amino acid sequences of the F protein. The US isolates were phylogenetically distinguishable from their European counterparts based on F gene nucleotide or predicted amino acid sequences. Lack of sequence heterogeneity among US APV subtypes indicates these viruses have maintained a relatively stable population since the first outbreak of TRT. Phylogenetic analysis of the F protein among APV isolates supports classification of US isolates as a new APV subtype C.

Amino Acid Sequence↗

PubMed1986

Antiherpetic effects of a human alpha interferon analog, IFN-alpha Con1, in hamsters.

The efficacy of a novel consensus form of human alpha interferon designated IFN-alpha Con1 was evaluated against herpesvirus infections in vitro and in vivo. At comparable antiviral concentrations, natural lymphoblastoid IFN, IFN-alpha Con1, the molecular subtype IFN-alpha, and the hybrid IFN-alpha AD(Bgl) obtained by recombinant DNA methods conferred similar protection against herpes simplex virus type 1 and type 2 (HSV-2) infections of human cells in vitro. Whereas 7 X 10(5) U of IFN-alpha AD(Bgl) administered in 7 intraperitoneal (i.p.) doses between -4 and 96 h relative to infection protected 90% of mice from a lethal HSV-2 infection, a similar treatment regimen with IFN-alpha Con1 conferred no protection. Systemic HSV-2 infection of hamsters was rapidly lethal, but a single i.p. treatment with 10(6) U of either IFN-alpha Con1 or IFN-alpha AD(Bgl) was highly effective and protected 90 and 75% of animals, respectively, when given 6 h before infection; treatment with IFN-alpha Con1 protected 45% of animals when administered 10 h after infection. In addition, IFN-alpha Con1 was highly protective against acute cervicovaginal HSV-2 infection of hamsters when administered either in a single i.p. dose of 10(6) U at -6 or 10 h relative to infection or in multiple i.p. doses of 10(6) U between -6 and 120 h relative to infection. Protection was manifested by a delay in the onset of and a reduction in duration of infection, a reduction in the number of positive cervicovaginal infections, and an increase in the survival rate.

Animals↗

PubMed1997

Cloning and expression of the neuromedin B receptor and the third subtype of bombesin receptor genes in the mouse.

We cloned the genes for the mouse homologue of the neuromedin B receptor (NMB-R) and the bombesin receptor subtype 3 (BRS-3). Both receptor genes consist of three exons with well-conserved intron-exon borders. Although the NMB-R gene spans more than 10 kb, the BRS-3 gene spans only about 4 kb. Comparison of the mouse and human receptor sequences indicates 90% (NMB-R) and 85% (BRS-3) sequence homology at the amino-acid level. In the adult mouse, the NMB-R mRNA is expressed in the brain, testis, esophagus, intestine and uterus, whereas the BRS-3 mRNA is expressed predominantly in the brain. In the brain, the NMB-R gene expression is prominent in the thalamic and olfactory regions, and the BRS-3 gene is expressed particularly in the hypothalamic region. In mouse testis, the NMB-R gene expression is prominent, and the expression of BRS-3 mRNA is barely detected. In contrast, BRS-3 has been shown to be expressed in rat testis and guinea-pig uterus, therefore it is possible that a different subtype of the bombesin receptor mediates the same response in different species. Together with the mouse GRP-R gene cloned previously, cloning of the mouse NMB-R and BRS-3 genes permits comparison of function and structure of the three bombesin receptor subtypes in the mouse.

Animals↗

PubMed1996

Genetic variability and function of the long terminal repeat from syncytium-inducing and non-syncytium-inducing human immunodeficiency virus type 1.

We analyzed sequence variability and function of the long terminal repeat (LTR) from syncytium-inducing (SI) and non-syncytium-inducing (NSI) HIV-1. Twenty LTR DNA clones were obtained by polymerase chain reaction amplification and molecular cloning from short-term cultures of SI and NSI viruses from an AIDS patient and two asymptomatic individuals, respectively. All the LTR clones tested contained multiple nucleotide changes (mostly G-to-A transitions), compared to the subtype B consensus sequence, which were clustered within the negative regulatory element, including NF-AT, USF, and TCF-1 alpha binding sites. The core promoter/TAR region sequences were highly conserved. The basal and Tat-mediated transcriptional activities of selected LTR clones tested were 0.1 to 1 and 0.2 to 0.5 times that of the control, respectively, regardless of the SI or NSI origin of the clones. Phylogenetic analysis revealed interi-solate sequence divergence in the LTR that was similar but not identical to previously analyzed vif sequences from the same samples. In particular, the inter-isolate distances from reference sequences differed for the LTR and vif. This raises the possibility that recombination occurred between corresponding LTR and vif loci of the quasi-species present in the isolates described here.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Clinical and molecular prognostic factors in operable laryngeal cancer.

Many factors affect the prognosis in operable laryngeal squamous cell carcinoma (LSCC). Many clinical factors have been implicated in tumor recurrence and poor survival of the patients. The aim of the present study is to investigate the demographic, clinical and histological characteristics as prognostic factors. Moreover, our aim is to analyze the role of modern molecular biomarkers in the prognosis of patients with LSCC. One hundred patients with operable laryngeal carcinoma underwent surgery as primary treatment between April 1999 and April 2002. Ninety-four of them were men and 6 women, with a median age of 62 years (39-77). All demographic data of the patients were recorded. Staging of the tumor revealed 20 cases with T2 cancer, 46 cases with T3 and 34 cases with T4, while N classification included 91 patients with N0 tumor, 3 with N1 and 6 with N2. Among the 100 cases, 47 were located in the glottis, 46 in the supraglottic region and 7 were transglottic. Histology grading revealed 35 cases of grade G1, 50 cases of G2 and 15 cases of G3. Postoperatively, all patients were followed regularly for the possibility of tumor relapse, with a median follow-up period of 40.2 months (4.8-58.4). During the operation, a tissue specimen was collected from the tumor. The specimens were used for RNA and DNA extraction. Isolated RNA was used to investigate the expression of wt-p53, bcl-2, VEGF and EGFR by the reverse transcriptase PCR method (RT-PCR) using specific primers, while genomic DNA was used for the detection of EBV and HPV (16/18 subtypes) by the consensus primer-mediated polymerase chain reaction method (PCR). All data such as tumor recurrence and survival were recorded. Statistical analysis was performed using the SPSS and STATA statistical packages in order to investigate the role of all clinical and molecular factors and their combinations as significant prognostic markers. The tumor recurrence rate was 31%, while the tumor associated death rate was 27% and total death rate 30%. Univariate analysis for overall survival showed significance for the T stage, TNM stage and site of the tumor. Univariate analysis for the time to progression showed significance for the T stage, N stage, TNM stage, site of the tumor and tumors simultaneously positive for EGFR and VEGF, while EGFR expression was borderline insignificant. Multivariate analysis revealed TNM stage as the only significant factor for overall survival, and TNM stage, site of the tumor and EGFR expression as significant factors for time to progression. The molecular biomarkers EGFR and VEGF have a prognostic significance in laryngeal cancer in addition to the established clinical prognostic factors such as the stage and site of the tumor. These markers, apart from their role in carcinogenesis, seem to play an important role in tumor relapse.

Adult↗

PubMed1988

Population genetics and molecular biology of the childhood chronic arthropathies.

Recent immunogenetic studies of JRA patients have both helped to clarify subdivision into distinctive subtypes and identified those subtypes which may be related to adult rheumatic disease. Despite the variability of HLA associations from different geographic sources, a consensus appears to be emerging as to the most important associations. In addition to the HLA-DR locus, distinct associations with the HLA-DP and HLA-DQ loci have been described. Family studies have suggested an increased risk with certain haplotypes, particularly in the EOPA JRA population. Although inheritance patterns remain to be defined, recent studies with monoclonal antibodies, alloreactive T cell clones, and DNA have identified the existence of specific epitopes encoded by a variety of Ia molecules which may be more directly related to disease susceptibility. The concept of an epitope dose effect is put forward to account for the variable HLA association with disease, particularly with regard to EOPA JRA. Further developments in the definition of micropolymorphisms of Ia molecules at the genomic level as well as the possible involvement of other genetic loci, in particular T cell receptor variable gene products, should help clarify our understanding of the role of genetic factors in the aetiology of JRA. The studies of the last two decades indicate that inferences made by Carter (1969) on the 'polygenic, weakly penetrant genetic effect' in autoimmune disease are indeed applicable to JRA.

Arthritis, Juvenile↗