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PubMed1999

Ultraviolet radiation induced signature mutations in photocarcinogenesis.

The photons of sunlight begin a series of genetic events in skin leading to cancer. UV signature mutations provide an alternative to inherited mutations as a way of identifying genes that are involved in cancer development. They augment epidemiologic and clinical data by serving as molecular evidence for the role of UV radiation in skin carcinogenesis. Signature mutations are present in TP53 and PTCH, two tumor suppressor genes responsible for non-melanoma skin cancer. We review evidence that clones of TP53-mutated cells are present in normal human and murine epidermis exposed to UVB and conclude that, in addition to being a tumorigenic mutagen, sunlight acts as a tumor promoter by favoring the clonal expansion of TP53 mutated cells. These combined actions of sunlight result in normal individuals' carrying a substantial burden of keratinocytes predisposed to cancer. Thus cancer involves both a single-cell problem and a multi-cell problem; in skin cancer, sunlight appears to drive both.

Adult↗

PubMed2005

Gene expression profiling of leukemic cell lines reveals conserved molecular signatures among subtypes with specific genetic aberrations.

Hematologic malignancies are characterized by fusion genes of biological/clinical importance. Immortalized cell lines with such aberrations are today widely used to model different aspects of leukemogenesis. Using cDNA microarrays, we determined the gene expression profiles of 40 cell lines as well as of primary leukemias harboring 11q23/MLL rearrangements, t(1;19)[TCF3/PBX1], t(12;21)[ETV6/RUNX1], t(8;21)[RUNX1/CBFA2T1], t(8;14)[IGH@/MYC], t(8;14)[TRA@/MYC], t(9;22)[BCR/ABL1], t(10;11)[PICALM/MLLT10], t(15;17)[PML/RARA], or inv(16)[CBFB/MYH11]. Unsupervised classification revealed that hematopoietic cell lines of diverse origin, but with the same primary genetic changes, segregated together, suggesting that pathogenetically important regulatory networks remain conserved despite numerous passages. Moreover, primary leukemias cosegregated with cell lines carrying identical genetic rearrangements, further supporting that critical regulatory pathways remain intact in hematopoietic cell lines. Transcriptional signatures correlating with clinical subtypes/primary genetic changes were identified and annotated based on their biological/molecular properties and chromosomal localization. Furthermore, the expression profile of tyrosine kinase-encoding genes was investigated, identifying several differentially expressed members, segregating with primary genetic changes, which may be targeted with tyrosine kinase inhibitors. The identified conserved signatures are likely to reflect regulatory networks of importance for the transforming abilities of the primary genetic changes and offer important pathogenetic insights as well as a number of targets for future rational drug design.

Acute Disease↗

PubMed2006

Gene expression signature of primary imatinib-resistant chronic myeloid leukemia patients.

Although the selective tyrosine kinase inhibitor imatinib is successfully used in the treatment of chronic myeloid leukemia (CML), inherent mechanisms confer primary resistance to leukemic patients. In order to search for potentially useful genes in predicting cytogenetic response, a retrospective gene expression study was performed. Leukocyte RNA isolated before imatinib from interferon-alpha-pretreated chronic phase CML patients (n=34) with or without major cytogenetic remission (< or =35% Philadelphia (Ph)+ metaphases) during the first year of treatment was comparatively analyzed using Affymetrix U133A chips. Using support vector machines for gene classification, an outcome-specific gene expression signature consisting of 128 genes was identified. Comparative expression data of specific genes point to changes in apoptosis (e.g. casp9, tumor necrosis factor receptor-associated protein 1, hras), DNA repair (msh3, ddb2), oxidative stress protection (glutathione synthetase, paraoxonase 2, vanin 1) and centrosomes (inhibitor of differentiation-1) within primary resistant patients. Independent statistical approaches and quantitative real-time reverse transcriptase-polymerase chain reaction studies support the clinical relevance of gene profiling. In conclusion, this study establishes a candidate predictor of imatinib resistance in interferon-alpha-pretreated CML patients to be subjected to future investigation in a larger independent patient cohort. The resulting expression signature point to involvement of BCR-ABL-independent mechanisms of resistance.

Antineoplastic Agents↗

PubMed2005

Gene expression analysis reveals a strong signature of an interferon-induced pathway in childhood lymphoblastic leukemia as well as in breast and ovarian cancer.

On the basis of epidemiological studies, infection was suggested to play a role in the etiology of human cancer. While for some cancers such a role was indeed demonstrated, there is no direct biological support for the role of viral pathogens in the pathogenesis of childhood leukemia. Using a novel bioinformatic tool that alternates between clustering and standard statistical methods of analysis, we performed a 'double-blind' search of published gene expression data of subjects with different childhood acute lymphoblastic leukemia (ALL) subtypes, looking for unanticipated partitions of patients, induced by unexpected groups of genes with correlated expression. We discovered a group of about 30 genes, related to the interferon response pathway, whose expression levels divide the ALL samples into two subgroups; high in 50, low in 285 patients. Leukemic subclasses prevalent in early childhood (the age most susceptible to infection) are over-represented in the high-expression subgroup. Similar partitions, induced by the same genes, were found also in breast and ovarian cancer but not in lung cancer, prostate cancer and lymphoma. About 40% of breast cancer samples expressed the 'interferon-related' signature. It is of interest that several studies demonstrated mouse mammary tumor virus-like sequences in about 40% of breast cancer samples. Our discovery of an unanticipated strong signature of an interferon-induced pathway provides molecular support for a role for either inflammation or viral infection in the pathogenesis of childhood leukemia as well as breast and ovarian cancer.

Base Sequence↗

PubMed2004

Classification of signatures of Bovine Spongiform Encephalopathy in serum using infrared spectroscopy.

Signatures of Bovine Spongiform Encephalopathy (BSE) have been identified in serum by means of "Diagnostic Pattern Recognition (DPR)". For DPR-analysis, mid-infrared spectroscopy of dried films of 641 serum samples was performed using disposable silicon sample carriers and a semi-automated DPR research system operating at room temperature. The combination of four mathematical classification approaches (principal component analysis plus linear discriminant analysis, robust linear discriminant analysis, artificial neural network, support vector machine) allowed for a reliable assignment of spectra to the class "BSE-positive" or "BSE-negative". An independent, blinded validation study was carried out on a second DPR research system at the Veterinary Laboratory Agency, Weybridge, UK. Out of 84 serum samples originating from terminally-ill, BSE-positive cattle, 78 were classified correctly. Similarly, 73 out of 76 BSE-negative samples were correctly identified by DPR such that, numerically, an accuracy of 94.4 % can be calculated. At a confidence level of 0.95 (alpha = 0.05) these results correspond to a sensitivity > 85% and a specificity > 90%. Identical class assignment by all four classifiers occurred in 75% of the cases while ambiguous results were obtained in only 8 of the 160 cases. With an area under the ROC (receiver operating charateristics) curve of 0.991, DPR may potentially supply a valuable surrogate marker for BSE even in cases in which a deliberate bias towards improved sensitivity or specificity is desired. To the best of our knowledge, DPR is the first and--up to now--only method which has demonstrated its capability of detecting BSE-related signatures in serum.

Animals↗

PubMed1999

Functional consequences of mutations in the conserved 'signature sequence' of the ATP-binding-cassette protein MalK.

The binding-protein-dependent maltose-transport system of enterobacteria, a member of the ATP-binding-cassette (ABC) transporter superfamily, is composed of two integral membrane proteins, MalF and MalG, and two copies of an ATPase subunit, MalK, which hydrolyze ATP, thus energizing the translocation process. Isolated MalK displays spontaneous ATPase activity, whereas in the assembled MalFGK2 complex, reconstituted in liposomes, ATP hydrolysis requires stimulation by the substrate-loaded extracellular maltose-binding protein, MalE. The ATPase domains of ABC transporters, including MalK, share a unique sequence motif ('LSGGQ', 'signature sequence' or 'linker peptide') with as yet unknown function. To elucidate its role in the transport process, we investigated the consequences of mutations affecting two highly conserved residues (G137, Q140) in the MalK-ATPase of Salmonella typhimurium, by biochemical means. Residues corresponding to Q140 in other ABC proteins have not yet been studied. All mutant alleles (G137--> A, V, T; Q140--> L, K, N) fail to restore a functional transport complex in vivo. In addition, the mutations increase the repressing activity of MalK on other maltose-regulated genes when compared with wild-type MalK. Purified variants of G137 have lost the ability to hydrolyze ATP but still display nucleotide-binding activity, albeit with reduced affinity. Binding of MgATP results in similar protection against trypsin, as observed with wild-type, indicating no major change in protein structure. In contrast, the variants of Q140 differ in their properties, depending on the chemical nature of the replacement residue. MalKQ140L fails to hydrolyze ATP and exhibits a strong intrinsic resistance to trypsin in the absence of MgATP, suggesting a drastically altered conformation. In contrast, the purified mutant proteins Q140K and Q140N display ATPase activities and MgATP-induced changes in the tryptic cleavage pattern similar to those of wild-type. However, mutant transport complexes containing the Q140K or Q140N variants, when studied in proteoliposomes, are severely impaired in MalE-maltose-stimulated ATPase activity. These results are discussed with respect to the crystal structure of the homologous HisP protein [Hung, L.-W., Wang, I.X., Nikaido, K., Liu, P.-Q., Ames, G.F.-L. & Kim, S.-H. (1998) Nature (London) 396, 703-707] and are interpreted in favor of a role of the signature sequence in activating the hydrolyzing activity of MalK upon substrate-initiated conformational changes in MalF/MalG.

ATP-Binding Cassette Transporters↗

PubMed2006

A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis.

BACKGROUND & AIMS: Small liver nodules approximately 2 cm are difficult to characterize by radiologic or pathologic examination. Our aim was to identify a molecular signature to diagnose early hepatocellular carcinoma (HCC). METHODS: The transcriptional profiles of 55 candidate genes were assessed by quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) in 17 dysplastic nodules (diameter, 10 mm) and 20 early HCC (diameter, 18 mm) from HCV cirrhotic patients undergoing resection/transplantation and 10 nontumoral cirrhotic tissues and 10 normal liver tissues. Candidate genes were confirmed by quantitative RT-PCR in 20 advanced HCCs and by immunohistochemistry in 75 samples and validated in an independent set of 29 samples (dysplastic nodules [10] and small HCC [19; diameter, 20 mm]). RESULTS: Twelve genes were significantly, differentially expressed in early HCCs compared with dysplastic nodules (>2-fold change; area under the receiver operating characteristic curve > or =0.8): this included TERT, GPC3, gankyrin, survivin, TOP2A, LYVE1, E-cadherin, IGFBP3, PDGFRA, TGFA, cyclin D1, and HGF. Logistic regression analysis identified a 3-gene set including GPC3 (18-fold increase in HCC, P = .01), LYVE1 (12-fold decrease in HCC, P = .0001), and survivin (2.2-fold increase in HCC, P = .02), which had a discriminative accuracy of 94%. The validity of the gene signature was confirmed in a prospective testing set. GPC3 immunostaining was positive in all HCCs and negative in dysplastic nodules (22/22 vs 0/14, respectively, P < .001). Nuclear staining for survivin was positive in 12 of 13 advanced HCC cases and in 1 of 9 early tumors. CONCLUSIONS: Molecular data based on gene transcriptional profiles of a 3-gene set allow a reliable diagnosis of early HCC. Immunostaining of GPC3 confirms the diagnosis of HCC.

Biomarkers, Tumor↗

PubMed2001

The nucleus together with the cytosol generates patterns of specific cellular calcium signatures in tobacco suspension culture cells.

Plant cell suspension cultures respond to osmotic changes by alterations in levels of free cellular calcium. Using the aequorin recombinant method, we have measured the spatial and temporal characteristics of calcium signatures in the nucleus and the cytosol of BY-2 tobacco suspension cells challenged with hypo- or hyper-osmotic shock. We show here that the nuclear compartment contributes together with the cytosol to produce calcium signal patterns that discriminate hypo- from hyper-osmotic treatments, i.e. turgor from tension. We also demonstrate that calcium responses in the nucleus and the cytosol are differentially modulated by the strength and the nature of hyper-osmotic treatments. We conclude that qualitative and quantitative changes in the parameters of an external stimulus such as osmotic changes are converted into calcium signatures, distinctive in their temporal and subcellular characteristics, involving both the nucleus and the cytosol. Our results illustrate the versatility of calcium signaling in plant cells. In addition to the physiological 'address' of the cell, the compartmentation of the calcium signal is probably an important parameter in encoding response specificity.

Calcium Channel Blockers↗

PubMed1999

The doctrine of signatures: a historical, philosophical and scientific view (I).

The evolution of the Doctrine of Signatures is presented, with reference to a physical as well as mental/spiritual mode of relating nature's medicinal substances to the human symptoms. Symbolism, intuition, biological observation, and the study of the medicinal properties serve as guides in the Doctrine of Signatures; modern science offers additional dimensions by relating physiological processes to physiology of disease.

Alchemy↗

PubMed2004

[The patient's signature of the physician's report at discharge from rehabilitation].

What follows for the outcome of rehabilitation, patients' satisfaction and work organisation in a rehabilitation hospital if the patients obtain their discharge reports for signature before they leave? This has been investigated in a pilot study at the University Rehabilitation Hospital in Bad Wurzach, Germany. The pilot study was so successful that the hospital continued to use the new procedure. Only very few refused their signature, most patients were happy to obtain their discharge reports immediately and to have the opportunity to discuss the report with their physician if desired. Physician judged patients' participation slightly more pointly while the known discrepancies between physicians' and patients' point of view remained, i. e. the physician doesn't "touch up" knowing the patient will read his report. Integrating the patient in the process is a major step towards patients' empowerment. Both the influence on patients' satisfaction and changes in work organisation are discussed in the paper. A timely discharge examination and an optimised computer-supported workflow, transformation of loosely coupled activities in a process managed by time frames are preconditions for being able to have the discharge report ready before the patients leave. Monitoring the timely delivery then becomes obsolete.

Efficiency↗

PubMed2005

Autoantibody signatures in prostate cancer.

BACKGROUND: New biomarkers, such as autoantibody signatures, may improve the early detection of prostate cancer. METHODS: With a phage-display library derived from prostate-cancer tissue, we developed and used phage protein microarrays to analyze serum samples from 119 patients with prostate cancer and 138 controls, with the samples equally divided into training and validation sets. A phage-peptide detector that was constructed from the training set was evaluated on an independent validation set of 128 serum samples (60 from patients with prostate cancer and 68 from controls). RESULTS: A 22-phage-peptide detector had 88.2 percent specificity (95 percent confidence interval, 0.78 to 0.95) and 81.6 percent sensitivity (95 percent confidence interval, 0.70 to 0.90) in discriminating between the group with prostate cancer and the control group. This panel of peptides performed better than did prostate-specific antigen (PSA) in distinguishing between the group with prostate cancer and the control group (area under the curve for the autoantibody signature, 0.93; 95 percent confidence interval, 0.88 to 0.97; area under the curve for PSA, 0.80; 95 percent confidence interval, 0.71 to 0.88). Logistic-regression analysis revealed that the phage-peptide panel provided additional discriminative power over PSA (P<0.001). Among the 22 phage peptides used as a detector, 4 were derived from in-frame, named coding sequences. The remaining phage peptides were generated from untranslated sequences. CONCLUSIONS: Autoantibodies against peptides derived from prostate-cancer tissue could be used as the basis for a screening test for prostate cancer.

Aged↗

PubMed1992

Use of forecasting signatures to help distinguish periodicity, randomness, and chaos in ripples and other spatial patterns.

Forecasting of one-dimensional time series previously has been used to help distinguish periodicity, chaos, and noise. This paper presents two-dimensional generalizations for making such distinctions for spatial patterns. The techniques are evaluated using synthetic spatial patterns and then are applied to a natural example: ripples formed in sand by blowing wind. Tests with the synthetic patterns demonstrate that the forecasting techniques can be applied to two-dimensional spatial patterns, with the same utility and limitations as when applied to one-dimensional time series. One limitation is that some combinations of periodicity and randomness exhibit forecasting signatures that mimic those of chaos. For example, sine waves distorted with correlated phase noise have forecasting errors that increase with forecasting distance, errors that are minimized using nonlinear models at moderate embedding dimensions, and forecasting properties that differ significantly between the original and surrogates. Ripples formed in sand by flowing air or water typically vary in geometry from one to another, even when formed in a flow that is uniform on a large scale; each ripple modifies the local flow or sand-transport field, thereby influencing the geometry of the next ripple downcurrent. Spatial forecasting was used to evaluate the hypothesis that such a deterministic process-rather than randomness or quasiperiodicity-is responsible for the variation between successive ripples. This hypothesis is supported by a forecasting error that increases with forecasting distance, a greater accuracy of nonlinear relative to linear models, and significant differences between forecasts made with the original ripples and those made with surrogate patterns. Forecasting signatures cannot be used to distinguish ripple geometry from sine waves with correlated phase noise, but this kind of structure can be ruled out by two geometric properties of the ripples: Successive ripples are highly correlated in wavelength, and ripple crests display dislocations such as branchings and mergers.

Journal Article↗

PubMed2005

Vibrational predissociation spectroscopy of the (H2O)(6-21)- clusters in the OH stretching region: evolution of the excess electron-binding signature into the intermediate cluster size regime.

We report vibrational predissociation spectra of the (H2O)n- cluster ions in the OH stretching region to determine whether the spectral signature of the electron-binding motif identified in the smaller clusters [Hammer et al. Science 306, 675 (2004)] continues to be important in the intermediate size regime (n = 7-21). This signature consists of a redshifted doublet that dominates the OH stretching region, and has been traced primarily to the excitation of a single water molecule residing in a double H-bond acceptor (AA) binding site, oriented with both of its H atoms pointing toward the excess electron cloud. Strong absorption near the characteristic AA doublet is found to persist in the spectra of the larger clusters, but the pattern evolves into a broadened triplet around n = 11. A single free OH feature associated with dangling hydrogen atoms on the cluster surface is observed to emerge for n > or = 15, in sharp contrast to the multiplet pattern of unbonded OH stretches displayed by the H+(H2O)n clusters throughout the n = 2-29 range. We also explore the vibration-electronic coupling associated with normal-mode displacements of the AA molecule that most strongly interact with the excess electron. Specifically, electronic structure calculations on the hexamer anion indicate that displacement along the -OH2 symmetric stretching mode dramatically distorts the excess electron cloud, thus accounting for the anomalously large oscillator strength of the AA water stretching vibrations. We also discuss these vibronic interactions in the context of a possible relaxation mechanism for the excited electronic states involving the excess electron.

Journal Article↗

PubMed2004

Signature quantization and representations of compact Lie groups.

We discuss some applications of signature quantization to the representation theory of compact Lie groups. In particular, we prove signature analogues of the Kostant formula for weight multiplicities and the Steinberg formula for tensor product multiplicities. Using symmetric functions, we also find, for type A, analogues of the Weyl branching rule and the Gel'fand-Tsetlin theorem.

Journal Article↗

PubMed2005

Identification of viral genes essential for replication of murine gamma-herpesvirus 68 using signature-tagged mutagenesis.

Gamma-herpesviruses, Epstein-Barr virus, and Kaposi's sarcoma-associated herpesvirus are important human pathogens, because they are involved in tumor development. Murine gamma-herpesvirus-68 (MHV-68 or gammaHV-68) has emerged as a small animal model system for the study of gamma-herpesvirus pathogenesis and host-virus interactions. To identify the genes required for viral replication in vitro and in vivo, we generated 1,152 mutants using signature-tagged transposon mutagenesis on an infectious bacterial artificial chromosome of MHV-68. Almost every ORF was mutated by random insertion. For each ORF, a mutant with an insertion proximal to the N terminus of each ORF was examined for the ability to grow in fibroblasts. Our results indicate that 41 genes are essential for in vitro growth, whereas 26 are nonessential and 6 attenuated. Replication-competent mutants were pooled to infect mice, which led to the discovery of ORF 54 being important for MHV-68 to replicate in the lung. This genetic analysis of a tumor-associated herpesvirus at the whole genome level validates signature-tagged transposon mutagenesis screening as an effective genetic system to identify important virulent genes in vivo and define interactions with the host immune system.

Animals↗

PubMed2005

An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival.

Perturbations of the p53 pathway are associated with more aggressive and therapeutically refractory tumors. However, molecular assessment of p53 status, by using sequence analysis and immunohistochemistry, are incomplete assessors of p53 functional effects. We posited that the transcriptional fingerprint is a more definitive downstream indicator of p53 function. Herein, we analyzed transcript profiles of 251 p53-sequenced primary breast tumors and identified a clinically embedded 32-gene expression signature that distinguishes p53-mutant and wild-type tumors of different histologies and outperforms sequence-based assessments of p53 in predicting prognosis and therapeutic response. Moreover, the p53 signature identified a subset of aggressive tumors absent of sequence mutations in p53 yet exhibiting expression characteristics consistent with p53 deficiency because of attenuated p53 transcript levels. Our results show the primary importance of p53 functional status in predicting clinical breast cancer behavior.

Breast Neoplasms↗

PubMed2002

Vanadate-catalyzed photocleavage of the signature motif of an ATP-binding cassette (ABC) transporter.

The maltose transport complex of Escherichia coli, a member of the ATP-binding cassette (ABC) superfamily, is made up of two nucleotide-binding subunits, MalK(2), which hydrolyze ATP with positive cooperativity, and two transmembrane subunits, MalF and MalG. The ABC family is defined in part by the canonical signature motif LSGGQ whose exact function remains controversial. Taking advantage of the dual function of vanadate as a transition state analogue and as a photoactive chemical, we demonstrate that vanadate catalyzes the UV-dependent cleavage of the polypeptide backbone at both the LSGGQ motif and the nucleotide-binding, or Walker A, motif when it is trapped in the nucleotide-binding site of the bacterial maltose transporter. This highly specific cleavage pattern indicates that residues in both motifs are immediately adjacent to ATP during hydrolysis, and are therefore likely to participate directly in ATP-binding and/or hydrolysis. Because the LSGGQ motif is too distant from the nucleotide in the structure of an ABC monomer for cleavage to occur, these data support a model in which the LSGGQ motif contacts the nucleotide across the interface of a MalK dimer, as seen in the crystal structure of Rad50. This architecture provides a basis for the cooperativity observed in the nucleotide-binding domains of ABC transporters and a function for this highly conserved family signature motif.

ATP-Binding Cassette Transporters↗

PubMed1996

Signature p53 mutation at DNA cross-linking sites in 8-methoxypsoralen and ultraviolet A (PUVA)-induced murine skin cancers.

A combination of psoralen and ultraviolet A radiation (PUVA) is widely used in the treatment of psoriasis. However, PUVA treatment increases the risk of developing skin cancer in psoriasis patients and induces skin cancer in mice. Since the DNA damage induced by PUVA is quite different from that induced by UV, we investigated whether PUVA-induced mouse skin cancers display carcinogen-specific mutations in the p53 tumor suppressor gene. The results indicated that 10 of 13 (77%) PUVA-induced skin tumors contained missense mutations predominantly at exons 6 and 7. In contrast, tumor-adjacent, PUVA-exposed skin from tumor-bearing animals did not exhibit p53 mutation in exons 4-8. Interestingly, about 40% of all mutations in PUVA-induced skin tumors occurred at 5'-TA sites, and an equal number of mutations occurred at one base flanking 5'TA or 5'-TAT sites. Since PUVA induces DNA cross-links exclusively at these sites and since UV "signature" mutations were rarely detected in PUVA-induced skin cancers, we can conclude that PUVA acts as a carcinogen by inducing unique PUVA signature mutations in p53. This finding may have implications for identifying the etiology of skin cancer in psoriasis patients who have undergone PUVA therapy.

Amino Acid Sequence↗