Thomas B. Shows

Bio: Thomas B. Shows is an academic researcher from Roswell Park Cancer Institute. The author has contributed to research in topics: Gene & Gene mapping. The author has an hindex of 79, co-authored 352 publications receiving 20810 citations. Previous affiliations of Thomas B. Shows include Boston Children's Hospital & Albert Einstein College of Medicine.

cDNA sequence and chromosomal localization of human platelet-derived growth factor A-chain and its expression in tumour cell lines

Abstract: The amino-acid sequence of the precursor of the human tumour cell line-derived platelet-derived growth factor (PDGF) A-chain has been deduced from complementary DNA clones and the gene localized to chromosome 7. The protein shows extensive homology to the PDGF B-chain precursor. Expression of the PDGF A-chain gene is independent of that of the PDGF B-chain in a number of human tumour cell lines, and secretion of a PDGF-like growth factor of relative molecular mass 31,000 correlates with expression of A- but not B-chain messenger RNA.

Molecular genetics of inherited variation in human color vision.

Abstract: The hypothesis that red-green "color blindness" is caused by alterations in the genes encoding red and green visual pigments has been tested and shown to be correct. Genomic DNA's from 25 males with various red-green color vision deficiencies were analyzed by Southern blot hybridization with the cloned red and green pigment genes as probes. The observed genotypes appear to result from unequal recombination or gene conversion (or both). Together with chromosome mapping experiments, these data identify each of the cloned human visual pigment genes.

A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome.

Abstract: Loss of imprinting at IGF2, generally through an H19-independent mechanism, is associated with a large percentage of patients with the overgrowth and cancer predisposition condition Beckwith–Wiedemann syndrome (BWS). Imprinting control elements are proposed to exist within the KvLQT1 locus, because multiple BWS-associated chromosome rearrangements disrupt this gene. We have identified an evolutionarily conserved, maternally methylated CpG island (KvDMR1) in an intron of the KvLQT1 gene. Among 12 cases of BWS with normal H19 methylation, 5 showed demethylation of KvDMR1 in fibroblast or lymphocyte DNA; whereas, in 4 cases of BWS with H19 hypermethylation, methylation at KvDMRl was normal. Thus, inactivation of H19 and hypomethylation at KvDMR1 (or an associated phenomenon) represent distinct epigenetic anomalies associated with biallelic expression of IGF2. Reverse transcription–PCR analysis of the human and syntenic mouse loci identified the presence of a KvDMR1-associated RNA transcribed exclusively from the paternal allele and in the opposite orientation with respect to the maternally expressed KvLQT1 gene. We propose that KvDMR1 and/or its associated antisense RNA (KvLQT1-AS) represents an additional imprinting control element or center in the human 11p15.5 and mouse distal 7 imprinted domains.

The Brn-3 family of POU-domain factors: Primary structure, binding specificity, and expression in subsets of retinal ganglion cells and somatosensory neurons

Abstract: A search for POU domain sequences expressed in the human retina has led to the identification of three closely related genes: Brn-3a, Brn-3b, and Brn-3c. The structure and expression pattern of Brn-3b was reported earlier (Xiang et al., 1993); we report here the structures and expression patterns of Brn-3a and Brn-3c. Antibodies specific for each Brn-3 protein were generated and shown to label only ganglion cells in a variety of vertebrate retinas. A complex pattern of strongly and weakly immunolabeled ganglion cells was observed in mouse, cat, and monkey retinae. In mouse and cat retinae, Brn-3a and Brn-3b proteins are found in a large fraction of ganglion cells, whereas Brn-3c is present in fewer ganglion cells. In the cat retina, anti-Brn-3a immunoreactivity was strong in the small ganglion cells (gamma cells) and weak in the remaining ganglion cells (alpha and beta cells); anti- Brn-3b immunoreactivity was present in all ganglion cells; and anti- Brn3c immunoreactivity was confined to the small ganglion cells. Immunolabeling of macaque retinae following retrograde labeling from the lateral geniculate nucleus revealed strong anti-Brn-3a immunoreactivity in a minority of retrogradely labeled P-type ganglion cells, and weak Brn-3a immunoreactivity in all of the remaining P- and M-type ganglion cells. In the same retinae, strong anti-Brn-3b immunoreactivity was seen in nearly all P-type ganglion cells and weak immunoreactivity in nearly all M-type ganglion cells. Each of the Brn-3- specific antibodies also labeled subsets of neurons in the dorsal root and trigeminal ganglia, suggesting that primary somatosensory neurons and retinal ganglion cells share genetic regulatory hierarchies. In vitro selection of an optimal DNA binding site using the Brn-3b POU domain has revealed a consensus [(A/G)CTCATTAA(T/C)] that is recognized by each of the Brn-3 POU domains and is distinct from binding sites previously described for other POU domain proteins.

Evolution of the functional human beta-actin gene and its multi-pseudogene family: conservation of noncoding regions and chromosomal dispersion of pseudogenes.

Abstract: We have assigned six members of the human beta-actin multigene family to specific human chromosomes. The functional gene, ACTB, is located on human chromosome 7, and the other assigned beta-actin-related sequences are dispersed over at least four different chromosomes including one locus assigned to the X chromosome. Using intervening sequence probes, we showed that the functional gene is single copy and that all of the other beta-actin related sequences are recently generated in evolution and are probably processed pseudogenes. The entire nucleotide sequence of the functional gene has been determined and is identical to cDNA clones in the coding and 5' untranslated regions. We have previously reported that the 3' untranslated region is well conserved between humans and rats (Ponte et al., Nucleic Acids Res. 12:1687-1696, 1984). Now we report that four additional noncoding regions are evolutionarily conserved, including segments of the 5' flanking region, 5' untranslated region, and, surprisingly, intervening sequences I and III. These conserved sequences, especially those found in the introns, suggest a role for internal sequences in the regulation of beta-actin gene expression.

Gene Selection for Cancer Classification using Support Vector Machines

Abstract: DNA micro-arrays now permit scientists to screen thousands of genes simultaneously and determine whether those genes are active, hyperactive or silent in normal or cancerous tissue. Because these new micro-array devices generate bewildering amounts of raw data, new analytical methods must be developed to sort out whether cancer tissues have distinctive signatures of gene expression over normal tissues or other types of cancer tissues. In this paper, we address the problem of selection of a small subset of genes from broad patterns of gene expression data, recorded on DNA micro-arrays. Using available training examples from cancer and normal patients, we build a classifier suitable for genetic diagnosis, as well as drug discovery. Previous attempts to address this problem select genes with correlation techniques. We propose a new method of gene selection utilizing Support Vector Machine methods based on Recursive Feature Elimination (RFE). We demonstrate experimentally that the genes selected by our techniques yield better classification performance and are biologically relevant to cancer. In contrast with the baseline method, our method eliminates gene redundancy automatically and yields better and more compact gene subsets. In patients with leukemia our method discovered 2 genes that yield zero leave-one-out error, while 64 genes are necessary for the baseline method to get the best result (one leave-one-out error). In the colon cancer database, using only 4 genes our method is 98% accurate, while the baseline method is only 86% accurate.

Vascular endothelial growth factor is a secreted angiogenic mitogen

Abstract: Vascular endothelial growth factor (VEGF) was purified from media conditioned by bovine pituitary folliculostellate cells (FC). VEGF is a heparin-binding growth factor specific for vascular endothelial cells that is able to induce angiogenesis in vivo. Complementary DNA clones for bovine and human VEGF were isolated from cDNA libraries prepared from FC and HL60 leukemia cells, respectively. These cDNAs encode hydrophilic proteins with sequences related to those of the A and B chains of platelet-derived growth factor. DNA sequencing suggests the existence of several molecular species of VEGF. VEGFs are secreted proteins, in contrast to other endothelial cell mitogens such as acidic or basic fibroblast growth factors and platelet-derived endothelial cell growth factor. Human 293 cells transfected with an expression vector containing a bovine or human VEGF cDNA insert secrete an endothelial cell mitogen that behaves like native VEGF.

Expression monitoring by hybridization to high density oligonucleotide arrays

Abstract: This invention provides methods of monitoring the expression levels of a multiplicity of genes. The methods involve hybridizing a nucleic acid sample to a high density array of oligonucleotide probes where the high density array contains oligonucleotide probes complementary to subsequences of target nucleic acids in the nucleic acid sample. In one embodiment, the method involves providing a pool of target nucleic acids comprising RNA transcripts of one or more target genes, or nucleic acids derived from the RNA transcripts, hybridizing said pool of nucleic acids to an array of oligonucleotide probes immobilized on surface, where the array comprising more than 100 different oligonucleotides and each different oligonucleotide is localized in a predetermined region of the surface, the density of the different oligonucleotides is greater than about 60 different oligonucleotides per 1 cm2, and the oligonucleotide probes are complementary to the RNA transcripts or nucleic acids derived from the RNA transcripts; and quantifying the hybridized nucleic acids in the array.

Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction

Abstract: Interspersed DNA elements of the form (dC-dA)n.(dG-dT)n constitute one of the most abundant human repetitive DNA families. We report that specific human (dC-dA)n.(dG-dT)n blocks are polymorphic in length among individuals and therefore represent a vast new pool of potential genetic markers. Comparison of sequences from the literature for (dC-dA)n.(dG-dT)n blocks cloned two or more times revealed length polymorphisms in seven of eight cases. Variations in the lengths of 10 (dC-dA)n.(dG-dT)n blocks were directly demonstrated by amplifying the DNA within and immediately flanking the repeat blocks by using the polymerase chain reaction and then resolving the amplified DNA on polyacrylamide DNA sequencing gels. Use of the polymerase chain reaction to detect DNA polymorphisms offers improved sensitivity and speed compared with standard blotting and hybridization.

The scanning model for translation: an update.

Abstract: The small (40S) subunit of eukaryotic ribosomes is believed to bind initially at the capped 5'-end of messenger RNA and then migrate, stopping at the first AUG codon in a favorable context for initiating translation. The first-AUG rule is not absolute, but there are rules for breaking the rule. Some anomalous observations that seemed to contradict the scanning mechanism now appear to be artifacts. A few genuine anomalies remain unexplained.